The Cyclosporine CSAE Flex® reagent cartridge is an in vitro diagnostic test intended to quantitatively measure cyclosporine A (CSA) in human whole blood for the Dimension® clinical chemistry system. Measurements of CSA are used as an aid in the management of heart, liver and kidney transplant patients.

Device Description

The Dimension® CSAE Cyclosporine Flex® reagent cartridge (DF108) is an in vitro rine Differences that consists of prepackaged reagents in a plastic eight well cartridge for use on the Dade Behring Dimension® clinical chemistry system for the quantitative determination cyclosporine A (CSA) in human whole blood.

AI/ML Overview

Here's an analysis of the provided text regarding the Dimension® Cyclosporine CSAE Flex® reagent cartridge, focusing on acceptance criteria and supporting studies:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state pre-defined acceptance criteria for most performance characteristics. Instead, it reports the performance values observed during the studies. For linearity and functional sensitivity, implicit criteria can be inferred.

Performance Characteristic	Acceptance Criteria (Implicit/Inferred)	Reported Device Performance
Reproducibility	Not explicitly stated	Whole Blood Pool 1:Repeatability SD: 12.21 (3.32%CV)Within-lab SD: 19.00 (5.16%CV)Whole Blood Pool 2:Repeatability SD: 30.65 (2.73%CV)Within-lab SD: 57.24 (5.10%CV)Whole Blood Pool 3:Repeatability SD: 46.72 (2.64%CV)Within-lab SD: 104.07 (5.29%CV)More Control 1:Repeatability SD: 13.99 (2.86%CV)Within-lab SD: 28.77 (5.89%CV)More Control 2:Repeatability SD: 18.61 (2.15%CV)Within-lab SD: 47.71 (5.51%CV)More Control 3:Repeatability SD: 34.41 (2.64%CV)Within-lab SD: 68.89 (5.29%CV)
Method Comparison	Not explicitly stated (Implicit: good correlation with predicate and LC/MS)	vs. Abbott TDx® (All):Slope: 1.13Intercept: -67.2Correlation Coefficient: 0.980vs. LCMS (All):Slope: 1.09Intercept: 17.1Correlation Coefficient: 0.986
Linearity	Deviation from estimated line < 15 ng/mL at 794.5 ng/mL. Lower limit ≥ 350.0 ng/mL.	Deviation from estimated line < 15 ng/mL at 794.5 ng/mL. Lower limit of linearity claim: 350.0 ng/mL.
Interference Testing	Inaccuracies (biases) < 10% (at 800 ng/mL CSA)	Substances listed in package insert do not interfere (i.e., cause < 10% bias).
Analytical Specificity	Not explicitly stated (Implicit: low cross-reactivity for metabolites)	AM1: 4.7%AM1c: 2.1%AM1c9: 3.9%AM4N: 3.1%AM9: 2.4%AM19: 3.0%
Recovery	Not explicitly stated (Implicit: close to 100%)	Range: 94.3% to 103.1%Mean: 101.0%
Functional Sensitivity	Intra-assay CV ≤ 20%	< 110 ng/mL (defined as the lowest concentration where intra-assay CV is not greater than 20%)

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

Test Set Sample Size:
- Reproducibility: Not explicitly stated as a number of unique patient samples, but specimens at each level (3 whole blood pools, 3 controls) were analyzed in duplicate, once a day, for 20 days. This indicates 6 levels * 2 duplicates * 20 days = 240 measurements in total for reproducibility. It's likely these were distinct samples or control aliquots rather than 240 individual patient samples.
- Method Comparison: 140 specimens (human whole blood). These were further categorized by transplant type: Heart (35), Liver (40), Kidney (60).
- Linearity: 8 equally spaced sample pools (likely prepared from high and low pools).
- Interference Testing: Not explicitly stated, but implies testing with various interfering substances.
- Analytical Specificity: Six major metabolites were evaluated.
- Recovery: 3 human whole blood samples with known CSA concentrations.
- Functional Sensitivity: Not explicitly stated as a sample size, but refers to the "lowest concentration" (110 ng/mL) at which a CV criterion is met.
Data Provenance: The document does not explicitly state the country of origin of the samples or if they were retrospective or prospective. However, based on the context of providing performance data for a 510(k) submission, it is assumed these were carefully controlled studies conducted by the manufacturer, likely in a laboratory setting, and would represent prospective data collection for the purpose of validating the device. The samples are referred to as "human whole blood."

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

This type of information is generally not applicable to an in vitro diagnostic (IVD) device like the Dimension® Cyclosporine CSAE Flex® reagent cartridge.

For IVDs that measure an analyte quantitatively, the "ground truth" is typically established by a reference method or a highly accurate comparative method. In this case, the LC/MS (Liquid Chromatography/Mass Spectrometry) technology serves as the comparative "gold standard" or reference method for the method comparison study. LC/MS is a very precise analytical technique, not reliant on expert interpretation in the same way an imaging study would be.
No human experts were needed or used to establish the ground truth for the analyte concentration in the samples.

4. Adjudication Method for the Test Set

Not applicable. As explained above, for a quantitative IVD, ground truth is established by a reference analytical method (LC/MS), not by expert consensus or 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 device is a fully automated in vitro diagnostic assay for measuring cyclosporine levels in blood. It does not involve human "readers" interpreting results in the way an imaging AI device would.
It is not an AI-assisted device. The comparison is between the new automated immunoassay and a predicate immunoassay (Abbott TDx® /TDx FLx®) and a reference method (LC/MS).

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

Yes, this study is inherently a standalone performance study. The device is an automated clinical chemistry system that measures cyclosporine directly. Its performance characteristics (reproducibility, linearity, method comparison, etc.) are evaluated based on its direct output, without human intervention or interpretation that would alter its result. The data presented demonstrates the device's inherent performance.

7. The Type of Ground Truth Used (Expert Consensus, Pathology, Outcomes Data, etc.)

The primary ground truth used for method comparison was LC/MS (Liquid Chromatography/Mass Spectrometry) technology. This is considered a highly specific and accurate analytical reference method for quantifying cyclosporine in biological samples. The predicate device, the Abbott TDx® /TDx FLx® Cyclosporine Monoclonal Whole Blood Assay, also served as a comparative method.

8. The Sample Size for the Training Set

The document does not provide information about a "training set" in the context of machine learning or AI. This device is an immunoassay, and its development typically involves chemical and biological optimization (e.g., antibody selection, reagent concentrations) and calibration, not a machine learning training phase with a dedicated dataset distinct from the validation studies. The studies described are validation and verification studies.

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

As there is no "training set" in the machine learning sense for this type of immunoassay, this question is not applicable. The assay's performance is established through empirical testing and optimization of its chemical and biological components.

Summary

{0}------------------------------------------------

SEP - 1 2005

510(k) Summary for the Dimension® Cyclosporine CSAE Flex® reagent cartridge (DF108)

A. 510(k) Number: K052017

B. Analyte: Cyclosporine

C. Type of Test: qualitative or quantitative homogeneous enzyme immunoassay

D. Applicant: Dade Behring Inc., P.O. Box 6101, Newark, DE 19714-6101 (302) 631-9454 Contact: Andrea M. Tasker, Regulatory Affairs and Compliance Manager

E. Proprietary and Established Names: Dimension® Cyclosporine CSAE Flex® reagent cartridge

F. Regulatory Information:

1.Regulation section: 21CFR §862.1235

Classification: Class II (Special Controls)
Product Code: MK W
Panel: Clinical Toxicology Test Systems

G. Intended Use:

l. Intended for Use:

2. Indications for Use:

Special condition for use statement(s): none

{1}------------------------------------------------

Special instrument Requirements: Dimension® clinical chemistry system with Heterogeneous Module.

H. Device Description:

I. Substantial Equivalence Information:

1. Predicate Device: Abbott TDx® /TDx FLx® Cyclosporine Monoclonal Whole Blood Assay
  ので、その他の人気の人気の人気の人気の人気の一つです。一般の一人の一つの一つの一つの一つの一つの一つの一つの一つの一つの一つの一つの一つの一つの一つの一つの一つの一つの一つ
1. Predicate K Number(s): P890025
1. Comparison with Predicate:

Item	DeviceDimension® CSAECyclosporine	PredicateAbbott TDx® /TDx FLx®Cyclosporine Assay
Intended Use	For the measurements ofCSA to be used as an aid inthe management of heart,liver and kidney transplantpatients.	For the measurements of CSAto be used as an aid in themanagement of heart, liverand kidney transplantpatients.
Sample Type	Whole Blood	Whole Blood
Technology	Affinity Particle MediatedImmunoassay	Fluorescence PolarizationImmunoassay
Antibody	Mouse monoclonal	Mouse monoclonal
Assay Range	350 -2000ng/mLa	25 - 1500 ng/mL

a. The Dimension® CSAE Extended Range Cyclosporine Assay is intended as a high range assay to compliment the low range assay, the Dimension® CSA Cyclosporine Assay, which has an assay range of 25 - 500ng/mL.

{2}------------------------------------------------

J. Standard/Guidance Document Referenced

Guidance;

Class II Special Controls Guidance Document: Cyclosporine and Tacrolimus Assays; Guidance for Industry and FDA, Document issued on: September 16, 2002.

Standards;

GP22-A	Continuous Quality Improvement Essential Management Approaches
ISO 15223	Medical devices - Symbols to be used with medical device labelingand information to be supplied
EN 1441:1997	Medical Devices - Risk Management
ISO 14971-1	Medical devices: Risk management - Part1: Application ofrisk analysis
EP9-A2	Method Comparison and Bias Estimation Using Patient Samples
EP7-A	Interference Testing in Clinical Chemistry
EP5-A	Evaluation of Precision Performance of Clinical Chemistry Devices
CEN 13640	Stability testing of In-Vitro Diagnostic Devices

K. Test Principle:

The automated Dimension® CSAE method uses an immunoassay technique in which free and CSA-bound antibody-enzyme species are separated using magnetic particles. The assay is performed using a method specific Flex® reagent cartridge. The calibrators and controls for this assay are sold separately.

{3}------------------------------------------------

L . Performance Characteristics:

1. Reproducibility

Reproducibility testing was done in accordance with the CLSI/NCCLS Approved Guideline for Evaluation of Precision Performance of Clinical Chemistry Devices (EPS-A. Feb.1999). Specimens at each level were analyzed in duplicate, once a day, for 20 days. The within-run (repeatability) and total (within-lab) standard deviations were calculated by analysis of variance (ANOVA) method.

Material	MeanUnits [SI Units]	Standard Deviation (%CV)Repeatability	Within-lab
Whole Blood pool 1	368.0 [306.2]	12.21 [10.16] (3.32)	19.00 [15.81] (5.16)
Whole Blood pool 2	1123.3 [934.6]	30.65 [25.50] (2.73)	57.24 [47.62] (5.10)
Whole Blood pool3	1750.1 [1456.1]	46.72 [38.87] (2.64)	104.07 [86.59] (5.29)
More Control 1	488.7 [406.6]	13.99 [11.64] (2.86)	28.77 [23.94] (5.89)
More Control 2	866.1 [720.6]	18.61 [15.48] (2.15)	47.71 [39.69] (5.51)
More Control 3	1301.9 [1083.2]	34.41 [28.63] (2.64)	68.89 [57.32] (5.29)

More Diagnostics Cyclosporine Control is a product of More Diagnostics Inc., Los Osos, CA. 93402

2. Method Comparison

A total of 140 specimens were tested with the Dimension® CSAE assay, with the Abbott TDx /TDx FLx Cyclosporine Monoclonal Whole Blood Assay and by LC/MS technology. Linear regression was used to calculate a slope, intercept and correlation coefficient. The model equation for regression statistics is: Result of Dimension® system = (Slope x comparative method result) + Intercept.

ComparativeMethod	Slope	Interceptng/mL[umol/L]	CorrelationCoefficient	n
Abbott TDx®
All	1.13	-67.2	0.980	140
Heart	0.996	2.52	0.982	35
Liver	1.11	-61.7	0.970	40
Kidney	1.09	-32.3	0.973	60
LCMS
All	1.09	17.1	0.986	140
Heart	0.93	93.7	0.983	35
Liver	1.00	59.9	0.980	40
Kidney	1.10	15.2	0.990	60

TDx® is the registered trademark of Abbott Diagnostics, Abbott Park, IL 60064

{4}------------------------------------------------

3. Linearity

Standard solutions were prepared by sequential mixing to create a set of eight equally spaced sample pools starting with a high and low pool of known analyte concentration. Theoretical concentrations were computed for all intermediate pools based on the initial concentrations of the high and low pools. The analysis of cyclosporine on the Dimension® RxL by the Dimension® CSAE method shows a deviation from the estimated line of less than 15 ng/mL [12.5 nmol/L] with 95% confidence at the analytical concentration of 794.5 ng/mL [662.1 nmol/L]. The lower limit of the linearity claim is 350.0 ng/mL [291.7 nmol/L].

4. Interference Testing

Interference testing was performed according to the CLSI/NCCLS Protocol EP-7A. A summary of the substances that do not interfere with the Dimension® Cyclosporine methods when present in whole blood at the concentrations indicated. Inaccuracies (biases) due to these substances are less than 10% at a CSA level equivalent to 800 ng/mL [665.6 nmol/L] can be found in the package insert.

5. Analytical Specificity

Six major metabolites were evaluated for cross-reactivity in the presence of 500 ng/mL [416 nmol/L] cyclosporine. The percent cross-reactivity was calculated as follows:

	% cross reactivity = = measured CSA-control CSA (500 ng/mL) [41.6 nmol/L] x
	100
	metabolite added

Cyclosporine	Metabolite Level Tested	Cross-Reactivity
Metabolite	ng/mL [nmol/L]	%
AM1 (M17)	1000 [821]	4.7
AM1c (M18)	1000 [821]	2.1
AM1c9 (M26)	1000 [810]	3.9
AM4N (M21)	1000 [842]	3.1
AM9 (M1)	1000 [821]	2.4
AM19 (M8)	1000 [810]	3.0

6. Recovery

Known amounts of CSA were added to human whole blood samples with concentrations of 610.0, 1232.2, and 1861.8 ng/mL [507.5, 1025.2, 1861.8 nmol/L]. CSA concentrations on these samples were then measured and the calculated percent recovery ranged from 94.3% to 103.1% with a mean recovery of 101.0%.

Value obtained - Baseline Percent Recovery == ------------------------------------------------------------------------------------------------ x 100 Amount Added

{5}------------------------------------------------

Functional Sensitivity

The functional sensitivity of the CSAE method was demonstrated to be less than 110 ranetional benefits 110 visual sensitivity is defined as the lowest concentration at which the intra-assay coefficient of variation is not greater than 20%.

Final: August 30, 2005

{6}------------------------------------------------

DEPARTMENT OF HEALTH & HUMAN SERVICES

Image /page/6/Picture/1 description: The image shows the seal of the U.S. Department of Health & Human Services. The seal features a stylized eagle with its wings spread, symbolizing protection and service. The eagle is positioned within a circular border. The text "DEPARTMENT OF HEALTH & HUMAN SERVICES USA" is arranged around the upper portion of the circle.

Public Health Service

Image /page/6/Picture/3 description: The image shows the text "SEP - 1 2005". The text is written in a simple, sans-serif font. The letters and numbers are all capitalized. The text is likely a date, indicating September 1, 2005.

Food and Drug Administration 2098 Gaither Road Rockville MD 20850

Ms. Andrea Tasker Regulatory Affairs and Compliance Manager Dade Behring, Inc. Glascow Business Community Bldg. 500 Mail Box 514 P.O. Box 6101 Newark, DE 19714-6101

Re: K052017

Trade/Device Name: Dimension® Cyclosporine Extended Range Assay (CSAE) Flex® reagent cartridge Regulation Number: 21 CFR 862.1235 Regulation Name: Cyclosporine test system Regulatory Class: Class II Product Code: MKW Dated: August 23, 2005 Received: August 23, 2005

Dear Ms. Tasker:

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 Title 21, Code of Federal Regulations (CFR), Parts 800 to 895. 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);

{7}------------------------------------------------

Page 2 -

This letter will allow you to begin marketing your device as described in your Section 510(k) rms lotter will and my you to FDA finding of substantial equivalence of your device to a legally prerketed predicate device results in a classification for your device and thus, permits your device to proceed to the market.

If you desire specific information about the application of labeling requirements to your device, rr you destro specific internation and advertising of your device, please contact the Office of In Vitro Diagnostic Device Evaluation and Safety at (240) 276-0484. Also, please note the regulation entitled "Misbranding by reference to premarket notification" (21CFR Part 807.97). You may obtain other general information on your responsibilities under the Act from the Division of Small Manufacturers, International and Consumer Assistance at its toll-free number (800) 638-2041 or (301) 443-6597 or at its Internet address http://www.fda.gov/cdrh/industry/support/index.html.

Sincerely yours,

Carol C. Benam

Carol C. Benson, M.A. Acting Director Division of Chemistry and Toxicology Office of In Vitro Diagnostic Device Evaluation and Safety Center for Devices and Radiological Health

Enclosure

{8}------------------------------------------------

Indications For Use Statement

510(k) Number (if known):

K052017

Device Name:

Dimension® CSAE Cyclosporine Extended Range Flex® reagent cartridge

Indications for Use:

The CSAE Flex® reagent cartridge is an in vitro diagnostic test intended to quantitatively measure cyclosporine A (CSA) in human whole blood for the Dimension® clinical chemistry system. Measurements of CSA are used as an aid in the management of heart, liver and kidney transplant patients.

Jam M. Tume
Andrew M. Turner

Andrea M. Tasker Regulatory Affairs and Compliance Manager June 29, 2005

Prescription Use
(Per 21 CFR 801 Subpart D)

AND/OR

Over-the-counter Use (21 CFR 801 Subpart C)

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

Concurrence of CDRH, Office of -In Vitro Diagnostic Devices-(OIVD)

Division Sign-Off

Office of In Vitro Diagnostic Device Evaluation and Safe

Regulation Number and Section

§ 862.1235 Cyclosporine test system.

(a)
Identification. A cyclosporine test system is a device intended to quantitatively determine cyclosporine concentrations as an aid in the management of transplant patients receiving therapy with this drug. This generic type of device includes immunoassays and chromatographic assays for cyclosporine.(b)
Classification. Class II (special controls). The special control is “Class II Special Controls Guidance Document: Cyclosporine and Tacrolimus Assays; Guidance for Industry and FDA.” See § 862.1(d) for the availability of this guidance document.