(65 days)
The ADVIA Centaur® Tnl-Ultra (Tnl-Ultra) method is for in vitro diagnosic use in the quantitative determination of cardiac troponin I in serum and heparinized and EDTA plasma. Cardiac troponin I determinations aid in the diagnosis of acute myocardial infarction and in the risk stratification of patients with non-ST segment elevation actie coronaly syndromes with respective to relative risk mortality, myocardian Tiffanction or increased probability of ischemic events requiring urgent revascularization procedures.
The ADVIA Centaur® Tnl-Ultra Calibrator is for the in vitro diagnostic use in the calibration of the Tnl-Ultra assay on the ADVIA Centaur® system.
Not Found
This response describes the acceptance criteria and study proving the device meets said acceptance criteria.
1. Table of Acceptance Criteria and Reported Device Performance
| Performance Metric | Acceptance Criteria | Reported Device Performance (ADVIA Centaur® TnI-Ultra) |
|---|---|---|
| Imprecision | Not explicitly stated as criteria, but compared to predicate devices. | Total CV: 2.7% - 4.6% (across various levels) |
| Within-run CV: 1.5% - 3.2% (across various levels) | ||
| Total CV < 10% | The troponin I concentration at a total CV of 10% was determined to be 0.042 ng/mL. | |
| Functional Sensitivity | Not explicitly stated. | <0.008 ng/mL (at 20% total C.V.) |
| Correlation (General) | Not explicitly stated as criteria, but strong correlation (r > 0.9) with predicate devices is implied. | Vs. Bayer ADVIA Centaur® cTnILinear Regression (346 samples): 1.26X - 0.52, r = 0.975Vs. ACS:180 cTnILinear Regression (334 samples): 1.4X - 0.51, r = 0.967 |
| Correlation (Clinically Significant Range < 4.0 ng/mL) | Not explicitly stated as criteria, but strong correlation (r > 0.9) with predicate devices is implied. | Vs. Bayer ADVIA Centaur® cTnILinear Regression (229 samples): 1.04X + 0.04, r = 0.946Vs. ACS:180 cTnILinear Regression (230 samples): 1.13X + 0.068, r = 0.943 |
| Clinical Utility Comparision (Concordance with 0.9 ng/mL cutoff) | Not explicitly stated. | Vs. ADVIA Centaur cTnI: 97.6% ConcordanceVs. ACS:180 cTnI: 93.9% Concordance |
| Interference | Not explicitly stated as criteria, but recovery within an acceptable deviation (e.g., < ±10%) is implied. | Hemoglobin (500 mg/dL): -1.7% Deviation Lipemia (1000 mg/dL): -0.9% Deviation Icterus (Conjugated bilirubin 20 mg/dL): -4.7% Deviation Icterus (Unconjugated bilirubin 20 mg/dL): -7.8% Deviation Human immunoglobulin (12 g/dL): -5.4% Deviation |
| Analytical Range | Not explicitly stated. | 0.008 ng/mL to 50 ng/mL |
| Minimum Detectable Concentration | Not explicitly stated. | 0.008 ng/mL |
| 99th Percentile Distribution (Healthy Donors) | Not explicitly stated, but established as a reference point. | 0.044 ng/mL |
| AMI Cutoff Value Equivalence | Equivalent to predicate's AMI cutoff (0.9 ng/mL). | The AMI cutoff value of ≥ 0.9 ng/mL for ADVIA Centaur® TnI-Ultra method is equivalent to the predicate's. This statement is the acceptance criteria itself. |
| Clinical Sensitivity & Specificity | Not explicitly stated as specific numerical criteria, but comparative performance to predicate devices is shown. | Vs. ACS:180 cTnI:Sensitivity: 97.3% (95% CI: 92.4 - 99.4)Specificity: 97.0% (95% CI: 93.1 - 99.0) |
2. Sample Sizes and Data Provenance for Test Set
- Imprecision Study: The document does not specify the exact number of samples used for the imprecision study but refers to levels (ng/mL) at which the CV was calculated. This indicates repeated measurements on control samples or spiked matrix.
- Correlation Study:
- Full Range (0.1 to >30 ng/mL):
- 346 serum samples for comparison with Bayer ADVIA Centaur® cTnI.
- 334 serum samples for comparison with ACS:180 cTnI.
- Clinically Significant Range (0.1 to 4.0 ng/mL):
- 229 serum samples for comparison with Bayer ADVIA Centaur® cTnI.
- 230 serum samples for comparison with ACS:180 cTnI.
- Full Range (0.1 to >30 ng/mL):
- Clinical Utility Comparison (0.9 ng/mL cutoff): The sample sizes align with the correlation studies: 371 samples for ADVIA Centaur cTnI comparison, and 359 samples for ACS:180 cTnI comparison.
- Interfering Substances: The number of samples for interfering substances testing is not specified, but it typically involves spiking known concentrations of interferents into samples.
- ** AMI Cutoff and Clinical Performance (Sensitivity/Specificity):**
- 112 patients for sensitivity calculation.
- 166 patients for specificity calculation.
- 99th Percentile Distribution: 648 serum samples from apparently healthy donors.
Data Provenance: The document does not explicitly state the country of origin. It indicates the data is from internal studies (e.g., "data from instructions for use"). Given the manufacturer is Bayer, a multinational corporation, the samples could be from various locations. The studies appear to be prospective in the sense that they were designed to evaluate the performance of the new device against predicate devices and establish performance characteristics.
3. Number and Qualifications of Experts for Ground Truth
For a device like a Troponin I assay, "experts" in the traditional sense of clinicians or radiologists is not applicable for establishing ground truth for the assay's performance metrics (imprecision, correlation, analytical range, etc.).
- Analytical Performance: The "ground truth" for analytical performance (e.g., imprecision, linearity, interference) is established by using reference materials, certified calibrators, and well-characterized samples with known concentrations measured by highly accurate reference methods or by gravimetric/volumetric preparation. The "experts" in this context are laboratory scientists or biochemists with expertise in assay development, validation, and quality control.
- Clinical Performance (Sensitivity/Specificity for AMI): While the document refers to "patients," the ground truth for "AMI" diagnosis against which the assay's performance is measured is not explicitly detailed. However, in such studies, the ground truth for AMI is typically established by clinical diagnosis based on a combination of:
- Characteristic rise and fall of cardiac biomarker levels (often including troponin)
- Evidence of myocardial ischemia (symptoms, ECG changes)
- Imaging evidence (e.g., echocardiography, MRI).
- This clinical diagnosis would be made by cardiologists and emergency physicians, whose qualifications (e.g., years of experience) are not specified in this document.
4. Adjudication Method for Test Set
The concept of "adjudication method" (e.g., 2+1, 3+1) is primarily relevant for studies where radiologists or other human experts are interpreting images or clinical data, and their disagreements need to be resolved to establish a robust ground truth.
For this in vitro diagnostic device (IVD) assay, adjudication methods as typically understood in imaging or clinical trials are not applicable. The "adjudication" for analytical performance is through rigorous laboratory protocols, use of reference standards, and statistical analysis of quantitative results. For clinical diagnostic performance, the reference standard for AMI diagnosis (the "ground truth") is a complex clinical assessment, not typically a "read" that undergoes adjudication.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
No, an MRMC comparative effectiveness study was not done. This type of study is specifically for evaluating the effectiveness of a diagnostic test when interpreted by multiple human readers, often with and without AI assistance, especially in radiology or pathology. The ADVIA Centaur® TnI-Ultra Assay is an automated in vitro diagnostic assay for quantitative measurement of a biomarker in blood, not interpreted by human readers in the same way as an imaging study. Therefore, the concept of "human readers improve with AI vs without AI" does not apply here.
6. Standalone (Algorithm Only) Performance Study
Yes, this entire submission describes a standalone performance study. The ADVIA Centaur® TnI-Ultra Assay is a fully automated system that measures troponin I levels in patient samples. The reported performance metrics (imprecision, analytical range, correlation, sensitivity, specificity, etc.) are the standalone performance of the algorithm and the associated hardware/reagents. There is no "human-in-the-loop" once the sample is loaded and the assay initiated. The output is a quantitative value, not an interpretation requiring human review or modification as part of its primary function.
7. Type of Ground Truth Used
- Analytical Performance (Imprecision, Analytical Range, Interference, Minimum Detectable Concentration): The ground truth for these aspects is intrinsically tied to reference materials, calibrators, and precise quantitative measurements using established laboratory techniques. For example, imprecision is assessed by repeatedly measuring samples with known (or target) concentrations. Interference is determined by spiking known amounts of interfering substances and measuring deviation from expected values.
- Correlation Studies: The "ground truth" here is the measurement result from the predicate devices (ADVIA Centaur® cTnI and ACS:180 cTnI), which are already cleared devices. The study compares the new device's results against these established methods.
- 99th Percentile Distribution: This is established by measuring troponin I levels in a large cohort of apparently healthy donors.
- AMI Cutoff and Clinical Performance (Sensitivity/Specificity): The ground truth for defining "AMI positive" and "AMI negative" in the sensitivity and specificity calculations would be a composite clinical diagnosis data (outcomes data) based on established criteria for acute myocardial infarction, typically involving a combination of clinical symptoms, ECG findings, and other biomarker results. While not explicitly stated, this is the standard for such IVD studies.
8. Sample Size for the Training Set
The document does not specify a separate "training set" sample size. For IVD assays like the Troponin I assay, the development process involves iterative testing and refinement, but a distinct "training set" in the machine learning sense (separate from validation/test sets) is not typically detailed in regulatory submissions for these types of devices. The data presented here is for the validation and verification of the final device, which functions based on established biochemical reaction principles and detection methods, rather than an AI model that learns from large datasets.
9. How the Ground Truth for the Training Set Was Established
As noted above, a distinct "training set" in the machine learning context is not applicable here. The "training" of such an assay involves:
- Chemical and biological research and development: Optimizing reagent formulations, reaction conditions, antibody specificity, detection methods.
- Calibration: Establishing a calibration curve using a series of known concentration standards. This is an iterative process where the assay is "trained" to accurately report concentrations based on its signal output. These standards serve as the "ground truth" for the calibration process.
- Internal validation and verification: Performing numerous internal tests (similar to those described in the acceptance criteria section) during development to ensure the assay performs as expected. The "ground truth" for these steps is based on reference methods, certified standards, and expected physiological ranges.
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DEC 3 0 2005
510(k) SUMMARY OF SAFETY AND EFFECTIVENESS Troponin I (TnI-Ultra) Assay for Bayer ADVIA Centaur®
This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of the Safe Medical Device Act of 1990 and 21 CFR 807.92.
The assigned 510(k) number is:
1. Intended Use
For in vitro diagnostic use in the quantitative determination of cardiac troponin I in serum, heparinized or EDTA plasma using ADVIA Centaur® system.
1053020
Cardiac troponin I determinations aid in the diagnosis of acute myocardial infarction and in the risk stratification of patients with non-ST segment elevation acute coronary syndromes with respect to relative risk mortality, myocaridal infarction or increased probability of ischemic events requiring urgent revascularization procedures.
The ADVIA Centaur® TnI-Ultra Calibrator is for the in vitro diagnostic use in the calibration of the TnI-Ultra assay on the ADVIA Centaur® system.
2. Predicate Devices
| Product Name | Reagent REF | Calibrator REF |
|---|---|---|
| ACS:180® and ADVIACentaur® Cardiac Troponin I(cTnI) Assay | ACS:18007572636 (50 test)00370639 (300 test)ADVIA Centaur07640356 (100 tests)0595168 (500 tests) | Kit component |
3. Device / Method
| Product Name | Reagent REF | Calibrator REF |
|---|---|---|
| ADVIA Centaur® TnI-UltraAssay | 02789602 (100 tests)02790309 (500 tests) | Kit component |
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4. Imprecision
| ADVIA Centaur®TnI-Ultra | ADVIA Centaur® cTnI* | ACS:180 cTnI* | |||
|---|---|---|---|---|---|
| Level(ng/mL) | TotalCV (%) | Level(ng/mL) | TotalCV (%) | Level(ng/mL) | TotalCV (%) |
| 0.1 | 4.6 | 0.94 | 6.6 | 0.8 | 7.5 |
| 0.24 | 3.5 | 2.38 | 5.0 | 1.37 | 6.7 |
| 0.85 | 2.7 | 3.72 | 3.0 | 15.73 | 5.0 |
| 3.91 | 2.8 | 8.08 | 4.4 | 33.83 | 5.3 |
| 14.47 | 3.4 | 13.29 | 3.9 | 43.01 | 5.8 |
| 37.8 | 3.5 | 15.95 | 3.9 | ||
| 43.62 | 3.6 |
| ADVIA Centaur®TnI-Ultra | Within-runCV(%) | ADVIA Centaur® cTnI* | Within-runCV(%) |
|---|---|---|---|
| Level(ng/mL) | Level(ng/mL) | ||
| 0.1 | 3.2 | 0.94 | 4.6 |
| 0.24 | 2.6 | 2.38 | 2.3 |
| 0.85 | 1.6 | 3.72 | 2.6 |
| 3.91 | 1.5 | 8.08 | 1.9 |
| 14.47 | 1.5 | 13.29 | 1.4 |
| 37.8 | 1.8 | 15.95 | 2.3 |
| 43.62 | 2.4 |
| ACS:180 cTnI* | |
|---|---|
| Level(ng/mL) | Within-runCV(%) |
| 0.8 | 4.4 |
| 1.37 | 4.2 |
| 15.73 | 2.2 |
| 33.83 | 2.3 |
| 43.01 | 3.0 |
| * data from |
instructions for use
The troponin I concentration at a total CV of 10% was determined to be 0.042 ng/mL.
Functional Sensitivity (20% total C.V.) was calculated as <0.008 ng/mL for ADVIA Centaur® TnI-Ultra Assay.
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| Specimen typeRegression method | ComparativeSystem (X) | N | RegressionEquation | SampleRange(ng/mL) |
|---|---|---|---|---|
| Serum Passing &Bablok | BayerADVIACentaur | 346 | $1.10X - 0.045$ | 0.1 to 34.8 |
| Linear Regression | BayerADVIACentaur | 346 | $1.26X - 0.52$$r = 0.975$ | 0.1 to 34.8 |
| Serum Passing &Bablok | ACS:180 | 334 | $1.2X - 0.032$ | 0.1 to 30.9 |
| Linear Regression | ACS:180 | 334 | $1.4X - 0.51$$r = 0.967$ | 0.1 to 30.9 |
5. Correlation (Y= ADVIA Centaur® TnI-Ultra, X = Comparative System)
In order to demonstrate equivalence between devices, the following correlations were generated using clinically significant troponin doses less than 4.0 ng/mL only.
| Specimen typeRegression method | ComparativeSystem (X) | N | RegressionEquation | SampleRange(ng/mL) |
|---|---|---|---|---|
| Serum Passing &Bablok | BayerADVIACentaur | 229 | 1.08X - 0.02 | 0.1 to 4.0 |
| Linear Regression | BayerADVIACentaur | 229 | 1.04X + 0.04r = 0.946 | 0.1 to 4.0 |
| Serum Passing &Bablok | ACS:180 | 230 | 1.17X - 0.006 | 0.1 to 4.0 |
| Linear Regression | ACS:180 | 230 | 1.13X + 0.068r = 0.943 | 0.1 to 4.0 |
Further comparison of clinical utility was done by comparing doses from ADVIA Centaur TnI-Ultra to ACS:180 and ADVIA Centaur cTnI. The WHO criteria cut-off of 0.9 ng/mL was used for this evaluation.
| ADVIA Centaur cTnI | ||
|---|---|---|
| ADVIA Centaur TnI- Ultra | < 0.9 ng/mL | ≥ 0.9 ng/mL |
| < 0.9 ng/mL | 101 | 2 |
| ≥ 0.9 ng/mL | 7 | 261 |
| Concordance = 97.6% |
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| ACS:180 cTnI | ||
|---|---|---|
| < 0.9 ng/mL | ≥ 0.9 ng/mL | |
| < 0.9 ng/mL | 101 | 2 |
| ≥ 0.9 ng/mL | 20 | 236 |
| Concordance = 93.9% |
6. Interfering substances
| InterferenceConcentration | Recovery(ng/mL) | % | ||
|---|---|---|---|---|
| Interference | Expected | Observed | Deviation | |
| Hemoglobin | 500 mg/dL | 1.17 | 1.15 | -1.7 |
| Lipemia | 1000 mg/dL | 1.06 | 1.05 | -0.9 |
| IcterusConjugated bilirubin | 20 mg/dL | 0.85 | 0.81 | -4.7 |
| IcterusUnconjugated bilirubin | 20 mg/dL | 1.16 | 1.07 | -7.8 |
| Human immunoglobulin | 12 g/dL | 1.10 | 1.04 | -5.4 |
7. Analytical Range
0.008 ng/mL to 50 ng/mL.
8. Minimum Detectable Concentration
| ADVIA Centaur®TnI-Ultra(ng/mL) | ADVIA Centaur® TnI(ng/mL) |
|---|---|
| 0.008 | 0.07 |
9. 99th Percentile Distribution and Functional Sensitivity
Based on 648 serum samples from apparently healthy donors, the upper 99th percentile Troponin I value is 0.044 ng/mL.
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10. Expected Results
The AMI cutoff value of ≥ 0.9 ng/mL is based on the data for the Bayer HealthCare The AMI Culori Vardo of = 0.5 hg mg mg Ma Centaur® TnI-Ultra method is equivalent.
| Method | % Sensitivity | % Specificity |
|---|---|---|
| ACS:180 cTnI | 97.3 | 97.0 |
| No. Patients (n) | 112 | 166 |
| 95% Confidence Interval | 92.4 - 99.4 | 93.1 - 99.0 |
| Alternate troponin I method | 96.4 | 93.4 |
| No. Patients (n) | 112 | 166 |
| 95% Confidence Interval | 91.1 - 99.0 | 88.5 - 96.7 |
December 28, 2005
Date
Andres Holle Manager Regulatory Affairs Bayer Corporation 511 Benedict Avenue Tarrytown, New York 10591-5097 914-524-3494
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DEPARTMENT OF HEALTH & HUMAN SERVICES
Public Health Service
Image /page/5/Picture/2 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo consists of a stylized caduceus symbol, which features three diagonal lines that resemble a human figure. The caduceus is surrounded by a circular border with the text "DEPARTMENT OF HEALTH & HUMAN SERVICES USA" written around it. The text is in all capital letters and is evenly spaced around the circle.
Food and Drug Administration 2098 Gaither Road Rockville MD 20850
DEC 3 0 2005
Mr. Andres Holle Manager Regulatory Affairs Bayer Corporation 511 Benedict Avenue Tarrytown, NY 10591-5097
Re: K053020
R055020
Trade/Device Name: Troponin I Ultra Assay and Calibrator for the ADVIA Centaur® System Regulation Number: 21 CFR 862.1215 Regulation Name: Creatine phosphokinase/creatine kinase or isoenzymes test system Regulatory Class: Class II Product Code: MMI, JIT Dated: October 21, 2005 Received: October 28, 2005
Dear Mr. Holle:
We have reviewed your Section 510(k) premarket notification of intent to market the device we nave reviewed your 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 for use stated in the encreated 776, the enactment date of the Medical Device Amendments, or to conimered prior of may 2011-11-11)
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). and Cosmetic Flor (110) that the device, subject to the general controls provisions of the Act. The r va may, attrols provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration.
If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to such additional controls. Existing major regulations affecting your device r may be found in Title 21, Code of Federal Regulations (CFR), Parts 800 to 895. 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 r reaso be action and 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 or any 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); and good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820).
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Page 2 -
This letter will allow you to begin marketing your device as described in your Section 510(k) I mis letter will anow you to begin mailieding of substantial equivalence of your device to a legally promatic. Inclineation: "The PDF in a classification for your device and thus, permits your device to proceed to the market.
If you desire specific information about the application of labeling requirements to your device, If you desire specific infortion and advertising of your device, please contact the Office of In of questions on the promotion and Safety at (240) 276-0484. Also, please note the v Itto Diagnostic Developmenting by reference to premarket notification" (21CFR Part 807.97). You may obtain other general information on your responsibilities under the Act from the Tou may obtain other general ers, International and Consumer Assistance at its toll-free number (800) 638-2041 or (301) 443-6597 or at its Internet address http://www.fda.gov/cdrh/industry/support/index.html.
Sincerely yours,
Alberto Guts
Alberto Gutierrez, Ph.D. Director Division of Chemistry and Toxicology Office of In Vitro Diagnostic Device Evaluation and Safety Center for Devices and Radiological Health
Enclosure
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Indications for Use
510(k) Number (if known): KD530 00
Device Name: Troponin I Ultra Assay and Calibrator for the ADVIA Centaur® System
Indications For Use:
The ADVIA Centaur® Tnl-Ultra (Tnl-Ultra) method is for in vitro diagnosic use in the The ADVIA Centadi Thi-Olira (Thi Ultra) moment serum and heparinized and Cardiac troponin I determinations aid in the diagnosis of acute EDTA plasma. EDTA plasma. Galulac troponin T decommination of patients with non-ST segment myocardial Tiffanction and In the Thor Stratinediter of elative risk mortality, myocardian elevation actie coronaly syndromes with respective to requiring urgent revascularization procedures.
The ADVIA Centaur® Tnl-Ultra Calibrator is for the in vitro diagnostic use in the The ADVIA Centaur Thi-Ultra Galbrator 15 The
Prescription Use
(Part 21 CFR 801 Subpart D)
(Part 21 CFR 801 Subpart D)
AND/OR
Over-The-Counter Use (21 CFR 807 Subpart C)
(PLEASE DO NOT WRITE"BELOW THIS LINE-CONTINUE ON ANOTHER PAGE IF NEEDED)
Cogcurrence of CDRH, Office of In Vitro Diagnostic Devices (OIVD)
Int. Ultra
Division Sign-Off
Office of in Vitro Diagnostic Device. Evaluation and Safety
Page 1 of
51062 k05302d
§ 862.1215 Creatine phosphokinase/creatine kinase or isoenzymes test system.
(a)
Identification. A creatine phosphokinase/creatine kinase or isoenzymes test system is a device intended to measure the activity of the enzyme creatine phosphokinase or its isoenzymes (a group of enzymes with similar biological activity) in plasma and serum. Measurements of creatine phosphokinase and its isoenzymes are used in the diagnosis and treatment of myocardial infarction and muscle diseases such as progressive, Duchenne-type muscular dystrophy.(b)
Classification. Class II.