The ADVIA Centaur Cyclosporine assay is an in vitro diagnostic immunoassay for the quantitative determination of cyclosporine in human whole blood using the ADVIA Centaur systems. This assay is intended for use as an aid in the management of cyclosporine therapy in kidney, heart, and liver transplant patients.

Device Description

The ADVIA Centaur® Cyclosporine assay is a competitive immunoassay using direct chemiluminescent technology. Cyclosporine in the patient sample competes with acridinium ester-labeled cyclosporine in the Lite Reagent for a limited amount of biotin-labeled monoclonal mouse anti-cyclosporine antibody. Biotinlabeled anti-cyclosporine binds to streptavidin that is covalently coupled to paramagnetic particles in the Solid Phase. In the ADVIA Centaur® Cyclosporine assay the sample is manually pretreated to lyse the cells and solubilize the cyclosporine. An inverse relationship exists between the amount of cyclosporine present in the patient sample and the amount of relative light units (RLUs) detected by the system.

AI/ML Overview

Here's a breakdown of the acceptance criteria and study details for the ADVIA Centaur® Cyclosporine Assay, based on the provided text:

Acceptance Criteria and Reported Device Performance

The provided document describes comparison studies for the ADVIA Centaur® Cyclosporine assay against two reference methods: Tandem Mass Spectrometry (Tandem-MS) and the Abbott TDx®TDxFLx® Cyclosporine Monoclonal Whole Blood assay (and also Abbott AxSym). The "acceptance criteria" are implied by the ranges of statistical measures (slope, intercept, and correlation coefficient) that demonstrate substantial equivalence to the predicate devices and reference method. While explicit acceptance thresholds aren't stated as pass/fail criteria, the reported performance metrics indicate the device's acceptable agreement with established methods.

Here's a table summarizing the reported device performance, categorized by the comparative method and patient group/site:

Table 1: Acceptance Criteria (Implied) and Reported Device Performance for ADVIA Centaur® Cyclosporine Assay

Comparative Method	Transplant Type	Patient Samples (n)	Slope (Desired: ~1.0)	Intercept (Desired: ~0.0)	Correlation Coefficient (Desired: ~1.0)	Interpretation of Performance
All Tandem-MS Comparisons
Tandem-MS	kidney	108	1.11	-8	0.962	Strong correlation, slope close to 1, small intercept.
Tandem-MS	liver	75	1.04	-5	0.967	Strong correlation, slope close to 1, small intercept.
Tandem-MS	heart	67	0.89	20	0.966	Strong correlation, slope slightly lower than 1, larger intercept.
Tandem-MS	all	250	1.03	-1	0.963	Overall strong correlation, slope close to 1, very small intercept.
Tandem-MS	site 1	97	0.88	13	0.979	Very strong correlation, slope slightly lower than 1, small intercept.
Tandem-MS	site 2	105	0.85	23	0.988	Very strong correlation, slope lower than 1, somewhat larger intercept.
Tandem-MS	site 3	48	1.11	46	0.965	Strong correlation, slope slightly higher than 1, larger intercept.
Tandem-MS	all (by site)	250	0.94	19	0.960	Overall strong correlation, slope close to 1, small intercept.
Tandem-MS	trough	182	1.02	8	0.909	Good correlation, slope close to 1, small intercept (slightly lower correlation).
Tandem-MS	peak	68	1.15	-104	0.898	Good correlation, slope higher than 1, larger negative intercept (slightly lower correlation).
Tandem-MS	all (by trough/peak)	250	1.03	-1	0.963	Overall strong correlation, slope close to 1, very small intercept.
Abbott TDx Comparisons
Abbott TDx	site 1	97	0.78	8	0.977	Strong correlation, slope lower than 1, small intercept.
Abbott TDx	site 2	97	0.68	-3	0.988	Very strong correlation, significantly lower slope, small intercept.
Abbott TDx	site 3	48	0.71	22	0.977	Strong correlation, significantly lower slope, small intercept.
Abbott TDx	all	242	0.72	6	0.977	Overall strong correlation, significantly lower slope, small intercept.
Abbott AxSym Comparisons
Abbott AxSym	site 1	219	0.68	18	0.960	Strong correlation, significantly lower slope, small intercept.

2. Sample Size and Data Provenance

Test Set Sample Size:
- Against Tandem-MS:
  - Kidney transplant patients: 108 samples
  - Liver transplant patients: 75 samples
  - Heart transplant patients: 67 samples
  - Total against Tandem-MS: 250 samples (across all transplant types)
  - Total against Tandem-MS (by site): 250 samples (97 at site 1, 105 at site 2, 48 at site 3)
  - Total against Tandem-MS (by trough/peak): 250 samples (182 trough, 68 peak)
- Against Abbott TDx: 242 samples (97 at site 1, 97 at site 2, 48 at site 3)
- Against Abbott AxSym: 219 samples (at site 1)
Data Provenance: The samples were from "three transplant patient groups (heart, kidney and liver)" and "three external sites." The text does not specify the country of origin, but given the submitter is Siemens Healthcare Diagnostics in Tarrytown, New York, USA, and the FDA submission, it's highly likely the data includes US patients. The study is retrospective, as it uses existing patient samples for comparison.

3. Number of Experts and Qualifications for Ground Truth

The study does not involve human readers/experts in the traditional sense of interpreting images or clinical data. Instead, it compares the performance of the ADVIA Centaur® Cyclosporine assay against established analytical methods. Therefore, the concept of "experts establishing ground truth" as it applies to subjective assessments is not directly relevant here.

The "ground truth" is established by:

Tandem Mass Spectrometry (Tandem-MS): This is a highly accurate and precise analytical method often considered a gold standard for quantifying small molecules like cyclosporine. The operators of these machines are typically highly trained laboratory professionals.
Abbott TDx®TDxFLx® Cyclosporine Monoclonal Whole Blood assay: This is a legally marketed predicate device, representing an established and accepted method for cyclosporine measurement.
Abbott AxSym: Another legally marketed device for comparison.

4. Adjudication Method for the Test Set

No adjudication method is described, as the "test set" involves analytical measurements rather than subjective interpretations requiring consensus. The "comparison" is statistical (Deming regression) between the new device and established reference methods.

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

No, an MRMC comparative effectiveness study was not done. This type of study is typically used for diagnostic imaging or subjective clinical assessments where multiple human readers interpret cases. The ADVIA Centaur® Cyclosporine assay is an in vitro diagnostic assay that produces a quantitative numerical result; its performance is evaluated by comparison to other quantitative methods, not by improvements in human reader performance.

6. Standalone (Algorithm Only) Performance

Yes, this entire study is a standalone performance study. The ADVIA Centaur® Cyclosporine assay itself (the "algorithm" in this context, albeit a chemical immunoassay) is being tested for its direct, unassisted performance in quantifying cyclosporine. There is no human-in-the-loop component being evaluated for its direct impact on the assay's result.

7. Type of Ground Truth Used

The ground truth used is based on:

Analytical Reference Method: Tandem Mass Spectrometry (Tandem-MS), which is typically considered a highly accurate and precise reference method for cyclosporine quantification.
Predicate Device Performance: The results from the legally marketed Abbott TDx®TDxFLx® Cyclosporine Monoclonal Whole Blood assay and Abbott AxSym are used as a comparative "truth" to establish substantial equivalence.

8. Sample Size for the Training Set

The document does not provide information about a separate "training set" for the assay. Immunoassays like the ADVIA Centaur® Cyclosporine assay are developed and optimized through laboratory procedures, reagent formulation, and calibration curves, rather than being "trained" on a dataset in the way a machine learning algorithm would be. The data presented in the tables are for performance validation (the "test set" in an ML context).

9. How Ground Truth for the Training Set Was Established

As noted above, the concept of a "training set" and its "ground truth" doesn't directly apply here in the way it would for a machine learning model. The assay's internal calibration and performance characteristics would have been established during its development and manufacturing process, likely using characterized reference materials and calibrators, not through a "ground truth" dataset in the clinical study sense. The reference calibrators themselves (ADVIA Centaur® Cyclosporine Calibrator) have their own manufacturing and quality control processes to establish their known concentrations.

Summary

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SEP 1 1 2008

510(k) Summary ADVIA Centaur® Cyclosporine Assay

This summary of 510(k) safety and effectiveness information is submitted in accordance with the requirements of SMDA 1990 and 21 CFR §807.92.

The assigned 510(k) number is: ______________________________________________________________________________________________________________________________________________________________________________

1. Manufacturer's Name, Address, Telephone, and Contact Person, Date of Preparation

Submitter:

Siemens Healthcare Diagnostics 511 Benedict Avenue Tarrytown, New York 10591-5097

Contact Information:

Mary Seeger, Ph.D. Phone: 914-524-2908 Fax : 914-524-2500

Date of Preparation:

August 19, 2008

2. Device Name / Classification

Common Name: Cyclosporine Trade Name: ADVIA Centaur® Cyclosporine Assay ADVIA Centaur® Cyclosporine Calibrator FDA Classification: Sec. 862.1235, 862.3200 Cyclosporine Test system - Class II Special controls Clinical Toxicology Calibrator

3. Identification of the Predicate Devices

Abbott TDx 77DxFLx® Cyclosporine Monoclonal Whole Blood assay, P890025

4. Device Description

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Solid Phase. In the ADVIA Centaur® Cyclosporine assay the sample is manually pretreated to lyse the cells and solubilize the cyclosporine.

An inverse relationship exists between the amount of cyclosporine present in the patient sample and the amount of relative light units (RLUs) detected by the system.

5. Device Intended Use

The ADVIA Centaur® Cyclosporine assay is an in vitro diagnostic immunoassay for the quantitative determination of cyclosporine in human whole blood using the ADVIA Centaur systems. This assay is intended for use as an aid in the management of cyclosporine therapy in kidney, heart, and liver transplant patients.

The ADVIA Centaur® Cyclosporine Calibrator is for in vitro diagnostic use in the calibration of the Cyclosporine assay on the ADVIA Centaur® system.

6. Comparison to Predicate Devices

The ADVIA Centaur® Cyclosporine assay is substantially equivalent to Abbott TDx 9TDxFLx® Cyclosporine Monoclonal Whole Blood assay in that:

Both are immunoassays intended for use in the quantitative measurement of cyclosporine in human . whole blood.
Both assays use mouse monoclonal antibody .
. Both assays require pretreatment of patient samples.

The ADVIA Centaur® Cyclosporine assay and Abbott TDx®TDxFLx® Cyclosporine Monoclonal Whole Blood assay differ in that:

The ADVIA Centaur® Cyclosporine assay does not require whole blood precipitation reagent before . testing.
. The ADVIA Centaur® Cyclosporine assay does not require pretreatment of calibrators.

Comparison Information

Method comparison studies were conducted at three external sites comparing the ADVIA Centaure Cyclosporine assay against two predicates:

. Tandem Mass Spectrometry, and
The Abbott TDx 77DxFLx® Cyclosporine Monoclonal Whole Blood assay. .

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Samples from three transplant patient groups (heart, kidney and liver) were used in the studies. The data
from all three sites were analyzed by Deming regression.

ComparativeMethod	TransplantType	Number ofPatientSamples	Slope	Intercept	CorrelationCoefficient
Tandem-MS	kidney	108	1.11	-8	0.962
Tandem-MS	liver	75	1.04	-5	0.967
Tandem-MS	heart	67	0.89	20	0.966
Tandem-MS	all	250	1.03	-1	0.963

ComparativeMethod	Site	Number ofPatientSamples	Slope	Intercept	CorrelationCoefficient
Tandem-MS	site 1	97	0.88	13	0.979
Tandem-MS	site 2	105	0.85	23	0.988
Tandem-MS	site 3	48	1.11	46	0.965
Tandem-MS	all	250	0.94	19	0.960
Abbott TDx	site 1	97	0.78	8	0.977
Abbott TDx	site 2	97	0.68	-3	0.988
Abbott TDx	site 3	48	0.71	22	0.977
Abbott TDx	all	242	0.72	6	0.977
Abbott AxSym	site 1	219	0.68	18	0.960

ComparativeMethod	Site	Number ofPatientSamples	Slope	Intercept	CorrelationCoefficient
Tandem-MS	trough	182	1.02	8	0.909
	peak	68	1.15	-104	0.898
	all	250	1.03	-1	0.963

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DEPARTMENT OF HEALTH & HUMAN SERVICES

Image /page/3/Picture/1 description: The image shows the logo for the Department of Health & Human Services USA. The logo features a stylized eagle with its wings spread, and the words "DEPARTMENT OF HEALTH & HUMAN SERVICES USA" are arranged in a circular pattern around the eagle. The image is in black and white.

Public Health Service

Food and Drug Administration 2098 Gaither Road Rockville MD 20850

SEP 1 1 2008

Siemens Medical Solutions Diagnostics c/o Dr. Mary Sceger Manager Regulatory Affairs 511 Benedict Avenue Tarrytown, NY 10591

Re: K071455

Trade/Device Name: Advia Centaur® Cyclosporine Assay and Advia Centaur® Cyclosporine Calibrator Regulation Number: 21 CFR 862.1235 Regulation Name: Cyclosporine Test System. Regulatory Class: Class II Product Code: MKW, DLJ Dated: September 3, 2008 Received: September 4, 2008

Dear Dr. Seeger:

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.

If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to such additional controls. Existing major regulations affecting your device can be found in Title 21, Code of Federal Regulations (CFR), Parts 800 to 895. 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); and good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820).

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Page 2 -

This letter will allow you to begin marketing your device as described in your Section 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 information about the application of labeling requirements to your device, or questions on the promotion and advertising of your device, please contact the Office of In Vitro Diagnostic Device Evaluation and Safety at (240) 276-0490. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21CFR Part 807.97). You may obtain other general information on your responsibilities under the Act from the Division of Small Manufacturers, International and Consumer Assistance at its toll-free number (800) 638-2041 or (240) 276-3150 or at its Internet address at http://www.fda.gov/cdrh/industry/support/index.html.

Sincerely yours.

Jean M. Cooper, M.S., D.V.M.

Yean M. Cooper, M.S., D.V.M. Director Division of Chemistry and Toxicology Office of In Vitro Diagnostic Device Evaluation and Safety Center for Devices and Radiological Health

Enclosure

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Indication for Use

510(k) Number (if known): K071455

Device Name: ADVIA Centaur Cyclosporine Assay and Calibrators

Indication For Use: The ADVIA Centaur Cyclosporine assay is an in vitro diagnostic immunoassay for the quantitative determination of cyclosporine in human whole blood using the ADVIA Centaur systems. This assay is intended for use as an aid in the management of cyclosporine therapy in kidney, heart, and liver transplant patients.

Prescription Use (21 CFR Part 801 Subpart D)

Over the Counter Use (21 CFR Part 801 Subpart C)

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

And/Or

Concurrence of CDRH, Office of In Vitro Diagnostic Device Evaluation and Safety (OVD)

Division Sign-Off Office of In Vitro Diagnostic Device Evaluation and Safety

510(k) K071455

Regulation Number and Section

§ 862.1235 Cyclosporine test system.

(a)
Identification. A cyclosporine test system is a device intended to quantitatively determine cyclosporine concentrations as an aid in the management of transplant patients receiving therapy with this drug. This generic type of device includes immunoassays and chromatographic assays for cyclosporine.(b)
Classification. Class II (special controls). The special control is “Class II Special Controls Guidance Document: Cyclosporine and Tacrolimus Assays; Guidance for Industry and FDA.” See § 862.1(d) for the availability of this guidance document.