The SIRO method is an in vitro diagnostic test for the quantitative measurement of Sirolimus in human whole blood on the Dimension® clinical chemistry system. Measurements of Sirolimus are used as an aid in the management of sirolimus therapy in renal transplant patients.
The Sirolimus Calibrator is an in vitro diagnostic product for the calibration of Sirolimus (SIRO) on the Dimension® clinical chemistry system.

Device Description

The automated Dimension® SIRO method uses an immunoassay technique in which free and sirolimus-bound antibody-enzyme conjugates are separated using magnetic particles. The assay is performed using a method specific Flex® reagent cartridge. The Flex® cartridge contains a pretreatment reagent, antibody-B-galactosidase conjugate, sirolimus immobilized on chromium dioxide particles, chlorophenol red ß-d-galactopyranoside (CPRG) substrate, and diluent to hydrate the tablets.
To perform the SIRO assay, a sample cup (or SSC) containing the whole blood sample to be analyzed and a SIRO Flex® reagent cartridge are placed appropriately on the Dimension® system. The Dimension® system mixes and lyses the whole blood sample. The lysed sample is then mixed with the antibody enzyme conjugate. The sirolimus present in the sample is bound by the sirolimus antibody conjugate reagent. Magnetic particles coated with sirolimus are added to bind free (unbound) antibody-enzyme conjugate. The reaction mixture is then separated magnetically. Following separation, the supernatant containing the sirolimus-antibody-enzyme complex is transferred to another cuvette and mixed with the substrate. B-galactosidase catalyzes the hydrolysis of CPRG (chlorophenol red ß-d-galactopyranoside) to produce CPR (chlorophenol red) that absorbs light maximally at 577 nm. The change in absorbance at 577 nm due to the formation of CPR is directly proportional to the amount of sirolimus in the patient's sample and is measured using a bichromatic (577, 700 nm) rate technique.
The Dimension® Sirolimus Calibrator (DC306) is an in-vitro diagnostic product intended to be used to calibrate the Dimension® Sirolimus method. It is a frozon liquid product packaged as a single vial for each of five levels. The matrix is human whole blood hemolysate with preservatives. Levels 2, 3, 4, and 5 contain sirolimus drug at target values of 5, 10, 20, and 31.5 ng/mL, respectively. Level 1 is a human whole blood hemolysate that does not contain sirolimus drug.

AI/ML Overview

Here's a summary of the acceptance criteria and study details for the Dimension SIRO Flex® reagent cartridge, based on the provided 510(k) summary:

1. Table of Acceptance Criteria and Reported Device Performance

The 510(k) summary focuses on demonstrating substantial equivalence to a predicate device (Abbott IMx Sirolimus) and uses specific performance characteristics as evidence. While explicit "acceptance criteria" for each performance metric are not strictly defined as numerical thresholds in the provided text beyond the predicate device's performance, the goal is to show comparable or improved performance.

Performance Metric	Predicate Device (Abbott IMx Sirolimus)	Acceptance Criteria (Implied by Substantial Equivalence to Predicate)	Reported Device Performance (Dimension SIRO)
Intended Use	Quantitative determination of sirolimus in human whole blood, aid in management of renal transplant patients.	Same intended use as predicate.	Quantitative measurement of Sirolimus in human whole blood, aid in management of sirolimus therapy in renal transplant patients. (Matches predicate)
Assay Technology	Enzyme immunoassay (Microparticle)	Comparable immunoassay technology.	Enzyme immunoassay (Affinity chrome mediated)
Sample Type	EDTA whole blood	Same sample type.	EDTA whole blood (Matches predicate)
Sample Pretreatment	Required	Improved/Comparable (Ideally none)	Not required (Improved over predicate)
Reportable Range	0 to 30 ng/mL	Comparable or wider range.	1.5 to 30 ng/mL (Slightly different lower limit, but overall comparable)
Functional Sensitivity	< 2.5 ng/mL	Comparable or better (lower value).	< 2.0 ng/mL (Better than predicate)
Calibration Interval	Calibration with each run.	Comparable or improved.	Calibration curve updated for each lot, using five levels every 30 days with the same reagent lot. (Improved frequency)
Sample Volume	150 uL	Comparable or smaller.	18 uL (Significantly improved/smaller than predicate)
Method Comparison (vs. HPLC/MS)	(Not explicitly stated in table for predicate, but generally good agreement is expected for any sirolimus assay)	Good agreement with reference method (HPLC/MS), ideally correlation coefficient > 0.95 and clinically acceptable slope/intercept.	Slope: 1.2, Intercept: -0.7 ng/mL, Correlation Coefficient: 0.95
Reproducibility (%CV)	(Not explicitly stated in table for predicate, but generally low %CV is desirable)	Low %CV for repeatability and within-lab variability, demonstrating consistency across different concentrations.	Repeatability: Level 1: 8.0% Level 2: 5.73% Level 3: 6.67% QC Level 1: 12.98% QC Level 2: 5.48% Within Lab: Level 1: 8.61% Level 2: 5.77% Level 3: 7.07% QC Level 1: 14.52% QC Level 2: 5.75%

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

Method Comparison (Test Set for demonstrating agreement with reference method):
- Sample Size: n = 119 patient samples.
- Data Provenance: The text states "A split patient sample (EDTA whole blood) method comparison." It does not explicitly state the country of origin or if it was retrospective or prospective, but "split patient sample" implies prospective collection from a patient population specifically for this comparison.
Reproducibility (Test Set for precision):
- Sample Size: Not explicitly stated as a single "test set" size. However, for each test level (3 whole blood pools and 2 QC levels), a single test from two independent cups was analyzed twice per day over an unspecified number of days/runs. This is repeated across one internal and two external locations.
- Data Provenance: Not explicitly stated, though the mention of "one internal and two external locations" suggests it likely involved multiple sites, potentially geographically diverse (though specific countries are not mentioned). It's a prospective study designed to assess precision.

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

For Method Comparison:
- The ground truth was established by HPLC/MS (High-Performance Liquid Chromatography/Mass Spectrometry), which is referred to as "the reference method." This is an analytical laboratory technique, not an expert human assessment.
For Reproducibility:
- The "ground truth" here is the expected value of the control materials (e.g., "Level 1 Whole Blood Pool" mean 4.41 ng/mL). These values are typically established through extensive testing by the manufacturer using validated methods, not by a panel of experts.

4. Adjudication Method for the Test Set

For Method Comparison: No adjudication method involving human experts is applicable as the comparison is against an instrumental reference method (HPLC/MS).
For Reproducibility: No adjudication method is applicable. The data is statistical analysis of repeated measurements of control materials.

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

This device is an in-vitro diagnostic (IVD) test for measuring a drug concentration (Sirolimus) in whole blood. It is an automated clinical chemistry system.
Therefore, an MRMC comparative effectiveness study where human "readers" (e.g., clinicians interpreting images or patient data) improve with "AI assistance" is not applicable to this type of device. There is no human interpretation of complex data that the device is intended to assist. The device provides a quantitative numerical result.

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

Yes, this is a standalone device. The performance data (method comparison, reproducibility) directly reflects the algorithm (the immunoassay technique and automated system) without human intervention in the result generation process. The device performs the measurement and outputs a quantitative value. Clinical interpretation of that value by a physician occurs after the device provides its result, but the device's performance itself is standalone.

7. The Type of Ground Truth Used

For Method Comparison: Analytical reference method (HPLC/MS).
For Reproducibility: Established mean values of control materials (whole blood pools and QC materials) through internal validation processes.

8. The Sample Size for the Training Set

The 510(k) summary does not provide details on a separate "training set" sample size. For IVD devices like this, the development process involves extensive internal testing and optimization of reagents and methods which could be considered "training data" in a broad sense, but it is not typically disclosed with sample sizes in the same way as machine learning models. The data presented here are for the validation of the final device.

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

As mentioned above, specific "training set" details are not provided. However, generally, for the development of such an immunoassay, the "ground truth" during development would be established similarly to the validation:
- Reference methods (like HPLC/MS) for accurate quantification of sirolimus.
- Known concentrations of sirolimus in prepared samples.
- Patient samples with clinically relevant sirolimus levels.
- The goal during development (training) would be to optimize reagent concentrations, reaction conditions, and calibration algorithms to achieve accurate and precise measurements against these known or reference values.

Summary

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

K081857

510k Summary

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.

Submitter's Name:	George M. PlummerSiemens Healthcare DiagnosticsP.O. Box 6101Newark, DE 19714-6101	OCT 30 2008
Date of Preparation:	June 26, 2008
Name of Product(s):	Dimension SIRO Flex® reagent cartridge
FDA Classification Name(s):	Sirolimus Test System(862.3840)Clinical Toxicology Calibrator(862.3200)
FDA Guidance Documents:	Class II Special Controls Guidance Document: Sirolimus Test Systems
Predicate Device(s):	Abbott IMx Sirolimus Microparticle Enzyme Immunoassay and IMxSirolimus Calibrator (K042411)

Device Description(s):

To perform the SIRO assay, a sample cup (or SSC) containing the whole blood sample to be analyzed and a SIRO Flex® reagent cartridge are placed appropriately on the Dimension® system. The Dimension® system mixes and lyses the whole blood sample. The lysed sample is then mixed with the antibody enzyme conjugate. The sirolimus present in the sample is bound by the sirolimus antibody conjugate reagent. Magnetic particles coated with sirolimus are added to bind free (unbound) antibody-enzyme conjugate. The reaction mixture is then separated magnetically. Following separation, the supernatant containing the sirolimus-antibody-enzyme complex is transferred to another cuvette and mixed with the substrate. B-galactosidase catalyzes the hydrolysis of CPRG (chlorophenol red ß-d-galactopyranoside) to produce CPR (chlorophenol red) that absorbs light maximally at 577 nm. The change in absorbance at 577 nm due to the formation of CPR is directly proportional to the amount of sirolimus in the patient's sample and is measured using a bichromatic (577, 700 nm) rate technique.

Sirolimus + Ab-β-gal	→	Sirolimus-Ab-β-gal + Ab-β-gal
Sirolimus-Ab-β-gal + Ab-β-gal +CrO2-Sirolimus	Magnetic separation	Sirolimus-Ab-β-gal(transferred to cuvette)
CPRG(non-absorbing at 577 nm)		CPR(absorbs at 577 nm)

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

A C A . CThe first to the many and the bith he half a free been and the been and the been and	------------------------------------------------------------------------------------------------------------------------------------------------------------------------------1	.Comments and propositions and provinces and consistent a provinces a province a commend a province a management of the commend of the many of the commend of the many of the c


------------------------------------------------------------------------------------------------------------------------------------------------------------------------------STATE AND THE COLLECTION STATES ASSOCIATION ASSOCIATION ASSOCIATION ASSOCIATION ASSOCIATION ASSOCIATION ASSOCIATION ASSOCIATION ASSOCIATION ASSOCIATION ASSOCIATION ASSOCIATIO		A B A B A BREAK BREAK BRIDGE . A R . B R . B . B . B . B . B . B . B . B . B . B . B . B . B . B . B . B . B . B . B . B . B . B . B . B . B . B . B . B . B . B . B . B . B .------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

The Dimension® Sirolimus Calibrator (DC306) is an in-vitro diagnostic product intended to be used to calibrate the Dimension® Sirolimus method. It is a frozon liquid product packaged as a single vial for each of five levels. The matrix is human whole blood hemolysate with preservatives. Levels 2, 3, 4, and 5 contain sirolimus drug at target values of 5, 10, 20, and 31.5 ng/mL, respectively. Level 1 is a human whole blood hemolysate that does not contain sirolimus drug.

Intended Use:

SIRO Flex® reagent cartridge

Sirolimus Calibrator

The Sirolimus calibrator is an in vitro diagnostic product for the calibration of Sirolimus (SIRO) on the Dimension® clinical chemistry system.

Substantial Equivalence:

A summary of the performance attributes of the Siemens SIRO Flex® reagent cartridge/SIRO Calibrator and the predicate Abbott IMx Sirolimus Microparticle Enzyme Immunoassay (K042411)/IMx Sirolimus Calibrator is provided in the following charts.

Item	Abbott Sirolimus	Dimension® SIRO
IntendedUse	The IMx® Sirolimus assay is an in vitroreagent system for the quantitativedetermination of sirolimus in humanwhole blood, as an aid in themanagement of renal transplant patientsreceiving therapy with sirolimus	The SIRO method is an in vitro diagnostictest for the quantitative measurement ofSirolimus in human whole blood on theDimension® clinical chemistry system.Measurements of Sirolimus are used as anaid in the management of sirolimustherapy in renal transplant patients.
AssayTechnology	Enzyme immunoassay (Microparticle)	Enzyme immunoassay (Affinity chromemediated)
SampleType	EDTA whole blood	EDTA whole blood
ExpectedValues(ReferenceInterval)	Not applicable for immunosuppressivedrug assays. Optimal ranges dependupon the patient's clinical state,individual differences in sensitivity toimmunosuppressive and nephrotoxiceffects of sirolimus, co-administrationof other immunosuppressants, time post	Not applicable for immunosuppressivedrug assays. Optimal ranges depend uponthe patient's clinical state, individualdifferences in sensitivity toimmunosuppressive and nephrotoxiceffects of sirolimus, co-administration ofother immunosuppressants, time post

Table of Similarities

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

	transplant and of other factors.	transplant and of other factors.
CalibratorMatrix	human whole blood containingsirolimus	human whole blood containing sirolimus

Table of Differences

Item	Abbott Sirolimus	Dimension® SIRO
Sample Pretreatment	Required	Not required
Reportable Range	0 to 30 ng/mL	1.5 to 30 ng/mL
Functional Sensitivity	< 2.5 ng/mL	< 2.0 ng/mL
Calibration Interval	Calibration with each run.	Calibration curve updated foreach lot, using five levelsevery 30 days with the samereagent lot.
Sample Volume	150 uL	18 uL

Method performance Summary:

Method Comparison

A split patient sample (EDTA whole blood) method comparison demonstrated good agreement between the Siemens Dimension® SIRO method and HPLC/MS, the reference method.

HPLC/MS SampleRange	Dimension®SampleRange	n	Slope	Intercept	CorrelationCoefficient
2.8 - 23.7 ng/mL	2.4 - 25.6 ng/mL	119	1.2	-0.7 ng/mL	0.95

The model equation for the Linear regression statistics is: [results for Dimension® Siro] = slope x [comparative method results] + intercept.

Reproducibility

Typical precision observed for the Dimension SIRO method is summarized below:

	Mean(ng/mL)	Repeatability		Within Lab
Sample		SD(ng/mL)	%CV	SD (ng/mL)	%CV
Level 1 Whole Blood Pool	4.41	0.35	8.0	0.38	8.61

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

Level 2 Whole Blood Pool	12.55	0.72	5.73	0.72	5.77
Level 3 Whole Blood Pool	25.35	1.69	6.67	1.79	7.07
Level 1 QC	2.7	0.35	12.98	0.39	14.52
Level 2 QC	10.58	0.58	5.48	0.61	5.75

The reproducibility testing was conducted in accordance with the CLSI Approved Guideline for User Evaluation of Precision Performance of Clinical Chemistry Devices EP5-A2. For each test level, a single test from two independent cups was analyzed twice per day. Testing was conducted with one reagent lot across multiple instruments at one internal and two external locations. The repeatability and within-lab standard deviations were calculated by the analysis of variance method independently for each site. The data above is representative of the results obtained in the reproducibility testing.

Comments on Substantial Equivalence and Conclusion:

Both the Abbott IMx Sirolimus (K042411) and the Siemens Dimension® Siro immunoassays arc intended for the quantitative determination of sirolimus. The Siemens Dimension® Siro and the predicate Abbott IMx Sirolimus immunoassays are substantially equivalent based on their intended use, performance characteristics, and method comparison to the reference HPLC/MS as described above.

George M. Plummer Regulatory Affairs Director June 26, 2008

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

DEPARTMENT OF HEALTH & HUMAN SERVICES

Image /page/4/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo consists of a stylized eagle with three tail feathers, representing the department's commitment to health, human services, and well-being. The eagle is positioned to the right of the department's name, which is arranged in a circular pattern around the logo. The text reads "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA".

Public Health Service

Food and Drug Administration 2098 Gaither Road Rockville MD 20850

Siemens Healthcare Diagnostics Inc. c/o Mr. George M. Plummer Director of Regulatory Affairs Rt. 896 GBC Drive B500 P.O. Box 6101 Newark, DE 19714-6101

OCT 3 0 2008

Re: K081857

Trade/Device Name: Dimension Sirolimus Flex Reagent Cartridge and Dimension Sirolimus Calibrator Regulation Number: 21 CFR 862.3840

Regulation Name: Sirolimus Test System Regulatory Class: Class II Product Code: NRP, DLJ Dated: September 24, 2008 Received: September 25, 2008

Dear Mr. Plummer:

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); labeling (21 CFR Parts 801 and 809); and good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820).

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

Page 2 -

This letter will allow you to begin marketing your device as described in your Section 510(k) premarket notification. The FDA finding of substantial equivalence of your device to a legally marketed 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, or questions on the promotion and advertising of your device, please contact the Office of In Vitro Diagnostic Device Evaluation and Safety at (240) 276-0490. 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 (240) 276-3150 or at its Internet address at http://www.fda.gov/cdrh/industry/support/index.html.

Sincerely yours,

Jean M. Cooper, M.S., D.V.M.
Jean M. Cooper, M.S., D.V.M.

Director Division of Chemistry and Toxicology Office of In Vitro Diagnostic Device Evaluation and Safety Center for Devices and Radiological Health

Enclosure

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

Indication for Use

510(k) Number (if known):

1081857

Device Name: Dimension® SIRO Flex® reagent cartridge

Indication For Use:

Prescription Use X (21 CFR Part 801 Subpart D)

And/Or

Over the Counter Use (21 CFR Part 801 Subpart C)

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

Concurrence of CDRH, Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD)

Signature

Division Sign-Off Office of In Vitro Diagnostic Device Evaluation and Safety

510(k) K081857

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

Indication for Use

510(k) Number (if known): CD81857

Device Name: Dimension® Sirolimus Calibrator

Indication For Use:

The Sirolimus Calibrator is an in vitro diagnostic product for the calibration of Sirolimus (SIRO) on the Dimension® clinical chemistry system.

Prescription Use X (21 CFR Part 801 Subpart D)

And/Or

Over the Counter Use (21 CFR Part 801 Subpart C)

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

Concurrence of CDRH, Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD)

Division Sign-Off Office of In Vitro Diagnostic Device Evaluation and Safety

510(k) K091857

Page 1 of 2

Regulation Number and Section

§ 862.3840 Sirolimus test system.

(a)
Identification. A sirolimus test system is a device intended to quantitatively determine sirolimus concentrations in whole blood. Measurements are used as an aid in management of transplant patients receiving therapy with sirolimus.(b)
Classification. Class II (special controls). The special control is FDA's guidance document entitled “Class II Special Controls Guidance Document: Sirolimus Test Systems.” See § 862.1(d) for the availability of this guidance document.