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510(k) Data Aggregation
(56 days)
For in vitro diagnostic use in the quantitative determination of cortisol in serum, plasma (EDTA and lithium heparin), and urine using the ADVIA Centaur® XP system.
Measurements of cortisol are used in the diagnosis and treatment of disorders of the adrenal gland.
The ADVIA Centaur Cortisol (COR) 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 (COR) 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).
This document is focused on the ADVIA Centaur Cortisol (COR) assay, specifically the addition of plasma (EDTA and lithium heparin) as a sample claim. It seeks to demonstrate substantial equivalence to an existing device (K142723) which already had claims for serum and urine.
Acceptance Criteria and Reported Device Performance
The core of the study is to prove that the performance of the assay with the new plasma sample types is equivalent to its performance with serum (the established sample type). The primary acceptance criteria for this type of submission involve showing a strong correlation and minimal bias between the new sample type and the established one.
Table of Acceptance Criteria and Reported Device Performance:
| Performance Metric | Acceptance Criteria (Implicit from Industry Standards like CLSI EP09-A3) | Reported Device Performance (ADVIA Centaur Cortisol (COR) with new plasma claims vs. Serum) |
|---|---|---|
| Correlation Coefficient (r) | Typically, a correlation coefficient (r) close to 1.00 (e.g., >0.975 or >0.98 is often considered good for method comparison studies) indicating a strong linear relationship between the new and established methods. | Dipotassium EDTA Plasma vs. Serum: 1.00 Lithium-Heparin Plasma vs. Serum: 1.00 |
| Slope (from Deming Regression) | A slope close to 1.00 (e.g., 0.95 to 1.05) indicating proportional agreement between the new and established methods. | Dipotassium EDTA Plasma vs. Serum: 0.95 Lithium-Heparin Plasma vs. Serum: 0.96 |
| Intercept (from Deming Regression) | An intercept close to 0 (e.g., within a predefined range that is considered clinically insignificant) indicating fixed bias between the new and established methods. | Dipotassium EDTA Plasma vs. Serum: 0.24 µg/dL Lithium-Heparin Plasma vs. Serum: 0.56 µg/dL |
| Bias from Interferents | Bias should be within acceptable limits for clinical significance (e.g., < ±10% or clinically insignificant change). While not explicitly stated as an acceptance criterion in terms of a percentage, the results are presented to demonstrate minimal impact, aligning with good laboratory practice and CLSI EP07-ed3. | Dipotassium EDTA (9.0 mg/mL): At 12.94 µg/dL: 0.5% bias At 50.39 µg/dL: -1.1% bias Heparin (75 U/mL): At 7.85 µg/dL: 2.9% bias At 46.50 µg/dL: -0.1% bias |
Study Details:
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Sample sizes used for the test set and data provenance:
- Dipotassium EDTA Plasma vs. Serum: N = 83 samples
- Lithium-Heparin Plasma vs. Serum: N = 99 samples
- Data Provenance: The document does not explicitly state the country of origin or whether the data was retrospective or prospective. However, given that it's a 510(k) submission for commercial use, it's highly probable these were prospective studies conducted in a controlled environment, likely in the US or a country with similar regulatory standards for medical device development.
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Number of experts used to establish the ground truth for the test set and the qualifications of those experts:
- This submission is for an in vitro diagnostic (IVD) quantitative assay, not an AI/imaging device requiring expert interpretation for ground truth.
- The "ground truth" for this type of device is established by the measurement itself using a reference method or the established method (serum measurement in this case). Therefore, there were no "experts" in the sense of radiologists or pathologists establishing subjective ground truth on the test set. The comparison is between different sample types on the same device.
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Adjudication method for the test set:
- Not applicable. This is a quantitative assay comparison, not subject to human adjudication methods like consensus reading for imaging. The comparison is statistical (Deming regression, bias calculation) between objective numerical results.
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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 not an AI/imaging device. It's a chemistry assay for quantitative determination of cortisol.
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If a standalone (i.e. algorithm only without human-in-the-loop performance) was done:
- Not applicable. This is a fully automated in vitro diagnostic assay. While the instrument performs the measurement "stand-alone" in terms of algorithm/chemistry, it's not an AI diagnostic algorithm in the context of imaging or clinical decision support where such a distinction is typically made. The performance presented is the "standalone" or instrument performance.
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The type of ground truth used:
- The "ground truth" here is the measurement obtained from the established sample type (serum) using the same ADVIA Centaur Cortisol (COR) assay. The study aims to show equivalence of the new sample types (plasma) to this established serum measurement. This is a form of comparative measurement validation.
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The sample size for the training set:
- Not applicable in the AI/machine learning sense. This is a traditional IVD assay based on competitive immunoassay and chemiluminescent technology. There is no "training set" in the context of deep learning models. The assay's chemical and optical parameters are inherently "tuned" during its development, but not using a machine learning training dataset.
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How the ground truth for the training set was established:
- Not applicable due to the nature of the device (traditional IVD assay). The development and calibration of the assay involve rigorous internal validation using well-characterized samples and reference methods, but it's not a "training set" with "ground truth" established by human experts in the ML sense. The calibration curve is generated on each instrument via a 2-point calibration and a master curve. The master curve materials have 7 levels of cortisol, likely used for establishing the assay's quantitative response profile.
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(189 days)
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.
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).
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.
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