The ADVIA Centaur Toxoplasma M (Toxo M) assay is an IgM antibody capture microparticle direct chemiluminometric in vitro diagnostic immunoassay intended for the qualitative detection of IgM antibodies to Toxoplasma gondii in serum or plasma (EDTA, heparin) using the ADVIA Centaur and ADVIA Centaur XP systems.

The ADVIA Centaur Toxo M assay is used to measure IgM antibody against T. gondii which is presumptive of an acute, recent, or reactivated toxoplasma infection. Any measurement of IgM antibody to T. gondii must be performed in conjunction with the determination of IgG antibody to T. gondii.

Device Description

The ADVIA Centaur Toxo M assay is an immunoqlobulin class-capture sandwich immunoassay using direct, chemiluminometric technology. The anti-human IgM monoclonal antibody is covalently coupled to paramagnetic particles in the Solid Phase. In the Lite Reagent, the T. gondii antigen is complexed with an anti-p30 monoclonal antibody (F(ab)> fragment) labeled with acridinium ester. Antibody-antigen complexes will form if toxoplasma IgM is present in the sample.

AI/ML Overview

The provided document describes a 510(k) premarket notification for a modified in vitro diagnostic immunoassay, the ADVIA Centaur Toxoplasma M (Toxo M) assay. The purpose of the submission is to demonstrate that the modified device is substantially equivalent to a legally marketed predicate device.

Here's an analysis of the acceptance criteria and the study proving the device meets them, based on the provided text:

Acceptance Criteria and Reported Device Performance

The document states that the purpose of the submission is to describe changes to the ADVIA Centaur Toxoplasma M (Toxo M) assay (K010755) and that the performance characteristics of the modified assay (precision, interference, and panel/patient sample testing) were evaluated and found comparable to those established for the previous version of the device (currently-marketed predicate).

The "Performance Characteristics" section in Table 2 (Similarities) lists the following for both the Predicate and Modified Device:

Type of Performance Characteristic	Acceptance Criteria (from Predicate Device)	Reported Device Performance (Modified Device)
Positive Percent Agreement	99.2%	Same (Implied to be 99.2% or comparable)
Negative Percent Agreement	99.2%	Same (Implied to be 99.2% or comparable)

The overall conclusion states: "The results of performance testing and verification activities demonstrate that the design modifications to the ADVIA Centaur Toxo M assay do not impact its safety or effectiveness and do not alter its performance claims or alter its intended use, as described in the labeling. Based on the results of comparative testing, the modified ADVIA Centaur Toxo M assay is substantially equivalent in principle and performance to the currently-marketed predicate device, ADVIA Centaur Toxo M, cleared under 510(k) K010755."

This implies that the modified device met the same performance metrics as the predicate, which serves as the acceptance criteria.

Study Details and Data Provenance

The document describes "performance testing and verification activities" and "comparative testing" against the predicate device.

1. Sample sizes used for the test set and the data provenance:

The document does not explicitly state the specific sample sizes used for the test set in the analytical performance and panel/patient sample testing. It mentions "testing with panel samples and patient samples."
Data Provenance: The document does not specify the country of origin for the data. It also does not explicitly state whether the studies were retrospective or prospective, though "performance testing and verification activities" would typically involve prospective testing with samples.

2. 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 device is an in vitro diagnostic immunoassay, and its performance is typically assessed against a known standard or reference method, rather than expert clinical interpretation of images. The ground truth for this type of test generally comes from well-characterized reference panels or clinically confirmed diagnoses.

3. Adjudication method (e.g. 2+1, 3+1, none) for the test set:

Adjudication methods like 2+1 or 3+1 are typically used for subjective assessments, such as image interpretation by radiologists. For an objective immunoassay, an "adjudication method" in this sense is not applicable. The outcome is a quantitative measurement translated into a qualitative result (reactive/nonreactive) based on a defined cutoff.

4. 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 is an in vitro diagnostic immunoassay, not an AI-assisted diagnostic imaging device that involves "human readers." Therefore, an MRMC comparative effectiveness study is not applicable and was not performed.

5. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done:

This is an immunoassay device, which by its nature operates "standalone" in that it provides a result (reactive/nonreactive) based on its chemical and detection processes. While a human operates the instrument and interprets the final qualitative result (Index Value to reactive/nonreactive), the core measurement is a direct output of the algorithm/instrument. The device itself is the "standalone" entity.

6. The type of ground truth used (expert concensus, pathology, outcomes data, etc):

The document mentions "panel samples" and "patient samples." For an immunoassay detecting antibodies, the ground truth would typically be established by:
- Reference laboratory testing using a gold standard method.
- Clinical diagnosis based on a combination of patient symptoms, additional laboratory tests, and clinical follow-up.
- Well-characterized control panels with known positive and negative status for T. gondii IgM antibodies.
The document does not explicitly state which specific type/combination was used, but it would not be expert consensus in the sense of subjective interpretation, nor pathology in the tissue sense, but rather definitive lab results or clinical outcomes.

7. The sample size for the training set:

This is a 510(k) submission for a modified immunoassay, not a machine learning or AI device that typically involves a distinct "training set." The development of the assay's cutoff values and optimization would have involved internal development processes, akin to "training," but the document does not specify a numerical sample size for this developmental phase.

8. How the ground truth for the training set was established:

Similar to the testing set, the ground truth for the development/optimization of the immunoassay would have been established through well-characterized samples, reference methods, or clinically confirmed cases. As it's not an AI model, the concept of "ground truth for training set" in the context of supervised learning does not directly apply in the same manner. The establishment of reagent formulations and reaction parameters is based on biochemical principles and empirical optimization using characterized samples.

In summary, the provided document focuses on demonstrating substantial equivalence of a modified immunoassay by showing its performance is comparable to the predicate device, especially in terms of positive and negative percent agreement. Many of the questions regarding MRMC studies, expert adjudication, and distinct training/test sets are more relevant to AI/ML or imaging devices than to the described immunoassay.

Summary

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Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002

December 22, 2015

SIEMENS HEALTHCARE DIAGNOSTICS, INC. MATTHEW GEE SENIOR MANAGER, REGULATORY AFFAIRS 511 BENEDICT AVENUE TARRYTOWN NY 10591

Re: K142826

Trade/Device Name: ADVIA Centaur Toxoplasma M (Toxo M) Regulation Number: 21 CFR 866.3780 Regulation Name: Toxoplasma gondii Serological Reagents Regulatory Class: II Product Code: LGD Dated: December 3, 2015 Received: December 4, 2015

Dear Mr. Gee:

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. 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 Parts 801 and 809); medical device reporting (reporting of medical device-related adverse events) (21 CFR 803); 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.

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If you desire specific advice for your device on our labeling regulations (21 CFR Parts 801 and 809), please contact the Division of Industry and Consumer Education at its toll-free number (800) 638 2041 or (301) 796-7100 or at its Internet address

http://www.fda.gov/MedicalDevices/Resourcesfor You/Industry/default.htm. 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

http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm for the CDRH's Office of Surveillance and Biometrics/Division of Postmarket Surveillance.

You may obtain other general information on your responsibilities under the Act from the Division of Industry and Consumer Education at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address

http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm.

Sincerely yours,

Ribhi Shawar -S

For Uwe Scherf, M.Sc., Ph.D. Director Division of Microbiology Devices Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health

Enclosure

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Indications for Use

510(k) Number (if known) K142826

Device Name ADVIA Centaur Toxoplasma M (Toxo M)

Indications for Use (Describe)

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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510(k) Summary of Safety and Effectiveness

This 510(k) Summary of Safety and Effectiveness is being submitted in accordance with the requirements of 21 CFR 807.92 and the Safe Medical Device Act of 1990.

The assigned 510(k) Number is: K142826

1. Date Prepared

April 9, 2015

2. Purpose for Submission

The purpose of this submission is to describe changes to the ADVIA Centaur Toxoplasma M (Toxo M) assay (K010755).

3. Measurand

Toxoplasma IgM antibodies

4. Type of Test

Immunoglobulin class-capture chemiluminescence immunoassay

Applicant Information 5.

Contact: Matthew Gee, M.Sc. Senior Manager, Regulatory Affairs
Address: Siemens Healthcare Diagnostics Inc. 511 Benedict Avenue Tarrytown, NY 10591-5097

Phone: 914-524-2099

Fax: 914-524-3579

Email: matthew.gee@siemens.com

Proprietary and Established Names 6.

ADVIA Centaur® Toxoplasma M (Toxo M)

Regulatory Information 7.

Regulation Section:	21CFR 866.3780; Toxoplasma gondii Serological Reagents
Classification:	Class II
Product Code:	LGD
Device Classification Name:	Enzyme linked immunoabsorbent assay, Toxoplasma gondii
Review Panel:	Microbiology (83)

8. Predicate Device Information

Name:	ADVIA Centaur Toxoplasma M (Toxo M)
Manufacturer:	Siemens Healthcare Diagnostics Inc.
510(K) Number:	K010755

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9. Intended Use

9.1 Intended Use

9.2 Indications for Use

Same as Intended Use

9.3 Special Conditions for Use Statement(s)

The detection of toxoplasma IgM in a given specimen, as determined by assays from different manufacturers, can vary due to differences in assay methods and reagent specificity. The results reported by the laboratory to the physician must include the identity of the toxoplasma IgM assay used. Values obtained with different assay methods cannot be used interchangeably. The reported IgM level cannot be correlated to an endpoint titer.

This assay is not intended for use in screening blood, plasma, or tissue donors. The effectiveness of this assay for use in screening blood, plasma, or tissue donors has not been established.

9.4 Special Instrument Requirements

ADVIA Centaur and ADVIA Centaur XP

Device Description 10.

The ADVIA Centaur Toxo M assay consists of the following:

Component	Volume	Ingredients
ADVIA Centaur Toxo MLite Reagent	10.0 mL/pack	partially purified T. gondii antigen (~3 µg/mL)complexed with a mouse anti- T.gondii p30monoclonal antibody (F(ab)2 fragment) labeled withacridinium ester in protein buffer with surfactant andpreservatives
ADVIA Centaur Toxo MSolid Phase	17.0 mL/pack	mouse anti-human IgMµ monoclonal antibody (~24 µg/mL) covalently coupled to paramagnetic particlesin protein buffer with surfactant and preservatives
ADVIA Centaur Toxo MCalibrators	600 µL/vial	defibrinated recalcified processed human plasmapositive for toxoplasma IgM antibodies withpreservatives
ADVIA Centaur Toxo MControls	1.5 mL/vial	defibrinated recalcified processed human plasmanegative and positive for toxoplasma IgM antibodieswith preservatives

Table 1. Summary of Ingredients of the ADVIA Centaur Toxo M Assay Components

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Purpose of the Submission 11.

The purpose of this submission is to submit a modification to the ADVIA Centaur Toxo M assay.

In addition to manufacturing process changes to improve operational effectiveness, and buffer changes to decrease the likelihood of non-specific binding, the main change to the ADVIA Centaur Toxo M assay is a truncation of the anti-p30 antibody in the Lite Reagent to remove the Fc portion of the molecule. This antibody is used to link the acridinium ester (chemiluminescent tag) to the toxoplasma p30 antigen. It is not involved in the binding of analyte from patient samples (i.e. not a component of reaction mechanism).

Comparison of Predicate Device and Modified Device 12.

Table 3 provides a list the similarities of the currently marketed predicate ADVIA Centaur Toxo M assay (with a whole IgG antibody in the Lite Reagent) and the modified ADVIA Centaur Toxo M assay with a F(ab), fragment in the Lite Reagent. Table 4 provides a list of differences between the predicate and modified devices.

Item	Predicate Device (K010755)	Modified Device
Intended Use	The ADVIA Centaur Toxoplasma M(Toxo M) assay is an IgM antibodycapture microparticle directchemiluminometric in vitro diagnosticimmunoassay intended for thequalitative detection of IgMantibodies to Toxoplasma gondii inserum or plasma (EDTA, heparin)using the ADVIA Centaur and ADVIACentaur XP systems.The ADVIA Centaur Toxo M assay is	Same
	used to measure IgM antibodyagainst T. gondii which ispresumptive of an acute, recent, orreactivated toxoplasma infection.Any measurement of IgM antibody toT. gondii must be performed inconjunction with the determination ofIgG antibody to T. gondii.
Instrument Platforms	ADVIA CentaurADVIA Centaur XP	Same
Methodology	Immunoglobulin class-capturesandwich immunoassay using direct,chemiluminometric technology	Same
Capture Antibody(Solid Phase)	Mouse anti-human IgMµmonoclonal antibody	Same
Tracer(Lite Reagent)	Toxoplasma p30 antigenbound to acridinium ester(via mouse anti-T. gondii p30monoclonal antibody)	Same

Table 2. Similarities of Modified ADVIA Centaur Toxo M Assay and Predicate

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510(k) Summary of Safety and Effectiveness

ltem	Predicate Device (K010755)	Modified Device
Specimen Type	Serum or plasma (EDTA, heparin)	Same
Sample Volume	10 µL	Same
Calibration	2-point calibration using Toxo M Cal	Same
PerformanceCharacteristics	Positive Percent Agreement: 99.2%Negative Percent Agreement: 99.2%	Same

Table 2. Similarities of Modified ADVIA Centaur Toxo M Assay and Predicate

Table 3. Differences Between Modified ADVIA Centaur Toxo M Assay and Predicate

Item	Predicate Device (K010755)	Modified Device
Toxoplasma IgM Source(Calibrators, Controls)	Toxoplasma IgM positivehuman plasma pools	Cell culture supernatant ofhuman anti-toxoplasma IgMmonoclonal antibody-producingcells
Particle Resuspension	Particle resuspension withwater	Particle resuspension with Wash1 (phosphate buffered saline)
Lite Reagent Conjugate*	Ab format = Whole IgGAb Concentration = 30 ng/mLConjugate Loading Ratio = 30:1	Ab format = F(ab)2 fragmentAb Concentration = 12.5 ng/mLConjugate Loading Ratio = 18:1
Solid Phase Buffer	Buffer: Tris (pH =8.0)NaCl: 150 mMSurfactant: CHAPS = 0.1 g/LBlocker: Gelatin = 22.2 g/LMouse IgG: 25 mg/LEDTA: none	Buffer: Tricine (pH = 8.0)NaCl: 300 mMSurfactant: Tween-20 = 2.2 g/LBlocker: sm-BSA = 10.0 g/LMouse IgG: 100 mg/LEDTA: 0.7 g/L
Claimed MeasuringRange^	0.10–40.00 Index	0.10–10.00 Index

The modified antibody in the Lite Reagent recognizes same epitope as the antibody in the cleared device. It is simply used to attach the acridinium ester (chemiluminescent tag) to the toxoplasma p30 antigen. It is not part of the analyte-binding reaction mechanism.

13. Standard/Guidance Document References

The following recognized standards from Clinical Laboratory Standards Institute (CLSI) were used as a basis of the study procedures described in this submission:

Evaluation of Precision Performance of Quantitative Measurement Methods; Approved Guideline - Second Edition (CLSI EP05-A2, 2004; Recognition No. 7-110)
l Interference Testing in Clinical Chemistry; Approved Guideline - Second Edition (CLSI EP07-A2, 2005; Recognition No. 7-127)
l Stability testing of in vitro diagnostic reagents (European Committee for Standardization EN 13640:2002; Recognition No. 7-84)
Medical devices - Application of risk management to medical devices (ANSI/AAMI/ISO 14971:2007/(R)2010; Recognition No. 5-70)

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14. Test Principle

ADVIA Centaur systems automatically perform the following steps for the Toxo M assay:

트 Dispenses 10 µL of sample into a cuvette.
I Dispenses 340 µL of Solid Phase and incubates the mixture for 18 minutes at 37°C.
. Separates the Solid Phase from the mixture and aspirates the unbound reagent.
I Washes the cuvette with Wash 1.
I Dispenses 200 µL Lite Reagent and incubates the mixture for 18 minutes at 37°C.
I Separates the Solid Phase from the mixture and aspirates the unbound reagent.
I Washes the cuvette with Wash 1.
. Dispenses 300 µL each of Acid Reagent and Base Reagent to initiate the chemiluminescent reaction.

A direct relationship exists between the amount of toxoplasma IgM activity present in the patient sample and the amount of relative light units (RLUs) detected by the system. A result of reactive (positive) or nonreactive (negative) is determined using an Index Value.

Performance Characteristics 15.

Analytical performance (precision, interference with endogenous substances and potentially interfering agents) and testing with panel samples and patient samples was evaluated using the modified ADVIA Centaur Toxo M assay. The results were comparable to those established for the previous version of the device (currently-marketed predicate).

16. Conclusions

The results of performance testing and verification activities demonstrate that the design modifications to the ADVIA Centaur Toxo M assay do not impact its safety or effectiveness and do not alter its performance claims or alter its intended use, as described in the labeling.

Based on the results of comparative testing, the modified ADVIA Centaur Toxo M assay is substantially equivalent in principle and performance to the currently-marketed predicate device, ADVIA Centaur Toxo M, cleared under 510(k) K010755.

Regulation Number and Section

§ 866.3780

Toxoplasma gondii serological reagents.(a)
Identification. Toxoplasma gondii serological reagents are devices that consist of antigens and antisera used in serological tests to identify antibodies toToxoplasma gondii in serum. Additionally, some of these reagents consist of antisera conjugated with a fluorescent dye (immunofluorescent reagents) used to identifyToxoplasma gondii from clinical specimens. The identification aids in the diagnosis of toxoplasmosis caused by the parasitic protozoanToxoplasma gondii and provides epidemiological information on this disease. Congenital toxoplasmosis is characterized by lesions of the central nervous system, which if undetected and untreated may lead to brain defects, blindness, and death of an unborn fetus. The disease is characterized in children by inflammation of the brain and spinal cord.(b)
Classification. Class II (performance standards).