HICHEM BUN/UREA REAGENT KIT by ELAN PHARMA, INC.

HiChem BUN/Urea Reagent (product no. 70006) is for the quantitative determination of urea nitrogen in serum. plasma and urine. Plasma urea levels are affected by a wide variety of factors including diet, increased protein catabolism and mild dehydration as well as many renal diseases. The major value of plasma urea measurement is in distinguishing between renal and non-renal related causes.

Device Description

The HiChem BUN/Urea Reagent determines urea nitrogen through enzymatic hydrolysis by urease. The rate of this reaction, and the quantity of urea nitrogen in the specimen is monitored through the measurement of the resulting ammonia which oxidizes NADH to NAD in the presence of ox-keto-glutarate and glutamate dehydrogenase. The reagent is supplied as two liquid-stable reagent components which are intended to be combined, either before or during use, in the approximate ratio of 1 part BUN/Urea Enzyme Reagent and 5 parts BUN/Urea Buffer. The BUN/Urea Enzyme Reagent can also be used as a start reagent and combined with the reagent buffer after sample addition.

AI/ML Overview

This document describes the performance of the HiChem BUN/Urea Reagent and compares it to existing reagents, rather than an AI-powered device. Therefore, many of the requested elements for an AI device study (e.g., sample size for AI test set, number of experts for ground truth, adjudication method, MRMC study, standalone performance, training set details) are not applicable.

However, I can extract the acceptance criteria and reported performance based on the provided text for the HiChem BUN/Urea Reagent.

1. Table of Acceptance Criteria and Reported Device Performance

The document doesn't explicitly state "acceptance criteria" with numerical thresholds for all evaluated aspects. Instead, it presents performance metrics and makes claims about substantial equivalence to predicate devices, linearity, and stability. I will infer acceptance criteria where possible from the claims made (e.g., linearity to at least 150 mgN/dL, shifts less than specified values for stability). For comparative studies, the acceptance is implied if the regression statistics (r², Sy.x) demonstrate strong agreement with the predicate device.

Manual Procedure:

Performance Characteristic	Acceptance Criteria (Inferred)	Reported Device Performance (HiChem BUN/Urea Reagent)
Precision	Demonstrated by replicate assay	Low serum control (n=30): Mean 8.7 mgN/dL, within run SD 0.48 mgN/dL, total SD 0.58 mgN/dL Mid. serum control (n=30): Mean 25.7 mgN/dL, within run SD 0.73 mgN/dL, total SD 0.70 mgN/dL High serum control (n=30): Mean 52.1 mgN/dL, within run SD 0.93 mgN/dL, total SD 1.02 mgN/dL Low urine pool (n=30): Mean 15.4 mgN/dL, within run SD 0.71 mgN/dL, total SD 0.90 mgN/dL High urine pool (n=30): Mean 53.3 mgN/dL, within run SD 1.20 mgN/dL, total SD 1.54 mgN/dL
Linearity	Linear to at least 150 mgN/dL	Regression: (HiChem Results) = 0.1 mgN/dL + 0.986 × (Standard Value), r² = 1.000, Sy.x = 0.5 mgN/dL. (Spans claimed linear range)
Method Comparison (Serum/Plasma vs. Sigma)	Demonstrates substantial equivalence and produces equivalent results with clinical purpose. Implied strong correlation (high r²) and low bias (Sy.x).	80 mixed serum and plasma specimens: (HiChem Results) = 0.7 mgN/dL + 0.977 × (Sigma Results) r² = 0.996, Sy.x = 1.00 mgN/dL
Method Comparison (Urine vs. BMD)	Demonstrates substantial equivalence and produces equivalent results with clinical purpose. Implied strong correlation (high r²) and low bias (Sy.x).	39 urine specimens: (HiChem Results) = 1.9 mgN/dL + 0.966 × (BMD Results) r² = 0.990, Sy.x = 1.82 mgN/dL
Interfering Substances (Additives)	Observed differences less than 1% and statistically insignificant	Use of sodium and lithium heparin, EDTA, citrate, and iodoacetate are acceptable. Observed differences < 1% and statistically insignificant in comparison of spiked and unspiked serum pools.
Reagent Stability (Combined Working Reagent)	Shifts in standard recovery less than the greater of 3 mgN/dL or 3%	Over 1 month at 2-8°C and 4 days at 18-25°C. In all cases, shifts in standard recovery were less than the greater of 3 mgN/dL or 3%.

Automated Hitachi 704 Procedure:

Performance Characteristic	Acceptance Criteria (Inferred)	Reported Device Performance (HiChem BUN/Urea Reagent on Hitachi 704)
Precision	Demonstrated by replicate assay	Low serum control (n=60): Mean 13.9 mgN/dL, within run SD 0.59 mgN/dL, total SD 0.81 mgN/dL Mid. serum control (n=60): Mean 52.7 mgN/dL, within run SD 0.60 mgN/dL, total SD 0.77 mgN/dL High serum control (n=60): Mean 78.8 mgN/dL, within run SD 0.70 mgN/dL, total SD 1.09 mgN/dL Low urine pool (n=60): Mean 21.9 mgN/dL, within run SD 0.54 mgN/dL, total SD 0.52 mgN/dL High urine pool (n=60): Mean 75.3 mgN/dL, within run SD 0.85 mgN/dL, total SD 2.91 mgN/dL
Linearity (vs. BMD standards)	Equivalent between HiChem and BMD BUN Reagents, spanning 0-150 mgN/dL	Regression: (HiChem Results) = 0.0 mgN/dL + 1.005 x (BMD Results), r² = 1.000, Sy.x = 0.6 mgN/dL. (Spans claimed linear range of 0 to 150 mgN/dL)
Method Comparison (Serum/Plasma vs. BMD)	Demonstrates substantial equivalence and produces equivalent results with clinical purpose. Implied strong correlation (high r²) and low bias (Sy.x).	190 mixed serum and plasma specimens: (HiChem Results) = 0.0 mgN/dL + 1.009 × (BMD Results) r² = 0.999, Sy.x = 0.6 mgN/dL
Method Comparison (Urine vs. BMD)	Demonstrates substantial equivalence and produces equivalent results with clinical purpose. Implied strong correlation (high r²) and low bias (Sy.x).	Not explicitly stated count, assumed part of 190 mixed specimens or similar: (HiChem Results) = 0.1 mgN/dL + 1.027 × (BMD Results) r² = 0.999, Sy.x = 0.7 mgN/dL
Calibration Stability	Observed shifts in recoveries less than the greater of 2 mgN/dL or 2% over 48 hours	Serum controls spanning 8 to 132 mgN/dL urea nitrogen. In all cases, shifts in recoveries over the calibration period were less than the greater of 2 mgN/dL or 2% over 48 hours.

2. Sample size used for the test set and the data provenance (e.g. country of origin of the data, retrospective or prospective)

Test Set Sample Sizes:
- Precision (Manual):
  - Low, Mid, High serum controls: n = 30 for each
  - Low, High urine pools: n = 30 for each
- Method Comparison (Manual):
  - Serum and plasma specimens vs. Sigma: n = 80
  - Urine specimens vs. BMD: n = 39 (diluted with normal saline)
- Interfering Substances: "Spiked and unspiked serum pools" (number not specified)
- Precision (Automated Hitachi 704):
  - Low, Mid, High serum controls: n = 60 for each
  - Low, High urine pools: n = 60 for each
- Method Comparison (Automated Hitachi 704):
  - Mixed serum and plasma specimens vs. BMD: n = 190 (diluted with normal saline)
  - Urine comparison: (assumed to be part of or similar to the 190 specimens, not explicitly stated as a separate count)
- Calibration Stability: Serum controls spanning 8 to 132 mgNdL (number not specified, but tested over time)
Data Provenance: The document does not specify the country of origin for the samples or whether the study was retrospective or prospective. Given the nature of a 510(k) submission for a diagnostic reagent in the USA, it is likely that the studies were conducted in the USA using samples that would be representative of a general patient population. The studies appear to be prospective experimental evaluations of the reagent's performance.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g. radiologist with 10 years of experience)

Not Applicable. This is a chemical reagent study, not an imaging or diagnostic AI study requiring expert adjudication of ground truth in the traditional sense. The "ground truth" for method comparisons is established by the results obtained from the predicate/comparable reagents (Sigma BUN (Rate) Reagent and BMD BUN Reagent), which are themselves established and validated clinical chemistry methods. For linearity and precision studies, the "ground truth" is based on known concentrations of standards and controls.

4. Adjudication method (e.g. 2+1, 3+1, none) for the test set

Not Applicable. As mentioned above, this is not an AI diagnostic study involving human interpretation that would require an adjudication method.

5. If a multi reader multi case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance

Not Applicable. This is a performance study for a chemical reagent, not an AI-assisted diagnostic device that would involve human readers.

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

Yes, this is essentially a standalone performance study. The HiChem BUN/Urea Reagent, both manually and on the Hitachi 704, operates as a standalone chemical test. Its performance is evaluated independently and then compared to predicate devices. There is no "human-in-the-loop" component in the direct measurement process of the reagent itself, beyond standard laboratory procedures for sample handling and instrument operation.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc)

The "ground truth" for this study is multifactorial:
- Known concentrations: For linearity and precision studies, commercially available control sera and urine pools, as well as linearity standards, are used, which have established, known concentrations of urea nitrogen.
- Reference Method/Predicate Device Results: For method comparison studies, the results from the predicate devices (Sigma BUN (Rate) Reagent and BMD BUN Reagent) are used as the reference "truth" against which the HiChem reagent's performance is compared. These are established and accepted clinical chemistry methods.

8. The sample size for the training set

Not Applicable. This is a chemical reagent, not a machine learning model, so there is no "training set."

9. How the ground truth for the training set was established

Not Applicable. As there is no training set for a chemical reagent, this question is irrelevant.

Summary

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KSC0115

MAR 2 9 1996

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.

The HiChem BUN/Urea Reagent is intended to be used with the HiChem Chemistry Standard, product no. 70023 or other compatible NIST traceable calibration standard either as a manual procedure or on clinical analyzers which can automate the required manipulations. The reagent is supplied as two liquid-stable reagent components which are intended to be combined, either before or during use, in the approximate ratio of 1 part BUN/Urea Enzyme Reagent and 5 parts BUN/Urea Buffer. The BUN/Urea Enzyme Reagent can also be used as a start reagent and combined with the reagent buffer after sample addition.

The HiChem BUN/Urea Reagent calibrated with the HiChem Chemistry Standard, product 70023 is substantially equivalent to the BMD BUN Reagent, product no. 704092 calibrated with Precical Calibrator Serum and Diluent. product no. 620213, both manufactured by Boehringer Mannheim Corp., Indianapolis, IN. and the Sigma BUN (Rate) Reagent, procedure no. 67-UV calibrated with Glucose/Urea Nitrogen Standard, product no. 16-300, both manufactured by Sigma Diagnostics, St. Louis, MO. Substantial equivalence between the HiChem and other calibrators for the purpose of calibrating urea nitrogen methods is also shown. All three reagent/calibrator pairs support the same intended use (with the exception of the specimen limitations for the Sigma reagent) and produce equivalent results with the same clinical purpose. In addition, they are all based on the same methodology which determines urea nitrogen through the rate of NADH depletion. Finally, all reagents are sold in a generic format with their use on various instruments supported through procedure supplements (application sheets).

The effectiveness of the manual procedure is shown by the recovery of linearity standards, the precision of control recoveries, a comparison of serum and plasma recoveries to the Sigma BUN (Rate) Reagent and a comparison of urine recoveries to the BMD BUN Reagent.

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

Specimen	n	mean	within run SD	total SD
Low serum control	30	8.7 mgN/dL	0.48 mgN/dL	0.58 mgN/dL
Mid. serum control	30	25.7 mgN/dL	0.73 mgN/dL	0.70 mgN/dL
High serum control	30	52.1 mgN/dL	0.93 mgN/dL	1.02 mgN/dL
Low urine pool	30	15.4 mgN/dL	0.71 mgN/dL	0.90 mgN/dL
High urine pool	30	53.3 mgN/dL	1.20 mgN/dL	1.54 mgN/dL

The recovery of urea nitrogen using HiChem BUN/Urea Reagent as a manual method is linear to at least 150 mgN/dL as shown by the recovery of linearity standards which span the claimed linear range. Regression statistics are shown below.

(HiChem Results) = 0.1 mgN/dL + 0.986 × (Standard Value), r2 = 1.000, Sy.x = 0.5 mgN/dL.

Urea nitrogen recoveries of 80 mixed serum and plasma specimens are compared between the HiChem and Sigma reagents. Ureanittogen recoveries of 39 urine specimens diluted with 20 parts normal saline are compared between the HiChem BUN/Urea Reagent and the BMD BUN Reagent used on the Hitachi 704. All reagents were calibrated with their recommended calibrators. Least squares regression statistics are shown below. .: I.AN

Diagnostics Division

HiChem

231 North Puente Street, Brea, California 92621 Telephone: (714) 871-8360 / (800) 422-3526 / Fax: (714) 871-2439

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Serum/Plasma Comparison
(HiChem Results) = 0.7 mgN/dL + 0.977 × (Sigma Results)	r2 = 0.996, Sy.x = 1.00 mgN/dL
Urine Comparison
(HiChem Results) = 1.9 mgN/dL + 0.966 × (BMD Results)	r2 = 0.990, Sy.x = 1.82 mgN/dL

The use of sodium and lithium heparin, EDTA, citrate, and iodoacetate are also shown to be acceptable chemical additives by comparison of spiked and unspiked serum pools. In all cases observed were less than 1% and statistically insignificant.

The stability of the combined working reagent over 1 month at 2-8°C and 4 days at 18-25°C are documented through the recovery of linearity standards which span the claimed linear range of the method. In all cases, the observed shifts in standard recovery were less than the greater of 3 mgN/dL or 3%.

The effectiveness of the automated Hitachi 704 procedure is shown by the precision of control recoveries, the recovery of linearity standards, and comparison of mixed serum and urine recoveries to the BMD BUN Reagent.

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

Specimen	n	mean	within run SD	total SD
Low serum control	60	13.9 mgN/dL	0.59 mgN/dL	0.81 mgN/dL
Mid. serum control	60	52.7 mgN/dL	0.60 mgN/dL	0.77 mgN/dL
High serum control	60	78.8 mgN/dL	0.70 mgN/dL	1.09 mgN/dL
Low urine pool	60	21.9 mgN/dL	0.54 mgN/dL	0.52 mgN/dL
High urine pool	60	75.3 mgN/dL	0.85 mgN/dL	2.91 mgN/dL

The recoveries of urea nitrogen standards, which span the claimed linear range of 0 to 150 mgN/dL, are equivalent between the HiChem and BMD BUN Reagents. Regression statistics are shown below.

(HiChem Results) = 0.0 mgN/dL + 1.005 x (BMD Results), r2 = 1.000, Sy.x = 0.6 mgN/dL.

Urea nitrogen recoveries of 190 mixed serum and plasma specimens diluted with 20 parts normal saline compared between the HiChem and BMD reagents using least squares regression, yield the following statistics.

Serum/Plasma Comparison

(HiChem Results) = 0.0 mgN/dL + 1.009 × (BMD Results) r2 = 0.999 . Sy.x = 0.6 mgN/dL. Urine Comparison (HiChem Results) = 0.1 mgN/dL + 1.027 × (BMD Results) r2 = 0.999. Sv.x = 0.7 mgN/dL.

The calibration stability claim of 48 hours is documented through the recovery of serum controls which span from 8 to 132 mgNdL urea nitrogen. In all cases, the observed shifts in recoveries over the calibration period are less than the greater of 2 mgN/dL or 2%.

The HiChem BUN/Urea Reagent, calibrated with the HiChem Chemistry Standard, is shown to be safe and effective and substantially equivalent to the Sigma BUN (Rate) Reagent, procedure no. 67-UV calibrated with Sigma Clucose/Urea Nitrogen Standard, product no. 16-300 and the BMD BUN Reagent, product no. 704092 calibrated with Precical Calibrator Serum and Diluent, product no. 620213.

Wynn Stocking
Manager, Regulatory Affairs.

Regulation Number and Section

§ 862.1770 Urea nitrogen test system.

(a)
Identification. A urea nitrogen test system is a device intended to measure urea nitrogen (an end-product of nitrogen metabolism) in whole blood, serum, plasma, and urine. Measurements obtained by this device are used in the diagnosis and treatment of certain renal and metabolic diseases.(b)
Classification. Class II.