For use in the calibration of the Vitros Immunodiagnostic System for the quantitative measurement of cardiac Troponin I (cTnI) in human heparin plasma.

Device Description

The Vitros Troponin I assay is performed using the Vitros Troponin I Reagent Pack and Vitros Immunodiagnostic Products Troponin I Calibrators on the Vitros ECi Immunodiagnostic System with Intellicheck ™ . An immunometric technique is used. Cardiac Troponin I present in the sample reacts simultaneously with a biotinylated antibody (mouse monoclonal anti-cTnI) and a horseradish peroxidase (HRP)-labeled antibody conjugate (affinity purified goat polyclonal anti-cTnI). The antigen-antibody complex is captured by streptavidin on the wells. Unbound materials are removed by washing. A reagent containing luminogenic substrates (a luminol derivative and a peracid salt) and an electron transfer agent (a substituted acetanilide) is added to the wells. The HRP in the bound conjugate catalyzes the oxidation of the luminol derivative, producing light. The electron transfer agent increases the level and duration of the light produced. The light signals are read by the Vitros ECi System. The amount of HRP conjugate bound is directly proportional to the concentration of cTnI present in the sample.

AI/ML Overview

This document describes the acceptance criteria and study proving the VITROS Immunodiagnostic Products Troponin I Reagent Pack and Calibrators meet the criteria.

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are implied by the comparison to the predicate device and the establishment of diagnostic thresholds.

Metric	Acceptance Criteria (Implied by Predicate & Clinical Diagnostic Use)	Reported Device Performance (VITSOS Troponin I Modification)
Correlation Coefficient (vs. Predicate)	Clinically acceptable correlation (e.g., above 0.9)	0.949
Upper Reference Limit of Normals (Plasma)	Established to distinguish normal from elevated levels	0.08 ng/mL (based on 90% CI of 99.0 percentile)
Higher Decision Limit (AMI cut-off) (Plasma)	Optimized for sensitivity and specificity of AMI diagnosis	0.4 ng/ml (85% Sensitivity, 91% Specificity)

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

Correlation Data Test Set:
- Sample Size: 198 samples
- Data Provenance: "panel of patient samples from a variety of clinical categories." (Retrospective, origin not specified beyond "patient samples")
Upper Reference Limit (URL) Test Set:
- Sample Size: 798 fresh heparin plasma samples
- Data Provenance: "normal blood donors between the ages of 18-89 (61.3% male donors and 38.7% female donors collected across six sites)." (Prospective or retrospective, origin not specified beyond "six sites"; implies multi-center U.S. data likely given FDA submission)
AMI Cut-off Test Set:
- Sample Size: 458 chest pain patients, where 78 were diagnosed with AMI.
- Data Provenance: "chest pain patients" (Retrospective clinical data, origin not specified beyond "patients")

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

The document does not specify the number or qualifications of experts used to establish ground truth for any of the test sets.

For the correlation data, the ground truth is implicitly the values obtained from the DADE Dimension™ RxL Cardiac Troponin-I (TROP) Method (the predicate device).
For the upper reference limit, "normal blood donors" classification would likely be based on standard health screenings, not expert consensus on troponin levels.
For the AMI cut-off, the "diagnosis of AMI" for the 78 patients would be the ground truth. This diagnosis is typically established by clinicians based on a combination of patient symptoms, ECG changes, and cardiac biomarker levels (including troponin, but not exclusively). The specific method or expert involvement in confirming these AMI diagnoses is not detailed.

4. Adjudication Method for the Test Set

The document does not describe any specific adjudication method for establishing ground truth for any of the test sets. Ground truth for the correlation data is the predicate device's measurement. Ground truth for normal donors is their clinical classification as healthy. Ground truth for AMI patients is their clinical diagnosis, but the process of this diagnosis (e.g., whether it involved multiple blinded reviewers) is not detailed.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, and the Effect Size of How Much Human Readers Improve with AI vs Without AI Assistance

This section is not applicable. The device is an in vitro diagnostic (IVD) assay measuring a biomarker (Troponin I). It is not an AI-assisted diagnostic imaging device or an algorithmic tool intended to directly assist human readers in interpreting complex visual or clinical data in the way an MRMC study would typically evaluate. The assay directly provides a quantitative result.

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

This section is applicable, and the studies outlined are standalone performance evaluations of the device. The device itself (the VITROS Troponin I assay) is an automated system that provides a quantitative measurement. The reported performance metrics (correlation coefficient, URL, AMI cut-off with sensitivity/specificity) are derived from the device's output without human intervention in the measurement process after sample introduction. The human "in-the-loop" would be the clinician interpreting the result, but the performance data presented is the "algorithm only" (assay only) output.

7. The Type of Ground Truth Used

Correlation Data: The ground truth was the measurements obtained from the predicate device (DADE Dimension™ RxL Cardiac Troponin-I (TROP) Method).
Upper Reference Limit: The ground truth was the clinical classification of "normal blood donors."
AMI Cut-off: The ground truth was the clinical diagnosis of "AMI" for 78 patients out of a total of 458 chest pain patients. This represents a form of outcomes data or clinical diagnosis.

8. The Sample Size for the Training Set

The document does not explicitly mention a separate "training set" in the context of machine learning. For IVD devices, method validation studies typically involve defining parameters (like the URL and cut-off points) based on observed performance in clinical populations rather than explicit "training" in the AI sense.

The upper reference limit (0.08 ng/mL) was established using a panel of 798 fresh heparin plasma samples from normal blood donors. This can be considered the "dataset used to define a normal range."
The AMI cut-off (0.4 ng/ml) was determined using 458 chest pain patients (78 with AMI) via Receiver Operator Characteristic (ROC) curve analysis. This can be considered the "dataset used to optimize a diagnostic threshold."

These datasets serve a similar purpose to a training set in that they are used to establish and optimize operating parameters for the device's interpretation.

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

For the Upper Reference Limit: The ground truth for the 798 samples was their status as "normal blood donors" (presumably healthy individuals without cardiac disease) aged 18-89. This classification would typically be based on standard donor screening procedures and health questionnaires.
For the AMI Cut-off: The ground truth for the 458 chest pain patients was their clinical diagnosis, specifically whether they were "diagnosed with AMI." This diagnosis would have been made by medical professionals based on clinical presentation, ECG findings, and other relevant diagnostic information available at the time of the patient's care.

Summary

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APR 1 2 2002

Attachment C - Revised 510(k) Summary

GENERAL INFORMATION 1.0

510(k) Summary 1.1

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 is KO 20662

1.1.1. Submitter Name, Address, Contact

Ortho-Clinical Diagnostics, Inc. 100 Indigo Creek Drive Rochester, New York 14626-5101 (716) 453-4041

Contact Person: Ann M Quinn

1.1.2. Preparation Date

Date 510(k) prepared: February 28, 2002

1.1.3. Device Name

Trade or Proprietary Name: VITROS Immunodiagnostic Products Troponin I Reagent Pack VITROS Immunodiagnostic Products Troponin I Calibrators

: TROPONIN I assay Common Name Classification Name: Troponin I (cTnI) Test System

1.1.4. Predicate Device

The VITROS Immunodiagnostic Products Troponin I Reagent Pack and VITROS Immunodiagnostic Products Troponin I Calibrators are substantially equivalent to the DADE Dimension™ RxL Cardiac Troponin-I (TROP) Method.

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1.1.5. Device Description

1.1.6. Device Intended Use

The VITROS Troponin I assay is intended for the in vitro quantitative measurement of Troponin I (cTnI) in human heparin plasma to aid in the diagnosis of myocardial infarction.

1.1.7. Comparison to Predicate Device

A comparison of the correlation data previously cleared (K992366) for Vitros Troponin I and modifications which are the subject of this Special 510 (k) are displayed in the table below.

This relationship was determined from a panel of patient samples from a variety of clinical categories.

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	Vitros Troponin IK992366	Vitros Troponin IModification
Number of Samples	122	198
Correlation Coefficient	0.983	0.949
Regression Equation	$Vitros = 1.04 x$$Dade -0.151 ng/ml$	$Vitros = 0.728 x Dade$$-0.093 ng/ml$
Range of Samples(Vitros Troponin IValues)	0.021 - 99.1 ng/ml	0.053 – 66.9 ng/ml

The upper reference limit for normals (URL) was set at 0.08 ng/mL based on a panel of 798 fresh heparin plasma samples from normal blood donors between the ages of 18-89 (61.3% male donors and 38.7% female donors collected across six sites). The observed values for the upper 97.5 percentile and the upper 99.0 percentile were 0.04 ng/mL (90% confidence interval 0.03 - 0.05 ng/mL) and 0.06 ng/mL (90% confidence interval 0.05 - 0.08 ng/mL), respectively. The URL represents the upper 90% confidence interval of the 99.0 percentile.

Data from a total of 458 chest pain patients, 78 of which were diagnosed with AMI were analyzed by Receiver Operator Characteristic (ROC) curve analysis to determine the best diagnostic cut-off for AMI using heparin plasma. The AMI cut-off was set at 0.4 ng/ml, representing a balance between sensitivity (85%) and specificity (91%).

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A comparison of these limits from the previously cleared 510 (k) -A comparison of these animal I and the modifications which are the subject of this Special 510 (k) are displayed in the table below.

Upper Reference Limit of Normals(Non AMI) in ng/ml	VitrosTroponin IK992366	VitrosTroponin IModification
Serum	0.1	NA
Plasma	0.08	0.08
Higher Decision Limit (AMI cut-off)in ng/ml
Serum	1.0	NA
Plasma	0.8	0.4

Conclusions 1.1.8

The intended use as cleared in K992366 is being limited from serum, EDTA and heparin plasma to heparin plasma only. The proposed changes described in this submission provide performance characteristics in line with this specimen type. These revisions provide data that continue to support the safe and effective use of the Vitros Troponin I Reagent Pack and Calibrators for use in quantitatively measuring Troponin I concentration in heparin plasma. Expected Values and Reporting Units.

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DEPARTMENT OF HEALTH & HUMAN SERVICES

Image /page/4/Picture/1 description: The image contains the logo of the U.S. Department of Health & Human Services. The logo features a stylized depiction of an eagle or bird-like figure with three wing-like extensions, symbolizing care and protection. The text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" is arranged in a circular fashion around the emblem.

Ms. Ann M. Quinn, RAC Manager, Regulatory Affairs Ortho Clinical Diagnostics, Inc. 100 Indigo Creek Drive Rochester, New York 14626-5101

APR 1 2 2002

Food and Drug Administration 2098 Gaither Road Rockville MD 20850

Re: K020662

Trade/Device Name: VITROS Immunodiagnostic Products Troponin I Reagent Pack and VITROS Immunodiagnostic Products Troponin I Calibrators

Regulation Number: 21 CFR § 862.1215

Regulation Name: Creatine Phosphokinase/Creatine Kinase or Isoenzymes Test System Regulatory Class: II Product Code: MMI Regulation Number: 21 CFR § 862.1150

Regulation Name: Calibrator Regulatory Class: II

Dated: February 28, 2002 Received: March 1, 2002

Product Code: JIT

Dear Ms. Quinn:

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. 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 (PMA), 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 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 801); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

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Page 2 -

This letter will allow you to begin marketing your device as described in your 510(k) premarket This letter will and in you ding of substantial equivalence of your device to a legally marketed predication. 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 1 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, (201) 59 rttact the Office of Compliance at (301) 594-4639. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21CFR 807.97). Other general information on your responsibilities under the Act may be obtained from the Division of Small manufacturers International and Consumer Assistance at its toll-free number (800) 638-2041 or 14.01) 443-6597 or at its internet address "http://www.fda.gov/cdrh/dsma/dsmamain.html".

Sincerely yours,

Steven Butman

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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CONFIDENTIAL AND PROPRIETARY

Statement of Intended Use 1.2

Page 1 of 1

510(k) Number (if known):

Device Name:

Indications for Use:

K020662

VITROS Immunodiagnostic Products Troponin I Reagent Pack

VITROS Immunodiagnostic Products Troponin I Calibrators

For the in vitro quantitative measurement of Troponin I (cTnI) in human heparin plasma to aid in the diagnosis of myocardial infarction.

For use in the calibration of the Vitros Immunodiagnostic System for the quantitative measurement of cardiac Troponin I (cTnI) in human heparin plasma.

on Sian-Off Asion of Clinical Laboratory Devices 510(k) Number

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

Concurrence of CDRH, Office of Device Evaluation (ODE)

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.