The IMx Sirolimus assay is an in vitro reagent system for the quantitative determination of sirolimus in human whole blood as an aid in the management of renal transplant patients receiving sirolimus therapy.

The IMx® Sirolimus Calibrators are for the calibration of the IMx Analyser when used for the quantitative determination of sirolimus in human whole blood.

The IMx® Sirolimus MODE 1 Calibrator is for the adjustment of the stored calibration of the IMx Analyser when used for the quantitative determination of sirolimus in human whole blood.

The IMx® Sirolimus Controls are for the verification of the calibration of the IMx Analyser when used for the quantitative determination of sirolimus in human whole blood.

The IMx Sirolimus Whole Blood Precipitation Reagent is for the extraction of sirolimus from samples (whole blood patient specimens, IMx® Sirolimus Calibrators and Controls) to be tested on the IMx® Sirolimus assay.

Device Description

Microparticle Enzyme Immunoassay (MEIA) for use on Abbott IMx® system.

Assay procedure:

Incubate the sample with the anti-sirolimus antibody-coated microparticles.
Add sirolimus alkaline phosphatase conjugate and incubate.
Transfer to matrix cell.
Wash to remove unbound substances.
Add substrate.
Measure fluorescent product.

AI/ML Overview

This document describes the performance characteristics and acceptance criteria for the Abbott IMx® Sirolimus Microparticle Enzyme Immunoassay (MEIA) test.

Here's the breakdown of the information requested:

1. Table of Acceptance Criteria and Reported Device Performance

Parameter	Acceptance Criteria (from predicate device or implied by comparison)	Reported Device Performance (IMx® Sirolimus MEIA Test)
Precision	Within-run CV of 2.2 - 7.0%; Between-run CV of 2.2 - 9.2% (CEDIA® Sirolimus Test)	Total imprecision of ≤ 15% through assay range of 5-22ng/ml
Recovery	Recovery of 101 - 112% of expected values (CEDIA® Sirolimus Test)	Mean recovery across samples of 90 - 110% of expected values.
Dilution Linearity	Recovery of 91 - 106% of expected values for a single high sample (CEDIA® Sirolimus Test)	Mean recovery across samples of 99 - 115% of expected values.
Analytical Sensitivity	4.0 ng/mL (CEDIA® Sirolimus Test)	≤ 1.5ng/ml
Functional Sensitivity	Not listed (CEDIA® Sirolimus Test)	≤ 2.5ng/ml
Specificity for Parent Compound (Cross-reactivity with metabolites)	11-hydroxy - 44%; 41-O- and 32-O-Demethyl - 73%; Trihydroxy and 41-O-didemethyl - 14%; 41-desmethyl-hydroxy- 10%; Fraction 2 and 7-O-desmethyl - 8.7%; Isomers of fraction 4 - 22%; Hydroxyl - 7%; N-oxide - 15%; Fraction 6 and isomers of Fraction 7 - 4% (CEDIA® Sirolimus Test)	11-hydroxy-sirolimus - 37%; 41-O-demethyl-sirolimus - 58%; 7-O-demethyl-sirolimus - 63%; 41-O-demethyl-hydroxyl-sirolimus - 6%
Co-Administered Drug Interference	<0.015% cross-reactivity for 42 drugs; Cyclosporine at 10,000ng/ml, Tacrolimus at 300ng/ml, Mycophenolic Acid at 100,000ng/ml (Tacrolimus showed 0.4% cross-reactivity, others <0.015%) (CEDIA® Sirolimus Test)	62 drugs tested; Gemfibrozil (75µg/ml), Itraconazole (10.5µg/ml), MPAG (1800µg/ml), OKT3(6.0µg/ml), Trimethoprim (40µg/ml) showed between 10% and 15% apparent interference with Medium Control.
Interference from Endogenous Compounds	No significant interference from: Unconjugated bilirubin up to 60mg/dl, Cholesterol up to 500mg/dl, Triglycerides up to 1500mg/dl, Rheumatoid Factor up to 573IU/ml, Protein (albumin) up to 11g/dl, Protein (gamma globulin) up to 4.9g/dl, Haematocrit levels between 20 – 60% (CEDIA® Sirolimus Test)	< 10% interference at levels: Bilirubin - 0.4mg/ml, Cholesterol - 5mg/ml, Triglycerides - 10mg/ml, Uric Acid - 0.2mg/ml, Rheumatoid Factor - 500IU/ml, Protein (Albumin) – 3-12g/dl, Protein (Gamma Globulin) - 3-12g/dl, HAMA - 60ng/ml; Haematocrit levels between 15-60% produced <25% interference.
Sample Storage Stability	1 week at 2-8°C and 2 years at -70°C (CEDIA® Sirolimus Test)	Specimens collected in EDTA tubes may be stored for up to 28 days at 2-8°C or -20°C prior to being tested. Repeated freezing and thawing (more than 3 freeze-thaw cycles) should be avoided.

Study Proving Device Meets Acceptance Criteria:

The document describes a 510(k) Pre-market Notification for the IMx® Sirolimus Microparticle Enzyme Immunoassay. This submission aims to demonstrate substantial equivalence to a legally marketed predicate device, the Microgenics CEDIA® Sirolimus Assay (K034069), and also includes a comparison to the current accepted reference method for sirolimus measurement, High Performance Liquid Chromatography-tandem Mass Spectrometry (HPLC/MS/MS).

The "acceptance criteria" are implied by the comparison to the predicate device's performance characteristics, and the IMx® Sirolimus MEIA Test reports its own performance to show it is comparable or superior. The comparison to HPLC/MS/MS provides further evidence of the device's accuracy.

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

Comparison to HPLC/MS/MS Method (Analytical Test Set):
- Sample Size: 221 samples ("n").
- Data Provenance: Not explicitly stated, but the study involved "All Sites," suggesting a multi-center study. The document is from Axis-Shield Diagnostics Ltd. in Scotland, UK, but the origin of the patient samples is not specified as domestic or international, nor if they were retrospective or prospective. It is likely that these were prospective samples collected specifically for method comparison, but this is an inference.
Performance Characteristics Comparison (IMx vs. CEDIA):
- The sample sizes for individual performance parameters (Precision, Recovery, Linearity, etc.) for the IMx® Sirolimus MEIA Test are not explicitly stated in the provided text. The results are reported as summary statistics (e.g., "Total imprecision of ≤ 15%", "Mean recovery across samples").
- Data Provenance: Not explicitly stated for these individual studies, but presumably conducted by Axis-Shield Diagnostics Ltd.

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

For the HPLC/MS/MS comparison: The ground truth is established by the HPLC/MS/MS method itself, which is described as the "current Device accepted reference method for sirolimus measurement." This is an instrumental method, not based on human expert consensus. Therefore, the concept of "experts used to establish ground truth" does not apply in the traditional sense for this part of the study.
For other performance characteristics: The ground truth for determining precision, recovery, linearity, sensitivity, specificity, and interference in laboratory assays is typically established by the inherent properties of the reference materials and methods used in the testing, not by expert consensus.

4. Adjudication Method for the Test Set

Not applicable. This study is for an in vitro diagnostic (IVD) quantitative assay. Adjudication methods (like 2+1 or 3+1) are typically used in imaging studies or clinical trials where human interpretation of data is subjective and requires consensus. For an IVD assay, performance is quantitatively measured against a reference method or known values, not adjudicated by experts in the same way.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done

No. This is an in vitro diagnostic (IVD) device, not an imaging or interpretive device that would typically involve a multi-reader multi-case study with human readers. The device provides a quantitative measurement, not an interpretation of a complex input that human readers would evaluate.

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

Yes, this is a standalone performance study. The document describes the performance of the IMx® Sirolimus Microparticle Enzyme Immunoassay (MEIA) test itself, as an automated system on the Abbott IMx® analyser. The results reported are directly from the device's measurement. While a human operates the device and interprets the numerical output in a clinical context, the performance characteristics detailed here (precision, sensitivity, comparison to HPLC/MS/MS) are inherent to the assay and instrument itself, without "human-in-the-loop" influencing the reported measurement accuracy or precision for these specific studies.

7. The Type of Ground Truth Used

Instrumental Reference Method: For the direct comparison study, the ground truth was the High Performance Liquid Chromatography-tandem Mass Spectrometry (HPLC/MS/MS) method, described as the "current Device accepted reference method for sirolimus measurement."
Known Reference Values/Spiked Samples: For parameters like Precision, Recovery, Dilution Linearity, Analytical Sensitivity, Specificity, and Interference, the ground truth is established using samples with known concentrations of sirolimus, its metabolites, or interfering substances. These known values act as the "ground truth" against which the device's measurements are compared.

8. The Sample Size for the Training Set

The document describes a 510(k) submission for a finished IVD product, not a deep learning or AI model that typically has a separate "training set." The IMx® Sirolimus assay is an established technology (Microparticle Enzyme Immunoassay - MEIA).
Therefore, the concept of a "training set" in the context of machine learning is not applicable to this type of device. The development and optimization of such an assay would involve internal R&D studies, but these are not referred to as "training sets" in the same way.

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

Not applicable. As explained above, there is no "training set" in the machine learning sense for this device. The development process would have involved rigorous analytical testing using reference materials and calibrated instruments to establish assay parameters, but not a "ground truth for a training set" as it would be understood for an AI algorithm.

Summary

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Image /page/0/Picture/1 description: The image is a black and white logo for the U.S. Department of Health & Human Services. The logo features a stylized emblem with three curved lines, resembling a human figure, and the text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" arranged in a circular pattern around the emblem. The text is in all caps and is slightly distorted due to the circular arrangement.

Food and Drug Administration 2098 Gaither Road Rockville MD 20850

MAY 1 6 2005

Ms. Susan Leonard Regulatory Affairs Manager Axis-Shield Diagnostics Ltd. The Technology Park Dundee, Tayside, Scotland United Kingdom DD21XA

Re: K042411

Trade/Device Name: IMx® Sirolimus Microparticle Enzyme Immunoassay, IMx® Sirolimus Calibrators, IMx® Sirolimus Controls Regulation Number: 21 CFR 862.3840 Regulation Name: Sirolimus Test System Regulatory Class: Class II Product Code: NRP, LAS, DLJ

Dear Ms. Leonard:

This letter corrects our substantially equivalent letter of April 7, 2005 regarding the cleared devices and their product codes. The original letter failed to mention the clearance of your calibrators and controls.

We have reviewed your Section 510(k) premarket notification of intent to market the devices 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.

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Page 2 - Ms. Susan Leonard

Please be advised that FDA's issuance of a substantial equivalence determinationdoes 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 (OS) regulation (21 CFR Part 820).

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) 276-0484. 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,

Albert
: 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

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3. INDICATIONS FOR USE

510(k) Number (if known): K042411

Device Name: IMx® Sirolimus Microparticle Enzyme Immunoassay

Indications For Use: The IMx Sirolimus assay is an in vitro reagent system for the quantitative determination of sirolimus in human whole blood as an aid in the management of renal transplant patients receiving sirolimus therapy.

The IMx® Sirolimus Calibrators are for the calibration of the IMx Analyser when used for the quantitative determination of sirolimus in human whole blood.

The IMx® Sirolimus MODE 1 Calibrator is for the adjustment of the stored calibration of the IMx Analyser when used for the quantitative determination of sirolimus in human whole blood.

The IMx® Sirolimus Controls are for the verification of the calibration of the IMx Analyser when used for the quantitative determination of sirolimus in human whole blood.

V Prescription Use AND/OR (Part 21 CFR 801 Subpart D)

Over-The-Counter Use (21 CFR 807 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)

Albert Satz'

(Division Sign-Off)
Division of Clinical Laboratory Devices
510(k) Number K042411

Page 1 of 1

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and the same of the same of the same of the same of the same of the same of the states of the states of the states of the states of the states of the states of the states of

Axis-Shield Diagnostics Ltd 26th January 2005

K042411 - IMx®Sirolimus Page 1 of 4

510(k) Summary

Introduction

The following summary is intended to support a claim for the Abbott IMx Sirolimus

Assay of substantial equivalence to the Microgenics CEDIA Sirolimus Assay

(K034069).

Submitter name, address, contact

Axis-Shield Diagnostics Ltd. The Technology Park Dundee DD2 1XA Scotland, UK Tel : +44 1382 422000 Fax: +44 1382 422088

Contact Person:	Susan Leonard
Email address:	susan_leonard@uk.axis-shield.com
Date Prepared:	January 26th, 2005

Device Name

Proprietary Name:	Abbott IMx® Sirolimus Microparticle Enzyme Immunoassay(MEIA) test
Common name:	Microparticle Enzyme Immunoassay (MEIA) for thedetermination of sirolimus.
Classification name:	Sirolimus test system
Product Code :	NRP	Classification:	Class IICFR 862.3840

Predicate Device

I i current Device accepted reference method for sirolimus measurement, which is High Performance Liquid Chromatography-tandem Mass Spectrometry (HPLC/MS/MS). There is also a comparison of performance characteristics for the IMx® Sirolimus Assay and the Microgenics CEDIA® Sirolimus Assay (K034069).

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510(k) Summary

Device Description

Competition format.

Competition tormal.
Microparticle Enzyme Immunoassay (MEIA) for use on Abbott IMx® system.

Assay procedure:

Incubate the sample with the anti-sirolimus antibody-coated microparticles. 프
and the same of the same of the same of the same of the same and the same and the seat and the seat and the search and
Add sirolimus alkaline phosphatase conjugate and incubate. ..
Transfer to matrix cell. 포
Wash to remove unbound substances. .
L Add substrate.
Measure fluorescent product. .

Intended Use

An in vitro reagent system for the quantitative determination of sirolimus in human whole blood, as an aid in the management of renal transplant patients receiving sirolimus therapy.

Comparison to HPLC/MS/MS Method

The Abbott IMx Sirolimus assay was compared to the HPLC/MS/MS method. The resulting Passing-Bablok correlation statistics are summarised in the following table:

ClinicalSite	Method X		Method Y		n	Min X	Max X	Min Y	Max Y	Passing /Bablok		r	Disp. ofResiduals
	Instrument	Unit	Instrument	Unit						B/P b	B/P a		md(68)	md(95)
All Samples
All Sites	LC/MS/MS	ng/ml	IMx	ng/ml	221	2.900	90.100	3.800	81.900	1.230	-0.250	0.956	1.057	2.745

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510(k) Summary

Performance Characteristics of Abbott IMx® Sirolimus MEIA Test vs the Microgenics CEDIA® Sirolimus Test:

Parameter	IMx® Sirolimus MEIA Test	CEDIA® Sirolimus Test(K034069)
Precision	Total imprecision of ≤ 15%through assay range of 5-22ng/ml	Within-run CV of 2.2 - 7.0%.Between-run CV of 2.2 - 9.2%.
Recovery	Mean recovery across samples of90 - 110% of expected values.	Recovery of 101 - 112% ofexpected values.
Dilution Linearity	Mean recovery across samples of99 - 115% of expected values.	Recovery of 91 - 106% ofexpected values for a singlehigh sample.
Analytical Sensitivity	≤ 1.5ng/ml	4.0 ng/mL
Functional Sensitivity	≤ 2.5ng/ml	Not listed.
Specificity for ParentCompound	Cross-reactivity seen at thefollowing levels with themetabolites studied:11-hydroxy-sirolimus - 37%41-O-demethyl-sirolimus - 58%7-O-demethyl-sirolimus - 63%41-O-demethyl-hydroxyl-sirolimus - 6%	Cross-reactivity seen at thefollowing levels with themetabolites studied:11-hydroxy - 44%41-O- and 32-O -Demethyl -73%Trihydroxy and 41-O-didemethyl - 14%41-desmethyl-hydroxy- 10%Fraction 2 and 7-O-desmethyl- 8.7%Isomers of fraction 4 - 22%Hydroxyl - 7%N-oxide - 15%Fraction 6 and isomers ofFraction 7 - 4%
Parameter	IMx® Sirolimus MEIA Test	CEDIA® Sirolimus Test(K034069)
Co-AdministeredDrug Interference	62 drugs tested. Of these, thefollowing showed between 10%and 15% apparent interferencewith the Medium Control:Gemfibrozil (75µg/ml) ;Itraconazole (10.5µg/ml) ;MPAG (1800µg/ml) ;OKT3(6.0µg/ml) ; Trimethoprim(40µg/ml).	42 drugs tested. These showed<0.015% cross-reactivity.3 co-administeredimmunosuppressants tested:Cyclosporine at 10,000ng/ml,Tacrolimus at 300ng/ml,Mycophenolic Acid at100,000ng/ml. Tacrolimusshowed 0.4% cross-rectivity.Others showed <0.015% cross-reactivity.
Interference fromEndogenousCompounds	< 10% interference indetecting sirolimus at thefollowing levels of potentiallyinterfering substances:Bilirubin - 0.4mg/mlCholesterol - 5mg/mlTriglycerides - 10mg/mlUric Acid - 0.2mg/mlRheumatoid Factor -500IU/mlProtein (Albumin) – 3-12g/dlProtein (Gamma Globulin) -3-12g/dlHAMA - 60ng/mlHaematocrit levels between15-60% produced <25%interference in the detectionof sirolimus.	No significant interference from :Unconjugated bilirubin up to60mg/dlCholesterol up to 500mg/dlTriglycerides up to 1500mg/dlRheumatoid Factor up to5731U/mlProtein (albumin) up to 11g/dlProtein (gamma globulin) up to4.9g/dlHaematocrit levels between 20 –60% produced no significantinterference.
SampleStorageStability	Specimens collected in EDTAtubes may be stored for up to28 days at 2-8°C or -20°Cprior to being tested.Repeated freezing andthawing (more than 3 freeze-thaw cycles) should beavoided.	1 week at 2-8°C and 2 years at-70°C.

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510(k) Summary

Performance Characteristics of Abbott IMx® Sirolimus MEIA Test (continued):

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.