(264 days)
Immunoassay for the in vitro quantitative determination of cortisol in human serum, and plasma. The determination of cortisol is used for the recognition and treatment of functional disorders of the adrenal gland. The electrochemiluminescence immunoassay "ECLIA" is intended for use on Elecsys and cobas e immunoassay analyzers.
Cortisol II CalSet is used for calibrating the quantitative Elecsys Cortisol II assay on the Elecsys and cobas e immunoassay analyzers.
The Elecsys Cortisol II assay makes use of a competition test principle using a monoclonal antibody which is specifically directed against cortisol. Endogenous cortisol which has been liberated from binding proteins with danazol competes with exogenous cortisol derivative in the test which has been labeled with ruthenium complex for the binding sites on the biotinylated antibody.
Results are determined via a calibration curve which is instrument specifically generated by 2point calibration and a master curve provided via reagent barcode.
The reagent working solutions include:
- rackpack (kit placed on instrument) .
- Streptavidin coated microparticles, ş
- Reagent 1 (Anti-cortisol-Ab~biotin) and ş
- Reagent 2 (Cortisol-peptide~Ru(bpy)2+3). ş
The Cortisol II CalSet is a lyophilized human serum with added cortisol in two concentration ranges.
The CalSet includes:
- Cal 1 (approximately 12.5 nmol/L cortisol in a human serum matrix) .
- Cal 2 (approximately 1000 nmol/L cortisol in a human serum matrix) .
The provided document describes the Elecsys Cortisol II immunoassay and its associated calibrator, Cortisol II CalSet. It details various non-clinical performance evaluations and one clinical performance evaluation.
Here's an analysis of the acceptance criteria and the studies that prove the device meets them:
1. A table of acceptance criteria and the reported device performance
The document does not explicitly state acceptance criteria in a dedicated table for each technical performance study. Instead, it presents the results of these studies and implies that these results demonstrate the device's performance is acceptable and supports substantial equivalence to the predicate device. For analytical specificity and method comparison, the document includes tables comparing some key characteristics with the predicate device. For other studies like precision, linearity, and sensitivity, it reports the performance without directly listing a pre-defined acceptance criterion.
However, I can extract the reported performance directly from the document for key metrics.
| Performance Characteristic | Predicate Device (Elecsys Cortisol - K070788) Performance | Candidate Device (Elecsys Cortisol II) Reported Performance |
|---|---|---|
| Measuring Range | 0.5 – 1750 nmol/L | 3.0 – 1750 nmol/L |
| Precision (Within-run) | Sample Mean (nmol/L) SD %CVHS 1: 208, 2.76, 1.3%HS 2: 561, 7.40, 1.3%HS 3: 1268, 14.0, 1.1%PCU* 1: 363, 5.08, 1.4%PCU* 2: 865, 8.54, 1.0% | Sample Mean (nmol/L) SD CVHS 1: 3.09, 0.219, 7.1%HS 2: 35.8, 0.718, 2.0%HS 3: 283, 7.29, 2.6%HS 4: 548, 10.4, 1.9%HS 5: 1592, 29.3, 1.8%PCU* 1: 308, 4.33, 1.4%PCU* 2: 719, 10.4, 1.4% |
| Precision (Total/Intermediate) | Sample Mean (nmol/L) SD %CVHS 1: 208, 3.29, 1.6%HS 2: 561, 8.36, 1.5%HS 3: 1268, 19.9, 1.6%PCU* 1: 363, 5.67, 1.6%PCU* 2: 865, 12.5, 1.4% | Sample Mean (nmol/L) SD CVHS 1: 3.09, 0.392, 12.7%HS 2: 35.8, 1.36, 3.8%HS 3: 283, 9.39, 3.3%HS 4: 548, 17.4, 3.2%HS 5: 1592, 42.7, 2.7%PCU* 1: 308, 8.35, 2.7%PCU* 2: 719, 18.0, 2.5% |
| Analytical Sensitivity | Limit of Detection = <0.500 nmol/L | Limit of Blank (LoB): = 1.0 nmol/mLLimit of Detection (LoD): = 1.5 nmol/mLLimit of Quantitation (LoQ): = 3.0 nmol/mL |
| Linearity | 1 to 59.8 µg/dL | 3.0 to 1750 nmol/mL (implied as achieved, comparing to predicate) |
| Bilirubin Interference | <60 mg/dL unaffected | ≤ 25 mg/dL unaffected |
| Hemolysis Interference | <1.9 g/dL unaffected | ≤ 0.5 g/dL unaffected |
| Lipemia Interference | <2700 mg/dL unaffected | ≤ 1500 mg/dL unaffected |
| Biotin Interference | <30 ng/mL unaffected | ≤ 30 ng/mL unaffected |
| Rheumatoid factors Interference | <1100 IU/mL unaffected | <600 IU/mL unaffected |
| Method Comparison (vs. LC-MS) | Not applicable (predicate compared to Enzymun-Test Cortisol) | Passing/Bablok: 1.022 (slope), 2.92 (intercept), 0.930 (R)Deming Regression: 1.055 (slope), -6.10 (intercept), 0.993 (R) |
| Reagent Stability (Onboard) | On the Analyzers - 30 days | On the Analyzers – 8 weeks (56 days) |
| Reagent Stability (After Opening) | After Opening at 2-8°C - 30 days | After Opening at 2-8°C - 12 weeks (84 days) |
| Calibration Interval | Once per lot (reagent), recommended renewed calibration after 28 days (same lot) / 7 days (same kit) | Once per lot (reagent), recommended renewed calibration after 8 weeks (same lot) / 7 days (same kit) |
2. Sample sizes used for the test set and the data provenance
- Precision (Human Serum)
- Test Set Sample Size: 5 human serum samples (native, diluted, spiked) and 2 controls (PC Universal).
- Data Provenance: Not explicitly stated, but implies laboratory testing internal to the manufacturer (Roche Diagnostics).
- Limit of Blank (LoB)
- Test Set Sample Size: 5 blank samples. A total of n = 60 LoB measurements were made.
- Data Provenance: Not explicitly stated, implies internal laboratory testing.
- Limit of Detection (LoD)
- Test Set Sample Size: 5 low-level human serum samples (diluted). A total of n = 60 LoD measurements were made.
- Data Provenance: Not explicitly stated, implies internal laboratory testing.
- Limit of Quantitation (LoQ)
- Test Set Sample Size: 9 human serum samples.
- Data Provenance: Not explicitly stated, implies internal laboratory testing.
- Linearity (Serum and Plasma)
- Test Set Sample Size: 19 concentrations (thereof 17 dilutions) prepared from a high analyte serum/plasma sample. Each assayed in 3-fold determination within a single run.
- Data Provenance: Not explicitly stated, implies internal laboratory testing.
- Analytical Specificity (Serum/Plasma)
- Test Set Sample Size: Two human serum sample pools.
- Data Provenance: Not explicitly stated, implies internal laboratory testing.
- Endogenous Interferences
- Test Set Sample Size: Three human serum samples (low, mid, high cortisol concentrations) for each interfering substance.
- Data Provenance: Not explicitly stated, implies internal laboratory testing.
- HASA Effect
- Test Set Sample Size: Two serum samples with cortisol concentrations of 173 and 789 nmol/L. Aliquots spiked with DASA and diluted in 10% increments.
- Data Provenance: Not explicitly stated, implies internal laboratory testing.
- Exogenous Interferences - Drugs
- Test Set Sample Size: Two human serum samples (native, diluted, spiked) for 16 pharmaceutical compounds; each tested in 3-fold determination.
- Data Provenance: Not explicitly stated, implies internal laboratory testing.
- Exogenous Interferences - Anticoagulants
- Test Set Sample Size: Minimum of 48 serum/plasma pairs per sample material (Serum, Li-Heparin, K2-EDTA-, K3-EDTA-plasma primary tubes and Li-Heparin Plasma Gel Separation Tubes). Each tested in duplicate.
- Data Provenance: Not explicitly stated, implies internal laboratory testing.
- Method Comparison 1: Elecsys Cortisol II vs. LC-MS (Reference Method)
- Test Set Sample Size: 208 human serum samples (all native single donors).
- Data Provenance: UZ Gent, Lab voor Klinische Biologie (Gent, Belgium); implies prospective collection for the study or a well-characterized archive.
- Method Comparison 2: Elecsys Cortisol II vs. Cortisol I (K070788)
- Test Set Sample Size: 536 human serum samples (all native single donors).
- Data Provenance: UZ Gent, LMU Großhadern, Uni Klinik Leipzig and Labor Limbach; implies prospective collection for the study or a well-characterized archive from multiple European sites.
- Reagent Stability (Onboard and After First Opening)
- Test Set Sample Size: 5 human serum samples (native, diluted, spiked) and 2 controls.
- Data Provenance: Not explicitly stated, implies internal laboratory testing.
- Reagent Stability (Real-time, ongoing)
- Test Set Sample Size: PreciControl Universal (Level 1 and 2) and human serum samples. Data for time-points at 0, 13, 16, 19 months (MP lot) and 0, 7, 16, 19 months (P2 and P3 lot)
- Data Provenance: Not explicitly stated, implies internal laboratory testing.
- Sample Stability (2-8°C, Room Temperature, -15 to -25°C)
- Test Set Sample Size: Twelve human serum, Li-Heparin, K2-EDTA, and K3-EDTA plasma samples (all single donors, native, spiked, diluted) for each study.
- Data Provenance: Not explicitly stated, implies internal laboratory testing.
- Calibration Stability (Lot and On-board)
- Test Set Sample Size: Five human serum samples (native, diluted, spiked) and two control samples.
- Data Provenance: Not explicitly stated, implies internal laboratory testing.
- Calibrator studies (Reconstitution, Stability)
- Test Set Sample Size: Not explicitly stated beyond "two sets of Cortisol II CalSet" for reconstitution, and "on-test and reference materials" for stability. PreciControl Universal used to assess CalSet stability.
- Data Provenance: Not explicitly stated, implies internal laboratory testing.
- Clinical Performance Evaluation (Reference Range)
- Test Set Sample Size: 296 individuals for 6-10 am sample collection, 300 individuals for 4-8 pm sample collection.
- Data Provenance: Three sites in the United States (one site in St Louis, Missouri for evaluation). These are prospective clinical samples.
- Training Set Sample Size: The document does not specify a separate "training set" for the Elecsys Cortisol II device. Immunoassays are not typically "trained" in the machine-learning sense with a distinct training dataset. Instead, they are developed, optimized, and then validated with performance studies. The "value assignment" for calibrators, and the master curves are part of the setup, but not a "training set" in the context of AI.
3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts
This information is not applicable or explicitly stated in the document for this type of medical device (an in-vitro diagnostic immunoassay). For immunoassays, ground truth (or reference values) is typically established through:
- Reference methods: Like LC-MS (Liquid Chromatography-Mass Spectrometry) as used in Method Comparison 1. These are highly accurate analytical techniques, not dependent on expert interpretation.
- Spiking studies/Dilution linearity: Known concentrations are added to samples, which serves as the "ground truth" for evaluating recovery and linearity.
- Clinical context: For reference ranges, the "truth" is derived statistically from a population of healthy individuals.
- Previous assay values: For comparative studies, the predicate device's results are used as a comparison point.
There are no mentions of human experts establishing "ground truth" in terms of interpreting clinical findings or images.
4. Adjudication method for the test set
Not applicable. This is not a device where human interpretation or adjudication is used to establish "ground truth" for the test results. The device measures a biomarker concentration.
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 document describes an immunoassay and calibrator, not an AI device that assists human readers in interpreting cases. There is no mention of human readers or AI assistance.
6. If a standalone (i.e. algorithm only without human-in-the loop performance) was done
This refers to an immunoassay, which is by nature a standalone analytical system. The Elecsys Cortisol II assay determines the quantitative concentration of cortisol in human serum and plasma directly. There is no human-in-the-loop performance component in the measurement process itself, although clinical interpretation of the results by a healthcare professional is expected.
7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.)
The types of "ground truth" or reference standards used in the studies include:
- Reference Method LC-MS: For Method Comparison 1, the Elecsys Cortisol II was compared against LC-MS, which serves as a highly accurate reference method for cortisol quantification.
- Predicate Device: For Method Comparison 2, the Elecsys Cortisol II was compared against the predicate Elecsys Cortisol (K070788) assay.
- Known Spiked/Diluted Concentrations: For studies like linearity, analytical specificity, and interference, known amounts of analyte or interfering substances were added to samples, establishing controlled "ground truth" for evaluation.
- Statistical Normative Data: For establishing the reference ranges, the results from a large cohort of self-reported healthy individuals were used to statistically define normal limits.
- Assigned Values: For calibrator and control stability, "assigned values" from independent measurements (e.g., using multiple analyzers and lots) were used as the reference.
8. The sample size for the training set
The document does not specify a "training set" in the context of machine learning for this immunoassay. Immunoassays typically involve development and optimization phases for reagent formulation, antibody selection, and instrument parameters, which could be seen as analogous to "training" in a broad sense, but not with a distinct training data set size as in AI/ML validation studies. Instead, the assay relies on a master curve (provided via reagent barcode) and 2-point calibration.
9. How the ground truth for the training set was established
As there is no distinct "training set" in the AI/ML sense, this question is not directly applicable. However, for the reference values that define the assay's performance and calibration, the following methods are mentioned:
- Master curve: Provided via reagent barcode for quantitative determination.
- Calibration: Results are determined via a calibration curve that is instrument specifically generated by 2-point calibration.
- Traceability: The Elecsys Cortisol II assay has been standardized against the IRMM (Institute for Reference Materials and Measurements)/IFCC 451 panel (ID GC/MS, isotope dilution-gas chromatography/mass spectrometry), which serves as a highly accurate reference.
- Calibrator Value Assignment: For the Cortisol II CalSet, target values are chosen for the best fit with the Master Calibration Curve and Rodbard curve parameters. Calibrators are run in duplicate on multiple analyzers (at least 3 cobas e 411 and at least 3 cobas e 601/cobas e 602/MODULAR ANALYTICS E170 analyzers) with all available reagent lots. The assigned value is the mean over at least six runs on at least three analyzers.
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Image /page/0/Picture/1 description: The image shows the logo for the Department of Health & Human Services - USA. The logo is circular, with the text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" arranged around the perimeter. In the center of the circle is a stylized image of three human profiles facing to the right, stacked on top of each other.
Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002
April 27, 2016
ROCHE DIAGNOSTICS KELLI TÜRNER REGULATORY AFFAIRS PRINCIPAL 9115 HAGUE ROAD INDIANAPOLIS IN 46250
Re: K15227
Trade/Device Name: Elecsys Cortisol II. Cortisol II CalSet Regulation Number: 21 CFR 862.1205 Regulation Name: Cortisol (hydrocortisone and hydroxycorticosterone) test system Regulatory Class: II Product Code: JFT, JIT Dated: March 24, 2016 Received: March 25, 2016
Dear Ms. Kelli Turner:
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) K152227
Device Name Elecsys Cortisol II
Indications for Use (Describe)
Immunoassay for the in vitro quantitative determination of cortisol in human serum, and plasma. The determination of cortisol is used for the recognition and treatment of functional disorders of the adrenal gland. The electrochemiluminescence immunoassay "ECLIA" is intended for use on Elecsys and cobas e immunoassay analyzers.
| 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) |
CONTINUE ON A SEPARATE PAGE IF NEEDED.
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DO NOT SEND YOUR COMPLETED FORM TO THE PRA STAFF EMAIL ADDRESS BELOW.
The burden time for this collection of information is estimated to average 79 hours per response, including the time to review instructions, search existing data sources, gather and maintain the data needed and complete and review the collection of information. Send comments regarding this burden estimate or any other aspect of this information collection, including suggestions for reducing this burden, to:
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"An agency may not conduct or sponsor, and a person is not required to respond to, a collection of information unless it displays a currently valid OMB number."
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DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration
Indications for Use
510(k) Number (if known)
K152227
Device Name Cortisol II CalSet
Indications for Use (Describe)
Cortisol II CalSet is used for calibrating the quantitative Elecsys Cortisol II assay on the Elecsys and cobas e immunoassay analyzers.
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)
CONTINUE ON A SEPARATE PAGE IF NEEDED.
This section applies only to requirements of the Paperwork Reduction Act of 1995.
DO NOT SEND YOUR COMPLETED FORM TO THE PRA STAFF EMAIL ADDRESS BELOW.
The burden time for this collection of information is estimated to average 79 hours per response, including the time to review instructions, search existing data sources, gather and maintain the data needed and complete and review the collection of information. Send comments regarding this burden estimate or any other aspect of this information collection, including suggestions for reducing this burden, to:
Department of Health and Human Services Food and Drug Administration Office of Chief Information Officer Paperwork Reduction Act (PRA) Staff PRAStaff(@fda.hhs.gov
"An agency may not conduct or sponsor, and a person is not required to respond to, a collection of information unless it displays a currently valid OMB number."
Form Approved: OMB No. 0910-0120 Expiration Date: January 31, 2017 See PRA Statement below.
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510(k) Summary
(K152227)
This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of 21 CFR 807.92.
| Submitter Name | Roche Diagnostics |
|---|---|
| Address | 9115 Hague RoadIndianapolis, IN 46250 |
| Contact | Kelli TurnerPhone: (317) 521-4515FAX: (317) 521-3080Email: kelli.turner@roche.com |
| Date Prepared | 04/22/2016 |
| Proprietary Name | 1) Elecsys Cortisol II2) Cortisol II CalSet |
| Common Name | 1) Cortisol II immunoassay2) Cortisol II CalSet |
| Classification Name | 1) Enzyme Immunoassay, Cortisol2) Secondary, calibrator |
| Product Codes | 1) JFT, 862.12052) JIT, 862.1150 |
| Predicate Devices | Elecsys Cortisol (K070788)Elecsys Cortisol CalSet (K070788) |
| Establishment Registration | Roche Diagnostics GmbH in Mannheim, Germany, is 9610126Roche Diagnostics GmbH in Penzberg, Germany, is 9610529Roche Diagnostics in the United States is 1823260 |
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1. DEVICE DESCRIPTION
The Elecsys Cortisol II assay makes use of a competition test principle using a monoclonal antibody which is specifically directed against cortisol. Endogenous cortisol which has been liberated from binding proteins with danazol competes with exogenous cortisol derivative in the test which has been labeled with ruthenium complex for the binding sites on the biotinylated antibody.
Results are determined via a calibration curve which is instrument specifically generated by 2point calibration and a master curve provided via reagent barcode.
1.1. Reagents
The reagent working solutions include:
- rackpack (kit placed on instrument) .
- Streptavidin coated microparticles, ş
- Reagent 1 (Anti-cortisol-Ab~biotin) and ş
- Reagent 2 (Cortisol-peptide~Ru(bpy)2+3). ş
Calibrator 1.2.
The Cortisol II CalSet is a lyophilized human serum with added cortisol in two concentration ranges.
The CalSet includes:
- Cal 1 (approximately 12.5 nmol/L cortisol in a human serum matrix) .
- Cal 2 (approximately 1000 nmol/L cortisol in a human serum matrix) .
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2. INDICATIONS FOR USE
2.1. Immunoassay
Immunoassay for the in vitro quantitative determination of cortisol in human serum, and plasma. The determination of cortisol is used for the recognition and treatment of functional disorders of the adrenal gland.
The electrochemiluminescence immunoassay "ECLIA" is intended for use on Elecsys and cobas e immunoassay analyzers.
2.2. Calibrator
Cortisol II CalSet is used for calibrating the quantitative Elecsys Cortisol II assay on the Elecsys and cobas e immunoassay analyzers.
TECHNOLOGICAL CHARACTERISTICS 3.
| Table 1: | Assay Comparison | |
|---|---|---|
| ---------- | -- | ------------------ |
| Assay Comparison | ||
|---|---|---|
| Feature | Predicate Device: Elecsys Cortisol(K070788) | Candidate Device: Elecsys Cortisol II |
| General Assay Features |
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| Assay Comparison | ||
|---|---|---|
| Intended Use/Indicationsfor Use | Immunoassay for the in vitro quantitativedetermination of cortisol in human serum,plasma, urine and saliva. The determinationof cortisol is used for the recognition andtreatment of functional disorders of theadrenal gland.The electrochemiluminescenceimmunoassay "ECLIA" is intended for use onElecsys and cobas e immunoassayanalyzers. | Immunoassay for the in vitro quantitative determination of cortisol inhuman serum, and plasma. The determination of cortisol is used forthe recognition and treatment of functional disorders of the adrenalgland.The electrochemiluminescence immunoassay "ECLIA" is intendedfor use on Elecsys and cobas e immunoassay analyzers. |
| AssayProtocol | The Elecsys Cortisol assay makes use of acompetition test principle using a polyclonalantibody which is specifically directedagainst cortisol. Endogenous cortisol whichhas been liberated from binding proteins withdanazol competes with exogenous cortisolderivative in the test which has been labeledwith ruthenium complex for the binding siteson the biotinylated antibody. | The Elecsys Cortisol II assay makes use of a competition testprinciple using a monoclonal antibody which is specifically directedagainst cortisol. Endogenous cortisol which has been liberated frombinding proteins with danazol competes with exogenous cortisolderivative in the test which has been labeled with rutheniumcomplex for the binding sites on the biotinylated antibody. |
| DetectionProtocol | Electrochemiluminescent Assay | Electrochemiluminescent Assay. |
| Applications | 18 minute application | 18 minute application. |
| InstrumentPlatform | Elecsys 1010, Elecsys 2010, MODULARANALYTIC E170 and cobas e analyzers. | cobas e 411 |
| SampleVolume | 20 µL | 10 µL. |
| SampleType | Human serum, plasma, saliva and urine. | Human serum, and plasma. |
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| Assay Comparison | ||
|---|---|---|
| Reagents | M Streptavidin-coated microparticles:Streptavidin-coated microparticles;preservative.R1 Anti-cortisol-Ab | M Streptavidin-coated microparticles: Streptavidin-coatedmicroparticles; preservative.R1 Anti-cortisol-Ab |
| Calibrator | Elecsys Cortisol CalSet | Elecsys Cortisol II CalSet |
| CalibrationInterval | Calibration must be performed once perreagent lot using fresh reagent (i.e. not morethan 24 hours since the reagent kit wasregistered on the analyzer). Renewedcalibration is recommended as follows:After 28 days when using the samereagent lot.After 7 days (when using the samereagent kit on the analyzer).As required: e.g. quality control findingsoutside the defined limits | Calibration must be performed once per reagent lot using freshreagent (i.e. not more than 24 hours since the reagent kit wasregistered on the analyzer). Renewed calibration is recommendedas follows:After 8 weeks when using the same reagent lot.After 7 days (when using the same reagent kit on the analyzer).As required: e.g. quality control findings outside the definedlimits |
| Controls | Elecsys PreciControl Universal | Elecsys PreciControl Universal |
| Traceability /Standardization | standardized against the Enzymun-TestCortisol method. | Standardized against the IRMM (Institute for Reference Materialsand Measurements)/IFCC 451 panel (ID GC/MS, isotope dilution-gas chromatography/mass spectrometry). |
| ReagentStability | When stored and handled as directed,reagents are stable until the expiration date.After Opening at 2-8°C - 30 daysOn the Analyzers - 30 days | Unopened: 2-8°C - Up to the stated expiration date.After Opening at 2-8°C - 12 weeksOn the Analyzers – 8 weeks |
| MeasuringRange | 0.5 – 1750 nmol/L | 3.0- 1750 nmol/L |
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| Assay Comparison | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Precision | Elecsys 2010/cobas e 411:Within-run | cobas e 411:SerumWithin-run (will be labeled Repeatability) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Sample Mean (nmol/L) SD %CV HS 1 208 2.76 1.3 HS 2 561 7.40 1.3 HS 3 1268 14.0 1.1 PCU* 1 363 5.08 1.4 PCU* 2 865 8.54 1.0 | Sample Mean (nmol/L) SD CV HS 1 3.09 0.219 7.1% HS 2 35.8 0.718 2.0% HS 3 283 7.29 2.6% HS 4 548 10.4 1.9% HS 5 1592 29.3 1.8% PCU* 1 308 4.33 1.4% PCU* 2 719 10.4 1.4% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Total Sample Mean (µg/dL) SD %CV HS 1 208 3.29 1.6 HS 2 561 8.36 1.5 HS 3 1268 19.9 1.6 PCU* 1 363 5.67 1.6 PCU* 2 865 12.5 1.4 *PreciControl Universal | Total (will be labeled Intermediate precision) Sample Mean (nmol/L) SD CV HS 1 3.09 0.392 12.7% HS 2 35.8 1.36 3.8% HS 3 283 9.39 3.3% HS 4 548 17.4 3.2% HS 5 1592 42.7 2.7% PCU* 1 308 8.35 2.7% PCU* 2 719 18.0 2.5% *PreciControl Universal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| AnalyticalSensitivity | Limit of Detection = <0.500 nmol/L | Limit of Blank (LoB): = 1.0 nmol/mLLimit of Detection (LoD): = 1.5 nmol/mLLimit of Quantitation (LoQ): = 3.0 nmol/mL |
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| AnalyticalSpecificity | Compound | Concentration(µg/mL) | %Cross-Reactivity | Cross reactant | concentrationtested(µg/mL) | Highestcross-reactivityobserved(%) |
|---|---|---|---|---|---|---|
| Allotetrahydro-Cortisol | 0.1 | 165 | 11-Deoxycorticosterone | 10 | 0.640 | |
| Corticosterone | 10 | 5.8 | 11-Deoxycortisol | 10 | 4.90 | |
| Cortisol 21-sulfate | 10 | 0.04 | 17-α-Hydroxyprogesterone | 10 | 0.080 | |
| Cortisone | 10 | 0.30 | Corticosterone | 10 | 2.48 | |
| 11-Deoxycortl-costerone | 10 | 0.69 | Cortisone | 10 | 6.58 | |
| 11-Deoxycortisol | 10 | 4.1 | Dexamethasone | 10 | Notdetectable | |
| Dexamethasone | 10 | 0.08 | Fludrocortisone | 10 | 0.200 | |
| 21-deoxycortisol | 1 | 45.4 | Prednisone | 10 | 2.23 | |
| 6-b-Hydroxycortisol | 1 | 158 | Progesterone | 10 | 0.035 | |
| 17-Hydroxy-progesterone | 10 | 1.5 | 21-Deoxycortisol | 1 | 2.40 | |
| 6-a-methyl-prednisolone | 0.1 | 389 | Prednisolone | 0.1 | 7.98 | |
| Prednisolone | 0.1 | 171 | 6-α-Methylprednisolone | 0.1 | 12.0 | |
| Prednisone | 10 | 0.28 | Androstendion | 10 | 0.1 | |
| Progesterone | 10 | 0.35 | Estradiol | 10 | 0.2 | |
| Estriol | 10 | Notdetectable | ||||
| Estron | 10 | 0.8 | ||||
| Linearity | 1 to 59.8 µg/dL | 3.0 to 1750 nmol/mL |
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| Assay Comparison | ||
|---|---|---|
| Limitations | When performed in serum and plasma, the assay is unaffected by:Bilirubin <60 mg/dLHemolysis < 1.9 g/dLLipemia < 2700 mg/dLBiotin< 30 ng/mLRheumatoid factors < 1100 IU/mLIn vitro tests were performed on 17commonly used pharmaceuticals. Nointerference with the assay was found.The risk of interference from potentialimmunological interactions between testcomponents and rare sera has beenminimized by the inclusion of suitableadditives. In rare cases, interference dueto extremely high titers of antibodies toanalyte-specific antibodies, streptavidinor ruthenium can occur. The testcontains additives which minimize theseeffects.Pregnancy, contraceptives and estrogentherapy give rise to elevated cortisolconcentrations.In samples from patients who have beentreated with prednisolone, 6 αMethylprednisolone or prednisone, falselyelevated concentrations of cortisol maybe determined.During metyrapon tests, 11 deoxycortisollevels are elevated. Falsely elevatedcortisol values may be deter-mined dueto cross reactions (see section onanalytical specificity).Patients suffering from 21 hydroxylasedeficiency exhibit elevated 21deoxycortisol levels and this can alsogive rise to falsely elevated cortisolresults.The time of sample collection must betaken into account when interpretingresults due to the cortisol secre-tioncircadian rhythm. Severe stress can alsogive rise to elevated cortisol levels.For diagnostic purposes, the results shouldalways be assessed in conjunction with thepatient's medical history, clinical examinationand other findings. | When performed in serum and plasma, the assay is unaffected by:Bilirubin ≤ 25 mg/dLHemolysis ≤ 0.5 g/dLLipemia ≤ 1500 mg/dLBiotin ≤ 30 ng/mLRheumatoid factors < 600 IU/mLIgG ≤ 50 g/LIgM ≤ 10 g/LIgA ≤ 10 g/LIn vitro tests were performed on 16 commonly usedpharmaceuticals. No interference with the assay was found.In rare cases, interference due to extremely high titers ofantibodies to analyte-specific antibodies, streptavidin orruthenium can occur. These effects are minimized by suitabletest design.Pregnancy, contraceptives and estrogen therapy give rise toelevated cortisol concentrations.In samples from patients who have been treated withprednisolone, 6 α Methylprednisolone or prednisone, falselyelevated concentrations of cortisol may be determined.During metyrapon tests, 11 deoxycortisol levels are elevated.Falsely elevated cortisol values may be deter-mined due tocross reactions (see section on analytical specificity).Patients suffering from 21 hydroxylase deficiency exhibitelevated 21 deoxycortisol levels and this can also give rise tofalsely elevated cortisol results.The time of sample collection must be taken into account wheninterpreting results due to the cortisol secre-tion circadianrhythm. Severe stress can also give rise to elevated cortisollevels.For diagnostic purposes, the results should always be assessed inconjunction with the patient's medical history, clinical examinationand other findings. |
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Assay Comparison
| Labeled Performance Characteristics | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| MethodComparison(LC/MS) | n = 208Min = 10.9 nmol/LMax = 1599 nmol/L | Passing/Bablok1.0222.920.930 | Deming regression1.055-6.100.993 | |||||||
| MethodComparison(Cortisol II (y)versus Cortisol(x)) | n = 536Min = 1.54 nmol/LMax = 1680 nmol/L | Passing/Bablok0.75810.200.8725 | Deming regression0.806-10.310.9676 | |||||||
| Subjectcohort | Samplesize | Min | Max | Mean | Median | 2.5th percen-tile | 5th percen-tile | 95th percen-tile | 97.5thpercen-tile | |
| Referencerangeserum/plasma | N | nmol/L | ||||||||
| 6 - 10 am | 296 | 23.7 | 835 | 316 | 303 | 133 | 166 | 507 | 537 | |
| LCL - UCL* | - | - | - | - | - | 70.1 - 161 | 133 - 183 | 488 - 537 | 511 - 584 | |
| 4 - 8 pm | 300 | 19.1 | 544 | 172 | 161 | 68.2 | 73.8 | 291 | 327 | |
| LCL - UCL* | - | - | - | - | - | 46 - 72 | 68 - 87 | 269 - 327 | 301 - 401 |
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| Characteristic | Predicate device: Elecsys Cortisol CalSet(K070788) | Candidate device: Cortisol II CalSet |
|---|---|---|
| Intended Use | Cortisol CalSet is used for calibrating thequantitative Elecsys Cortisol assay on theElecsys and cobas e immunoassayanalyzers. | Cortisol II CalSet is used for calibrating thequantitative Elecsys Cortisol IIassay on the Elecsys and cobas eimmunoassay analyzers. |
| Analyte | Cortisol (synthetic) | Same |
| Matrix | Human serum matrix | Same |
| Levels | Two | Same |
| Target Ranges | Cal 1: 12.5 nmol/LCal 2: 1000 nmol/L | Same. |
| Format | Lyophilized | Same |
| Traceability | standardized against the Enzymun-TestCortisol method. | The Elecsys Cortisol II assay has beenstandardized against the IRMM(Institute forReference Materials andMeasurements)/IFCC-451 panel (ID-GC/MS,isotope dilution- gas chromatography/massspectrometry) |
| Handling | Carefully dissolve the contents of one bottleby adding exactly 1.0 mL of distilled ordeionized water and allow to stand closed for15 minutes to reconstitute. Mix carefully,avoiding foam formation.Transfer aliquots of the reconstitutedcalibrators into empty labeled snap-capbottles (CalSet Vials). Attach the suppliedlabels to the additional bottles. Store thealiquots immediately at -20 °C.Perform only one calibration procedure peraliquot. | Same. |
Table 2: CalSet Comparison
4. NON-CLINICAL PERFORMANCE EVALUATION
Non-clinical performance evaluations for the Elecsys Cortisol II executed with the study briefly summarized.
4.1. Precision (Human Serum)
Precision of the Elecsys Cortisol II assay was evaluated on one cobas e 411 Immunoassay Analyzer according to CLSI EP5-A2 guideline. One reagent lot was evaluated.
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The protocol consisted of testing 2 replicates each of the controls (PC Universal) and 5 human serum samples (HS) per run, 2 runs per day for 21 days. The samples were run in randomized order on the analyzer. Samples used were native, diluted and spiked human serum pools.
Repeatability and Intermediate precision were calculated according to EP5-A2.
Limit of Blank 4.2.
For the analytical sensitivity studies, 2 cobas e 411 analyzers and 2 lots of reagents were used. The Limit of Blank (LoB) was determined using native human serum pools and Universal Diluent. A total of n = 60 LoB measurements were made (5 blank samples, 1 replicate, 2 runs per day on 2 instruments over 3 days). The LoB was calculated according to CLSI EP17-A2 (non-parametric approach).
Limit of Detection 4.3.
For the analytical sensitivity studies, 2 cobas e 411 analyzer and 2 lots of reagents were used. The Limit of Detection (LoD) was determined using 5 low-level human serum samples (diluted). A total of n = 60 LoD measurements were made (5 samples, 2 runs per day on 2 instruments over 3 days). The LoD was calculated according to CLSI EP17-A2.
Limit of Quantitation 4.4.
The Limit of Quantitation (LoQ) was determined using a set of nine human serum samples, three reagent lots on two cobas e 411 analyzer. The Limit of Quantitation (LoQ) was determined in accordance with CLSI Guideline EP17-A2. Each sample was analyzed in replicates of 2, two runs per day over 3 days.
Linearity 4.5.
4.5.1. Serum
The linearity results were obtained with serum samples on the cobas e 411 Immunoassay analyzer. A high analyte serum sample (pooled human serum sample, spiked) was diluted with Diluent Universal (protein matrix). 19 concentrations (thereof 17 dilutions) throughout the
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measuring range were prepared. Samples were assayed in 3-fold determination within a single run.
The linearity data were analyzed with regards to linear, quadratic and cubic polynomials according to CLSI EP6-A. In a first step, a linearity check was performed with a first order (linear) regression and then with higher order models (quadratic and cubic).
4.5.2.
Linearity of the Elecsys Cortisol II assay was assessed on the cobas e 411 Immunoassay Analyzer according to CLSI EP6-A.
A high analyte plasma sample (pooled human plasma sample, spiked) was diluted with Diluent Universal (protein matrix). 19 concentrations (thereof 17 dilutions) throughout the measuring range were prepared. Samples were assayed in 3-fold determination within a single run.
The linearity data were analyzed with regards to linear, quadratic and cubic polynomials according to CLSI EP6-A. In a first step, a linearity check was performed with a first order (linear) regression and then with higher order models (quadratic and cubic).
Analytical Specificity 4.6.
4.6.1. Serum/Plasma
The specificity of the Elecsys Cortisol II assay was determined using two human serum sample pools (diluted as well as spiked) spiked with potential cross-reactant compounds. The analyte concentration of the samples was at approx. 60 and 300 µg/L Cortisol (conversion factor: µg/L x 2.7586 = nmol/L). The spiked and non-spiked samples were tested in duplicates on the cobas e 411 Immunoassay Analyzer. Cross-reactivity results will be reported in the method sheet.
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Endogenous Interferences 4.7.
The effect on quantitation of analyte in the presence of endogenous interfering substances using the Elecsys Cortisol II assay was determined on the cobas e 411 Immunoassay analyzer using human serum samples (single samples as well as pools, native, diluted and spiked).
For each interfering substance three human serum samples containing low, mid and high concentrations of Cortisol were tested. The recovery for each sample was calculated by comparison to the reference sample. Predefined acceptance criterion was met. The claims included in the method sheet were set to the specification concentration.
4.8. HASA Effect
The effect of the presence of human anti-sheep antibodies (HASA) on the Elecsys Cortisol II assay was assessed on the cobas e 411 analyzer.
As no native human sample with this type of interference was available the effect of human antisheep antibodies was investigated in a model system using donkey anti-sheep polyclonal antibodies (DASA).
Two serum samples with cortisol concentrations of 173 respectively 789 nmol/L were divided into two aliquots each. One aliquot was spiked with the 20ug/mL DASA and was then diluted with the unspiked aliqout of the serum sample in 10% increments.
The recovery for each sample was calculated by comparison to the unspiked reference sample.
Exogenous Interferences- Drugs 4.9.
The effect on quantitation of analyte in the presence of drugs was determined by comparing values obtained from samples spiked with 16 pharmaceutical compounds spiked into two human serum samples (native, diluted and spiked human serum pools as well as single samples) and tested on the cobas e 411 Immunoassay Analyzer. The analyte concentrations of the samples were approximately 170 and 750 nmol/L. The drug concentrations tested are in accordance with the recommendation (if available) given in the CLSI guideline EP7-A2. The two serum samples were divided into aliquots and spiked with the potential interferents. The reference sample without interferent was spiked with the respective amount of solvent only.
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The Cortisol II concentration of the spiked aliquots was determined in 3-fold determination and compared to the Cortisol concentration determined for the reference aliquot (also in 3-fold determination) on one cobas e 411 Immunoassay Analyzer.
4.10. Exogenous Interferences- Anticoagulants
The effect on quantitation of analyte in the presence of anticoagulants with the Elecsys Cortisol II Immunoassay was determined by comparing values obtained from samples (native, diluted and spiked human serum pools as well as single samples) drawn into Serum, Li-Heparin, K2-EDTA-, K3-EDTA-plasma primary tubes and Li-Heparin Plasma Gel Separation Tubes. A minimum of 48 serum/plasma pairs per sample material were tested in duplicate with one reagent lot on one cobas e 411 Immunoassay Analyzer. Potential effects are assessed by regression analysis.
4.11. Method Comparison
To show correlation, the following two method comparisons were performed:
Method Comparison 1: Elecsys Cortisol II vs. LC-MS (Reference Method)
Method Comparison 2: Elecsys Cortisol II vs. Cortisol I (K070788)
4.11.1. Method Comparison 1: Elecsys Cortisol II vs. LC-MS (Reference Method)
A total of 208 human serum samples (all native single donors) were measured in singleton covering the entire measuring range. The study was performed on the cobas e 411 (Y) and the LC-MS method (X) at UZ Gent, Lab voor Klinische Biologie (Gent, Belgium).
4.11.2. Method Comparison 2: Elecsys Cortisol II vs. Cortisol I (K070788)
The second method comparison shows the correlation of the Elecsys Cortisol II to the current Elecsys Cortisol assay. The expected differences due the improved specificity of the Elecsys Cortisol II assay are shown. The study was performed on the cobas e 411 (Y and X) analyzer at UZ Gent, LMU Großhadern, Uni Klinik Leipzig and Labor Limbach, respectively. A total of 536 human serum samples (all native single donors) were measured.
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4.12. Reagent Stability
To test reagent stability, three studies were executed with two studies completed.
4.12.1. Study 1. Reagent stability onboard (8 weeks)
Reagent onboard stability for the Elecsys Cortisol II assay was tested on one cobas e 411 Immunoassay Analyzer.
A fresh reagent rackpack was placed on the analyzer and calibrated. Reference values for the samples tested were determined. After measurement the rackpack was removed from the analyzer and kept at 20°C + 3°C (on-board condition). On day 8, 36 and day 64, the same samples were measured with this reagent kit using the calibration curves established on day 1, 29 and 57, respectively.
Samples tested in duplicate include five human serum (HS) samples and two controls. Native, diluted and spiked human serum samples were used.
4.12.2. Study 2. Reagent stability after first opening at 2-8°C (84 days)
Reagent stability after first opening for the Elecsys Cortisol II assay was tested on one cobas e 411 Immunoassay Analyzer.
A fresh reagent rackpack was placed on the analyzer and calibrated. Reference values for the samples tested were determined. After measurement the kit was removed from the analyzer and kept at 2-8 °C for 29 days, 57 days and 92 days. After 29 days, 57 days and 92 days the kit was placed on the analyzer again, calibrated and the test samples were determined.
Samples tested in duplicate include five human serum (HS) samples and two controls. Native, diluted and spiked human serum samples were used.
4.12.3. Study 3: A real-time stability study is ongoing to support shelf-life stability claim. In the ongoing real-time stability study, the Elecsys Cortisol II assay material is stored at 2-8°C. The stored assay reagents are tested at time point T=0 and at specified intervals over the shelf life of the device up to the planned shelf life plus one month. Testing will be performed using
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PreciControl Universal. Level 1 and 2 (lyophylized, stored at -20°C) and human serum samples (stored at -80°C).
Data for the time-points at 0, 13, 16 and 19 months for MP lot and at 0, 7, 16 and 19 months for P2 and P3 lot tested in duplicate will be available. The average on-test recovery value will be calculated as percent recovery compared to the reference value (Assigned value for PreciControl Universal, Level 1 and 2).
4.13. Sample Stability
To test sample stability, three studies were completed. Because these studies are not analyzer dependent, and the assay is a global product currently available rest of world (ROW), the studies were executed on the cobas e 601. Study results can be applied to the cobas e 411 since sample stability is independent of the analyzer. For each study, the samples used were all single donors (native, spiked and diluted) and the following acceptance criteria was applied.
4.13.1. Study 1. Sample stability at 2-8°C
Twelve human serum, Li-Heparin, K2-EDTA, and K3-EDTA plasma samples were aliquoted and measured fresh (reference value) and after storage at 2-8°C for 4 days.
Measurements were performed with three-fold determination on a cobas e 601 Immunoassay Analyzer and recovery was calculated as percent of the reference value.
The human serum samples used were native, spiked and diluted single donors.
Study 2. Sample stability at Room Temperature (15-25°C) 4.13.2.
Twelve human serum, Li-Heparin, K2-EDTA, and K3-EDTA plasma samples were aliquoted and measured fresh (reference value) and after storage at 20-25°C for 24 hours.
Measurements were performed with three-fold determination on a cobas e 601 Immunoassay
Analyzer and recovery was calculated as percent of the reference value.
The human serum samples used were native, spiked and diluted single donors.
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4.13.3. Study 3. Sample stability -15 to -25°C
Twelve human serum. Li-Heparin, K2-EDTA, and K3-EDTA_plasma samples were aliquoted and measured fresh (reference value) and after storage of 12 months at -15 to -25°C.
Measurements were performed with three-fold determination on a cobas e 601 Immunoassay Analyzer and recovery was calculated as percent of the reference value.
The human serum samples used were native, spiked and diluted single donors.
4.14. Calibration Stability
To test calibration stability, two studies were completed, including:
- . Study 1. Lot calibration stability
- Study 2. On-board calibration stability
4.14.1. Study 1
Calibration of an Elecsys Cortisol II reagent lot is recommended every 8 weeks. During that time period fresh reagent kits of the same lot can be used without calibration using the calibration curve of the Day 1 reagent kit.
Elecsys Cortisol II was calibrated with a fresh reagent kit on Day 1 using a cobas e 411 Immunoassay Analyzer. After 29 days, 57 days and 92 days a new reagent kit of the same lot was used and recovery of samples was determined using the calibration curve of day 1.
Five human serum (HS) samples and two control samples were tested; each sample was tested with two-fold determination. The human serum samples used were native, diluted and spiked.
4.14.2. Study 2
Reagent Calibration Stability for the Elecsys Cortisol II assay was tested on one cobas e 411 Immunoassay Analyzer.
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A fresh Reagent Rack-Pack was placed on the analyzer and calibrated. All samples were measured on day 1. On day 8 the same samples were measured with the same reagent kit kept at 20°C + 3°C (on-board condition) using the calibration curves established on day 1.
Five human serum (HS) samples and two control samples were tested; each sample was tested with two-fold determination. The human serum samples used were native, diluted and spiked.
4.15. Calibrator studies
The Elecsys Cortisol II CalSet was evaluated for value assignment, reconstitution and stability.
4.15.1. Value assignment
Value assignment testing was conducted and passed pre-defined acceptance criteria. The target values for the two levels of the Cortisol II CalSet kit are chosen to obtain the best fit with the Master Calibration Curve, together with the Rodbard curve parameters encoded in the reagent barcode. For each Elecsys Cortisol II CalSet lot manufactured, the calibrators are run in duplicate on at least three (3) cobas e 411 analyzers and at least three (3) cobas e 601/cobas e 602/MODULAR ANALYTICS E170 analyzers with all Cortisol II reagent lots available. The assigned value of each calibrator is defined as the mean value obtained over at least six (6) runs on at least three (3) analyzers) of the respective calibrator.
Measurement values for PreciControl Universal (Levels 1 & 2), a multi-analyte control recommended for use to monitor accuracy and precision of specified analytes, are read from the calibration curves generated. The pre-defined acceptance criteria for PreciControl Universal have to be met to release the Assigned Values for Cortisol II CalSet.
4.15.2. Reconstitution
Reconstitution time for the lyophilized Cortisol II CalSet was tested. Two sets of Cortisol II CalSet were reconstituted, one for 15 minutes and the other for 30 minutes. Signal recovery after 30 minutes reconstitution was compared to the signal value after 15 minutes.
Cortisol II CalSet was evaluated in duplicate on the cobas e 411 analyzer.
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4.15.3. Stability
Three studies were performed in order to verify the stability claims for the Cortisol II CalSet. Stability studies after reconstitution and an accelerated stability study were completed on the Elecsys 2010.
4.15.3.1. Study 1- Stability at -20°C (after reconstitution)
The on-test and reference materials were tested in duplicate on the Elecsys 2010. The on-test material was reconstituted and stored in closed vials for 3 months at -20°C. The on-test signal recovery was calculated as percent of the reference value.
4.15.3.2. Study 2- Onboard stability at 20-25°C after reconstitution
The on-test and reference materials were tested in duplicate on the Elecsys 2010. The on-test material was reconstituted and stored in open vials for 4 hours at 20-25°C. The on-test signal recovery was calculated as percent of the reference value.
4.15.3.3. Real-time Stability
Since there was no change in formulation and target values to the Cortisol II CalSet the real-time stability data (18 months at 2-8°C) of the current Cortisol CalSet is applicable.
In the real-time stability study, the Cortisol CalSet on-test material was stored at 2 - 8°C. The CalSets were tested at specified intervals over the shelf life of the device up to the planned shelf life plus one month.
Data for the time-points after manufacturing, 7 (Lot 1), 6 (Lot 2 & 3), 14 (Lot 1), 13 (Lot 2 & 3), and 19 months were tested in duplicate. The stability of the CalSet was assessed via accurate recovery of PreciControl Universal.
4.15.3.4. Reconstitution study
Reconstitution time for the lyophilized Cortisol II CalSet was tested. Two sets of Cortisol II CalSet were reconstituted, one for 15 minutes and the other for 30 minutes. Signal recovery after
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30 minutes reconstitution was compared to the signal value after 15 minutes. Cortisol II CalSet was evaluated in duplicate on the cobas e 411 analyzer.
CLINICAL PERFORMANCE EVALUATION 5.
Clinical samples were collected at three sites in the United States in order to establish the reference range values for the Elecsys Cortisol II assay. Reference ranges for self-reported healthy males and females were determined using the median value, the 5th -95th and the 2.5th -97.5th percentiles (nmol/L) as lower and upper limit of normal, respectively. The evaluation was done at one site in St Louis, Missouri with one reagent lot (MP) using one cobas e 411 analyzer. Samples were all native human serum samples measured in singleton, over 2 runs within 10 days.
6. ADDITIONAL INFORMATION
Two additional products are used with the Elecsys Cortisol II assay; Cortisol CalCheck and the PreciControl Universal. There has been no change to the manufacturing process, value assignment process, product stability or specifications of these products.
The Elecsys Cortisol CalCheck labeling has been updated to incorporate the Cortisol II information and has been included for review.
7. CONCLUSIONS
The information provided in this Premarket Notification [510(k)] will support a determination of substantial equivalence for the Elecsys Cortisol II, and Elecsys Cortisol II CalSet. The data supports a safe, effective device which performs as well as or better than the predicate devices.
§ 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.