(588 days)
For in vitro diagnostic use in the quantitative determination of digoxin in serum and plasma (EDTA and lithium heparin) using the ADVIA Centaur® XP systems.
Measurements obtained by this device are used in the diagnosis and treatment of digoxin overdose and in monitoring levels of digoxin to ensure appropriate therapy.
The ADVIA Centaur Digoxin assay reagents come in the following configurations:
5 ReadyPack primary reagent packs containing ADVIA Centaur DIG Lite Reagent and Solid Phase, ADVIA Centaur DIG Master Curve card (250 Tests)
1 ReadyPack primary reagent pack containing ADVIA Centaur DIG Lite Reagent and Solid Phase, ADVIA Centaur DIG Master Curve card (50 Tests)
The ReadyPack consists of the following:
ADVIA Centaur DIG ReadyPack® primary reagent pack; Lite Reagent: 2.5 ml/reagent pack monoclonal mouse anti-digoxin antibody (~26.4 ng/mL) labeled with acridinium ester in protein buffered saline with sodium azide (0.11%) and preservatives.
ADVIA Centaur DIG ReadyPack primary reagent pack; Solid Phase Reagent: 12.5 mL/reagent pack digitoxin (~2 ng/mL) covalently coupled to paramagnetic particles in protein buffered saline with sodium azide (0.11%) and preservatives.
The provided document pertains to the 510(k) summary for the ADVIA Centaur Digoxin assay, specifically regarding the addition of plasma sample types (EDTA and lithium heparin) to its indications for use. It's a submission for an in vitro diagnostic (IVD) device, not an AI/ML-based medical device that relies on complex image analysis or similar algorithms. Therefore, many of the requested details about acceptance criteria, test sets, expert ground truth, MRMC studies, standalone performance, and training sets are not applicable to this type of device and its regulatory submission.
The "acceptance criteria" for this device are demonstrated through analytical performance studies, specifically specimen equivalency and interference studies, to confirm that adding plasma as a sample type does not negatively impact the assay's performance compared to the previously cleared serum sample type.
Here’s an attempt to structure the available information relevant to your request, while highlighting the parts that are not applicable to this specific device (as it's an IVD test, not an AI/ML diagnostic system):
Device: ADVIA Centaur® Digoxin assay
Purpose of Study: To demonstrate substantial equivalence for the addition of plasma (EDTA and lithium heparin) as a valid sample type for the ADVIA Centaur® Digoxin assay.
1. Table of Acceptance Criteria and Reported Device Performance
For an IVD assay like the ADVIA Centaur Digoxin assay, "acceptance criteria" are typically defined by precision, accuracy (often assessed through method comparison/equivalent methods), interference, linearity, and analytical sensitivity. The provided document focuses on demonstrating specimen equivalency and interference for the new sample types.
| Performance Characteristic | Acceptance Criteria (Implied) | Reported Device Performance |
|---|---|---|
| Specimen Equivalency | Regression statistics indicating strong agreement with serum (e.g., slope near 1.0, intercept near 0, high correlation coefficient). | Dipotassium EDTA plasma vs. Serum:Regression Equation: y = 1.02x - 0.02 ng/mLCorrelation Coefficient (r): 0.996Lithium heparin plasma vs. Serum:Regression Equation: y = 1.06x - 0.03 ng/mLCorrelation Coefficient (r): 0.990 |
| Interference | Clinically insignificant bias (e.g., less than a certain percentage) when interfering substances are present at relevant concentrations. | Canrenone: 2.7% (at 1.11 ng/mL Digoxin), -0.5% (at 2.12 ng/mL Digoxin)Dipotassium EDTA: -0.4% (at 0.91 ng/mL Digoxin), -1.1% (at 3.12 ng/mL Digoxin)Heparin: 8.9% (at 0.61 ng/mL Digoxin), -1.7% (at 3.66 ng/mL Digoxin)Potassium Canrenoate: 2.8%, -1.0%Spironolactone: 1.0%, 2.5% |
Note: The document implies that the observed regression statistics and low bias values are acceptable for demonstrating substantial equivalence.
2. Sample Sizes Used for the Test Set and Data Provenance
- Dipotassium EDTA plasma: 51 samples
- Lithium heparin plasma: 50 samples
- Data Provenance: The document does not specify the country of origin of the data or whether the studies were retrospective or prospective. Typically, such analytical validation studies for IVDs are prospective and conducted in a controlled lab environment.
3. Number of Experts Used to Establish Ground Truth for the Test Set and Qualifications
N/A. This is an IVD assay measuring a chemical concentration. "Ground truth" is established by the analytical method itself and comparison to a reference method or validated primary sample type (serum in this case). It does not involve expert interpretation of images or clinical data in the way an AI diagnostic would require. The "experts" are the analytical chemists and lab professionals performing and validating the assay.
4. Adjudication Method for the Test Set
N/A. Adjudication methods (like 2+1, 3+1) are common in clinical trials or studies where human interpretation or consensus is required to establish ground truth from ambiguous or complex data (e.g., radiology images). For an IVD assay, the comparison is against an established analytical method (serum) or reference standard; there's no need for adjudication of readings.
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was Done
N/A. MRMC studies are used to assess the effectiveness of diagnostic tools, particularly imaging, by comparing the performance of multiple human readers across multiple cases, often with and without AI assistance. This is not applicable to a quantitative biochemical assay.
6. If a Standalone (Algorithm Only Without Human-in-the-Loop Performance) was Done
The entire test (ADVIA Centaur Digoxin assay) is a standalone system for measuring digoxin concentration. Its performance is measured directly (e.g., accuracy, precision). There is no "human-in-the-loop" performance in the sense of clinical decision support from an AI. The device directly produces a numerical result.
7. The Type of Ground Truth Used
The "ground truth" for specimen equivalency was the measurement of digoxin in serum samples using the predicate ADVIA Centaur Digoxin assay (which was already cleared). The new plasma results were compared against these serum results. For interference, the ground truth is the known concentration of digoxin in the spiked samples.
8. The Sample Size for the Training Set
N/A. This is an IVD assay, not an AI/ML model that requires training data. The assay's reagents and methodology are developed through R&D, not trained on a dataset.
9. How the Ground Truth for the Training Set was Established
N/A. (See point 8).
Conclusion from the Document:
The study concludes that the modified ADVIA Centaur® Digoxin assay, with the addition of plasma sample types, is substantially equivalent in principle and performance to the Predicate Device (ADVIA Centaur® Digoxin assay cleared under 510(k) K931213). This equivalence is based on the analytical performance data, specifically the specimen equivalency and interference studies.
{0}------------------------------------------------
Image /page/0/Picture/0 description: The image contains the logo of the U.S. Food and Drug Administration (FDA). On the left is the Department of Health & Human Services logo. To the right of that is the FDA logo, which is a blue square with the letters "FDA" in white. To the right of the square is the text "U.S. FOOD & DRUG ADMINISTRATION" in blue.
July 16, 2021
Siemens Healthcare Diagnostics, Inc. Anoop Joy Regulatory Affairs Specialist 511 Benedict Avenue Tarrytown, New York 10591
Re: K193397
Trade/Device Name: ADVIA Centaur Digoxin assay Regulation Number: 21 CFR 862.3320 Regulation Name: Digoxin Test System Regulatory Class: Class II Product Code: KXT Dated: October 16, 2020 Received: October 19, 2020
Dear Anoop Joy:
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. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database located at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. 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 Part
{1}------------------------------------------------
801 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR 803) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-products); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
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 https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.
For comprehensive regulatory information about medical devices and radiation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).
Sincerely,
Marianela Perez-Torres, Ph.D. Deputy Director Division of Chemistry and Toxicology Devices OHT7: Office of In Vitro Diagnostics and Radiological Health Office of Product Evaluation and Quality Center for Devices and Radiological Health
Enclosure
{2}------------------------------------------------
Indications for Use
510(k) Number (if known) K193397
Device Name ADVIA Centaur® Digoxin assay
Indications for Use (Describe)
For in vitro diagnostic use in the quantitative determination of digoxin in serum and plasma (EDTA and lithium heparin) using the ADVIA Centaur® XP systems.
Measurements obtained by this device are used in the diagnosis and treatment of digoxin overdose and in monitoring levels of digoxin to ensure appropriate therapy.
| 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."
{3}------------------------------------------------
510(k) Summary of Safety and Effectiveness
ADVIA Centaur® Digoxin assay
This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of SMDA 1990 and 21 CFR 807.92.
The assigned 510(k) Number: K193397.
l. APPLICANT
Siemens Healthcare Diagnostics Inc. 511 Benedict Avenue, Tarrytown, NY 10591 USA
| Contact: | Anoop Joy |
|---|---|
| Regulatory Clinical Affairs Specialist | |
| Phone: | (914) 524-2273 |
| Fax: | (914) 524-2101 |
| E-mail: | anoop.joy@siemens-healthineers.com |
Date Prepared: July 16, 2021
Regulatory Information II.
Name of Device: ADVIA Centaur® Digoxin assay Classification: Class II Regulation Section: 21 CFR § 862.3320 Product Code: KXT Panel: Toxicology
PREDICATE DEVICE lll.
Name of Device: ADVIA Centaur® Digoxin assay 510 (k): K931213
{4}------------------------------------------------
DEVICE DESCRIPTION IV.
The ADVIA Centaur Digoxin assay reagents come in the following configurations:
| Contents | Number of Tests |
|---|---|
| 5 ReadyPack primary reagent packs containing ADVIA CentaurDIG Lite Reagent and Solid Phase, ADVIA Centaur DIG MasterCurve card | 250 |
| 1 ReadyPack primary reagent pack containing ADVIA CentaurDIG Lite Reagent and Solid Phase, ADVIA Centaur DIG MasterCurve card | 50 |
The ReadyPack consists of the following:
ADVIA Centaur DIG ReadyPack® primary reagent pack; Lite Reagent
2.5 ml/reagent pack monoclonal mouse anti-digoxin antibody (~26.4 ng/mL) labeled with acridinium ester in protein buffered saline with sodium azide (0.11%) and preservatives.
ADVIA Centaur DIG ReadyPack primary reagent pack; Solid Phase Reagent
12.5 mL/reagent pack digitoxin (~2 ng/mL) covalently coupled to paramagnetic particles in protein buffered saline with sodium azide (0.11%) and preservatives.
INTENDED USE >
For in vitro diagnostic use in the quantitative determination of digoxin in serum and plasma (EDTA and lithium heparin) using the ADVIA Centaur® XP systems.
Measurements obtained by this device are used in the diagnosis and treatment of digoxin overdose and in monitoring levels of digoxin to ensure appropriate therapy.
INDICATIONS FOR USE VI.
Same as Intended use
COMPARISION OF TECHNOLOGICAL CHARACTERISTICS WITH THE VII. PREDICATE DEVICE
The following table provides a comparison between the predicate and candidate device.
{5}------------------------------------------------
| Predicate Device | Candidate Device(Modified Device) | |
|---|---|---|
| Item | ADVIA Centaur® Digoxin assay | ADVIA Centaur® Digoxin assay |
| Intended Use | For in vitro diagnostic use in thequantitative determination ofdigoxin in serum using the ADVIACentaur®, ADVIA Centaur XP,and ADVIA Centaur XPT systems. | For in vitro diagnostic use in thequantitative determination ofdigoxin in serum and plasma(EDTA and lithium heparin) usingthe ADVIA Centaur® XP systems.Measurements obtained by thisdevice are used in the diagnosisand treatment of digoxin overdoseand in monitoring levels of digoxinto ensure appropriate therapy. |
| Measurement | Quantitative | Same |
| Assay Range | 0.1–5.0 ng/mL | Same |
| Assay Principle | competitive immunoassay | Same |
| Technology | Direct chemiluminescent | Same |
| Sample Type | Serum | Serum and plasma (EDTA andlithium heparin) |
| Sample Volume | 50 µL | same |
| ReagentVolume | 50 µL of Lite Reagent and250 µL of Solid Phase | same |
| IncubationTime | Lite Reagent: 5.0 minutes at 37°CSolid Reagent: 2.5 minutes at37°C. | same |
| Standardization | Traceable to an internal standardmanufactured using U.S.P.(United States Pharmacopeia)material | Same |
| Calibration | 2-point | Same |
| Calibrators | ADVIA Centaur Calibrator B | Same |
| Number ofCalibratorLevels | Two levels | Same |
| Controls | Commercial Controls | Same |
| DetectionAntibody | monoclonal mouse anti-digoxinantibody labeled with acridiniumester | Same |
| CaptureAntibody | digitoxin covalently coupled toparamagnetic particles | Same |
Table 1: Substantial Equivalence Comparison
VIII. PERFORMANCE CHARACTERISTICS DATA
Addition of plasma sample type claim was demonstrated by performing specimen equivalency studies, precision studies and interference studies using EDTA and
{6}------------------------------------------------
Heparin. Since the assay principle, design or formulation has not changed from original device (K931213), the analytical performance data previously reviewed for the ADVIA Centaur® Digoxin assay continues to apply to this assay.
Specimen Equivalency
Specimen equivalency was determined with the Deming linear regression model in accordance with CLSI Document EP09-A3. The following results were obtained:
| Tube (y) vs. Serum (x) | Regression Equation | Sample Interval | Na | rb |
|---|---|---|---|---|
| Dipotassium EDTA plasma | y = 1.02x - 0.02 ng/mL(y = 1.02x - 0.03 nmol/L) | 0.14–4.81 ng/mL(0.18–6.16 nmol/L) | 51 | 0.996 |
| Lithium heparin plasma | y = 1.06x - 0.03 ng/mL(y = 1.06x - 0.04 nmol/L) | 0.14–4.88 ng/mL(0.18–6.25 nmol/L) | 50 | 0.990 |
a Number of samples tested.
b Correlation coefficient.
Interferences
Interference testing was performed in accordance with CLSI Document EP07-ed3. The following results were obtained:
| Substance | Substance Test Concentration | Analyte Concentrationng/mL (nmol/L) | Bias (%) |
|---|---|---|---|
| Canrenone | 1000 ng/mL | 1.11 (1.42) | 2.7 |
| 2.12 (2.71) | -0.5 | ||
| Dipotassium EDTA | 9.0 mg/mL | 0.91 (1.16) | -0.4 |
| 3.12 (3.99) | -1.1 | ||
| Heparin | 75 U/mL | 0.61 (0.78) | 8.9 |
| 3.66 (4.68) | -1.7 | ||
| Potassium Canrenoate | 1000 ng/mL | 1.07 (1.37) | 2.8 |
| 2.08 (2.66) | -1.0 | ||
| Spironolactone | 1000 ng/mL | 1.04 (1.33) | 1.0 |
| 2.00 (2.56) | 2.5 |
X. CONCLUSION
Comparative testing of the modified ADVIA Centaur® Digoxin assay is substantially equivalent in principle and performance to the Predicate Device - ADVIA Centaur® Digoxin assay cleared under 510(k) K931213.
§ 862.3320 Digoxin test system.
(a)
Identification. A digoxin test system is a device intended to measure digoxin, a cardiovascular drug, in serum and plasma. Measurements obtained by this device are used in the diagnosis and treatment of digoxin overdose and in monitoring levels of digoxin to ensure appropriate therapy.(b)
Classification. Class II.