FDA 510(k) Search - By Innolitics (SaMD and AI Experts)

The ADVIA Centaur Syphilis (SYPH) assay is an in-vitro diagnostic immunoassay for the qualitative determination of antibodies to Treponema pallidum in human serum or plasma (EDTA. lithium or sodium heparinized, citrate) using the ADVIA Centaur® and ADVIA Centaur® XP systems as an aid in the diagnosis of syphilis. The ADVIA Centaur Syphilis assay is not intended for blood and tissue donor screening.

ADVIA® Centaur Syphilis Quality Control Materials are for in-vitro diagnostics use to monitor the performance of the Syphilis assay on the ADVIA Centaur® systems. The performance of the SYPH quality control material has not been established with any other Syphilis assay.

Device Description

The ADVIA Centaur syphilis assay is a fully automated, antigen sandwich assay, using direct chemiluminometric technology. The ancillary pack reagent containing acridinium-ester-labeled T. pallidum recombinant antigens is added to the sample. These T. pallidum antigens complex with the antibodies in the sample. The solid phase containing biotinylated T. pallidum recombinant antigens preformed to streptavidin-coated magnetic latex particles, is then added to the sample. These particles capture the T. pallidum antigen-antibody complexes. Antibody-antigen complexes will form if Syphilis antibodies are present in the sample. A direct relationship exists between the level of antibodies to T. pallidum present in the patient sample and the amount of relative light units (RLUs) detected by the system. A result of reactive, nonreactive, or equivocal is determined according to the Index Value established with the calibrators.

The Syphilis kit contains the following:

1 ReadyPack® primary reagent pack containing ADVIA Centaur Syphilis Solid Phase Reagent (20 mL);
1 Ancillary pack containing ADVIA Centaur Syphilis Ancillary Reagent (10mL)
ADVIA Centaur Syphilis Master Curve card
2 vials of Syphilis Low Calibrator (2 mL fill volume)
2 vials of Syphilis High Calibrator (2 mL fill volume)
ADVIA Centaur Syphilis Calibrator Assigned Value cards

In addition Syphilis quality control materials (2 vials of negative control and 2 vials of positive control with 7 mL fill volume each) are provided separately.

AI/ML Overview

The provided 510(k) summary describes the ADVIA® Centaur Syphilis Assay, an in-vitro diagnostic immunoassay for the qualitative determination of antibodies to Treponema pallidum.

Here's an analysis of the acceptance criteria and the study proving the device meets them:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are implied by the comparison to the predicate device and the performance metrics required for substantial equivalence. The document primarily focuses on establishing substantial equivalence through performance characteristics like precision, reproducibility, interference, cross-reactivity, and clinical evaluation (method comparison).

Performance Characteristic	Acceptance Criteria (Implied by Predicate & Equivalence)	Reported Device Performance (ADVIA® Centaur Syphilis Assay)
Precision	CV% values at various concentrations within acceptable limits for a diagnostic immunoassay.	Demonstrated low CV% values across different sample pools and calibrator levels:Calibrator High: Total CV 3.69%Calibrator Low: Total CV 3.32%Control Positive: Total CV 3.69%Plasma sample (mod positive): Total CV 3.43%Serum sample 5 (high positive): Total CV 4.20%
Reproducibility	Consistent results across different sites, lots, and days, with acceptable CV% values.	Demonstrated low CV% values across 3 external sites and 2 reagent lots:Negative Control: Total SD 0.01 (CV not applicable due to low mean)Serum Pool 2 (high negative): Total CV 2.3%Serum Pool 3 (low positive): Total CV 2.4%Serum Pool 5 (high positive): Total CV 2.6%Positive Control: Total CV 2.5%
Interference	No significant interference (e.g., >10% variance) from common endogenous substances at specified concentrations.	No indication of interference up to the tested levels, with the exception of gamma globulin at concentrations above 30 mg/dL for syphilis positive samples exhibiting Negative Percent Agreement: 99.4% (1382/1391), 95% CI: 98.8 to 99.7%Positive Percent Agreement: 97.9% (700/715), 95% CI: 96.6 to 98.8%
Expected Positive Population:Positive Agreement: 99.4% (535/538), 95% CI: 98.4 to 99.9%Negative Agreement: 100% (23/23), 95% CI: 85.2 to 100.0%
Samples Sent for Syphilis Testing:Positive Agreement: 98.2% (160/163), 95% CI: 94.7 to 99.6%Negative Agreement: 98.4% (568/577), 95% CI: 97.1 to 99.3%

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

Precision Test Set: 5 serum-based samples, 3 plasma-based samples (2 controls, 1 plasma pool), and 2 calibrators. Each assayed in duplicate over 20 days (40 runs, 80 replicates). Data provenance not explicitly stated, but likely from laboratory-prepared pools.
Reproducibility Test Set: Sample pools and control materials (negative and positive). Assayed over 10 days, 2 runs/day, 4 replicates/run for pools, 8 replicates/run for controls (Negative Control: 480 replicates total, Positive Control: 480 replicates total, Serum Pools: 240 replicates each total). Data collected from three external sites. Provenance of the samples is not explicitly stated beyond being "serum pools" and "control materials."
Interference Test Set: Three syphilis levels (negative, low positive, high positive) were used as serum pools spiked with interferents. Provenance not explicitly stated.
Cross-reactivity Test Set:
- 211 cord blood samples, 15 samples from pregnant women (1st, 2nd, 3rd trimester), 48 pediatric samples, 51 hospitalized samples, and 20 transplant samples.
- 265 specimens from 20 groups of potential cross-reactant disease states. These were provided by respective vendors and had known activity to the potential cross-reactant (determined by FDA-cleared methods).
- Provenance is mixed; some are specific clinical categories (cord blood, trimester, hospitalized, pediatric, transplant), others are disease-state specific and sourced from vendors. All samples were likely retrospective clinical samples.
Clinical Evaluation (Method Comparison) Test Set:
- All Sites Pooled: 2108 samples.
- Expected Positive Population: 561 samples (TPPA-Reactive and Medically Diagnosed).
- Samples Sent for Syphilis Testing: 741 samples.
- Data collected from three clinical trial sites. The samples are described as "samples from various patient populations." This strongly suggests prospective or retrospective clinical samples collected at these sites.

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

Precision, Reproducibility, Interference: These studies do not typically involve human experts for establishing ground truth, as they evaluate the analytical performance of the assay based on known concentrations or characteristics of the samples.
Cross-reactivity: The cross-reactivity samples with known activity to potential cross-reactants had this activity "determined by FDA-cleared methods." For the "all samples that demonstrated a positive result (with the exception of two HAV-positive samples) were also confirmed positive by other tests (TPPA or RRP)," these confirmatory tests serve as the ground truth, implying expert interpretation of these results. No specific number or qualifications of experts are mentioned.
Clinical Evaluation (Method Comparison):
- The predicate device results served as the primary comparator.
- For the "Expected Positive Population," ground truth was established by:
  - TPPA-Reactive: This refers to the Treponema pallidum particle agglutination assay, a highly specific confirmatory test for syphilis. The results of this assay would be considered expert-interpreted or based on established laboratory criteria.
  - Medically Diagnosed: This implies a clinical diagnosis made by healthcare professionals (experts) based on various factors, including clinical signs, symptoms, and other laboratory tests.
- No specific number or qualifications of individual experts are detailed.

4. Adjudication Method for the Test Set

For the analytical studies (precision, reproducibility, interference), no adjudication method is relevant.
For cross-reactivity, samples positive on the new device were cross-referenced with the predicate device and "confirmed positive by other tests (TPPA or RRP)." This implies a form of consensus or confirmatory testing rather than direct human adjudication of discordant results between the new device and the predicate.
For the clinical evaluation (method comparison), the comparison is directly between the new device and the predicate device. Discordant results are not mentioned as undergoing a formal adjudication process; instead, the overall agreement rates are presented. The "Expected Positive Population" analysis further validates the device against established external criteria (TPPA and medical diagnosis).

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done

No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not conducted. This device is an automated in-vitro diagnostic immunoassay, meaning its output is quantitative (Index Value) and then categorized as reactive, non-reactive, or equivocal, directly by the instrument based on established cut-offs. There is no human "reader" independently interpreting the primary output of the device itself. Therefore, the concept of improving human reader performance with or without AI assistance is not applicable here.

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

Yes, the studies presented are essentially standalone performance studies for the device. The ADVIA® Centaur Syphilis Assay is a fully automated immunoassay system. All performance characteristics (precision, reproducibility, interference, cross-reactivity, and method comparison) evaluate the performance of the algorithm/system in determining the presence of T. pallidum antibodies without direct human intervention in the interpretation of each individual test result. The output (reactive, non-reactive, equivocal) is generated solely by the device.

7. The Type of Ground Truth Used

The ground truth for the test sets in the clinical evaluation was primarily established by:

Predicate Device Results: The IMMULITE 2000 Syphilis Screen Test System, a previously cleared device for the same intended use.
Confirmatory Assays: For cross-reactivity and the "Expected Positive Population," confirmed positive results by established tests like TPPA (Treponema pallidum particle agglutination assay) and RPR (Rapid Plasma Reagin) served as ground truth for true syphilis infection/reactivity.
Medical Diagnosis: For the "Expected Positive Population," some cases were identified as "Medically Diagnosed," indicating a clinical ground truth established by healthcare professionals.
Known Activity to Potential Cross-Reactants: For some cross-reactivity samples, the activity was determined by FDA-cleared methods and provided by vendors.

8. The Sample Size for the Training Set

The document does not explicitly mention a separate "training set" or its sample size. For in-vitro diagnostic assays, particularly predicate-based submissions, the focus is typically on validation of the final, locked algorithm/reagent formulation rather than iterative training and testing cycles common in AI/ML software development. The "training" phase would have occurred during the development of the assay by the manufacturer, but details are not provided in this 510(k) summary.

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

Since no explicit "training set" is mentioned, the method for establishing its ground truth is also not specified. It can be inferred that during the development of the assay, the manufacturer would have used panels of well-characterized samples (positive for syphilis, negative for syphilis, and those with various interfering/cross-reacting conditions) to optimize the assay's antigens, reagents, and cutoff values. The ground truth for these development/training samples would likely have been established using reference methods, confirmatory tests (like TPPA), and clinical diagnosis.

Summary

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).