The ADVIA Centaur® Cortisol (COR) Assay is for in vitro diagnostic use in the quantitative determination of cortisol in serum or urine using the ADVIA Centaur XP system. Measurements of cortisol are used in the diagnosis and treatment of disorders of the adrenal gland.

Device Description

The ADVIA Centaur Cortisol assay is a competitive immunoassay using direct chemiluminescent technology. Results are determined using a calibration curve that is generated specifically on each instrument by a 2-point calibration and a master curve with the reagent bar code. The ADVIA Centaur Cortisol Assay is intended for use on the ADVIA Centaur Family of analyzers. The ADVIA Centaur Calibrator E is a set of 2 level calibrators for the assay. Siemens recommends the use of commercially available quality control materials with at least two levels (low and high).

AI/ML Overview

Here's a breakdown of the acceptance criteria and the study details for the ADVIA Centaur® Cortisol (COR) Assay, based on the provided FDA 510(k) summary:

1. Table of Acceptance Criteria and Reported Device Performance

Acceptance Criteria Category	Specific Criteria/Test	Acceptance Criteria (Implicit from satisfactory results)	Reported Device Performance (Summary)	Comment
Precision	CLSI EP05-A2 protocol (20-day study, 2 reps/run, 2 runs/day)	Within-Lab %CV should be acceptable	Serum: 4.4% - 6.0% (Controls), 4.9% - 5.3% (Samples) Direct Urine: 6.8% - 9.1% Extracted Urine: 6.8% - 9.2%	Performance appears to be within generally accepted clinical chemistry precision standards, demonstrating good reproducibility.
Linearity/Assay Range	Linearity across the measuring range (EP06-A)	% Recovery should be acceptable, high r² (correlation)	Serum: Y=1.057x - 0.051, r²=0.9991, % Recovery 96.0-109.3% Direct Urine: Y=1.011x + 0.090, r²=0.9975, % Recovery 94.7-119.6% Extracted Urine: Y=0.914x + 0.017, r²=0.9997, % Recovery 82.7-100.9%	Strong linearity demonstrated with high r² values close to 1, indicating a good proportional relationship between expected and observed values over the claimed analytical range. The urine recoveries showed a slightly wider range but were still deemed acceptable.
Analytical Detection Limits	LoB, LoD, LoQ (EP17-A2)	Values should be below claimed measuring range	LoB: Serum 0.06 µg/dL, Direct Urine 0.19 µg/dL, Extracted Urine 0.18 µg/dL LoD: Serum 0.14 µg/dL, Direct Urine 0.45 µg/dL, Extracted Urine 0.44 µg/dL LoQ: Serum 0.31 µg/dL, Direct Urine 0.48 µg/dL, Extracted Urine 0.44 µg/dL	The determined detection limits are well below the lower end of the claimed measuring range (0.50 µg/dL), supporting the device's ability to accurately measure low concentrations.
Analytical Specificity (Interference)	Endogenous substances (EP07-A2)	% Interference ≤ 10%	All tested endogenous substances (Hemoglobin, Triglycerides, Bilirubin, Protein, NaCl, Urea, Creatinine, Glucose, Boric Acid) showed % Interference within -5% to 5%.	The device demonstrates good resistance to interference from common endogenous substances in both serum and urine, ensuring reliable results in various patient samples.
Analytical Specificity (Cross-reactivity)	Potential cross-reactant compounds	Low cross-reactivity with structurally similar compounds	Most compounds showed low cross-reactivity (<5%). Higher cross-reactivity noted for Allotetrahydrocortisol (11.9%), 11-deoxycortisol (18.3%), 21-deoxycortisol (10.3%), Prednisolone (92%), and 6-methyl-prednisolone (23.1%), Prednisone (10.7%).	The higher cross-reactivity for certain steroids (especially synthetic ones like Prednisolone) is a known limitation for cortisol immunoassays and would typically be noted in the device's labeling to inform users.
Expected Values (Reference Intervals)	Establish or verify reference intervals (EP28-A3c)	Established or verified intervals consistent with clinical expectations	AM Serum (7-9 AM): 5.27-22.45 µg/dL (n=127) PM Serum (3-5 PM): 3.44-16.76 µg/dL (n=125) Direct Urine: 20.9-292.3 µg/24-hr (n=105, verified) Extracted Urine: 9.5-136.2 µg/24-hr (n=105, verified)	New serum reference intervals established; urine reference intervals from the predicate device were successfully verified. This ensures appropriate interpretation of results.
Method Comparison	Comparison to predicate device	Strong correlation and agreement with predicate	Serum: Modified Device = 1.00(Unmodified Device) + 0.07 µg/dL (r=0.996) Direct Urine: Modified Device = 1.11(Unmodified Device) + 0.68 µg/dL (r=0.969) Extracted Urine: Modified Device = 0.86(Unmodified Device) + 0.38 µg/dL (r=0.991)	Excellent correlation (r values close to 1) indicates substantial equivalence to the predicate device, although slight biases were observed in urine measurements.
Dilution Recovery	High samples diluted and recovered accurately	% Recovery acceptable	Mean % Recovery of 109% (range 106-111%) for auto-diluted vs. manual-diluted serum samples (n=5).	Demonstrates the ability of the device to accurately measure high cortisol samples after dilution, extending the effective measuring range.
Reagent Stability	Shelf-life and on-system stability	Meet specified duration and temperature	Shelf-life: 15 months (unopened, 2-8°C) for reagent kit; 16 months for Calibrator E; 22 months for Master Curve Material. On-system stability: 10 days (reagent kit); 4 hours (Calibrator E, MCM)	Confirms the practical usability and storage conditions of the reagents and calibrators.
Traceability	Standardization to a recognized reference method	Internal standards traceable to GC-MS	Internal standards manufactured analytically traceable to Gas Chromatography-Mass Spectrometry (GC-MS).	Provides confidence in the accuracy and consistency of the assay results by linking them to a highly accurate reference method.

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

Precision: 80 replicates per sample type (controls, serum, urine pools) over 20 days.
Linearity/Assay Range: Patient serum and urine samples (number not explicitly stated but "equally spaced dilutions across the assay range" were used and assayed in triplicate).
Analytical Detection Limits (LoB, LoD, LoQ):
- LoB: 6 blank samples, 5 replicates/day over 3 days (n=90).
- LoD: 5 low cortisol serum samples, 5 replicates/day over 3 days (n=75).
- LoQ: 6 samples with GCMS assigned doses, 5 replicates/day over 3 days (n=60).
Analytical Specificity (Interference): 2 sample pools per interference (serum and urine) for each interferent, run in triplicate.
Analytical Specificity (Cross-reactivity): 2 human serum sample pools per cross-reactant, run in triplicate.
Expected Values (Reference Intervals):
- New Serum Intervals: 252 serum samples (127 AM, 125 PM) from apparently healthy individuals.
- Verified Urine Intervals: 20 24-hour direct urine specimens and 20 24-hour extracted urine specimens.
Method Comparison:
- 243 serum samples
- 98 24-hour direct urine samples
- 111 24-hour extracted urine samples
Dilution Recovery: 5 human serum samples.

Data Provenance: The document does not explicitly state the country of origin for the data (e.g., patient samples for reference intervals, linearity, method comparison). However, it is an in vitro diagnostic device for global use, and such studies are typically multicenter or at least conducted with diverse populations relevant to the intended market. Given Siemens' global presence, it's likely a well-controlled study, but specific geographical details are not provided. The studies appear to be prospective as they were specifically designed and executed to evaluate the performance of the modified device against defined protocols.

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

There were no human "experts" establishing ground truth in the traditional sense (e.g., radiologists interpreting images). This device is a quantitative in vitro diagnostic assay. The ground truth for its performance characteristics is established through:

Reference Methods: Such as GC-MS for traceability and potentially for assigning values to samples for linearity or detection limit studies.
Calibrators and Controls: Professionally manufactured and value-assigned reagents.
Statistical Analysis: CLSI guidelines (EP05-A2, EP06-A, EP17-A2, EP28-A3c, EP07-A2) dictate the statistical methods to define acceptance ranges and assess performance.
Predicate Device: For method comparison, the predicate device acts as a reference standard.

Therefore, the "ground truth" is derived from established analytical methodologies and accepted clinical laboratory standards, rather than expert consensus on individual cases.

4. Adjudication Method for the Test Set

Not applicable. As a quantitative in vitro diagnostic assay, there is no "adjudication" of results in the way there is for image interpretation by clinicians. Results are numerical measurements subjected to statistical analysis and comparison against predefined performance criteria or reference methods.

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

Not applicable. This is an in vitro diagnostic assay, not an AI-powered diagnostic imaging device that assists human readers.

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

Yes, the studies presented are all standalone performance evaluations of the ADVIA Centaur® Cortisol (COR) Assay system. The device itself performs the quantitative determination of cortisol in serum or urine. There is no "human-in-the-loop" performance component described in the context of the assay's function.

7. The Type of Ground Truth Used

The primary types of "ground truth" used are:

Reference Method Traceability: Especially evident in the standardization of internal standards to Gas Chromatography-Mass Spectrometry (GC-MS).
Assigned Values: For calibrators, controls, and Master Curve Materials.
Statistical Acceptance Criteria: Defined by CLSI (Clinical and Laboratory Standards Institute) guidelines, which represent a consensus on best practices and acceptable performance limits in clinical laboratories.
Predicate Device Measurements: Used as a comparative gold standard in the method comparison study.

8. The Sample Size for the Training Set

The document does not explicitly delineate a "training set" in the context of an AI/machine learning model. This device is a competitive immunoassay based on established chemical and immunological principles, not a machine learning algorithm that is "trained" on data in the conventional sense.

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

Not applicable. As mentioned above, there isn't a "training set" for an assay of this type. The "ground truth" for the method's development and validation (e.g., antibody specificity, reagent concentrations, instrument parameters) would have been established through extensive research, development, and internal testing by Siemens Healthcare Diagnostics. The studies presented here are validation studies to demonstrate the final product's performance and substantial equivalence.

Summary

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

SIEMENS HEALTHCARE DIAGNOSTICS INC. FATIMA PACHECO REGULATORY CLINICAL AFFAIRS SPECIALIST 511 BENEDICT AVENUE TARRYTOWN NY 10591-5097

March 31, 2015

Re: K142723

Trade/Device Name: ADVIA Centaur® Cortisol (COR) Assay Regulation Number: 21 CFR 862.1205 Regulation Name: Cortisol (hydrocortisone and hydroxycorticosterone) test system Regulatory Class: II Product Code: JFT Dated: February 18, 2015 Received: February 19, 2015

Dear Ms. Fatima Pacheco:

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,

Katherine Serrano -S

For : Courtney H. Lias, Ph.D. Director Division of Chemistry and Toxicology 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) K142723

Device Name

ADVIA Centaur® Cortisol (COR) Assay

Indications for Use (Describe)

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

Introduction: According to the requirements of SMDA 1990 and 21 CFR 807.92, the following information provides sufficient details to understand the basis for determination of substantial equivalence.

The assigned 510(k) Number: K142723

SUBMITTER I.

Siemens Healthcare Diagnostics Inc. 511 Benedict Avenue, Tarrytown, NY 10591 USA

Contact: Fatima Pacheco Regulatory Clinical Affairs Specialist Phone: (914) 524-2450 (914) 524-3579 Fax: E-mail: fatima.pacheco@siemens.com

Date Prepared: March 25, 2015

II. DEVICE

ADVIA Centaur® Cortisol (COR) Assay Name of Device:

Regulatory Information:

Product Code	Classification	Regulation	Panel
JFT	Class II	21 CFR 862.1250Cortisol (hydrocortisone andhydroxycorticosterone) test system	ClinicalChemistry (75)

III. PREDICATE DEVICE

Name of Device:	ADVIA Centaur® Cortisol (COR) Assay
510 (k):	K962559

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DEVICE DESCRIPTION IV.

The ADVIA Centaur COR reagent kit contains the following:

ADVIA Centaur ReadyPack® primary reagent pack contains Lite Reagent and Solid Phase ● Reagent
Materials Required but Not provided
· ADVIA Centaur Calibrator E: consists of 2 levels (low and high) of multi-analyte calibrators; lyophilized human plasma spiked with analytes (cortisol, progesterone, and testosterone), sodium azide (0.1%) and preservatives.
Optional Reagents
· ADVIA Centaur Multi-Diluent 3 is a human plasma solution with sodium azide (0.1%)
· ADVIA Centaur COR Master Curve Material is a set of 7 levels of cortisol (MCM1-7) spiked in lyophilized human plasma and sodium azide (0.1%).
Cortisol Urine Reconstitution Buffer is a protein buffer solution with sodium azide (0.1%). .

V. INDICATIONS FOR USE

The ADVIA Centaur Cortisol assay is for in vitro diagnostic use in the quantitative determination of cortisol in serum or urine using the ADVIA Centaur XP system. Measurements of cortisol are used in the diagnosis and treatment of disorders of the adrenal gland.

INTENDED USE VI.

Same as Indications for Use

Special Conditions for Use Statement(s): For prescription use only Special Instrument Requirements: ADVIA Centaur® XP System

COMPARISION OF TECHNOLOGICAL CHARACTERISTICS WITH THE VII. PREDICATEDEVICE

The following table provides a comparison between the unmodified predicate ADVIA Centaur COR assay and the modified ADVIA Centaur COR assay (new antibody pool).

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Table 1: Substantial Equivalence Comparison
Trade Name	Candidate Device	Predicate Device
	ADVIA Centaur® Cortisol(COR) Assay – Modified Device	ADVIA Centaur® Cortisol(COR) Assay
Intended Use	For in vitro diagnostic use in thequantitative determination ofcortisol in serum or urine usingthe ADVIA Centaur XP system.	Same
Measurement	Quantitative	Same
Sample Type	Serum, Urine	Same
Assay Range	Serum: 0.50–75 µg/dLUrine: 0.50–53 µg/dL	0.20–75µg/dL
Operating Principle	Competitive immunoassay	Same
Technology	Direct chemiluminescent	Same
Sample Type	Serum, Urine	Same
Sample Volume	20 µL (serum)	Same
Standardization	Internal Standards traceable toGCMS	Same
Calibration	2-point	Same
Calibrator/Levels	Calibrator E/2 levels	Same
Controls/Levels	Commercial Controls /3 levels	Same
Master Curve Materials	Seven levels (MCM1–7)	Same
Detection Mechanism	cortisol labeled with acridiniumester	Same
Capture Antibody	polyclonal rabbit anti-cortisolantibody in the Solid Phase	Same
Reagent StorageTemperature	2–8°C	Same

Standard/Guidance Document Reference VIII.

. Evaluation of Precision Performance of Quantitative Measurement Methods; Approved Guideline-Second Edition (EP05-A2).
Evaluation of the Linearity of Quantitative Measurement Procedures; A Statistical ● Approach; Approved Guideline-First Edition (EP06-A).
Interference Testing in Clinical Chemistry; Approved Guideline-Second Edition (EP07-● A2).

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Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures: . Approved Guideline- Second Edition (EP17-A2).
Defining, Establishing and Verifying Reference Intervals in the Clinical Laboratory; . Approved Guideline - Third Edition (EP28-A3c).

XI. TEST PRINCIPLE

The ADVIA Centaur Cortisol assay is a competitive immunoassay using direct chemiluminescent technology. Cortisol in the patient sample competes with acridinium ester labeled cortisol in the Lite Reagent for binding to polyclonal rabbit anti-cortisol antibody in the Solid Phase. The polyclonal rabbit anti-cortisol antibody is bound to monoclonal mouse antirabbit antibody, which is covalently coupled to paramagnetic particles in the Solid Phase.

X. PERFORMANCE CHARATERISTICS DATA

The following data represents typical performance for the ADVIA Centaur Cortisol Assay. The data was collected on the ADVIA Centaur XP system. Substantial equivalence was demonstrated by testing several performance characteristics including imprecision, interfering and crossreacting substances, and method comparison. All the studies evaluated produced acceptable results when compared to the Predicate and were deemed verified.

1. Precision

A 20-day precision study was performed according to CLSI EP05-A2. The samples consisted of calibrators, controls, serum, and urine pools. Each sample was tested in 2 replicates per run, 2 runs per day for 20 days for a total of 80 replicates. Results from a representative lot are presented below.

Sample	Mean	Repeatability		Within Lab
	(ug/dL)	SD	%CV	SD	%CV
Serum Control 1	2.8	0.10	3.7	0.16	6.0
Serum Control 2	22.3	0.65	2.9	1.00	4.5
Serum Control 3	34.2	1.16	3.4	1.50	4.4
Serum 1	5.7	0.19	3.3	0.30	5.3
Serum 2	50.5	2.10	4.2	2.49	4.9
Direct Urine 1	9.2	0.40	4.3	0.63	6.8
Direct Urine 2	25.6	0.91	3.5	1.73	6.8
Direct Urine 3	50.2	1.99	4.0	4.59	9.1
Extracted Urine 1	9.8	0.33	3.3	0.67	6.8
Extracted Urine 2	26.9	0.99	3.7	1.92	7.2
Extracted Urine 3	40.4	2.12	5.3	3.47	8.6
Extracted Urine 4	51.1	2.97	5.8	4.69	9.2

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2. Linearity/Assay Range

A linearity study was performed across the assay measuring range 0.50-75 ug/dL. The samples were prepared using patient serum and urine samples. Linearity of the ADVIA Centaur COR assay was assessed according to EP06-A by evaluating equally spaced dilutions across the assay range. The patient serum and urine samples were assayed in triplicate and the mean of triplicate results was used for the analyses. Results of %recovery of all the serum samples are summarized below:

Serum	Expected	ObservedMean(ug/dL)	% Recovery(Observed vsExpected)	Fitted Results
Level	(ug/dL)			Linear	Fitted	0/0Deviation
	0.50	0.48	96.0	0.48	0.48
2	10.38	10.14	97.7	10.91	10.29	-7.61
3	20.25	21.83	107.8	21.35	21.00	2.20
ব	30.13	32.94	109.3	31.78	32.17	3.50
ર	40.00	42.08	105.2	42.22	43.36	-0.34
6	49.88	54.14	108.5	52.66	54.11	2.75
7	59.75	64.0	107.1	63.09	64.00	1.39
8	69.63	72.81	104.6	73.53	72.58	-0.98
g	79.50	79.31	99.8	83.96	79.40	-5.87

The observed vs. expected linear regression analysis for all samples generated a weighted linear fit regression as follows:

Y= 1.057x - 0.051, r2=0.9991

Results of % recovery of all the extracted urine samples are summarized below:

Extracted Urine Level	Expected X (µg/dL)	Observed Mean Y (µg/dL)	% Recovery (Observed vs Expected)	Fitted Result		%Bias (observed v/s Linear fit)
1	0.38	0.37	97.4	0.36	0.36	0.8
2	1.50	1.24	82.7	1.39	1.39	-10.7
3	10.9	11.0	100.9	9.97	9.97	10.2
4	20.3	19.73	97.2	18.56	18.56	6.2
5	29.7	27.89	93.9	27.14	27.14	2.7
6	39.1	37.21	95.17	35.72	35.72	4.1
7	48.5	43.6	89.9	44.31	44.31	-1.7
8	57.9	52.30	90.3	52.89	52.89	-1.2
9	67.2	61.23	91.1	61.47	61.47	-0.3
10	76.6	72.92	95.2	70.06	70.06	4.1

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The observed vs. expected linear regression analysis for all samples generated a weighted linear fit regression as follows: Y=0.914x +0.017. r2=0.9997

			Fitted Result
DirectUrineLevel	ExpectedX(µg/dL)	ObservedMeanY (µg/dL)	% Recovery(Observedvs Expected)	Linear	Fitted	%Deviationfrom fitted
1	0.46	0.55	119.6	0.55	0.54	-1.11
2	4.58	4.56	99.6	4.72	5.19	-3.60
3	10.68	11.24	105.2	10.90	11.86	3.08
4	16.79	18.49	110.1	17.07	18.24	7.69
5	22.90	24.24	105.9	23.25	24.35	4.10
6	29.01	29.88	103.0	29.42	30.18	1.53
7	35.11	35.68	101.6	35.60	35.73	0.22
8	41.22	41.71	101.2	41.77	41.01	-0.16
9	47.33	45.64	96.4	47.95	46.02	-5.05
10	53.43	50.59	94.7	54.13	50.74	-6.98

Results of % recovery of all the direct urine samples are summarized below:

The observed vs. expected linear regression analysis for all samples generated a weighted linear fit regression as follows:

Y= 1.011x +0.090, r2=0.9975

The linearity study supports the sponsor's claim that the measuring range of ADVIA Centaur COR assay is 0.50-75 ug/dL (serum) and 0.50-53 ug/dL (urine).

Analytical Detection Limits 3.

The estimations of the Limit of Blank (LoB), Limit of Detection (LoD), and Limit of Quantitation (LoQ) were performed according to CLSI guideline EP17-A2.

Limit of Blank (LoB) was determined by calculating the 95th percentile of distribution of the test values of 6 blank samples, assayed in 5 replicates per day over 3 days (n=90). The Limit of Detection (LoD) is the smallest amount that the assay can reliably detect to determine presence or absence of an analyte. The LoD was determined using five low cortisol serum samples tested over 3 days, 5 replicates per day (n=75). The Limit of Quantitation (LoQ) was determined from the precision profile as the concentration of the analyte having a predicted with-in laboratory CV of 20% and not less than the LoD. Six samples with GCMS assigned doses were tested over 3 days, in 5 replicates (n=60). The LoB/LoD/LoO estimates are summarized below:

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	Serum	Direct Urine	Extracted Urine
LoB	0.06 µg/dL (1.7 nmol/L)	0.19 µg/dL (5.2 nmol/L)	0.18 µg/dL (5.0 nmol/L)
LoD	0.14 µg/dL (3.9 nmol/L)	0.45 µg/dL (12.4 nmol/L)	0.44 µg/dL (12.1 nmol/L)
LoQ	0.31 µg/dL (8.6 nmol/L)	0.48 µg/dL (13.2 nmol/L)	0.44 µg/dL (12.1 nmol/L)

The measuring range of the ADVIA Centaur COR assay is 0.50-75 µg/dL (serum) and 0.50–53 µg/dL (urine).

4. Analytical Specificity

Endogenous Interference: The effect on quantitation of analyte in the presence of endogenous substances using the ADVIA Centaur COR assay was determined. Potential interfering substances in serum and urine (24-hr direct urine) were evaluated with an acceptable % Interference ≤ 10%. Each potential interfering substances was spiked with into 2 sample pools at different concentration of the analyte targeted approximately at 5μg/dL and 30 µg/dL. The same sample pools were used as controls for each interferent by adding equivalent volumes of the appropriate solvent or diluent originally used to dissolve individual interferents. All samples were run in triplicate with one reagent lot. The results of testing at the highest dose of the endogenous substance without interference effects on analyte quantitation are summarized below:

	Low Cortisol			High Cortisol
EndogenousSubstance	Dose WithoutEndogenousSubstance(µg/dL)	Dose WithEndogenousSubstance(µg/dL)	%Interference	Dose WithoutEndogenousSubstance(µg/dL)	Dose WithEndogenousSubstance(µg/dL)	%Interference
Serum Cortisol Measurement
Hemoglobin(500 mg/dL)	4.96	4.83	-3%	23.38	23.64	1%
Triglycerides(1500 mg/dL)	4.78	4.89	2%	22.82	23.08	1%
Conjugated Bilirubin(20 mg/dL)	5.82	5.69	-2%	28.56	27.30	-4%
UnconjugatedBilirubin(20 mg/dL)	4.81	5.07	5%	20.67	21.19	3%
Urine Cortisol Measurement
Protein(60 mg/dL)	6.27	6.49	3%	21.29	21.68	2%
Sodium Chloride1 M(5844 mg/dL)	6.57	6.22	-5%	21.35	20.26	-5%
Urea350 mM	6.60	6.40	-3%	21.25	21.42	1%

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	Low Cortisol			High Cortisol
EndogenousSubstance	Dose WithoutEndogenousSubstance(µg/dL)	Dose WithEndogenousSubstance(µg/dL)	%Interference	Dose WithoutEndogenousSubstance(µg/dL)	Dose WithEndogenousSubstance(µg/dL)	%Interference
(2102 mg/dL)
Creatinine5 mM(56.6 mg/dL)	6.27	6.28	0%	21.28	21.87	3%
Glucose2 mM(36 mg/dL)	6.41	6.43	0%	21.36	21.74	2%
Boric Acid10g/dL	6.48	6.53	1%	21.51	21.67	1%

Cross-reactivity: The specificity of the modified ADVIA Centaur COR assay was determined using two human serum sample pools spiked with potential cross-reactant compounds. The sample analyte concentrations were approximately 0 and ~5 µg/dL cortisol. Potential cross reactants were spiked into each sample at concentrations 50-1000 µg/dL for cross-reactivity evaluation. The spiked and unspiked samples were tested in triplicate. The cross-reactivity results are summarized in the table below:

Cross reactant Tested	ConcentrationTested	% Cross-reactivity
Aldosterone	1,000 ug/dL	0.4
Allotetrahydrocortisol	100 µg/dL	11.9
Androstenedione	1,000 ug/dL	0.2
Corticosterone	1,000 µg/dL	2.6
Cortisone	100 µg/dL	ાં 1.5
a-Cortol	1,000 ug/dL	0.6
α-Cortolone	1,000 µg/dL	0.1
B-Cortol	1,000 µg/dL	0.1
B-Cortolone	1,000 ug/dL	0.0
Dehydrocorticosterone	1,000 µg/dL	2.7
11-deoxycorticosterone	1,000 µg/dL	0.9
11-deoxycortisol	100 µg/dL	18.3
21-deoxycortisol	100 µg/dL	10.3
20 α-dihydrocortisol	1,000 µg/dL	2.5
20 ß-dihydrocortisol	1,000 µg/dL	2.5
20 α-dihydrocortisone	1,000 µg/dL	0.5

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Cross reactant Tested	ConcentrationTested	% Cross-reactivity
20 β-dihydrocortisone	1,000 µg/dL	0.3
11 β-hydroxyandrosterone	1,000 µg/dL	0.0
6-β hydroxycortisol	1,000 µg/dL	2.3
11 β-hydroxyetiocholanone	1,000 µg/dL	0.0
11 β-hydroxyprogesterone	1,000 µg/dL	1.0
17α-hydroxyprogesterone	1,000 µg/dL	1.4
17α-hydroxypregnenolone	1,000 µg/dL	0.1
11-keto-androsterone	1,000 µg/dL	0.0
11-keto-etiochalanonlone	1,000 µg/dL	0.0
Pregnanetriol	1,000 µg/dL	0.0
Pregnenolone	1,000 µg/dL	0.1
Progesterone	1,000 µg/dL	0.5
Spironolactone	1,000 µg/dL	0.1
Testosterone	1,000 µg/dL	0.3
Tetrahydrocortisol	1,000 µg/dL	1.1
Tetrahydrocortisone	1,000 µg/dL	0.5
Tetrahydro-11-deoxycortisol	1,000 µg/dL	0.7
Prednisolone	50 µg/dL	92
6-methyl-prednisolone	100 µg/dL	23.1
Dexamethasone	1,000 µg/dL	0.5
Prednisone	100 µg/dL	10.7
Canrenone	1,000 µg/dL	0.2

Expected Values (Reference Intervals) ട.

A reference interval study was performed according to CLSI EP28-A3c using the ADVIA Centaur COR assay on 252 serum samples from apparently healthy male and female individuals. Based on a central 95% interval, the following reference intervals were established:

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Sample Category	N	Reference Intervals
		( $\mu g/dL$ )	(nmol/L)
AM Serum (7-9 AM)	127	5.27-22.45	145.4-619.4
PM Serum (3-5 PM)	125	3.44-16.76	94.9-462.4

Reference intervals for 24 hour direct urine and extracted urine, previously established with the unmodified predicate ADVIA Centaur COR assay, were verified for the modified ADVIA Centaur COR assay following the protocol established by CLSI EP28-A3c. For the verification study24-hour direct urine specimens (n=20) and 24-hour extracted urine. Since <10% of specimens fell outside of the previously-established reference intervals, the existing claim continues to be valid.

	N	Reference Intervals
Sample Category		(ug/24-hr)	(nmol/24-hr)
Direct Urine	105	20.9-292.3	57.7-806.8
Extracted Urine	105	9.5-136.2	26.2-375.9

Siemens provides this information for reference. As with all in vitro diagnostic assays, each laboratory should determine its own reference ranges for the diagnostic evaluation of patient results.

6. Method Comparison with predicate device

Method comparison studies were performed by comparing the modified device to the currently-marketed predicate device (unmodified ADVIA Centaur COR assay) with twohundred and forty-three (243) serum samples, ninety-eight (98) 24-hour direct urine, and one-hundred and eleven (111) distributed over the assay range. The analysis was performed using Weighted Deming regression. The regression equations and sample ranges from the analyses are presented below.

SampleCategory	N	Range	Regression Equation
Serum	243	0.53-67.42 µg/dL	Modified Device= 1.00(Unmodified Device) + 0.07 µg/dL(r = 0.996)
DirectUrine	98	2.64-47.00 µg/dL	Modified Device = 1.11(Unmodified Device) + 0.68 µg/dL(r = 0.969)
ExtractedUrine	111	1.13-50.69 µg/dL	Modified Device = 0.86(Unmodified Device) + 0.38 µg/dL(r = 0.991)

Based on this study data the sponsor claims sample type's serum and urine (direct and extracted) are acceptable for ADVIA Centaur COR assay.

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7. Dilution Recovery

Dilution studies were performed to demonstrate that the high cortisol samples with concentrations greater the 75 ug/dL can be auto-diluted using a ratio 1:2 dilution with Multi-Diluent 3 and assayed for recovery versus a 1:2 manual dilution can be accurately measured by the ADVIA Centaur Cortisol assay. Five human serum samples in the range of 63.3-76.5 ug/dL were used and the % Recovery was determined by dividing the dose (Auto dilution) by the dose (Manual dilution). The recoveries ranged from 106-111% with a mean of 109%. Results are summarized below:

Sample ID	Auto Dilution	Manual Dilution	% Recovery
	(µg/dL)	(ug/dL)
	74.4	67.0	111
2	76.5	69.1	111
3	63.3	59.7	106
4	72.9	66.5	110
റ	70.3	66.1	106
			Mean: 109

8. Reagent Stability

The shelf-life of the ADVIA Centaur Cortisol assay is 15 months when properly stored unopened at 2-8°C. The expiration date is printed on the carton. On-system (open packs in use) are stable for up to 10 days.

The shelf-life of the ADVIA Centaur Calibrator E is 16 months when properly stored unopened at 2-8°C; reconstituted open vial stable for 14 days; on-system stable for 4 hours. The expiration date is printed on the carton.

The shelf-life of the ADVIA Centaur Cortisol Master Curve Material is 22 months when properly stored unopened at 2-8°C; reconstituted open vial stable for 14 days; on-system stable for 4 hours. The expiration date is printed on the bag label.

9. Traceability

The ADVIA Centaur Cortisol assay is standardized using internal standards manufactured analytically which are traceable to the gas chromatography-mas spectroscopy (GC-MS). Assigned values for Calibrator E and MCMs are traceable to this standardization.

Production lots of Calibrator E are value assigned using 2 reagent lots, 6 replicates, 2 runs on 3 different ADVIA Centaur systems for a total of 72 replicates. The average dose obtained at value assignment for a new calibrator lot are the assigned values.

Production lots of ADVIA Centaur Cortisol MCMs are value assigned using assigned reference calibrators and MCMs. A nested testing protocol consisting of 20 replicates per

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level using one reagent lot and one ADVIA Centaur system. The new MCM doses must fall within the final value assignment specification for COR MCMs. The MCMs dose values are generated using the two-point calibration. The new MCM dose is calculated based on the relationship between the observed reference MCM dose and its assigned value.

XI. CLINICAL STUDIES

Not applicable.

CLINICAL CUT-OFF XII.

Not applicable.

PROPOSED LABELING XIII.

The labeling is sufficient and it satisfies the requirements of 21 CFR Part 809.10.

XIV. CONCLUSION

The submitted information in this premarket notification is complete and supports a substantial equivalence decision.

Regulation Number and Section

§ 862.1205 Cortisol (hydrocortisone and hydroxycorticosterone) test system.

(a)
Identification. A cortisol (hydrocortisone and hydroxycorticosterone) test system is a device intended to measure the cortisol hormones secreted by the adrenal gland in plasma and urine. Measurements of cortisol are used in the diagnosis and treatment of disorders of the adrenal gland.(b)
Classification. Class II.