For the quantitative determination of cardiac troponin I in serum or heparinized plasma using the Bayer Diagnostics ACS:180® and ADVIA® Centaur™ Automated Chemiluminescent Systems. 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 of mortality, myocardial infarction or increased probability of ischemic events requiring urgent revascularization procedures.

Device Description

Troponin is a structural protein which regulates the contraction of striated muscle. It consists of three subunits which are located periodically along the thin filament of the myofibrils. Troponin C binds calcium, troponin T attaches to tropomyosin on the thin filament, and troponin I inhibits actomyosin ATPase. Troponin I (Tnl), an inhibitory protein of the troponin-tropomyosin complex, exists in three distinct isoforms: cardiac muscle, slow-twitch skeletal muscle, and fast-twitch, skeletal muscle. The cardiac form (cTnl) is further unique having 31 additional amino acid residues on its N-terminal, not present in the skeletal forms, which allows for specific polyclonal and monoclonal antibody development. The cardiac specificity of this isoform improves the accuracy of diagnosis in patients with acute or chronic skeletal muscle injury and possible concomitant myocardial injury, and is the basis for its selection as a cardiac marker in the diagnosis of acute myocardial infarction.

AI/ML Overview

Here's an analysis of the provided text to extract information about the acceptance criteria and the study that proves the device meets them:

Acceptance Criteria and Device Performance for Bayer Diagnostics ACS:180 & ADVIA Centaur Troponin I Immunoassay

The provided document describes the performance characteristics of the Bayer Diagnostics ACS:180 and ADVIA Centaur Troponin I Immunoassay.

1. Table of Acceptance Criteria and Reported Device Performance

Note: The document explicitly states "Acceptance Criteria" for analytical sensitivity and provides results. For method comparison, it provides correlation data, which serves as a measure of agreement between the new device and a predicate, implicitly defining an acceptance threshold for similar performance.

Acceptance Criterion	Reported Device Performance
Analytical Sensitivity (Minimum Detectable Concentration) for cTnI	0.10 ng/mL (µg/L)
Method Comparison (Correlation between ADVIA Centaur cTnI and ACS:180 cTnI)	r = 0.99
Method Comparison (Linearity of relationship between ADVIA Centaur cTnI and ACS:180 cTnI)	ADVIA Centaur cTnl = 1.00 (ACS:180 cTnl) + 0.00

2. Sample Size Used for the Test Set and Data Provenance

Sample Size for Method Comparison Test Set: 381 samples
Data Provenance for Method Comparison Test Set: Not explicitly stated but implied to be clinical samples used to compare two devices. The document does not specify country of origin or if it was retrospective/prospective.
Sample Size for Clinical Performance/Risk Stratification Test Set: 681 patients.
Data Provenance for Clinical Performance/Risk Stratification Test Set: This was a "multicenter substudy of a clinical trial designed to assess the efficacy of low molecular weight heparin in the treatment of unstable angina and non-Q wave myocardial infarction." The data is prospective in nature, as it involved monitoring clinical outcomes up to 43 days from hospital presentation. Country of origin not specified.

3. Number of Experts Used to Establish Ground Truth for the Test Set and Their Qualifications

The document does not mention the use of experts to establish a "ground truth" for the test set in the traditional sense of medical image interpretation or diagnostic agreement. The ground truth for the clinical performance study likely relied on established clinical outcomes and definitions for events like myocardial infarction, death, and urgent revascularization.

4. Adjudication Method for the Test Set

Adjudication methods (e.g., 2+1, 3+1) are typically used for subjective diagnostic interpretations or image-based studies. This product is an immunoassay, and its clinical performance was assessed against objective clinical endpoints (death, confirmed MI, urgent revascularization). Therefore, no traditional adjudication method as described would be applicable or mentioned.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done

No, an MRMC comparative effectiveness study was not done. This type of study is relevant for diagnostic modalities where human readers interpret results (e.g., radiology). The device is an automated immunoassay, and its performance is evaluated objectively by measuring analyte concentrations.

6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) was done

Yes, the performance data presented (analytical sensitivity, method comparison) represents the standalone performance of the assay. The clinical performance section also details how the assay results correlated with patient outcomes, demonstrating the algorithm's utility without direct human interpretation of the assay itself being modified or enhanced.

7. The Type of Ground Truth Used

For Analytical Sensitivity/Method Comparison: The ground truth for these analytical parameters is based on established laboratory standards, reference methods, and comparison against a legally marketed predicate device (Bayer Diagnostics ACS:180 Troponin I Immunoassay).
For Clinical Performance (Risk Stratification): The ground truth was based on objective clinical outcomes:
- Death
- Development of confirmed myocardial infarction after initial hospital presentation
- Need for urgent revascularization procedures as necessitated by recurrent episodes of angina.

8. The Sample Size for the Training Set

The document does not provide information about a separate "training set" for the assay. For an immunoassay like this, the development process involves reagent optimization, calibration, and validation, which might use various sample sets, but the specific term "training set" (common in AI/ML contexts) is not used. The data reported is for validation and performance assessment.

9. How the Ground Truth for the Training Set Was Established

As no training set is explicitly mentioned, the method for establishing its ground truth is also not detailed. Immunoassays are generally developed and validated against quantitative standards and known samples, rather than a "ground truth" like that established for diagnostic imaging algorithms.

Summary

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DEC - 6 1999

Summary of Safety and Effectiveness

As required by 21 CFR 807.92, the following 510(k) Summary is provided:

1. Submitters Information

Contact person:	William J. PignatoDirector of Regulatory Affairs
Address:	Bayer Diagnostics Corporation63 North StreetMedfield, MA 02052
PhoneFax	(508) 359-3825(508) 359-3356
Date Summary Prepared:	September 30, 1999

2. Device Information

Proprietary Name:	Bayer Diagnostics ACS:180 & ADVIA CentaurTroponin I Immunoassay
Common Name:	Troponin I Immunological test system
Device Classification:	Class II

3. Predicate Device Information

Name: Bayer Diagnostics ACS:180 Troponin I Immunoassay

Manufacturer: Bayer Diagnostics Corporation

4. Device Description

Troponin I (Tnl), an inhibitory protein of the troponin-tropomyosin complex, exists in three distinct isoforms: cardiac muscle, slow-twitch skeletal muscle, and fast-twitch, skeletal muscle. The cardiac form (cTnl) is further unique having 31 additional amino acid residues on its N-terminal, not present in the skeletal forms, which allows for specific polyclonal and monoclonal antibody development. The cardiac

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specificity of this isoform improves the accuracy of diagnosis in patients with acute or chronic skeletal muscle injury and possible concomitant myocardial injury, and is the basis for its selection as a cardiac marker in the diagnosis of acute myocardial infarction.

Because of its cardiac specificity and sensitivity, cTnl has been used as a reliable marker in the diagnosis of perioperative myocardial infarction in patients undergoing cardiac surgery. It also provides useful information for evaluating patients with unstable angina, a condition implying increased risk of myocardial infarction and sudden death. Unstable angina patients with minimal values of cTnl are predicted to have a higher risk of short-term mortality. As the cTnl value progressively increases, the risk of mortality increases, presumably because the amount of myocardial damage also increases. Measuring cTnl provides useful prognostic information for evaluating patients with unstable angina, permitting early identification of patients at increased risk of death.

5. Statement of Intended Use

For the quantitative determination of cardiac troponin I in serum or heparinized plasma. using the Bayer Diagnostics ACS:180® (ADVIA® Centaur™ ) Automated Chemiluminescence Systems.

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 of mortality, myocardial infarction or increased probability of ischemic events requiring urgent revascularization procedures.

6. Performance Characteristics

Sensitivity and Assay Reportable Range

The ACS:180 cTnl assay measures cTnl concentrations up to 50 ng/mL (µg/L) with a minimum detectable concentration (analytical sensitivity) of 0.10 ng/mL (ug/L). Analytical sensitivity is defined as the concentration of cTnl that corresponds to the RLUs that are two standard deviations greater than the mean RLUs of 20 replicate determinations of the cTnl zero standard.

Method Comparison

Method comparative studies of the ACS:180 cTnl assav and ADVIA Centaur cTnl assay gave the following relationship when analyzed by least squares linear regression. A total of 381 samples in the range of 0.17 to 49.47 ng/mL were tested.

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ADVIA Centaur cTnl= 1.00 (ACS:180 cTnl) +0.00, r = 0.99

7. Clinical Performance Characteristics

Assessment of Patients with Acute Coronary Syndromes

In a multicenter substudy of a clinical trial designed to assess the efficacy of low molecular weight heparin in the treatment of unstable angina and non-Q wave myocardial infarction, blood specimens from 681 patients were analyzed for cardiac troponin-1. The 444 patients with levels of cardiac troponin I of at least 0.10 ng/mL had higher risk of morbidity and mortality than the 237 patients whose levels were less than 0.10 ng/mL. Cardiac troponin I levels for risk assessment were determined within 24 hours after initial patient presentation with clinical and electrocardiographic symptoms of unstable angina or non-ST segment elevation myocardial infarction. Morbidity and mortality criterion included death, development of confirmed myocardial infarction after initial hospital presentation, and the need for urgent revascularization procedures as necessitated by recurrent episodes of angina. Clinical outcomes were monitored up to 43 days from hospital presentation.

8. Conclusions:

The Bayer ACS:180 and ADVIA Centaur cardiac troponin I assays have demonstrated the ability to act as an aid in the risk stratification of patients with acute coronary syndromes in addition to the approved indication of aiding in the diagnosis of acute myocardial infarction. The change in Minimal Detectable Concentration is verified by repeat analysis of the zero standard and determination of the concentration that corresponds to two standard deviations of the mean signal of that standard.

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Image /page/3/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo consists of a stylized eagle with three lines forming its body and wings. The text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" is arranged in a circular fashion around the eagle.

Food and Drug Administration 2098 Gaither Road Rockville MD 20850

DEC - 6 1999

Mr. William J. Pignato Director of Regulatory Affairs Bayer Corporation Business Group Diagnostics 63 North Street Medfield, Massachusetts 02052-1688

Re: K993309

Trade Name: Bayer Diagnostics ACS:180 and ADVIA Centaur Troponin I Assay Regulatory Class: II Product Code: MMI Dated: September 30, 1999 Received: October 4, 1999

Dear Mr. Pignato:

We have reviewed your Section 510(k) notification of intent to market the device referenced above and we 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). 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.

If your device is classified (see above) into either class II (Special Controls) or class III (Premarket Approval), it may be subject to such additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 895. A substantially equivalent determination assumes compliance with the Current Good Manufacturing Practice requirements, as set forth in the Quality System Regulation (QS) for Medical Devices: General regulation (21 CFR Part 820) and that, through periodic QS inspections, the Food and Drug Administration (FDA) will verify such assumptions. Failure to comply with the GMP regulation may result in regulatory action. In addition, FDA may publish further announcements concerning your device in the Federal Register. Please note: this response to your premarket notification submission does not affect any obligation you might have under sections 531 through 542 of the Act for devices under the Electronic Product Radiation Control provisions, or other Federal laws or regulations.

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Under the Clinical Laboratory Improvement Amendments of 1988 (CLIA-88), this device may require a CLIA complexity categorization. To determine if it does, you should contact the Centers for Disease Control and Prevention (CDC) at (770) 488-7655.

This letter will allow you to begin marketing your device as described in your 510(k) premarket notification. The FDA finding of substantial equivalence of your device to a legally marketed predicate device results in a classification for your device and thus, permits your device to proceed to the market.

If you desire specific advice for your device on our labeling regulation (21 CFR Part 801 and additionally 809.10 for in vitro diagnostic devices), please contact the Office of Compliance at (301) 594-4588. Additionally, for questions on the promotion and advertising of your device, please contact the Office of Compliance at (301) 594-4639. Also, please note the regulation entitled. "Misbranding by reference to premarket notification"(21 CFR 807.97). Other general information on your responsibilities under the Act may be obtained from the Division of Small Manufacturers Assistance at its toll-free number (800) 638-2041 or (301) 443-6597, or at its internet address "http://www.fda.gov/cdrh/dsma/dsmamain.html".

Sincerely yours,

Steven Putman

Steven I. Gutman, M.D. M.B.A. Director Division of Clinical Laboratory Devices Office of Device Evaluation Center for Devices and Radiological Health

Enclosure

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510(k) Number (if known): _

Device Name: Bayer Diagnostics ACS:180 and ADVIA Centaur Troponin I Assay

14993309

Indications for Use:

(PLEASE DO NOT WRITE BELOW THIS LINE--CONTINUE ON ANOTHER PAGE, IF NEEDED)

Prescription Use(Per 21 CFR 801.109)	OR	Over-The-Counter Use(Optional Format 1-2-96)
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(Division Sign-Off)
Division of Clinical Laboratory Devices

510(k) Number	993309
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Concurrence of CDRH, Office of Device Evaluation (ODE)

Regulation Number and Section

§ 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.