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510(k) Data Aggregation
(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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(145 days)
Immunological in vitro assay for the quantitative determination of cortisol in human serum, plasma and urine. 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 the Roche Elecsys® 1010 / 2010 and Modular Analytics E170 (Elecsys module) Immunoassay Analyzers.
The ELECSYS® Cortisol Assay a two step sandwich immunoassay with streptavidin microparticles and electrochemiluminescence detection. Results are determined using a calibration curve that is generated specifically on each instrument by a 2-point calibration and a master curve provided with the reagent bar code.
The information provided describes the Elecsys® Cortisol Assay and its substantial equivalence to a predicate device (Bayer Diagnostics ACS:180 Cortisol Assay). It focuses on comparing the new device's performance characteristics to the predicate device to demonstrate substantial equivalence, rather than detailing a specific study proving the device meets acceptance criteria with predefined thresholds. Therefore, some of the requested information cannot be fully extracted as it pertains to a typical clinical validation study with explicitly stated acceptance criteria and a detailed study design.
Here's the breakdown of what can be extracted and what is not available in the provided text:
1. Table of acceptance criteria and the reported device performance:
The document doesn't explicitly state "acceptance criteria" through specific numerical thresholds for each performance characteristic. Instead, it demonstrates performance by comparing the new device's data directly to that of the predicate device, implying that performance comparable to the legally marketed predicate device is the de facto acceptance criteria for substantial equivalence.
| Feature | Acceptance Criteria (Implied: Comparable to Predicate) | New Device (ELECSYS Cortisol) Reported Performance | Predicate Device (Bayer ACS:180 Cortisol) Reported Performance |
|---|---|---|---|
| Intra-assay precision (%CV) (Urine) | Comparable to Predicate's Intra-assay precision | • 2.2% at 22.3 µg/dl • 2.3% at 33.2 µg/dl • 2.9% at 41.9 µg/dl • 2.3% at 61.0 µg/dl | • 5.7% at 3.04 µg/dl • 5.1% at 5.43 µg/dl • 4.5% at 14.90 µg/dl • 6.4% at 18.98 µg/dl • 7.0% at 31.79 µg/dl • 7.5% at 38.67 µg/dl |
| Interassay precision (%CV) (Urine) | N/A (Predicate data not fully provided) | • 2.5% at 23.2 µg/dl • 3.2% at 33.4 µg/dl • 2.5% at 42.1 µg/dl • 1.8% at 58.9 µg/dl Control: 4.7% at 2.82 µg/dl | N/A |
| Total precision (%CV) | Comparable to Predicate's Total precision | N/A | • 9.1% at 3.04 µg/dl • 8.0% at 5.43 µg/dl • 6.4% at 14.90 µg/dl • 8.2% at 18.98 µg/dl • 9.2% at 31.79 µg/dl • 9.7% at 38.67 µg/dl |
| Functional sensitivity | Comparable or better than Predicate's functional sensitivity | < 0.29 µg/dl | 0.2 µg/dl |
| Measuring range | Comparable to Predicate's measuring range | 1.0 - 1750 nmol/L | 5.5 - 2069 nmol/L |
| Limitations (Interference in Urine) | Unaffected by specified concentrations of substances as per Predicate | • 60 mg/dl protein • 750 mmol/l NaCl • 350 mmol/l urea • 5 mmol/l creatinine • 2 mmol/l glucose | • 60 mg/dl protein • 750 mmol/l NaCl • 350 mmol/l urea • 5 mmol/l creatinine • 2 mmol/l glucose |
| On-board stability | Sufficient for clinical use, comparable to predicate | Elecsys® 2010 / E170: 6 weeks Elecsys® 1010: 6 weeks (stored alternately in refrigerator and analyzer at ambient temperature 20-25 C) Up to 20 hr. opened in total | until expiration date on the vial label or cumulative 32 hrs at room temperature. |
| Calibration frequency | Appropriate for maintaining accuracy, comparable to predicate | Elecsys® 2010 / E170: Once per lot, after one month, after 7 days, controls out of range Elecsys® 1010: With every kit, after 7 days (20-25°C), after 3 days (25-32°C), controls out of range | Every 7 days, when changing lot numbers, when replacing system components, when QC results are out of range |
2. Sample size used for the test set and the data provenance (e.g. country of origin of the data, retrospective or prospective)
This information is not provided in the given text. The document refers to "performance characteristics" but does not detail the specific study designs, sample sizes, or data provenance (e.g., retrospective/prospective, country of origin) for the tests conducted to derive these characteristics.
3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g. radiologist with 10 years of experience)
This is a an in vitro diagnostic (IVD) device for quantitative determination of cortisol. The ground truth for such devices is typically established through analytical methods and reference materials, not through expert reading or consensus in the way a diagnostic imaging device would require. Therefore, this question is not applicable in the context of this device and information is not provided.
4. Adjudication method (e.g. 2+1, 3+1, none) for the test set
As this is an IVD device measuring an analyte, adjudication methods involving human experts (like 2+1 for radiology images) are not applicable. The ground truth is analytical.
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
This is an IVD assay, not an AI-powered diagnostic imaging device that assists human readers. Therefore, an MRMC comparative effectiveness study involving human readers and AI assistance is not applicable.
6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done
The entire device (ELECSYS® Cortisol Assay) operates as a standalone analytical system to quantitatively determine cortisol. The performance characteristics listed (precision, functional sensitivity, measuring range, etc.) represent the standalone performance of the algorithm and associated instrumentation.
7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.)
For an in vitro diagnostic assay like the ELECSYS® Cortisol Assay, the "ground truth" for reported performance characteristics such as precision and sensitivity is established through analytical reference methods and certified reference materials. These involve meticulously prepared samples with known concentrations of cortisol, against which the device's measurements are compared. The document does not explicitly state the specific reference methods or materials used but implies their use through the reporting of these analytical performance metrics.
8. The sample size for the training set
This information is not provided. The document is a 510(k) submission for substantial equivalence, which typically focuses on performance data for the final product, not the developmental or training data used in its creation (especially for traditional IVD assays not based on machine learning in the way a modern AI device would be).
9. How the ground truth for the training set was established
As per point 8, information about a "training set" and its ground truth establishment is not provided and likely not relevant in the context of this type of established IVD technology. The development of such assays involves rigorous analytical testing against reference standards, but this is distinct from the machine learning "training set" paradigm.
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