(189 days)
No
The summary describes a standard immunoassay with calibration based on a master curve and 2-point calibration, which is a traditional method and does not indicate the use of AI/ML. There are no mentions of AI, ML, or related concepts like training/test sets for algorithmic development.
No
This device is an in vitro diagnostic (IVD) assay used to quantitatively determine cortisol levels, which aids in the diagnosis and treatment of adrenal gland disorders. It is not directly therapeutic; rather, it provides diagnostic information that informs treatment decisions.
Yes
The "Intended Use / Indications for Use" section explicitly states that the assay is for "in vitro diagnostic use" and that "Measurements of cortisol are used in the diagnosis and treatment of disorders of the adrenal gland."
No
The device is an in vitro diagnostic assay, which is a reagent-based test used on a specific hardware analyzer (ADVIA Centaur Family of analyzers). It is not solely software.
Yes, this device is an IVD (In Vitro Diagnostic).
Here's why:
- Intended Use/Indications for Use: The very first sentence explicitly states, "The ADVIA Centaur® Cortisol (COR) Assay is for in vitro diagnostic use..." This is the most direct indicator.
- Purpose: The intended use describes the quantitative determination of cortisol in serum or urine, and how these measurements are used in the "diagnosis and treatment of disorders of the adrenal gland." This clearly indicates a diagnostic purpose performed outside of the body (in vitro).
- Device Description: The description details an "immunoassay" and its use on an "analyzer," which are typical components of IVD systems used for laboratory testing of biological samples.
- Sample Types: The assay is designed to analyze "serum or urine," which are biological specimens commonly used in in vitro diagnostic testing.
N/A
Intended Use / Indications for Use
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.
Product codes
JFT
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).
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%). .
Mentions image processing
Not Found
Mentions AI, DNN, or ML
Not Found
Input Imaging Modality
Not Found
Anatomical Site
Not Found
Indicated Patient Age Range
Not Found
Intended User / Care Setting
Prescription Use
Care Setting: Not Found (implies clinical laboratory)
Description of the training set, sample size, data source, and annotation protocol
Not Found
Description of the test set, sample size, data source, and annotation protocol
Not Found
Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)
-
Precision Study:
- Study Type: 20-day precision study performed according to CLSI EP05-A2.
- Sample Size: Not explicitly stated, but 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.
- Key Results: Acceptable precision results for serum controls, serum samples, direct urine samples, and extracted urine samples. %CVs ranged from 2.9% to 5.8% for repeatability and 4.4% to 9.2% for within-lab variability.
-
Linearity/Assay Range Study:
- Study Type: Linearity study performed according to EP06-A.
- Sample Size: Not explicitly stated, but samples were prepared using patient serum and urine samples. Patient serum and urine samples were assayed in triplicate.
- Key Results:
- Serum: Covered 0.50-79.50 µg/dL, showing % Recovery mainly in the range of 96.0% to 109.3%. Linear regression: Y= 1.057x - 0.051, r2=0.9991.
- Extracted Urine: Covered 0.38-76.6 µg/dL, showing % Recovery mainly in the range of 82.7% to 100.9%. Linear regression: Y=0.914x +0.017, r2=0.9997.
- Direct Urine: Covered 0.46-53.43 µg/dL, showing % Recovery mainly in the range of 94.7% to 119.6%. Linear regression: 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 Study:
- Study Type: Estimations of LoB, LoD, and LoQ performed according to CLSI guideline EP17-A2.
- Sample Size: LoB: 6 blank samples, 5 replicates per day over 3 days (n=90). LoD: five low cortisol serum samples, 5 replicates per day over 3 days (n=75). LoQ: Six samples with GCMS assigned doses, 5 replicates over 3 days (n=60).
- Key Results:
- Serum: LoB = 0.06 µg/dL, LoD = 0.14 µg/dL, LoQ = 0.31 µg/dL.
- Direct Urine: LoB = 0.19 µg/dL, LoD = 0.45 µg/dL, LoQ = 0.48 µg/dL.
- Extracted Urine: LoB = 0.18 µg/dL, LoD = 0.44 µg/dL, LoQ = 0.44 µg/dL.
-
Analytical Specificity Study (Endogenous Interference):
- Study Type: Evaluation of potential interfering substances in serum and urine.
- Sample Size: Not explicitly stated, but each potential interfering substance was spiked into 2 sample pools. All samples were run in triplicate with one reagent lot.
- Key Results: Acceptable % Interference ≤ 10% for Hemoglobin, Triglycerides, Conjugated Bilirubin, Unconjugated Bilirubin (serum), Protein, Sodium Chloride, Urea, Creatinine, Glucose, Boric Acid (urine).
-
Analytical Specificity Study (Cross-reactivity):
- Study Type: Determination of specificity using human serum sample pools spiked with potential cross-reactant compounds.
- Sample Size: Two human serum sample pools. Spiked and unspiked samples tested in triplicate.
- Key Results: % Cross-reactivity presented for various compounds. Notably, Prednisolone showed 92% cross-reactivity and 6-methyl-prednisolone showed 23.1% cross-reactivity.
-
Expected Values (Reference Intervals) Study:
- Study Type: Reference interval study performed according to CLSI EP28-A3c. Verification study for urine.
- Sample Size: 252 serum samples from healthy individuals. 24-hour direct urine specimens (n=20) and 24-hour extracted urine for verification.
- Key Results:
- AM Serum (7-9 AM): 5.27-22.45 µg/dL (145.4-619.4 nmol/L) based on 127 samples.
- PM Serum (3-5 PM): 3.44-16.76 µg/dL (94.9-462.4 nmol/L) based on 125 samples.
- Direct Urine: 20.9-292.3 ug/24-hr (57.7-806.8 nmol/24-hr) based on 105 samples.
- Extracted Urine: 9.5-136.2 ug/24-hr (26.2-375.9 nmol/24-hr) based on 105 samples.
-
Method Comparison with predicate device Study:
- Study Type: Comparison of the modified device to the currently-marketed predicate device.
- Sample Size: 243 serum samples, 98 24-hour direct urine samples, and 111 extracted urine samples.
- Key Results: Weighted Deming regression results:
- 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)
- The study data supports that serum and urine (direct and extracted) are acceptable sample types.
-
Dilution Recovery Study:
- Study Type: Dilution studies to demonstrate auto-dilution capability.
- Sample Size: Five human serum samples.
- Key Results: Recoveries ranged from 106-111% with a mean of 109% for auto-dilution vs. manual dilution.
-
Reagent Stability Study:
- Study Type: Not explicitly a "study", but states stability data.
- Key Results: Shelf-life of ADVIA Centaur Cortisol assay is 15 months (unopened, 2-8°C). On-system stability is up to 10 days. Calibrator E shelf-life 16 months (unopened, 2-8°C), 14 days (reconstituted open vial), 4 hours (on-system). Master Curve Material shelf-life 22 months (unopened, 2-8°C), 14 days (reconstituted open vial), 4 hours (on-system).
-
Traceability:
- Study Type: Not a "study", but describes standardization and value assignment processes.
- Key Results: Standardized using internal standards traceable to gas chromatography-mass spectrometry (GC-MS). Production lots of Calibrator E and MCMs are value assigned using specific protocols.
Key Metrics (Sensitivity, Specificity, PPV, NPV, etc.)
LoB, LoD, LoQ, % Interference, % Cross-reactivity, % Recovery, Regression Equations (slope, intercept, r-value), Precision (SD, %CV), Reference Intervals
Predicate Device(s)
ADVIA Centaur® Cortisol (COR) Assay - K962559
Reference Device(s)
Not Found
Predetermined Change Control Plan (PCCP) - All Relevant Information
Not Found
§ 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.
0
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.
1
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
2
Indications for Use
510(k) Number (if known) K142723
Device Name
ADVIA Centaur® Cortisol (COR) Assay
Indications for Use (Describe)
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.
| 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 862.1250 | |
| Cortisol (hydrocortisone and | |||
| hydroxycorticosterone) test system | Clinical | ||
| Chemistry (75) |
III. PREDICATE DEVICE
| Name of Device: | ADVIA Centaur® Cortisol (COR) Assay |
|---|---|
| 510 (k): | K962559 |
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SIEMENS
DEVICE DESCRIPTION IV.
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).
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 the | |
| quantitative determination of | ||
| cortisol in serum or urine using | ||
| the ADVIA Centaur XP system. | Same | |
| Measurement | Quantitative | Same |
| Sample Type | Serum, Urine | Same |
| Assay Range | Serum: 0.50–75 µg/dL | |
| Urine: 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 to | |
| GCMS | 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 acridinium | |
| ester | Same | |
| Capture Antibody | polyclonal rabbit anti-cortisol | |
| antibody in the Solid Phase | Same | |
| Reagent Storage | ||
| Temperature | 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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SIEMEN
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 | Observed
Mean
(ug/dL) | % Recovery
(Observed vs
Expected) | Fitted Results | | |
|-------|----------|-----------------------------|-----------------------------------------|----------------|--------|------------------|
| Level | (ug/dL) | | | Linear | Fitted | 0/0
Deviation |
| | 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 | ||||||
|---|---|---|---|---|---|---|
| Direct | ||||||
| Urine | ||||||
| Level | Expected | |||||
| X | ||||||
| (µg/dL) | Observed | |||||
| Mean | ||||||
| Y (µg/dL) | % Recovery | |||||
| (Observed | ||||||
| vs Expected) | Linear | Fitted | % | |||
| Deviation | ||||||
| from 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 | |||||
|---|---|---|---|---|---|---|
| Endogenous | ||||||
| Substance | Dose Without | |||||
| Endogenous | ||||||
| Substance | ||||||
| (µg/dL) | Dose With | |||||
| Endogenous | ||||||
| Substance | ||||||
| (µg/dL) | % | |||||
| Interference | Dose Without | |||||
| Endogenous | ||||||
| Substance | ||||||
| (µg/dL) | Dose With | |||||
| Endogenous | ||||||
| Substance | ||||||
| (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% |
| Unconjugated | ||||||
| Bilirubin | ||||||
| (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 Chloride | ||||||
| 1 M | ||||||
| (5844 mg/dL) | 6.57 | 6.22 | -5% | 21.35 | 20.26 | -5% |
| Urea | ||||||
| 350 mM | 6.60 | 6.40 | -3% | 21.25 | 21.42 | 1% |
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| Low Cortisol | High Cortisol | |||||
|---|---|---|---|---|---|---|
| Endogenous | ||||||
| Substance | Dose Without | |||||
| Endogenous | ||||||
| Substance | ||||||
| (µg/dL) | Dose With | |||||
| Endogenous | ||||||
| Substance | ||||||
| (µg/dL) | % | |||||
| Interference | Dose Without | |||||
| Endogenous | ||||||
| Substance | ||||||
| (µg/dL) | Dose With | |||||
| Endogenous | ||||||
| Substance | ||||||
| (µg/dL) | % | |||||
| Interference | ||||||
| (2102 mg/dL) | ||||||
| Creatinine | ||||||
| 5 mM | ||||||
| (56.6 mg/dL) | 6.27 | 6.28 | 0% | 21.28 | 21.87 | 3% |
| Glucose | ||||||
| 2 mM | ||||||
| (36 mg/dL) | 6.41 | 6.43 | 0% | 21.36 | 21.74 | 2% |
| Boric Acid | ||||||
| 10g/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 | Concentration
Tested | % 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 | Concentration
Tested | % 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