HICHEM CK/NAC REAGENT KIT by ELAN PHARMA, INC.

HiChem CK/NAC Reagent (product no. 70003) is intended for the quantitation of creatine kinase in serum and n homent of had not headly no room, seevated serum creatine kinase are diseases of the heart and skeletal muscle.

Device Description

The HiChem CK/NAC Reagent determines creatine kinase by enzymation of adenosine diphosphate in the The rionoment of creatine the sphosphate. The rate of this reaction, and the activity of creatine kinase in the sociment is determined through the measurement of NADH which is formed through a series of linked enzymatic reactions.

The HiChern CK/NAC Reagent is intended to be used either as a manual procedure or on clinical analyzers which can THE HONEY ON WO Treagon IS The reagent is supplied as two liquit-stable components which are combined, ether adomails no roquined manyalance "The reason is to to series CK/NAC Reagent Buffer. The CK/NAC Bubstrate can also be used as a start reagent and combined with the Reagent Buffer following sample addition.

AI/ML Overview

Here's an analysis of the provided text, focusing on the acceptance criteria and the study that proves the device meets them:

Device: HiChem CK/NAC Reagent (product no. 70003)
Intended Use: Quantitation of creatine kinase in serum. Elevated serum creatine kinase levels indicate diseases of the heart and skeletal muscle.

1. Table of Acceptance Criteria and Reported Device Performance

The document describes several performance characteristics for both manual and automated (Hitachi 704) procedures. The acceptance criteria are implicitly derived from the reported performance, as the document states these demonstrate the effectiveness of the reagent. For linearity and precision, the reported values often serve as the acceptance criteria themselves within the context of demonstrating "effectiveness." For comparison studies and stability, the acceptance criteria are explicitly stated as biases/shifts being below certain thresholds or strong correlation coefficients.

Performance Metric	Acceptance Criteria (Implicit/Explicit)	Reported Device Performance (Manual Procedure)	Reported Device Performance (Automated Hitachi 704)
Linearity	Recovery of linearity standards should span the claimed linear range with strong correlation (high r²) and low standard error (s_yx). For 30°C: linear to at least 2000 U/L. For 37°C: linear to at least 2000 U/L.	30°C: Linear to at least 2000 U/L. (Recoveries at 30°C) = 6.1 U/L + 0.9918 x (Standard Activity), r² = 0.9998, s_yx = 8.1 U/L. 37°C: Linear to at least 2000 U/L. (Recoveries at 37°C) = 2.5 U/L + 0.9867 x (Standard Activity), r² = 0.9998, s_yx = 10.7 U/L.	Linear to at least 2,400 U/L. (HiChem Recoveries) = -0.2 U/L + 1.0013 x (Activity), r² = 1.0000, s_yx = 3.4 U/L.
Precision (Within-run SD & Total SD)	Implied acceptable precision for different concentration levels.	Serum control 1 (50 U/L): Within-run SD = 1.5 U/L, Total SD = 1.6 U/L. Serum control 2 (378 U/L): Within-run SD = 5.3 U/L, Total SD = 7.8 U/L. Serum control 3 (1048 U/L): Within-run SD = 10.3 U/L, Total SD = 18.6 U/L.	Serum control 1 (53 U/L): Within-run SD = 0.9 U/L, Total SD = 1.2 U/L. Serum control 2 (415 U/L): Within-run SD = 1.4 U/L, Total SD = 3.0 U/L. Serum control 3 (1183 U/L): Within-run SD = 3.4 U/L, Total SD = 6.9 U/L.
Method Comparison (Reference Reagent)	Strong correlation (high r²) and low standard error (s_yx) when compared to a legally marketed predicate device, with an acceptable slope and intercept close to 1 and 0, respectively.	Compared to Sigma Reagent: (HiChem Results) = 0.6 U/L + 0.990 x (Sigma Results), s_yx = 8.5 U/L, r² = 0.991.	Compared to BMD Reagent: (HiChem Results) = 0.0 U/L + 1.048 x (BMD Results), r = 0.9994, s_yx = 3.05 U/L.
Chemical Additives (Heparin, EDTA)	Biases observed should be less than 2% and statistically insignificant at the 95% confidence level compared to unspiked pools.	Biases less than 2% and statistically insignificant at the 95% confidence level.	Not applicable (not mentioned for automated procedure specifically).
Reagent Stability (Combined Working Reagent)	Observed shifts in standard recovery should be less than the greater of 4 U/L or 5% (for 2 weeks at 2-8°C and 1 day at 18-25°C).	Observed shifts in standard recovery were less than the greater of 4 U/L or 5%. (Tested over 2 weeks at 2-8°C and 1 day at 18-25°C with control sera from 50 to 1200 U/L CK at 37°C).	Not applicable (not mentioned for automated procedure specifically, but general stability is addressed below).
Calibration Stability	Observed shifts in recoveries over 24 hours without calibration should be less than the greater of 1 U/L or 0.25%.	Not applicable (specific to automated procedure).	Observed shifts in recoveries over 24 hours without calibration were less than the greater of 1 U/L or 0.25%. (Tested with control sera spanning 50 to 1,200 U/L CK).
On-Board Stability	Observed shifts in recoveries over the 21-day stability claim should be no greater than 3.5%.	Not applicable (specific to automated procedure).	Observed shifts in recoveries over the 21-day stability claim were no greater than 3.5%. (Tested with the same serum controls).

Study that Proves the Device Meets the Acceptance Criteria:

The document itself constitutes the summary of the studies performed to demonstrate safety and effectiveness, and ultimately, substantial equivalence to predicate devices. It describes a series of experiments and analyses for both manual and automated use of the HiChem CK/NAC Reagent.

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

Linearity (Manual): "linearity standards" (number not specified explicitly, but implies multiple points across the range).
Precision (Manual): 30 replicates per serum control level (3 levels tested).
Method Comparison (Manual): 90 mixed serum and plasma specimens.
Chemical Additives (Manual): "spiked and unspiked serum pools" (number of pools/samples not specified, but implies comparative testing).
Reagent Stability (Manual): "serum controls" (number of controls/data points not specified explicitly, but ranges from 50 to 1200 U/L CK).
Linearity (Automated): "eleven linearity standards."
Precision (Automated): 60 replicates per serum control level (3 levels tested).
Method Comparison (Automated): 126 mixed serum and plasma specimens.
Calibration Stability (Automated): "serum controls" spanning approximately 50 to 1,200 U/L CK (number of controls/data points not specified explicitly).
On-board Stability (Automated): "the same serum controls" as for calibration stability (number of controls/data points not specified explicitly).

Data Provenance: Not explicitly stated (e.g., country of origin, retrospective or prospective). Given the nature of laboratory reagent testing for product submission, it is typically understood that these are prospective studies conducted in a controlled lab environment.

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

This type of study does not involve "experts" establishing ground truth in the traditional sense of medical image interpretation (e.g., radiologists). Instead, the "ground truth" for the test set is established by:

Reference materials: Known concentration "linearity standards" for linearity testing, "commercially available control sera" with known target values for precision testing.
Predicate devices: The legally marketed Sigma Diagnostics Creatine Kinase (CK) Reagent and BMD CK/NAC Reagent serve as the reference standard (the "ground truth" or comparative standard) for method comparison studies.

Therefore, the concept of "number of experts" and their "qualifications" is not applicable here.

4. Adjudication Method for the Test Set

Not applicable. This is not a study requiring adjudication of interpretations (e.g., by multiple readers). The results are quantitative measurements compared against known values or established predicate methods.

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 devices that involve human interpretation of images or other subjective data, which is not the case for a quantitative chemical reagent.

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

This is essentially a standalone (algorithm/reagent only) performance study. The reagent itself, combined with either manual pipetting and spectrophotometry or an automated analyzer, generates the results. There isn't a "human-in-the-loop" component in the interpretation of the result from the device, only in the operation of the manual procedure. The automated procedure is even less human-in-the-loop for the measurement process.

7. The Type of Ground Truth Used

The ground truth used several forms:

Reference Standards/Materials: For linearity, commercially prepared "linearity standards" with known, accurate creatine kinase concentrations are used. For precision, "commercially available control sera" with established target values are used.
Predicate Device Measurements: For method comparison, the measurements obtained from legally marketed predicate devices (BMD CK/NAC Reagent and Sigma Diagnostics Creatine Kinase (CK) Reagent) on the same patient specimens serve as the comparative ground truth.

8. The Sample Size for the Training Set

Not applicable. This is a chemical reagent, not a machine learning algorithm that requires a "training set." The performance characteristics are derived from direct experimental measurements. The phrase "training set" is generally used in the context of AI/ML model development.

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

Not applicable, as there is no training set for this type of device.

Summary

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K962247

HiChem

SUMMARY OF 510(K) SAFETY AND EFFECTIVENESS INFORMATION

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.

AUG 1 5 1996

The HiChem CK/NAC Reagent is substantially equivalent to the BMD CK/NAC Reagent, product no. 816360, manufactured by The hiloger Manhheim Corp., Indianapolis, IN., and the Sigma Diagnostics Creatine Kinase (CK) Reagent, procedure no. 47-Doomings maintinent ookin maanstics, St. Louis, MO. All three reagents support the same intended use and produce e vivalent results with the same clinical purpose. In addition, they are methodology which determines creatine kinse (CK ) through the measurement of NADH production. Finally, all reagents are sold in a generic format which evealine made (UT) infough the neadly one of supports its use on various instruments through procedure supplements (application sheets).

The effectiveness of the manual procedure is shown by the recovery of linearity standards, the precision of control recoveries, The comparison of the mandal procedure to the Sigme Creatine Kinase (CK) Reagent and the validation of the chemical additives and reconstituted stability claims.

The recovery of creatine kinase using HiChem CK/NAC Reagent as a manual method at both 30°C and 37°C reaction temperatures is linear to at least 2000 U/L as shown by the recovery of linearity standards which span the claimed linear range. Regression statistics are shown below.

(Recoveries at 30°C) = 6.1 U/L + 0.9918 x (Standard Activity),	$r^2$ = 0.9998,	$s_{yx}$ = 8.1 U/L
(Recoveries at 37°C) = 2.5 U/L + 0.9867 x (Standard Activity),	$r^2$ = 0.9998,	$s_{yx}$ = 10.7 U/L

Precision, demonstrated by replicate assay of commercially available control sera, is shown below.

Specimen	n	mean	within-run SD	total SD
Serum control 1	30	50 U/L	1.5 U/L	1.6 U/L
Serum control 2	30	378 U/L	5.3 U/L	7.8 U/L
Serum control 3	30	1048 U/L	10.3 U/L	18.6 U/L

Creatine kinase recoveries of 90 mixed serum and plasma specimens are compared between the HiChem and Sigma reagents. Least squares regression statistics are shown below.

(HiChem Results) == 0.6 U/L + 0.990 x (Sigma Results) S yx = 8.5 U/L. r2 = 0.991.

The use of heparin and EDTA are shown to be acceptable chemical additives by comparison of spiked and unspiked serum pools. In all cases, the biases observed were less than 2% and statistically insignificant at the 95% confidence level.

The stability of the combined working reagent over 2 weeks at 2-8°C and 1 day at 18-25°C are documented through the recovery of serum controls which range from 50 to 1200 U/L CK at 37 C. In all cases, the observed shifts in standard recovery were less than the greater of 4 U/L or 5%.

The effectiveness of the automated Hitachi 704 procedure is shown by the recovery of linearity standards, the precision of control recoveries, the recovery of serum controls over both the callbration stability claim, and the comparison of patient specimen recoveries to the BMD CK/ NAC Reagent.

The recovery of creatine kinase using HiChern CK/NAC Reagent as an automated method is linear to at least 2,400 U/L as shown by the recovery of eleven linearity standards which span the claimed linear range. Regression statistics are shown below.

Syx = 3.4 U/L. (HiChem Recoveries) = -0.2 U/L + 1.0013 x (Activity), r2 = 1.0000,

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Precision, demonstrated by replicate assay of commercially available control sera, is shown below.

Specimen	n	mean	within-run SD	total SD
Serum control 1	60	53 U/L	0.9 U/L	1.2 U/L
Serum control 2	60	415 U/L	1.4 U/L	3.0 U/L
Serum control 3	60	1183 U/L	3.4 U/L	6.9 U/L

Creatine kinase recoveries of 126 mixed serum and plasma speciment the HiChern and BMD reagents using least squares regression, yield the following statistics.

Sy.x = 3.05 U/L. (HiChem Results) = 0.0 U/L + 1.048 x (BMD Results) r = 0.9994.

The 24 hour calibration stability claim is documented through the recovery of serum controls which span from approximately 50 to 1,200 U/L CK. In all cases, the observed shifts in recoveries over 24 hours without calibration are less than the greater of 1 U/L or 0.25%. The on-board stability cleim is documented through the recovery of the same serum controls. The observed shifts in recoveries over the 21 day stability claim are no greater than 3.5%.

The HiChem CK/NAC Reagent is shown to be safe and effective and substantially equivalent to the BMD CK/NAC Reagent, moduct no. 816360, manufactured by Boehringer Mannheim Corp., Indianapolis, IN., and the Sigma Diagnostics Creatine Kinase (CK) Reagent, procedure no. 47-UV manufactured by Sigma Diagnostics, St. Louis, MO.

Wynn Stoker

Manager of Regulatory A HiChem Diagnostics

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.