The ARK Voriconazole II Assay is a homogeneous enzyme immunoassay intended for the quantitative determination of voriconazole in human serum on automated clinical chemistry analyzers. The measurements obtained are used in monitoring levels of voriconazole to help ensure appropriate therapy. The assay should only be used in conjunction with information available from clinical evaluations and other diagnostic procedures.

ARK Voriconazole II Calibrator is intended for use in calibration of the ARK Voriconazole II Assay.

ARK Voriconazole II Control is an assayed quality control material intended for use in quality control of the ARK Voriconazole II Assay.

Device Description

The ARK Voriconazole II Assay Test System consists of the ARK Voriconazole II Assay, the ARK Voriconazole II Calibrator, and the ARK Voriconazole II Control.

The ARK Voriconazole II Assay consists of:

Reagent R1: rabbit polyclonal antibodies to voriconazole, glucose-6-phosphate, nicotinamide adenine dinucleotide, bovine serum albumin, sodium azide, and stabilizers.
Reagent R2: voriconazole labeled with bacterial G6PDH buffer, bovine serum albumin, sodium azide, and stabilizers.

The ARK Voriconazole II Calibrator has six levels and consists of voriconazole, buffer, bovine serum albumin, and sodium azide.

The ARK Voriconazole II Control has three levels and consists of voriconazole, buffer, bovine serum albumin, and sodium azide.

AI/ML Overview

Here's a breakdown of the acceptance criteria and the study details for the ARK Voriconazole II Assay Test System, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are generally implied by the special controls and the types of studies performed, aiming for performance characteristics that make the device fit for its intended use. Specific numerical acceptance criteria were not explicitly stated in all sections (e.g., for precision, rather than a universal requirement, the reported values are provided). However, for interference studies, a clear threshold was defined.

Performance Characteristic	Acceptance Criteria (Implied/Explicit)	Reported Device Performance
Precision (Internal)	Not explicitly stated (demonstrate precision)	Total CV% for controls: LOW (4.9), MID (4.3), HIGH (4.5). Total CV% for human serum: LOW (4.6), MID (4.3), HIGH (4.2). Second internal study Total CV%: LOW (5.9), MID (5.1), HIGH (6.3).
Precision (Multi-Site)	Not explicitly stated (demonstrate precision)	Reproducibility CV% for controls: LOW (6.0), MID (5.5), HIGH (6.5). Reproducibility CV% for human serum: LOW (5.4), MID (5.2), HIGH (5.5).
Linearity/Reportable Range	Claimed measuring range (0.5 to 14.0 ug/mL) supported by regression.	Y = 1.0209 X - 0.0416, R²: 0.9995. Supports range 0.5 to 14.0 ug/mL.
Analytical Recovery	Not explicitly stated (assess recovery).	Ranged from 90.0% to 104.9%.
Traceability	Calibrators traceable to certified standard.	Calibrators traceable to USP Reference Standard.
Detection Limit	LoB, LoD, LoQ determined per CLSI EP17-A2. LoQ bias ≤15% and within-lab precision ≤10%.	LoB = 0.003 ug/mL. LoD = 0.05 ug/mL. LoQ = 0.5 ng/mL (0.0005 ug/mL). Note: The text states 0.5 ng/mL but the linear range is 0.5 ug/mL, implying a discrepancy or typo in the LoQ value in the document. Assuming it meant 0.5 ug/mL for consistency with the linear range.
Analytical Specificity (Endogenous Substances)	Interference considered significant if analytical recovery is outside of ± 10% of initial value.	All reported percentage recoveries for endogenous substances at 1.0 µg/mL and 5.0 µg/mL voriconazole were within 90-110%.
Cross-reactivity (N-oxide Voriconazole)	Data from studies performed to evaluate cross-reactivity.	Non-significant (≤ 3.0%) cross-reactivity observed.
Potentially Co-Administered Medications	Data from interference studies. Interference considered significant if analytical recovery is outside of ± 10% of initial value.	No significant interference observed. All reported percentage recoveries were within the 90-110% range.
Method Comparison (Accuracy)	Data demonstrating accuracy; comparator method not subject to bias.	Passing Bablok regression slope 0.98-0.99 (95% CI covering 1), intercept 0.05-0.08 (95% CI covering 0), R² 0.95-0.97.

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

Precision (Internal Study 1): 160 replicates for each of 3 control levels and 3 human serum pools. Likely internal ARK data.
Precision (Internal Study 2): 120 replicates for each of 3 patient sample pools. Likely internal ARK data.
Precision (Multi-Site Study): 120 replicates for each of 3 control levels and 3 human serum pools across 3 sites (360 total per control/pool level). Data from ARK and two external sites.
Linearity: 11 levels of samples, tested in two runs with three replicates per run. Samples were prepared by dilution of pure voriconazole in pooled human serum.
Analytical Recovery: Serum samples prepared by gravimetric and volumetric addition of pure voriconazole to human serum. Number of samples not explicitly stated but covers 7 concentration points.
Detection Limit Studies:
- LoB: 20 blank patient specimens tested.
- LoD/LoQ: A low concentration pooled serum sample.
Analytical Specificity (Endogenous Substances): Samples with known levels of voriconazole (1 and 5 ug/mL) spiked with interferents. Each sample tested in two runs with three replicates per run.
Cross-reactivity: N-oxide-voriconazole at 5.0 ug/mL and 10.0 µg/mL levels, tested in absence or presence of voriconazole.
Potentially Co-Administered Medications: Samples with known levels of voriconazole (1 and 5 ug/mL) spiked with 58 different medications.
Method Comparison Study: 165 serum specimens. Samples represented a diverse population of in-hospital patients. Tested at 3 study sites. Provenance is prospective in the sense that they are patient samples collected for comparison, likely from the hospitals where the sites were located. Origin (country) not specified.

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

Not Applicable. This device is an in-vitro diagnostic test for measuring an analyte (voriconazole concentration) in human serum. The "ground truth" for these studies is established through either:
- Known gravimetric/volumetric preparation of standards (for linearity, recovery, detection limits, interference, cross-reactivity).
- Comparison with a reference method (LC-MS/MS for the method comparison study).
  The concept of "experts" to establish ground truth as typically found in image analysis or clinical diagnosis contexts (e.g., radiologists, pathologists) does not apply here.

4. Adjudication Method for the Test Set

Not Applicable. As explained above, ground truth is established through analytical means or comparison to a reference method, not through human expert adjudication.

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 an in-vitro diagnostic device for quantitative measurement, not an AI-assisted diagnostic imaging or interpretation device that involves human "readers."

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

Yes, this is a standalone device validation. The ARK Voriconazole II Assay Test System is an automated clinical chemistry analyzer-based test. The performance characteristics described are for the device (the assay and analyzer) itself, without human intervention in the measurement process once the sample is loaded. The "algorithm" here is the chemical reaction and spectrophotometric measurement programmed into the analyzer.

7. The Type of Ground Truth Used

Known concentrations: For precision, linearity, analytical recovery, detection limits, endogenous substance interference, cross-reactivity, and co-administered medication interference studies, the "ground truth" was either:
- Gravimetrically/volumetrically prepared samples with known concentrations of voriconazole or interferents.
- Pooled human serum samples with established mean concentrations.
Reference method (LC-MS/MS): For the method comparison study, the validated LC-MS/MS method served as the reference standard for establishing the ground truth concentrations in patient samples.

8. The Sample Size for the Training Set

Not Applicable. This is an in-vitro diagnostic assay based on a homogeneous enzyme immunoassay principle, not a machine learning or AI algorithm that requires a "training set" in the conventional sense. The "training" of the device involves calibration using the provided ARK Voriconazole II Calibrators.

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

Not Applicable. As above, it's not an AI/ML training set. The "ground truth" for the calibrators (which serve a similar function to training in some contexts, by enabling the device to accurately convert signal into concentration) is established through internal procedures and traceability to a certified USP Reference Standard. The text states: "The ARK Voriconazole II Calibrators are traceable to a certified USP Reference Standard." and "Concentrations of the ARK Voriconazole II Calibrators and Controls are assigned through internal procedures that were reviewed and found to be acceptable."

Summary

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EVALUATION OF AUTOMATIC CLASS III DESIGNATION FOR ARK Voriconazole II Assay Test System

DECISION SUMMARY

A. DEN Number:

DEN160033

B. Purpose for Submission:

De Novo request for evaluation of automatic class III designation of the ARK Voriconazole II Assay Test System

C. Measurand:

Voriconazole

D. Type of Test:

Homogenous Enzyme Immunoassay

E. Applicant:

ARK Diagnostics, Inc.

F. Proprietary and Established Names:

ARK Voriconazole II Assay Test System includes the following: ARK Voriconazole II Assay ARK Voriconazole II Calibrator ARK Voriconazole II Control

G. Regulatory Information:

1. Regulation:
  21 CFR 862.3970
1. Classification:
  Class II (Special Controls)

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3. Product code:

PUJ

4. Panel:

91 - Toxicology

H. Indications for use:

1. Indication(s) for use:
  ARK Voriconazole II Assay Test System includes separately provided test kits for the ARK Voriconazole II Assay, ARK Voriconazole II Calibrator, and ARK Voriconazole II Control.

ARK Voriconazole II Calibrator is intended for use in calibration of the ARK Voriconazole II Assay.

ARK Voriconazole II Control is an assayed quality control material intended for use in quality control of the ARK Voriconazole II Assay.

1. Special conditions for use statement(s):
  For prescription use only.

The assay should only be used in conjunction with information available from clinical evaluations and other diagnostic procedures.

3. Special instrument requirements:

The assay was validated on the Roche cobas c 501 analyzer

I. Device Description:

The ARK Voriconazole II Assay Test System consists of the ARK Voriconazole II Assay, the ARK Voriconazole II Calibrator, and the ARK Voriconazole II Control.

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The ARK Voriconazole II Assay consists of:

. Reagent R1: rabbit polyclonal antibodies to voriconazole, glucose-6-phosphate, nicotinamide adenine dinucleotide, bovine serum albumin, sodium azide, and stabilizers.
. Reagent R2: voriconazole labeled with bacterial G6PDH buffer, bovine serum albumin, sodium azide, and stabilizers.

The ARK Voriconazole II Calibrator has six levels and consists of voriconazole, buffer, bovine serum albumin, and sodium azide.

The ARK Voriconazole II Control has three levels and consists of voriconazole, buffer, bovine serum albumin, and sodium azide.

J. Standards/Guidance Documents Referenced:

CLSI document EP5-A3, Evaluation of Precision of Quantitative Measurement . Procedures
CLSI Guideline EP6-A: Evaluation of the Linearity of Quantitative Measurement ● Procedures: A Statistical Approach
CLSI Protocol EP7-A2: Interference Testing in Clinical Chemistry
CLSI Guideline EP9-A3: Measurement Procedure Comparison and Bias Estimation . Using Patient Samples
CLSI Protocol EP17-A2: Evaluation of Detection Capability for Clinical Laboratory . Measurement Procedures

K. Test Principle:

ARK Voriconazole II Assay is a homogeneous enzyme immunoassay based on competition between drug in the specimen and voriconazole-conjugated glucose-6-phosphate dehydrogenase (voriconazole-G6PDH) for binding to the antibody reagent. As voriconazole-G6PDH binds antibody, voriconazole-G6PDH enzyme activity decreases. In the presence of drug from the specimen, enzyme activity increases and is directly proportional to the drug concentration. Active voriconazole-G6PDH enzyme converts the coenzyme nicotinamide adenine dinucleotide (NAD) to NADH that is measured spectrophotometrically as a rate of change in absorbance. Endogenous plasma G6PDH does not interfere with the results because the coenzyme NAD functions only with the bacterial enzyme used in the assay.

L. Performance Characteristics:

The following performance characteristics were obtained on the Roche cobas c 501 analyzer.

1. Analytical performance:

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a. Reproducibility/Precision

Internal Precision Study:

An internal 20-day precision study was performed by testing tri-level controls and three samples from pooled human serum. Each level was tested over 20 days, with 2 runs per day and 4 replicates per run. The following results were obtained:

Sample	N	Mean(µg/mL)	Within Run		Between Run		Between Day		Total
			SD	CV (%)	SD	CV (%)	SD	CV (%)	SD	CV (%)
ARK Voriconazole II Control
LOW	160	1.03	0.047	4.6	0.030	2.9	0.022	2.1	0.051	4.9
MID	160	4.91	0.194	3.9	0.124	2.5	0.101	2.1	0.209	4.3
HIGH	160	9.39	0.394	4.2	0.242	2.6	0.207	2.2	0.426	4.5
Human Serum
LOW	160	1.02	0.043	4.2	0.029	2.8	0.024	2.4	0.047	4.6
MID	160	5.03	0.182	3.6	0.149	3.0	0.111	2.2	0.217	4.3
HIGH	160	9.80	0.334	3.4	0.286	2.9	0.221	2.3	0.407	4.2

Another internal precision study was performed by testing three voriconazole patient sample pools using three lots of the ARK Voriconazole II Assay reagents. Each level was tested over 5 days, with 2 runs per day and 4 replicates per run. The following results were obtained:

Sample	N	Mean(µg/mL)	Within Run		BetweenRun		BetweenDay		Between Lot		Total
			SD	CV(%)	SD	CV(%)	SD	CV(%)	SD	CV(%)	SD	CV(%)
LOW	120	1.00	0.042	4.2	0.023	2.3	0.021	2.1	0.034	3.4	0.059	5.9
MID	120	4.83	0.234	4.8	0.069	1.4	0.048	1.0	0.102	2.1	0.248	5.1
HIGH	120	10.59	0.621	5.9	0.293	2.8	0.266	2.5	0.096	0.9	0.667	6.3

Multi-Site Precision Study

Precision was also evaluated at three sites (ARK and two external sites) over 5 nonconsecutive days. ARK tri-level voriconazole controls and three samples from pooled human serum were tested over 5 days, with 2 runs per day and 4 replicates per run. The overall (across sites) precision study results are shown below:

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Sample	N	Mean(µg/mL)	Repeatability		Between-Run		Between-Day		Reproducibility
			SD	CV (%)	SD	CV (%)	SD	CV (%)	SD	CV (%)
ARK Voriconazole II Control
LOW	120	1.08	0.054	5.0	0.044	4.1	0.036	3.4	0.064	6.0
MID	120	5.04	0.247	4.9	0.171	3.4	0.144	2.9	0.275	5.5
HIGH	120	9.93	0.466	4.7	0.480	4.8	0.320	3.2	0.645	6.5
Human Serum
LOW	120	1.06	0.047	4.4	0.040	3.8	0.032	3.0	0.057	5.4
MID	120	5.12	0.251	4.9	0.148	2.9	0.120	2.3	0.265	5.2
HIGH	120	10.13	0.510	5.0	0.338	3.3	0.292	2.9	0.561	5.5

b. Linearity/assay reportable range:

Linearity

Pure voriconazole (USP, 99.7% purity) was added to pooled human serum to obtain a concentration of 20.0 ug/mL. Dilutions of this 20.0 ug/mL high concentration sample were made proportionally using human serum negative for voriconazole. Eleven levels of samples were tested in two runs with three replicates per run. Regression analysis was performed between the measured mean voriconazole and calculated values for each dilution. The linear regression results are shown below.

Y = 1.0209 X - 0.0416 R2: 0.9995

These results support the claimed measuring range of 0.5 to 14.0 ug/mL.

Analytical Recovery

Analytical recovery throughout the measurement range was assessed. Serum samples were prepared by gravimetric addition of pure voriconazole (USP, 99.7% purity) to methanol and volumetric addition of this stock solution to human serum negative for voriconazole. The percentage recovery ranged from 90.0% to 104.9%, as shown below:

Calculated Concentration	Measured Concentration	Percent Recovery
(ug/mL)	(ug/mL)
0.50	0.45	90.0
1.20	1.19	99.2
3.00	3.05	101.7
6.00	ર : 86	97.7
9.00	8.74	97.1
12.00	11.44	તે જેવી તેમ જ દૂધની ડેવી જેવી સવલતો પ્રાપ્ય થયેલી છે. આ ગામનાં લોકોનો મુખ્ય વ્યવસાય ખેતી, ખેતમજૂરી તેમ જ પશુપાલન છે. આ ગામમાં પ્રાથમિક શાળા, પંચાયતઘર, આંગણવાડી તેમ જ દૂધની ડ
15.00	15.75	104.9

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c. Traceability, Stability, Expected values (controls, calibrators, or methods):

Traceability

The ARK Voriconazole II Calibrators are traceable to a certified USP Reference Standard.

Value Assignment

Concentrations of the ARK Voriconazole II Calibrators and Controls are assiened through internal procedures that were reviewed and found to be acceptable.

Stability:

Accelerated stability studies were performed to support a shelf-life stability claim of up to 12 months for the ARK Voriconazole II Reagents, Calibrators and Controls when stored unopened at 2-8°C. Real time stability studies to support shelf-life stability claims are ongoing. Real-time testing for on-board stability of ARK Voriconazole II Reagents was performed and supports an in-use stability claim of 60 days for reagents. Specimen stability was also evaluated and was shown to be stable for up to a week at 2-8°C and up to four weeks at -20 °C.

d. Detection limit
The Limit of Blank, Limit of Detection and Limit of Quantitation were determined in accordance with CLSI EP17-A2.

The Limit of Blank (LoB) was evaluated by testing 20 blank patient specimens over 3 days using 3 lots of ARK Voriconazole II reagents, and was determined to be 0.003 ug/mL.

The Limit of Detection (LoD) was calculated based on the LoB and the standard deviation of a low concentration pooled serum sample tested over 3 days using 3 lots of ARK Voriconazole II reagents, and was determined to be 0.05 ug/mL.

The Limit of Quantitation (LoQ) was defined as the lowest Voriconazole concentration that shows bias ≤15% and within-laboratory precision of ≤ 10%, and was determined to be 0.5 ng/mL.

e. Analytical specificity:

Interference studies were conducted using CLSI Protocol EP7-A2 as a guideline. Clinically high concentrations of potentially interfering substances were spiked into serum samples with known levels of voriconazole (approximately 1 and 5 ug/mL). Each sample was then tested in two runs with three replicates per run using the ARK Voriconazole II Assay, along with a serum control of voriconazole. The percentage recovery relative to the measurement of voriconazole in the serum control was calculated. The sponsor states that interference is considered to be significant if the

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analytical recovery is outside of ± 10% of the initial value.

Endogenous Substances

Interference studies were conducted for endogenous substances with serum samples at 1.0 and 5.0 µg/mL of voriconazole. The concentration tested for each endogenous substance and percent recovery results are shown below.

Interfering Substance	Interferentconcentrationtested	Percentage Recovery1.0 µg/mLVoriconazole	Percentage Recovery5.0 µg/mLVoriconazole
Human Albumin	12 g/dL	103.8	98.7
Bilirubin (Conjugated)	70 mg/dL	99.0	99.6
Bilirubin (Unconjugated)	70 mg/dL	102.9	95.7
Cholesterol	617 mg/dL	95.8	98.3
Hemoglobin	1000 mg/dL	102.9	93.5
Rheumatoid Factor	1000 IU/mL	103.8	100.2
Human IgG	12 g/dL	105.8	97.8
Triglycerides	1000 mg/dL	107.5	99.2
Uric Acid	30 mg/dL	105.8	96.2

Cross-reactivity of N-oxide Voriconazole

A cross-reactivity study was conducted for the major metabolite of voriconazole, Noxide-voriconazole at 5.0 ug/mL and 10.0 µg/mL levels. The results demonstrated non-significant (≤ 3.0%) cross reactivity from N-oxide-voriconazole when tested in the absence or presence of voriconazole in human serum.

N-oxide-Voriconazole(µg/mL)	Measured Voriconazole in Absence/Presence ofMetabolite (µg/mL)
	VoriconazoleAbsent(0.0 µg/mL)	VoriconazolePresent(1.0 µg/mL)	VoriconazolePresent(5.0 µg/mL)
0.0	0.00	1.06	4.99
5.0	0.04	1.17	4.96
10.0	0.10	1.23	5.29

Potentially Co-Administered Medications

Interference studies were conducted for structurally related compounds, medications routinely co-administered with voriconazole, and other potentially co-administered drugs, at serum concentrations of 1.0 and 5.0 µg/mL of voriconazole. The concentration tested for each potentially interfering compound and percent recovery results are shown below. No significant interference was observed.

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#	Compound	Concentration tested (µg/mL)	Percentage Recovery
			1.0 µg/mL Voriconazole	5.0 µg/mL Voriconazole
1	Abacavir	30	100	96.6
2	Acetaminophen	200	100	90.9
3	Alprazolam	5	100	97.4
4	Amikacin	100	99	100.4
5	Amphotericin	100	92.5	96.7
6	Amprenavir	30	99	96.4
7	Atazanavir	30	102.1	95.4
8	Atovaquone	100	94.8	93
9	Bendamustine	30	98	96.4
10	Bosutinib	100	104.1	94.6
11	Cefepime	500	96.9	92.8
12	Ceftazidime	500	99	93.8
13	Ciprofloxacin	100	96.1	96
14	Citalopram	10	100	95.4
15	Clonazepam	10	99	99.2
16	Codeine	10	99	102
17	Colistimethate Na	100	99	98.4
18	Cyclosporine A	40	99	99.2
19	Darunavir	30	100	94.3
20	Dasatinib	100	99	100.8
21	Efavirenz	30	95.1	93.9
22	Emtricitabine	30	99	92.6
23	Erythromycin	200	99	91.5
24	Fluconazole	30	101.8	97.2
25	Fosamprenavir	30	97	100.4
26	Gabapentin	100	98.2	95.3
27	Gentamicin	100	98.1	100
28	Itraconazole	20	97.2	93.4
29	Lamivudine	30	96.3	99.2
30	Lopinavir	30	94.4	99.2
31	Lorazapam	10	98.1	101
32	Maraviroc	10	99.1	100.8
33	Meropenem	500	92.5	96.4
34	Methotrexate	100	95.3	94.4
35	Metronidazole	200	93.4	95.8
36	Micafungin	300	98.1	101.2
37	Morphine	10	96.3	91.7
38	Mycophenolic acid	40	97	91.1
39	Nelfinavir	30	93.4	94.7
40	Nevirapine	30	94.4	94.3
#	Compound	Concentrationtested (µg/mL)	Percentage Recovery
			1.0 µg/mLVoriconazole	5.0 µg/mLVoriconazole
41	Olanzapine	10	98	91.1
42	Penicillin V	100	98.1	102.4
43	Piperacillin	500	93.1	92.2
44	Posaconazole	20	99.1	93
45	Prednisolone	200	102.9	91.3
46	Ritonavir	30	100	99.2
47	Sirolimus	10	104.7	101.6
48	Stavudine	30	96.3	101.5
49	Tazobactam	100	99	90.2
50	Tacrolimus	10	98	94.6
51	Tenofovir	30	98	96.7
52	Tipranavir	30	96.3	102.4
53	Tobramycin	100	100	96.3
54	Trimethoprim	50	93.9	91.8
55	Sulfamethoxazole	400	97	91.8
56	Vancomycin	250	98.2	101.2
57	Vincristine	100	93.1	92
58	Zolpidem	30	102.8	91.2

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2. Comparison studies:

a. Method comparison study:

Method comparison studies were performed following CLSI Protocol EP9-A3 at 3 study sites. Results from 165 serum specimens tested with the ARK Voriconazole II Assay on Roche cobas c 501 analyzers at 3 sites were compared to those from a validated LC-MS/MS method. The samples represented a diverse population of inhospital patients with voriconazole concentrations ranging from 0.5 to 13.9 µg/mL by the LC-MS/MS method. The Passing Bablok regression analysis results are presented below.

Site	N	Slope(95% CI)	Intercept(95% CI)	R2(95% CI)	Sample RangeTested(concentrationon LC-MS/MS)
1	165	0.99(0.96 to 1.03)	0.08(0.04 to 0.16)	0.96(0.94 to 0.96)	0.5 to 13.9 µg/mL
2		0.99(0.96 to 1.02)	0.05(-0.03 to 0.15)	0.95(0.93 to 0.96)
3		0.98(0.95 to 1.01)	0.06(-0.01 to 0.11)	0.97(0.95 to 0.97)

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b. Matrix comparison:
Not applicable
1. Clinical studies:
  Not applicable
1. Expected Values
  Not applicable.

M. Labeling

The labeling is sufficient and satisfies the requirements of 21 CFR Parts 801 and 809, and the special controls for this type of device.

N. Identified Risks to Health and Identified Mitigations

Identified Risks to Health	Identified Mitigations
Clinical action (e.g., dose adjustments) based onfalsely elevated inaccurate voriconazole results maylead to decreased clinical efficacy of the drug andconsequently poorer clinical outcomes.	General controls and special controls (1),and (2)
Clinical action (e.g. dose adjustments) based onfalsely low inaccurate voriconazole results may leadto an increased risk of toxicity.	General controls and special controls (1),and (2)

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O. Benefit/Risk Analysis

	Summary
Summaryof theBenefit(s)	Voriconazole is characterized by a narrow therapeutic spectrum, non-linearpharmacokinetics, and frequent inter-individual and intra-individual variabilityin voriconazole serum concentrations. It is metabolized in the liver by severalcytochrome P450 isoenzymes; however, voriconazole is primarily metabolizedby CYP2C19. The CYP2C19 gene is known to have several different geneticpolymorphisms which are known to differentially affect voriconazolemetabolism. For these above-mentioned reasons, voriconazole therapeutic drugmonitoring (TDM) can assist clinicians in determining adequate dose exposurelevels when evaluating patients' overall clinical response. Clinical decisionmaking should not be based solely on review of voriconazole TDM whenassessing patients' risk of drug toxicity or therapeutic benefit. VoriconazoleTDM should be used only as an adjunct to clinical care and not as a sole meansof determining clinical response.
Summaryof theRisk(s)	Although, there is generally no accepted voriconazole TDM target range, severalstudies propose voriconazole TDM cut-off ranges anywhere from 1-5.5 µg/mLor 2-6 µg/mL, where a trough of 2 µg/mL is generally acceptable amongpatients with more severe illness. Studies have linked voriconazole levels of<1.0 µg/mL with therapeutic failure (Chen J, et al., Therapeutic drug monitoringof voriconazole in children, Ther Drug Monit 2012; 34:77-84).Therefore, the risk of a falsely elevated voriconazole value is decreased clinicalefficacy of the drug and consequently poorer clinical outcomes, as the physicianmay erroneously believe that voriconazole is within an effective range based on the inaccurate voriconazole TDM value. This is of particular concern for individuals with life-threatening fungal infections, among whom the proportion of patients with potentially sub-therapeutic levels may be high (Trifilio S, et al.,Monitoring plasma voriconazole levels may be necessary to avoid subtherapeutic levels in hematopoietic stem cell transplant recipients, Cancer2007; 109:1532-1535). A falsely elevated TDM value could result in a physician prematurely discontinuing voriconazole therapy out of concern that at elevated levels the patient may be subject to increased toxicity (Potoski B,Brown J, The safety of voriconazole, Clin Infect Dis 2002; 35: 1273-1275;Lutsar I, et al., Voriconazole treatment for less-common, emerging, or refractory fungal infections, Clin Infect Dis 2003; 36: 1122-1131).The risk of a falsely low voriconazole value is increased risk of toxicity if voriconazole is continued at the same dose, or a potential increase in the dose based on a falsely low level. The population of patients taking voriconazole generally has significant co-morbidities (e.g., hematopoietic stem cell transplant patients at increased risk for graft-versus-host disease (GVHD) or patients may be receiving concomitant medications which are also metabolized through the same metabolic pathways as voriconazole). Therefore, physicians may opt to routinely follow clinically relevant biochemical parameters, such as liver enzyme studies, to ensure that there is no worsening of these parameters.Therapeutic dose levels should be monitored alongside patients' overall clinical progress, as false readings in any direction may adversely affect patients'clinical outcomes. Voriconazole levels should be used as an adjunct to clinical judgment and clinical monitoring and not as a sole means of assessing the adequacy of voriconazole dosing, or voriconazole toxicity, or as a surrogate for patient outcomes.
Summaryof OtherFactors	As specified in the label, a voriconazole level may be used as an adjunct to clinical judgment and clinical monitoring and should not be used as a sole means of assessing the adequacy of voriconazole dosing, or toxicity. Additionally, analytical risks are mitigated by in vitro diagnostic (IVD) labelling compliant with 21 CFR 809.10.

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Conclusions

Do the probable benefits outweigh the probable risks?

Yes, the probable benefits outweigh the probable risks of this device in light of the special controls assigned, along with general controls, including design controls.

Patient Perspectives:

This submission did not include specific information on patient perspectives for this device.

P. Conclusion:

Product Code:	PUJ
Device Type:	Voriconazole test system
Class:	II (special controls)
Regulation:	21 CFR 862.3970

a) Identification. A voriconazole test system is a device intended to measure voriconazole in human serum. Measurements obtained by this device are used in monitoring levels of voriconazole to ensure appropriate therapy.
b) Classification. Class II (special controls). A voriconazole test system must comply with the following special controls:
- 1. Premarket notification submissions must include the following information:
  - A. Data demonstrating the precision of the voriconazole test system. Precision studies must include a minimum of three samples containing different concentrations of voriconazole, including near medical decision points at the high and low end of the expected therapeutic range. Samples with concentrations near medical decision points must be clinical specimens collected from patients taking voriconazole.
  - B. Method comparison data demonstrating accuracy of the voriconazole test system. Method comparison data must be collected at three laboratory sites. The comparator method must not be subject to bias due to non-specific detection of voriconazole.
  - C. Data from interference studies performed to evaluate potential interference from co-administered medications used for conditions in which voriconazole is indicated.
  - D. Data from studies performed to evaluate cross reactivity of the major metabolite, N-oxide voriconazole.
- 1. Your 809.10(b)(5)(ii) compliant labeling must include a warning statement as follows: "This assay should only be used in conjunction with information available from clinical evaluations and other diagnostic procedures."

Regulation Number and Section

§ 862.3970 Voriconazole test system.

(a)
Identification. A voriconazole test system is a device intended to measure voriconazole in human serum. Measurements obtained by this device are used in monitoring levels of voriconazole to ensure appropriate therapy.(b)
Classification. Class II (special controls). The special controls for this device are:(1) Design verification and validation must include the following information:
(i) Data demonstrating the precision of the voriconazole test system. Precision studies must include a minimum of three samples containing different concentrations of voriconazole, including near medical decision points at the high and low end of the expected therapeutic range. Samples with concentrations near medical decision points must be individual or pooled clinical specimens, collected from patients taking voriconazole.
(ii) Method comparison data demonstrating accuracy of the voriconazole test system. Method comparison data must be collected at three laboratory sites. The comparator method must not be subject to bias due to nonspecific detection of voriconazole.
(iii) Data from interference studies performed to evaluate potential interference from co-administered medications used for conditions in which voriconazole is indicated.
(iv) Data from studies performed to evaluate cross reactivity of the major metabolite, N-oxide voriconazole.
(2) The labeling required under § 809.10(b) of this chapter must include a warning statement as follows: “This assay should only be used in conjunction with information available from clinical evaluations and other diagnostic procedures.”