The ACCESS® Troponin I assay is a paramagnetic-particle, chemiluminescent immunoassay for the quantitative determination of cardiac troponin I levels in human serum and plasma (EDTA), using the ACCESS® Immunoassay System.

Device Description

AI/ML Overview

The ACCESS® Troponin I assay is a chemiluminescent immunoassay designed for the quantitative determination of cardiac troponin I levels in human serum and plasma. The study aimed to establish the clinical performance characteristics of the device and demonstrate its substantial equivalence to a previously cleared troponin I assay (Baxter Stratus® Cardiac Troponin-I) and CK-MB, which was considered the "gold standard" biochemical marker at the time.

Here's a breakdown of the acceptance criteria and study details:

1. Table of Acceptance Criteria and Reported Device Performance

Acceptance Criteria Category	Specific Metric	Acceptance Criterion (Implicit)	Reported Device Performance
Analytical Performance	Precision	Acceptable CV range	5.97% CV (high control) to 13.53% CV (low control)
	Dilution Recovery	Average recovery close to 100%	93.5% average recovery
	Correlation with Predicate Device (Stratus®)	Strong correlation (r)	r = 0.87, y = 0.136x -0.088 (189 samples)
	Analytical Sensitivity	Low detectable level	0.03 ng/ml (95% confidence)
Clinical Performance	Optimal Cutoff for AMI	Clinically relevant cutoff	0.15 ng/ml
	Clinical Sensitivity (at cutoff 0.15 ng/ml)	High sensitivity for AMI	89%
	Clinical Specificity (at cutoff 0.15 ng/ml)	High specificity for AMI	91%
	Concordance with Predicate Device (Stratus®)	High concordance	90% (201 patients)
	Concordance with Gold Standard (CK-MB)	High concordance	90% (208 subjects)
	Specificity in Skeletal Muscle Injury	High specificity	86% (58 patients)
	Specificity in Renal Disease	High specificity	96% (81 subjects)

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

Sample Size:
- Clinical Performance Study: 289 subjects presenting to the emergency department with chest pain.
  - 45 subjects were ruled-in for Acute Myocardial Infarction (AMI).
- Correlation with Stratus® (clinical): 201 patients.
- Concordance with CK-MB (clinical): 208 subjects.
- Specificity in Skeletal Muscle Injury: 58 patients.
- Specificity in Renal Disease: 81 subjects.
- Correlation with Stratus® (analytical): 189 samples.
Data Provenance: The study was described as a "multi-site prospective study." The country of origin is not explicitly stated, but given the 510(k) submission to the FDA, it is highly probable the data was collected within the United States.

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

The document does not specify the number of experts or their qualifications used to establish the ground truth for the clinical diagnosis of AMI (rule-in/rule-out). However, the "gold standard biochemical marker, CK-MB" was used as a comparative measure, suggesting that a combination of clinical assessment and established biochemical markers (like CK-MB) likely formed the basis for the ground truth determination rather than solely expert consensus on imaging or other modalities.

4. Adjudication Method for the Test Set

The document does not explicitly state an adjudication method (e.g., 2+1, 3+1). The diagnosis of AMI was established by following subjects serially (minimum of two serum samples) to "rule-in or rule-out AMI," implying a standard clinical diagnostic process was followed rather than a specific expert adjudication process for the test results themselves.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done

No, an MRMC comparative effectiveness study was not done. This study is for an in-vitro diagnostic (IVD) assay that measures a biomarker, not an imaging device or AI-assisted diagnostic tool that would typically involve human readers. Therefore, there is no effect size reported for human readers improving with or without AI assistance.

6. If a Standalone (Algorithm Only Without Human-in-the-Loop Performance) Was Done

Yes, the primary clinical performance (sensitivity, specificity, concordance) was assessed for the ACCESS® Troponin I assay as a standalone device (i.e., algorithm only if you consider the "algorithm" to be the assay's chemical reaction and measurement process). There is no mention of a human-in-the-loop component for the performance evaluation itself. The device provides a quantitative measurement, and a cutoff is applied to this measurement for clinical interpretation.

7. The Type of Ground Truth Used

The ground truth for the clinical performance assessment of AMI (rule-in/rule-out) was based on:

Clinical diagnosis of AMI: This would typically involve a combination of patient symptoms (chest pain of 20 minutes duration), serial measurements of cardiac markers, and potentially ECG findings.
Comparison to a "gold standard biochemical marker, CK-MB": This served as a key reference for determining the clinical accuracy of the Troponin I assay.

8. The Sample Size for the Training Set

The document does not explicitly state the sample size for a "training set." This type of IVD device typically undergoes extensive analytical validation (precision, linearity, sensitivity) and then clinical validation. The "optimal cutoff of 0.15 ng/ml" was determined from ROC curve analysis on "all subject results" (which included the 289 subjects in the multi-site prospective study), suggesting that the clinical validation set was also used for defining this cutoff rather than a separate, explicitly defined "training set" in the machine learning sense.

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

As noted above, a distinct "training set" in the machine learning sense is not explicitly described. However, if the determination of the "optimal cutoff of 0.15 ng/ml" is considered part of a "training" or optimization process, then the ground truth for this optimization was established using the clinical diagnosis of AMI (rule-in or rule-out) for the 289 subjects in the prospective study. This clinical diagnosis would have been based on standard medical criteria at the time.

Summary

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Summary of 510(k) Safety and Effectiveness NOV 10 1997

1. General Information

Device Generic Name: Device Trade Name: Applicant's Name and Address:

Enzyme Immunoassay, Troponin I ACCESS® Troponin I assay Sanofi Diagnostics Pasteur, Inc. 1000 Lake Hazeltine Drive Chaska, MN 55318

2. Predicate Device

Baxter Stratus® Cardiac Troponin-I Fluorometric Enzyme Immunoassay Baxter Diagnostics, Inc. Deerfield, IL 60015-4633

Device Description 3.

4. Comparison of Technological Characteristics

The ACCESS® Troponin I test and the Stratus® Cardiac Troponin-I test are for the measurement of cardiac Troponin I in human serum. Both tests utilize the binding of cardiac Troponin I to specific monoclonal antibodies in a two site "sandwich" immunoassay. Both tests utilize alkaline phosphatase enzyme conjugated to monoclonal antibody.

The ACCESS® Troponin I test uses a dioxetane-based chemiluminescent substrate, while the Stratus® Cardiac Troponin I test uses 4-Methylumberlliferyl Phosphate as the substrate. The ACCESS® Troponin I test measures light production from a chemiluminescent reaction while the Stratus® Cardiac Troponin I test measures front surface fluorescence. The ACCESS® Troponin I test uses lyophilized calibrators prepared from buffered human serum matrix with human cardiac troponin I at specified levels, while the Stratus® Cardiac Troponin I test uses liquid calibrators (shipped frozen on dry ice) prepared from buffered bovine protein matrix and human cardiac troponin I at specified levels.

5. Summary of Analytical Studies

Precision study: Total imprecision ranges from 5.97% CV (high human serum based control) to 13.53% CV (low human serum based control).

Dilution Recovery: Linearity studies performed by diluting four human serum samples containing Troponin I with Troponin I Diluent gives an average recovery of 93.5%.

Correlation: A comparison of serum Troponin I values from 189 samples run in both the ACCESS® Troponin I assay and the Stratus® Cardiac Troponin I test gives the following statistical data: r = 0.87, y = 0.136x -0.088.

Analytical Sensitivity: The lowest detectable level of troponin I distinguishable from zero (Troponin Calibrator S0) with 95% confidence is 0.03 ng/ml.

Summary of Clinical Performance 6.

The purpose of this multi-site prospective study was to 1) establish the clinical performance characteristics of the ACCESS® Troponin I assay, and 2) demonstrate substantially equivalent performance to a previously cleared troponin I assay and to the current gold standard biochemical marker, CK-MB.

For this study, 289 subjects presenting to the emergency department with chest pain of 20 minutes duration were followed serially to rule-in or rule-out AMI. Each patient contributed a minimum of two serum samples to establish the diagnosis. Forty five (45) subjects ruled-in for AMIs.

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Summary of 510(k) Safety and Effectiveness (con't)

ROC curve analysis of all subject results demonstrated an optimal cutoff of 0.15 ng/ml for this clinical indication. Using 0.15 ng/ml as a decision level, the ACCESS® Troponin I assay demonstrated a clinical sensitivity of 89% and a clinical specificity of 91%. Results from 201 patients in which both the ACCESS® Troponin I and the Stratus® Troponin I assays were used, demonstrate 90% concordance. ACCESS® Troponin I assay results were 90% concordant with CK-MB results in 208 subjects tested with both devices.

The sensitivity and specificity of the ACCESS® Troponin I assay was similar to both CK-MB and Stratus® Troponin I when analyzed as a function of time. All assays showed peak sensitivity at 5-11 hours after the onset of chest pain. Both troponin I assays demonstrated peak specificity at 12-23 hours after the onset of chest pain.

ACCESS® Troponin I demonstrated a high degree of specificity in subjects with skeletal muscle injuries and renal disease, two clinical groups that can confound the diagnosis of AMI. The specificity of ACCESS® Troponin I in 58 skeletal injury patients was 86%, which is similar to that of Stratus® Troponin I. For renal disease patients, the specificity of ACCESS® Troponin I assay was 96% for 81 subjects tested.

In conclusion the data demonstrate acceptable diagnostic efficiency of the ACCESS® Troponin I assay reagents when utilized with the ACCESS® Immunoassay Analyzer.

7. Conclusion

The ACCESS® Troponin | reagents when utilized with the ACCESS® Immunoassay Analyzer are substantially equivalent to another test currently in commercial distribution for the measurement of cardiac Troponin I.

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Image /page/2/Picture/2 description: The image shows the logo for the Department of Health & Human Services USA. The logo is circular, with the text "DEPARTMENT OF HEALTH & HUMAN SERVICES USA" arranged around the perimeter. In the center of the circle is an abstract symbol that resembles a stylized caduceus or a human figure with outstretched arms. The logo is black and white.

Food and Drug Administration 2098 Gaither Road Rockville MD 20850

NOV 10 1997

· Jan Olsen Supervisor, Regulatory Affairs Beckman Instruments, Inc. 1000 Lake Hazeltine Drive Chaska, MN 55318

Re: K974075

Trade Name: ACCESS® Troponin I Regulatory Class: II Product Code: MMI Dated: October 28, 1997 Received: October 29, 1997

Dear Ms. Olsen:

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 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 requirement, 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 at (301) 443-6597 or at its internet address "http://www.fda.gov/cdrh/dsmamain.html"

Sincerely yours,

Steven Autman

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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Page 1 of 1

510(k) Number (if known): K97407S

Device Name: ACCESS® Troponin I

Indications For Use:

Summary and Explanation:

Cardiac troponin I (cTnl, molecular weight : 22,500 Da) is a contractile protein exclusively present in the cardiac muscle (1,2). Troponin I is one of three subunits of the troponin complex (I, T, C), which with tropomyosin are bound to actin in the thin filament of the myofibril. Its physiological.role is to inhibit the ATPase activity of the actin-myosin complex in the absence of calcium, and therefore, to prevent muscular contraction (3).

Three tissue isoforms have been identified:

fast troponin I and slow troponin I with molecular weights of 19,800 Da each, expressed in fast i twitch and slow twitch skeletal muscle fibers, respectively.
cardiac troponin I with a N-terminal site having an additional chain of 30 amino acid residues. --

Cardiac Troponin I levels in acute myocardial infarction (AMI) exhibit similar rise and fall patterns to those found in CK-MB. Cumulative data from several studies indicate Troponin I levels are detectable (above quoted values for non-AMI samples) 3-6 hours after the onset of chest pain. Troponin I levels peak at approximately 12-16 hours and can remain elevated for 4-9 days post AMI. These same studies noted that the time to peak concentration of cTnl occurred later in patients who did not receive thrombolytic therapy (4,5,6).

Sequencing of cardiac troponin I from mammals has shown important differences between the cardiac (7) and skeletal (8) forms. Skeletal muscle does not express cardiac troponin I, either during development or in response to stimuli (9). No cross reactivity with skeletal troponin I isoforms allows distinction between cardiac and skeletal injuries, and allows diagnosis of myocardial infarction associated with muscle lesions (rhabdomyolysis, polytraumatism) (6,9,10,11).

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

Concurrence of CDRH, Office of Device Evaluation (ODE)

Patricia Bernhardt (f/k/a Montgomery)
Phillip Montgomery

Division of Clinical Laboratory Devices
510(k) Number K974075

Prescription Use /
(Per 21 CFR 801.109)

Over-The Counter Use

(Optional Format 1-2-96)

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.