Immunoassay for the in vitro qualitative detection of total antibodies (IgG and IgM) to Treponema pallidum in human serum and plasma. The test is intended as an aid in the diagnosis of syphilis infection in conjunction with clinical signs and symptoms.

The Elecsys Syphilis immunoasay is not in screening blood or tissue donors. The effectiveness of this assay in testing blood or tissue donors has not been established.

The electrochemiluminescence immunoassay "ECLIA" is intended for use on cobas e immunoassay analyzers.

Device Description

The Elecsys Syphilis immunoassay is a fully automated, qualitative assay that uses a double antigen sandwich format for the detection of IgM and IgG antibodies to T. pallidum.

Recombinant T. pallidum antigens labeled with either biotin or a ruthenium complex bind to T. pallidum-specific IgG or IgM to form a double antigen sandwich complex. The sandwich complex binds to streptavidin-coated microparticles which can be immobilized magnetically to the surface of an electrode. Unbound substances are removed during a wash step using ProCell. A chemiluminescent substrate is then added to the reaction tube. Application of a voltage to the electrode induces a chemiluminescent emission which is measured by a photomultiplier.

The presence or absence of anti-TP antibodies in the specimen is determined by comparing the chemiluminescent signal in the reaction to the cutoff index (COI) determined from an active calibration. The strength of the signal generated is proportional to the amount of bound conjugate and thus the amount of anti-T. pallidum antibodies present in the specimen. If the chemiluminescent signal in the reaction is greater than or equal to the cutoff signal, the specimen is considered reactive for anti-TP antibodies. If the chemiluminescent signal is below the cutoff signal, the specimen is considered nonreactive for the anti-TP antibodies.

AI/ML Overview

The provided text describes the Elecsys Syphilis immunoassay, an in vitro diagnostic device, and its evaluation for substantial equivalence to a predicate device (Elecsys Syphilis K160910) following an update to improve biotin tolerance.

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

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria for this 510(k) submission revolve around demonstrating that the updated Elecsys Syphilis assay is as safe and effective as the predicate device, with the added benefit of improved biotin tolerance. The document states that "All performance specifications were met." While specific numerical acceptance criteria for each study (e.g., precision coefficients of variation, acceptable bias for method comparison) are not explicitly detailed as a formal table with pass/fail values, the reported device performance indicates that these criteria were satisfied.

Study Type	Acceptance Criteria (Implied/General)	Reported Device Performance
Precision (CLSI EP5-A3)	Demonstrate acceptable repeatability and intermediate imprecision for controls and human serum samples.	Repeatability (CV%): HS, negative 1: 1.5; HS, negative 2: 2.0; HS, positive 1: 1.6; HS, positive 2: 2.4; HS, positive 3: 2.9; HS, positive 4: 2.5; HS, positive 5: 2.4; PC Syphilis 1: 1.1; PC Syphilis 2: 2.1 Intermediate Precision (CV%): HS, negative 1: 1.7; HS, negative 2: 3.0; HS, positive 1: 2.4; HS, positive 2: 3.1; HS, positive 3: 3.6; HS, positive 4: 3.6; HS, positive 5: 3.3; PC Syphilis 1: 1.4; PC Syphilis 2: 2.6 (These values are generally considered excellent for immunoassays, implying they met the internal acceptance limits.)
Biotin Interference (CLSI EP07-A3)	No significant interference with analyte quantitation up to a specified biotin concentration.	Maximum value with no interference observed was 2400 ng/mL. The claim in the Instruction for Use will be < 1200 ng/mL. (This indicates a significant improvement over the predicate device's tolerance of ≤ 60 ng/mL, and the device met the new, higher biotin tolerance.)
Method Comparison with Predicate	Demonstrate substantial equivalence (e.g., high positive and negative agreement) between the updated and predicate device across the measuring range using samples from the intended use population.	Positive Agreement and Negative Agreement were calculated between the current (predicate) and updated assay. The resulting data "support the equivalence of the current non-biotin and biotin-updated assay." (Specific percentages for agreement are not provided, but the statement indicates they met the substantial equivalence criteria.)
Reagent and Calibration Stability	Demonstrate stability over time under specified storage conditions to support labeled claims.	Stability studies and acceptance criteria were reviewed and found acceptable. The stability data "supports Roche Diagnostic's claims as reported in the package labeling."
Lot Calibration Stability	Demonstrate consistent calibration performance across different manufacturing lots.	(Implied to be met as part of the overall stability acceptance.)

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

Precision Study:
- Sample Size: Two aliquots of each of two levels of controls and 7 human serum samples were tested per run. This was done for 2 runs per day for 21 days. (Total of 9 distinct samples tested repeatedly).
- Data Provenance: Not explicitly stated, but "human serum samples" suggests clinical samples. The text does not specify country of origin or if they were retrospective or prospective, but for precision studies, these factors are usually less critical than for clinical performance studies.
Biotin Interference Study:
- Sample Size: Three serum samples (negative, close to cut-off, positive) were used. These were typically pooled samples.
- Data Provenance: Not explicitly stated, but implies human serum.
Method Comparison Study:
- Sample Size: A total of 232 samples from the intended use population.
- Data Provenance: Not explicitly stated, but "samples from the intended use population" implies clinical samples. The text does not specify country of origin or if they were retrospective or prospective.

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

This information is not provided in the document. The Elecsys Syphilis assay is an in vitro diagnostic device that detects antibodies. Its performance is typically assessed by comparing its results to established reference methods (e.g., other FDA-cleared syphilis tests, Western Blot) or by using samples with a known status (e.g., from syphilis patients or healthy controls). The ground truth for this type of device is usually based on the results of these reference methods or known clinical status, rather than expert adjudication of images or clinical cases.

4. Adjudication Method (for the test set)

Adjudication methods (like 2+1, 3+1) are typically used in studies where human readers interpret complex data (e.g., medical images) to establish a consensus ground truth. This is not applicable to this type of in vitro diagnostic device study, as the ground truth is established through laboratory reference methods or known sample status.

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

This information is not applicable to this device. The Elecsys Syphilis is a fully automated immunoassay, not an AI-powered diagnostic device that assists human readers. Therefore, an MRMC study and analysis of human reader improvement with AI assistance are not relevant to this submission.

6. If a Standalone (i.e. algorithm only without human-in-the-loop performance) was Done

The Elecsys Syphilis immunoassay is a standalone device in the sense that it is a fully automated assay that produces a result (Reactive or Nonreactive) without human interpretation steps in the analytical measurement process. Its performance (precision, biotin tolerance, method comparison) reflects its standalone analytical accuracy and reliability. However, its stated "Indications for Use" mention that it is an "aid in the diagnosis... in conjunction with clinical signs and symptoms" and that results "should always be interpreted in conjunction with additional treponemal or non-treponemal serologic test results." This implies that while the assay itself operates standalone, the final diagnosis based on its results involves a human clinician and other diagnostic information. Nevertheless, the performance studies described (precision, biotin tolerance, method comparison) represent the standalone analytical performance of the device.

7. The Type of Ground Truth Used

The ground truth for the test set samples used in the method comparison and potentially the precision studies is implied to be:

Clinical Status/Reference Method: Samples "from the intended use population" were used, suggesting samples from individuals with known or suspected syphilis status, likely confirmed by a reference method or a panel of tests. The comparison to the predicate device (another immunoassay) also helps establish agreement against a cleared standard.
Known Concentration/Status: For precision and biotin interference studies, samples might include negative, low positive, and high positive samples, or samples close to the cutoff, where their status or concentration is well-characterized.

The document states that results "should always be interpreted in conjunction with additional treponemal or non-treponemal serologic test results (as appropriate), the patient's clinical symptoms, medical history, and other clinical and/or laboratory findings to produce a diagnosis of syphilis by disease stage." This holistic approach suggests the ultimate ground truth for a diagnosis is a comprehensive clinical assessment, but for assay performance evaluation, it relies on reference methods and known sample characteristics.

8. The Sample Size for the Training Set

This information is not provided. This device is an immunoassay, not a machine learning or AI algorithm in the context of typical "training sets." Immunoassays are developed based on chemical and biological principles (e.g., antibody-antigen binding, chemiluminescence) and calibrated, rather than "trained" with a dataset in the AI sense. Calibration involves using a small set of calibrator materials (Syphilis Cal1 and Cal2 mentioned).

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

As explained above, the concept of a "training set" and "ground truth for a training set" in the AI sense does not directly apply to this immunoassay. The device is calibrated using specific calibrator materials (Syphilis Cal1 and Cal2), which are human serum preparations with known (negative or reactive) anti-TP antibody status, as stated in the device description. These calibrators establish the signal cutoff for reactive vs. nonreactive results.

Summary

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Image /page/0/Picture/0 description: The image shows the logo of the U.S. Food and Drug Administration (FDA). On the left is the seal of the Department of Health & Human Services. To the right of the seal is the FDA logo in blue, with the words "U.S. FOOD & DRUG" on one line and "ADMINISTRATION" on the line below. The logo is simple and professional, and it is easily recognizable.

Roche Diagnostics Bin Sun Regulatory Affairs Program Manager 9115 Hague Road Indianapolis, Indiana 46250

Re: K211302

Trade/Device Name: Elecsys Syphilis Regulation Number: 21 CFR 866.3830 Regulation Name: Treponema pallidum treponemal test reagents Regulatory Class: Class II Product Code: LIP, JJX Dated: April 28, 2021 Received: April 29, 2021

Dear Bin Sun:

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. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database located at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. 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. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.

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, 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

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801 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR 803) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-products); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4. Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.

For comprehensive regulatory information about mediation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).

Sincerely,

Maria Garcia, Ph.D. Branch Chief Division of Microbiology Devices OHT7: Office of In Vitro Diagnostics and Radiological Health Office of Product Evaluation and Ouality Center for Devices and Radiological Health

Enclosure

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Indications for Use

510(k) Number (if known)

K211302

Device Name Elecsys Syphilis

Indications for Use (Describe)

The Elecsys Syphilis immunoasay is not in screening blood or tissue donors. The effectiveness of this assay in testing blood or tissue donors has not been established.

The electrochemiluminescence immunoassay "ECLIA" is intended for use on cobas e immunoassay analyzers.

Type of Use (Select one or both, as applicable)
☑ Prescription Use (Part 21 CFR 801 Subpart D)	☐ Over-The-Counter Use (21 CFR 801 Subpart C)

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Submitter Name	Roche Diagnostics
Address	9115 Hague RoadP.O. Box 50416Indianapolis, IN 46250-0457
Contact	Bin SunPhone: (317) 521-3107FAX: (317) 521-2324Email: bin.sun.bs2@roche.comTammy DeanPhone: (317) 450-5193FAX: (317) 521-2324Email: tammy.dean@roche.com
Date Prepared	April 28, 2021
Proprietary Name	Elecsys Syphilis
Common Name	Syphilis assay
Classification Name	Treponema pallidum treponemal test reagent
Product Codes,Regulation Numbers	Product Code: LIP; 21CFR866.3830
Predicate Devices	Elecsys Syphilis (K160910)
EstablishmentRegistration	Roche Diagnostics GmbH Mannheim, Germany: 9610126Roche Diagnostics GmbH Penzberg, Germany: 9610529Roche Diagnostics Indianapolis, IN United States: 1823260.

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1. DEVICE DESCRIPTION

The Elecsys Syphilis immunoassay is a fully automated, qualitative assay that uses a double antigen sandwich format for the detection of IgM and IgG antibodies to T. pallidum.

The results are printed out as follows:

Reactive COI ≥ 1.00

COI < 1.00 Nonreactive

Interpretation of results:

Reactive for treponemal antibodies Reactive Nonreactive for treponemal antibodies Nonreactive

Test results are intended to aid in diagnosis only. As with all serological tests for syphilis, results should always be interpreted in conjunction with additional treponemal or non-treponemal serologic test results (as appropriate), the patient's clinical symptoms, medical history, and other clinical and/or laboratory findings to produce a diagnosis of syphilis by disease stage.

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All initially reactive samples should be retested in duplicate with the Elecsys Syphilis assay. If cutoff index values < 1.00 are found in both cases, the samples are considered negative for anti-Treponema pallidum antibodies.

Initially reactive samples with cutoff index values of ≥ 1.00 in either of the retests are considered repeatedly reactive. Repeatedly reactive samples must be confirmed according to recommended confirmatory algorithms.

The PreciControl Syphilis 1 and 2 controls and Syphilis Call and Cal2 calibrators are for use with the Elecsys Syphilis Assay.

The reagent working solutions include:

Streptavidin-coated microparticles, 1 bottle, 14.1 mL: Streptavidin-coated microparticles 0.72 mg/mL; preservative.
. R1 TP-specific recombinant antigens (E. coli)~biotin, 1 bottle, 19.7 mL: Biotinylated TP-specific recombinant antigens (E. coli) 0.7 mg/L; MESa) buffer 50 mmol/L, pH 6.5; preservative.
TP-specific recombinant antigens (E. coli)~Ru(bpy) 3 * , 1 bottle, 19.7 mL: . R2 TP specific recombinant antigens labeled with ruthenium complex 0.7 mg/L; MES buffer 50 mmol/L, pH 6.5; preservative.
a) MES = 2-morpholino-ethane sulfonic acid
- . Negative calibrator 1 (lyophilized), 1 bottle for 1.0 mL: Cal 1 Human serum, non-reactive for anti TP antibodies; preservative.
- Positive calibrator 2 (lyophilized), 1 bottle for 1.0 mL: . Cal2 Human serum, reactive for anti TP antibodies; preservative.

INDICATIONS FOR USE 2.

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The Elecsys Syphilis immunoassay is not intended for use in screening blood or tissue donors.

The effectiveness of this assay in testing blood or tissue donors has not been established.

The electrochemiluminescence immunoassay "ECLIA" is intended for use on cobas e immunoassay analyzers.

TECHNOLOGICAL CHARACTERISTICS 3.

The following table compare the Elecsys Syphilis with its predicate device, Elecsys Syphilis (K160910).

Feature	Candidate DeviceUpdated Elecsys Syphilis	Predicate DeviceElecsys Syphilis (K160910)
Intended Use	Immunoassay for the in vitroqualitative detection of totalantibodies (IgG and IgM) toTreponema pallidum in humanserum and plasma. The test isintended as an aid in the diagnosisof syphilis infection in conjunctionwith clinical signs and symptoms.The Elecsys Syphilis immunoassayis not intended for use in screeningblood or tissue donors. Theeffectiveness of this assay in testingblood or tissue donors has not beenestablished.The electrochemiluminescenceimmunoassay “ECLIA” is intendedfor use on cobas e analyzer.	Same
Assay Method	Double antigen sandwich assay	Same
Detection Method	Electrochemiluminescence (ECLIA)	Same
Instrument Platform	cobas e 801	Same
Test Time	18 min	Same
Test Type	Qualitative	Same

Technical Characteristics Comparison Table between Current Elecsys Syphilis and the Updated Elecsys Syphilis Immunoassay

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Feature	Candidate DeviceUpdated Elecsys Syphilis	Predicate DeviceElecsys Syphilis (K160910)
Sample material	Serum collected using standardsampling tubes or tubes containingseparating gel. Li-heparin,Na-heparin, K2-EDTA, K3-EDTA,CPDA and Na-citrate plasma. Li-heparin plasma tubes containingseparating gel can be used.	Same
Biotin tolerance	$ \le $ 1200 ng/mL	$ \le $ 60 ng/mL
Calibration	2-point	Same
Controls	PreciControl Syphilis	Same

NON-CLINICAL PERFORMANCE EVALUATION 4.

A limited number of studies were conducted to verify the assay performance cleared under K160910 was not affected by the changes made to improve tolerance to elevated levels of biotin. The following performance data are provided in support of the substantial equivalence determination:

Precision according to CLSI EP5-A3 .
Biotin interference study according to CLSI EP07-A3 .
Matrix Comparison with clinical samples .
Reagent and calibration stability studies .
Lot calibration stability .

All performance specifications were met.

4.1. Precision

The precision of the Elecsys Syphilis assay was evaluated on one cobas e 801 immunoassay analyzer with one reagent lot. The protocol consisted of testing 2 aliquots of each of two levels of controls and 7 human serum samples per run, 2 runs per day for 21 days. The samples were run in randomized order on the analyzer. Repeatability and Intermediate imprecision were

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cobas e 801 analyzer
		Repeatability		Intermediate precision
Sample	MeanCOI	SDCOI	CV%	SDCOI	CV%
HS1), negative 1	0.125	0.00192	1.5	0.00210	1.7
HS, negative 2	0.888	0.0175	2.0	0.0264	3.0
HS, positive 1	1.09	0.0173	1.6	0.0260	2.4
HS, positive 2	4.11	0.0983	2.4	0.126	3.1
HS, positive 3	6.88	0.198	2.9	0.249	3.6
HS, positive 4	15.8	0.395	2.5	0.574	3.6
HS, positive 5	16.4	0.395	2.4	0.540	3.3
PC2) Syphilis 1	0.0951	0.00107	1.1	0.00130	1.4
PC Syphilis 2	5.90	0.126	2.1	0.155	2.6

calculated according to CLSI EP05-A3 including the 95% confidence interval and a summary of the results is shown below.

HS = human serum
PC = PreciControl

4.2. Biotin Interference

The effect on quantitation of analyte in the presence of biotin using the updated Elecsys Syphilis assay was determined using three serum samples (negative, close to cut-off, positive) according to CLSI EP07-A3 Appendix A.

One aliquot of each serum sample was spiked with the interfering substance (biotin), another aliquot was spiked with the same volume of the respective solvent (dilution pool). The interfering pool was then incrementally diluted into the dilution pool. The recovery for each sample was calculated by comparison to the analyte concentration of the respective dilution pools.

For samples "close to cut-off" and "low positive", samples were prepared by pooling native serum samples with high and low concentrations.

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The maximum value with no interference observed was 2400 ng/mL. The claim of the Instruction for Use will be set to < 1200 ng/mL.

4.3. Method Comparison to Predicate

A method comparison was performed using the Elecsys Syphilis updated assay (candidate device) and the current Elecsys Syphilis immunoassay (predicate device) to assess the bias between the two assays. A total of 232 samples from the intended use population were measured with one reagent lot of the current assay and three different reagent lots of the updated assay in single determination on the cobas e 801 analyzer covering the entire measuring range. From these measurements, Positive Agreement and Negative Agreement between the current and updated assay were calculated. The resulting data support the equivalence of the current nonbiotin and biotin-updated assay.

4.4. Stability

The stability studies and acceptance criteria have been reviewed and found to be acceptable. The stability data supports Roche Diagnostic's claims as reported in the package labeling.

ADDITIONAL INFORMATION 5.

The Elecsys Syphilis is intended to be used with the following calibrators and controls:

. Syphilis Call and Syphilis Cal2, which is included in the kit
. PreciControl Syphilis

There have been no changes to these items marketed with the new Elecsys Syphilis immunoassay.

PreciControl Syphilis, product code JJX, is a Class I 510(k) Exempt device; therefore, it is not included with this submission.

CONCLUSIONS 6.

The information provided in this 510(k) Premarket Notification is complete and supports a substantial equivalence decision. The data from the analytical studies demonstrate that the device

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is as safe, as effective, and performs as well as the legally marketed predicate device with improved biotin tolerance level up to 1200 ng/mL.

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).