CEDIA CYCLOSPORINE PLUS ASSAY

K023208 · Microgenics Corp. · MKW · Oct 24, 2002 · Clinical Chemistry

Device Facts

• Record ID: K023208
• Device Name: CEDIA CYCLOSPORINE PLUS ASSAY
• Applicant: Microgenics Corp.
• Product Code: MKW · Clinical Chemistry
• Decision Date: Oct 24, 2002
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 862.1235
• Device Class: Class 2

Indications for Use

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 Story

The CEDIA Cyclosporine Plus Assay is a two-reagent homogeneous enzyme immunoassay used with automated clinical chemistry analyzers to measure cyclosporine levels in human whole blood. The assay utilizes recombinant DNA technology to produce two inactive fragments of the bacterial enzyme β-galactosidase: Enzyme Acceptor (EA) and Enzyme Donor (ED). In the assay, cyclosporine in the patient sample competes with cyclosporine conjugated to ED for antibody binding sites. If cyclosporine is present, it binds to the antibody, allowing the ED-cyclosporine conjugate to reassociate with EA, forming active β-galactosidase. This active enzyme cleaves a substrate to produce a color change measured spectrophotometrically. The resulting absorbance is proportional to the cyclosporine concentration. The device is used in clinical laboratory settings by technicians to assist physicians in monitoring immunosuppressive therapy for transplant patients, helping to optimize dosing and improve patient outcomes.

Clinical Evidence

Clinical performance evaluated via method comparison against an HPLC reference method across heart, lung, and kidney transplant samples. Results: Low range (25-450 ng/mL) y=0.99x+8, r=0.93, S.E.E.=25.79; High range (450-2000 ng/mL) y=0.97x+98, r=0.970, S.E.E.=80.65. Within-run imprecision (CVs) 3.0-8.0%; total imprecision (CVs) 4.5-9.6%.

Technological Characteristics

Two-reagent homogeneous enzyme immunoassay. Uses recombinant β-galactosidase fragments (Enzyme Acceptor and Enzyme Donor). Requires lysing reagent for whole blood pretreatment. Operates on automated clinical chemistry analyzers via spectrophotometric measurement of color change. US Patent No. 4708929.

Indications for Use

Indicated for quantitative determination of cyclosporine in human whole blood to aid in therapeutic management of kidney, liver, and heart transplant patients.

Regulatory Classification

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.

Special Controls

*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.

Predicate Devices

• EMIT 2000 Cyclosporine Specific Assay (P920031)

Submission Summary (Full Text)

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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: [phone] |
| | FAX: [phone] |

- 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))

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.

Microgenics Corporation CEDIA Cyclosporine Plus Assay 510(k) Submission

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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.

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

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.

# 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<br>(P920031) | CEDIA Cyclosporine Plus Assay<br>(new device) |
|---------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Device Name | | |
| Indications<br>for Use | The Emit 2000 Cyclosporine Specific<br>Assay is for in vitro diagnostic use on the<br>Roche Diagnostics Systems COBAS MIRA,<br>COBAS MIRA S and COBAS MIRA Plus<br>chemistry systems for the quantitative<br>analysis of cyclosporine (CsA) in human<br>whole blood as an aid in the management<br>of cyclosporine therapy in kidney, heart,<br>and liver transplants. | The CEDIA Cyclosporine Plus<br>Assay is for the quantitative<br>determination of cyclosporine in<br>human whole blood using<br>automated clinical chemistry<br>analyzers as an aid in the<br>management of therapy in kidney,<br>liver, and heart transplants. The<br>CEDIA Cyclosporine Calibrators<br>are used to calibrate the CEDIA<br>Cyclosporine Plus Assay in<br>human whole blood. |
| Method<br>Principle | The assay uses a mouse monoclonal antibody<br>with specificity to cyclosporine and a second<br>mouse monoclonal antibody specific for a<br>major metabolite of cyclosporine, AM9 (M1)<br>to prevent metabolite binding to the primary<br>antibody.<br><br>The assay is based on competition for<br>cyclosporine antibody binding sites between<br>analyte in the sample and cyclosporine labeled<br>with G6-PDH. Active (unbound) enzyme<br>converts NAD to NADH, resulting in an<br>absorbance change measured | The CEDIA Cyclosporine Plus Assay is<br>a two-reagent set intended to be used<br>with automated clinical chemistry<br>analyzers. The assay uses recombinant<br>DNA technology (US Patent No.<br>4708929) to produce a unique<br>homogeneous enzyme immunoassay<br>system. The assay is based on the<br>bacterial enzyme $ β $ -galactosidase,<br>which has been genetically engineered<br>into two inactive fragments. These<br>fragments, termed Enzyme Acceptor<br>(EA) and Enzyme Donor (ED) |
| Device Name | EMIT 2000 Cyclosporine Specific Assay<br>(P920031) | CEDIA Cyclosporine Plus Assay<br>(new device) |
| Method<br>Principle,<br>continued | spectrophotometrically.<br><br>Before testing, samples are pretreated with<br>methanol. The pretreatment lyses the cells,<br>solubilizes the cyclosporine, and precipitates<br>most of the blood proteins. The samples are<br>centrifuged, and an aliquot of the resulting<br>supernatant is then assayed | (EA) and Enzyme Donor (ED),<br>spontaneously reassociate to form fully<br>active enzyme, which, in the assay<br>format, cleaves a substrate to generate a<br>color change that can be measured<br>spectrophotometrically.<br>In the CEDIA Cyclosporine Plus<br>Assay, cyclosporine in the sample<br>competes with the cyclosporine<br>conjugated to ED for antibody binding<br>sites. If cyclosporine is present in the<br>sample, it binds to the antibody, leaving<br>the ED-cyclosporine conjugate free to<br>reassociate with EA to form active β-<br>galactosidase. If no cyclosporine is<br>present in the sample, antibody binds to<br>the ED-conjugate, inhibiting the<br>reassociation of inactive β-<br>galactosidase fragments, and thus<br>reducing the amount of active enzyme<br>formed. The amount of active enzyme<br>formed and the resulting absorbance<br>change are proportional to the amount<br>of cyclosporine present in the sample.<br>The pretreatment reagent lysis the cell |
| Components | - Reagent A<br>- Enzyme B Reagent | and solubilizes the whole blood for<br>testing.<br>- Enzyme Acceptor Reagent<br>- Enzyme Acceptor Buffer<br>- Enzyme Donor Reagent<br>- Enzyme Donor Buffer<br>- Lysing Reagent |
| Risk to patient | An in vitro diagnostic device that can be<br>used as an aid in the management of<br>cyclosporine therapy. | An in vitro diagnostic device that can<br>be used as an aid in the<br>management of patients receiving<br>cyclosporine. |
| Clinical<br>Performance | Accuracy: (See Attachment B: Predicate<br>Device Labeling, Section 11, Table 10.) The<br>Syva Emit Package Insert provides Method<br>Comparison Data from studies at four separate<br>sites. Below our the results from one repre-<br>sentative study comparing all 3 transplant<br>types (heart, lung, kidney) to an HPLC<br>Reference Method: | Accuracy: Method comparison of all<br>transplant types to an HPLC reference<br>method yielded the following results:<br>Low range y = 0.99x + 8<br>r = 0.93, S.E.E. = 25.79; |
| Device Name | EMIT 2000 Cyclosporine Specific Assay<br>(P920031) | CEDIA Cyclosporine Plus Assay<br>(new device) |
| Clinical<br>Performance,<br>continued | Site 4: y=1.05 + 12; r = 0.96, S.E.E. = 25.33<br>Assay Range: 0 to 500 ng/mL. | High range y = 0.97x + 98<br>r = 0.970, S.E.E. = 80.65;<br>Assay Range: Low 25 to 450 ng/mL.<br>High 450 to 2000 ng/mL. |
| | Within Imprecision: Percent CVs across 3<br>levels of cyclosporine concentrations were<br>between 3.0% and 5.0%.<br>Total Imprecision: Percent CVs across 3 levels<br>of cyclosporine concentrations were between<br>4.5% and 10.5%. | Within Run Imprecision: Percent CVs<br>across 5 levels of cyclosporine<br>concentrations were between 3.0% and<br>8.0%.<br>Total Imprecision: Percent CVs across<br>5 levels of cyclosporine concentrations<br>were between 4.5% and 9.6% or S.D<br>$=7.4$ 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

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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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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 [phone]. Additionally, for questions on the promotion and advertising of your device, please contact the Office of Compliance at [phone]. 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 [phone] or [phone] 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:

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.

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) | |

OR

Over-the-Counter Use ______

Concurrence of CDRH, Office of Device Evaluation (ODE)

Microgenics Corporation

CEDIA Cyclosporine Plus Assay

510(k) Submission

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