The CEDIA Cyclosporine Plus Assay is for the quantitative determination of cyclosporine in human whole blood using automated clinical chemistry analyzers as an aid in the management of therapy in kidney, liver, and heart transplants. The CEDIA Cyclosporine Calibrators are used to calibrate the CEDIA Cyclosporine Plus Assay in human whole blood.

Device Description

The CEDIA Cyclosporine Plus Assay is a two-reagent set intended to be used with automated clinical chemistry analyzers. The assay uses recombinant DNA technology (US Patent No. 4708929) to produce a unique homogeneous enzyme immunoassay system. The assay is based on the bacterial enzyme ß galactosidase, which has been genetically engineered into two inactive fragments, termed Enzyme Acceptor (EA) and Enzyme Donor (ED) spontaneously reassociate to form fully active enzyme that, in the assay format, cleaves a substrate, to generate a color change that can be measured spectrophotometrically.

In the CEDIA Cyclosporine Plus Assay, drug in the sample competes with drug conjugated to ED for antibody binding sites. If drug is present in the sample, it binds to antibody, leaving the EDdrug conjugate free to reassociate with EA to form active ß-galactosidase. If no drug is present in the sample, antibody binds to the ED-cyclosporine conjugate, inhibiting the reassociation of inactive B-galactosidase fragments, and thus reducing the amount of active enzyme formed. The amount of active enzyme formed, and resulting absorbance change, is proportional to the amount of CEDIA Cyclosporine Plus Assay present in the sample.

AI/ML Overview

The provided 510(k) summary for the CEDIA® Cyclosporine Plus Assay details the device's technical specifications and a comparison to a predicate device, but does not describe an acceptance criteria table, a study explicitly proving the device meets said criteria, or several of the specific points requested (e.g., sample size for test set, number of experts, adjudication method, MRMC study, training set details).

The document focuses on demonstrating substantial equivalence to the EMIT 2000 Cyclosporine Specific Assay (P920031) through a comparison of their intended use, method principle, components, risk to patient, and clinical performance.

However, based on the information provided under "Clinical Performance," we can infer the performance metrics reported for the device, which serve as the basis for demonstrating its suitability.

Here's an attempt to answer the questions based on the available information:

Acceptance Criteria and Reported Device Performance

1. Table of acceptance criteria and the reported device performance

Since explicit "acceptance criteria" are not listed in the document, we infer them from the reported performance of the predicate device and the new device. The predicate device's performance often sets the benchmark for the new device to demonstrate substantial equivalence.

Performance Metric	Acceptance Criteria (Inferred from Predicate/General Standards)	CEDIA® Cyclosporine Plus Assay (Reported Performance)
Accuracy (Low Range)	Comparable to predicate (y = 1.05x + 12; r = 0.96, S.E.E. = 25.33 for one site)	y = 0.99x + 8; r = 0.93, S.E.E. = 25.79
Accuracy (High Range)	Not explicitly given for predicate, but expected to be good.	y = 0.97x + 98; r = 0.970, S.E.E. = 80.65
Assay Range (Low)	0 to 500 ng/mL (Predicate)	25 to 450 ng/mL (New Device)
Assay Range (High)	Not explicitly given for predicate, but expected to be good.	450 to 2000 ng/mL (New Device)
Within Run Imprecision	Percent CVs between 3.0% and 5.0% (Predicate, across 3 levels)	Percent CVs between 3.0% and 8.0% (across 5 levels)
Total Imprecision	Percent CVs between 4.5% and 10.5% (Predicate, across 3 levels)	Percent CVs between 4.5% and 9.6% OR S.D=7.4 for a control at 46 ng/mL (across 5 levels)

Note: The acceptance criteria are inferred based on the direct comparison with the predicate device's reported performance, indicating that the new device should perform equivalently or within acceptable clinical limits. Specific numeric acceptance thresholds are not explicitly stated as "acceptance criteria" in this document.

Study Details

2. Sample size used for the test set and the data provenance

Sample Size for Test Set: Not specified in the provided document. The "Clinical Performance" section mentions "Method comparison of all transplant types to an HPLC reference method" but does not give a specific number of samples.
Data Provenance: Not specified (e.g., country of origin). The studies appear to be clinical performance evaluations, but whether they are retrospective or prospective is not explicitly stated. The predicate device's data specifically mentions "studies at four separate sites," implying multi-center data, but this level of detail is not provided for the new device.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts

This information is not applicable to this type of device (a quantitative assay). Ground truth for these assays is established by a reference method, not expert consensus.

4. Adjudication method for the test set

Not applicable as the ground truth is established by an analytical reference method (HPLC), not human expert review.

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 is not an AI/imaging device. Therefore, an MRMC study is not applicable.

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

Yes, the performance reported for the CEDIA® Cyclosporine Plus Assay is "standalone" in nature, meaning it represents the algorithm's direct measurement output compared to a reference method, without human intervention in the result determination process. The assay produces a quantitative value.

7. The type of ground truth used

The ground truth for accuracy validation was established using a High-Performance Liquid Chromatography (HPLC) reference method. This is explicitly stated: "Method comparison of all transplant types to an HPLC reference method yielded the following results."

8. The sample size for the training set

This information is not provided. For this type of immunoassay, while calibration and optimization are performed, explicit "training set" sizes in the context of machine learning are not typically defined or reported in this manner.

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

Ground truth for assay calibration (analogous to a training set for machine learning) would be established using known concentrations of cyclosporine, likely prepared gravimetrically or against certified reference materials, and then analyzed by the assay to establish the calibration curve. Specific details are not provided in this document.

Summary

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K023208

OCT 2 4 2002

510(k) 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.

The assigned 510(k) number is: K . . . . . . .

Submitter Information (21 CFR 807.92(a)(1))

Submitter:	Microgenics Corporation
	46360 Fremont Boulevard
	Fremont, CA 94538
	Phone: 1-510-979-5169
	FAX: 1-510-979-5455

Name Contact: Regulatory Specialist
June 11, 2002 Summary date:

Name of Device and Classification (21 CFR 807.92(a)(2))

CEDIA® Cyclosporine Plus Assay Name (trade):

Name (usual): Cyclosporine Assay

Classification: Unknown

Identification of Legally Marketed Predicate Device(s) (21 CFR 807.92 (a)(3))

CEDIA Cyclosporine Plus Assay is substantially equivalent to EMIT 2000 Cyclosporine Specific Assay (Dade Behring Inc., San Jose, CA), cleared under premarket notification P920031

CEDIA Cyclosporine Plus Assay is identical or similar to its predicate in terms of intended use, method principle, device components, risk to the patient, and clinical performance.

Description of Device (21 CFR 807.92 (a)(4))

Microgenics Corporation CEDIA Cyclosporine Plus Assay 510(k) Submission

Page 30 of 33

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Intended Use (21 CFR 807.92 (a)(5))

Similarities to the Predicate(s) (21 CFR 807.92 (a)(6))

A summary table of the similarities and difference between CEDIA Cyclosporine Plus Assay and the predicate device follows.

Comparison Table:

CEDIA Cyclosporine Plus Assay vs. EMIT 2000 Cyclosporine Specific Assay

	EMIT 2000 Cyclosporine Specific Assay(P920031)	CEDIA Cyclosporine Plus Assay(new device)
Device Name
Indicationsfor Use	The Emit 2000 Cyclosporine SpecificAssay is for in vitro diagnostic use on theRoche Diagnostics Systems COBAS MIRA,COBAS MIRA S and COBAS MIRA Pluschemistry systems for the quantitativeanalysis of cyclosporine (CsA) in humanwhole blood as an aid in the managementof cyclosporine therapy in kidney, heart,and liver transplants.	The CEDIA Cyclosporine PlusAssay is for the quantitativedetermination of cyclosporine inhuman whole blood usingautomated clinical chemistryanalyzers as an aid in themanagement of therapy in kidney,liver, and heart transplants. TheCEDIA Cyclosporine Calibratorsare used to calibrate the CEDIACyclosporine Plus Assay inhuman whole blood.
MethodPrinciple	The assay uses a mouse monoclonal antibodywith specificity to cyclosporine and a secondmouse monoclonal antibody specific for amajor metabolite of cyclosporine, AM9 (M1)to prevent metabolite binding to the primaryantibody.The assay is based on competition forcyclosporine antibody binding sites betweenanalyte in the sample and cyclosporine labeledwith G6-PDH. Active (unbound) enzymeconverts NAD to NADH, resulting in anabsorbance change measured	The CEDIA Cyclosporine Plus Assay isa two-reagent set intended to be usedwith automated clinical chemistryanalyzers. The assay uses recombinantDNA technology (US Patent No.4708929) to produce a uniquehomogeneous enzyme immunoassaysystem. The assay is based on thebacterial enzyme $ β $ -galactosidase,which has been genetically engineeredinto two inactive fragments. Thesefragments, termed Enzyme Acceptor(EA) and Enzyme Donor (ED)
Device Name	EMIT 2000 Cyclosporine Specific Assay(P920031)	CEDIA Cyclosporine Plus Assay(new device)
MethodPrinciple,continued	spectrophotometrically.Before testing, samples are pretreated withmethanol. The pretreatment lyses the cells,solubilizes the cyclosporine, and precipitatesmost of the blood proteins. The samples arecentrifuged, and an aliquot of the resultingsupernatant is then assayed	(EA) and Enzyme Donor (ED),spontaneously reassociate to form fullyactive enzyme, which, in the assayformat, cleaves a substrate to generate acolor change that can be measuredspectrophotometrically.In the CEDIA Cyclosporine PlusAssay, cyclosporine in the samplecompetes with the cyclosporineconjugated to ED for antibody bindingsites. If cyclosporine is present in thesample, it binds to the antibody, leavingthe ED-cyclosporine conjugate free toreassociate with EA to form active β-galactosidase. If no cyclosporine ispresent in the sample, antibody binds tothe ED-conjugate, inhibiting thereassociation of inactive β-galactosidase fragments, and thusreducing the amount of active enzymeformed. The amount of active enzymeformed and the resulting absorbancechange are proportional to the amountof cyclosporine present in the sample.The pretreatment reagent lysis the cell
Components	- Reagent A- Enzyme B Reagent	and solubilizes the whole blood fortesting.- Enzyme Acceptor Reagent- Enzyme Acceptor Buffer- Enzyme Donor Reagent- Enzyme Donor Buffer- Lysing Reagent
Risk to patient	An in vitro diagnostic device that can beused as an aid in the management ofcyclosporine therapy.	An in vitro diagnostic device that canbe used as an aid in themanagement of patients receivingcyclosporine.
ClinicalPerformance	Accuracy: (See Attachment B: PredicateDevice Labeling, Section 11, Table 10.) TheSyva Emit Package Insert provides MethodComparison Data from studies at four separatesites. Below our the results from one repre-sentative study comparing all 3 transplanttypes (heart, lung, kidney) to an HPLCReference Method:	Accuracy: Method comparison of alltransplant types to an HPLC referencemethod yielded the following results:Low range y = 0.99x + 8r = 0.93, S.E.E. = 25.79;
Device Name	EMIT 2000 Cyclosporine Specific Assay(P920031)	CEDIA Cyclosporine Plus Assay(new device)
ClinicalPerformance,continued	Site 4: y=1.05 + 12; r = 0.96, S.E.E. = 25.33Assay Range: 0 to 500 ng/mL.	High range y = 0.97x + 98r = 0.970, S.E.E. = 80.65;Assay Range: Low 25 to 450 ng/mL.High 450 to 2000 ng/mL.
	Within Imprecision: Percent CVs across 3levels of cyclosporine concentrations werebetween 3.0% and 5.0%.Total Imprecision: Percent CVs across 3 levelsof cyclosporine concentrations were between4.5% and 10.5%.	Within Run Imprecision: Percent CVsacross 5 levels of cyclosporineconcentrations were between 3.0% and8.0%.Total Imprecision: Percent CVs across5 levels of cyclosporine concentrationswere between 4.5% and 9.6% or S.D$=7.4$ for a control at 46 ng/mL.

Microgenics Corporation CEDIA Cyclosporine Plus Assay 510(k) Submission

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Microgenics Corporation
CEDIA Cyclosporine Plus Assay
510(k) Submission

Page 32 of 33

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End of 510(k) Summary

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DEPARTMENT OF HEALTH & HUMAN SERVICES

Image /page/4/Picture/1 description: The image is a black and white logo for the U.S. Department of Health & Human Services. The logo features the department's symbol, which consists of three stylized human profiles facing right, arranged in a stacked formation. The profiles are depicted with simple, curved lines. The symbol is encircled by the text "DEPARTMENT OF HEALTH & HUMAN SERVICES • USA", which is arranged in a circular fashion around the symbol.

Food and Drug Administration 2098 Gaither Road Rockville MD 20850

Mr. Mark Hamilton Smith Regulatory Specialist Microgenics Corporation 46360 Fremont Boulevard Fremont, CA 94538

Re: K023208

Trade/Device Name: CEDIA® Cyclosporine Plus Assay Regulation Number: 21 CFR 862.1235 Regulation Name: Cyclosporine test system Regulatory Class: Class II Product Code: MKW; JIS Dated: September 24, 2002 Received: September 25, 2002

Dear Mr. Smith:

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 the Code of Federal Regulations, Title 21, Parts 800 to 898. 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 Part 801); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

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Page 2 -

This letter will allow you to begin marketing your device as described in your 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 advice for your device on our labeling regulation (21 CFR Part 801 and ' additionally 809.10 for in vitro diagnostic devices), please contact the Office of Compliance at (301) 594-4588. Additionally, for questions on the promotion and advertising of your device, please contact the Office of Compliance at (301) 594-4639. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21CFR 807.97). Other general information on your responsibilities under the Act may be obtained 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/cdrl/dsmaldsmamain.html".

Sincerely yours,

Steven Butman

Steven I. Gutman, M.D., M.B.A. Director Division of Clinical Laboratory-Devices Office of Device Evaluation Center for Devices and Radiological Health

Enclosure

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STATEMENT OF INTENDED USE

510(K) Number (if known): not known KOA 3308

Device Name: CEDIA® Cyclosporine Plus Assay

Indications for Use:

Jean Cooper

(Division Sign-Off)
Division of Clinical Laboratory Devices
510(k) Number K023208

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

Prescription Use	✓
(Per 21 CFR 801.109)

Over-the-Counter Use ______

Concurrence of CDRH, Office of Device Evaluation (ODE)

Microgenics Corporation

CEDIA Cyclosporine Plus Assay

510(k) Submission

Page 14 of 33

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.