IMMULITE® 2000 Cortisol

K202826 · Siemens Healthcare Diagnostics Products, Ltd. · CGR · Jan 15, 2021 · Clinical Chemistry

Device Facts

• Record ID: K202826
• Device Name: IMMULITE® 2000 Cortisol
• Applicant: Siemens Healthcare Diagnostics Products, Ltd.
• Product Code: CGR · Clinical Chemistry
• Decision Date: Jan 15, 2021
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 862.1205
• Device Class: Class 2

Intended Use

For in vitro diagnostic use with the IMMULITE® 2000 Systems Analyzers — for the quantitative measurement of cortisol (hydrocortisone, Compound F) in serum, as an aid in the clinical assessment of adrenal status.

Device Story

IMMULITE® 2000 Cortisol is a solid-phase, enzyme-labeled chemiluminescent competitive immunoassay. Input: human serum sample. Operation: patient sample and enzyme-conjugated cortisol compete for limited polyclonal rabbit anti-cortisol antibody binding sites on a bead; 30-minute incubation; centrifugal washes remove unbound components; chemiluminescent substrate added. Output: signal inversely proportional to bound enzyme, representing cortisol concentration. Used in clinical laboratories on IMMULITE® 2000 Systems Analyzers. Output aids clinicians in assessing adrenal status. Benefit: provides quantitative diagnostic data for adrenal function evaluation.

Clinical Evidence

No clinical data. Performance supported by analytical bench testing, including precision, linearity, interference studies (bilirubin, hemoglobin, lipids, biotin), and a method comparison study (N=149) against the predicate device showing high correlation (r=0.981).

Technological Characteristics

Solid-phase, enzyme-labeled chemiluminescent competitive immunoassay. Components: polyclonal rabbit anti-cortisol antibody-coated beads, alkaline phosphatase-conjugated cortisol. Sample volume: 10 µL. Calibration range: 1-50 µg/dL. Instrument: IMMULITE 2000. Testing performed per CLSI guidelines (EP06-A, EP07, EP09c, 17-A2).

Indications for Use

Indicated for the quantitative measurement of cortisol in serum to aid in the clinical assessment of adrenal status in patients.

Regulatory Classification

Identification

A cortisol (hydrocortisone and hydroxycorticosterone) test system is a device intended to measure the cortisol hormones secreted by the adrenal gland in plasma and urine. Measurements of cortisol are used in the diagnosis and treatment of disorders of the adrenal gland.

Predicate Devices

• IMMULITE® 2000 Cortisol (K931409)

Submission Summary (Full Text)

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January 15, 2021

Siemens Healthcare Diagnostics Products Ltd. Malgorzata Robak Regulatory Affairs Supervisor Glyn Rhonwy. Llanberis Caernarfon, Gwynedd LL55 4EL UK

Re: K202826

Trade/Device Name: IMMULITE® 2000 Cortisol Regulation Number: 21 CFR 862.1205 Regulation Name: Cortisol (Hydrocortisone And Hydroxycorticosterone) Test System Regulatory Class: Class II Product Code: CGR Dated: September 22, 2020 Received: September 24, 2020

Dear Malgorzata Robak:

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. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database located at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. 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. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.

If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to 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

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requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR 803) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-products); good manufacturing practice requirements as set forth in the quality systems (OS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.

For comprehensive regulatory information about mediation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email ([e-mail]) or phone [phone] or 301-796-7100).

Sincerely,

Kellie B. Kelm, Ph.D. Director Division of Chemistry and Toxicology Devices OHT7: Office of In Vitro Diagnostics and Radiological Health Office of Product Evaluation and Quality Center for Devices and Radiological Health

Enclosure

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#### Indications for Use

510(k) Number (if known) k202826

Device Name IMMULITE® 2000 Cortisol

Indications for Use (Describe)

For in vitro diagnostic use with the IMMULITE® 2000 Systems Analyzers - for the quantitative measurement of cortisol (hydrocortisone, Compound F) in serum, as an aid in the clinical assessment of adrenal status.

| Type of Use (Select one or both, as applicable) |
|-------------------------------------------------|
|-------------------------------------------------|

X Prescription Use (Part 21 CFR 801 Subpart D)

| Over-The-Counter Use (21 CFR 801 Subpart C)

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### 510(k) Summary of Safety and Effectiveness for IMMULITE® 2000 Cortisol

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.

- A. 510(k) Number:_k202826
- B. Purpose of the Submission Modified Device - new supplier of the antibody
- C. Applicant:

| Contact: | Malgorzata Robak |
|----------|-------------------------------------------------|
| | Regulatory Affairs Supervisor |
| Address: | Siemens Healthcare Diagnostics Products Limited |
| | Glyn Rhonwy |
| | Llanberis, Caernarfon |
| | LL55 4EL |
| | United Kingdom |
| Phone: | [phone] |
| E-mail: | [e-mail] |
| Date: | January 8, 2021 |

#### D. Proprietary and Established Name:

IMMULITE® 2000 Cortisol

#### E. Measurand

Cortisol

#### F. Regulatory Information

| Trade Name: | IMMULITE® 2000 Cortisol |
|----------------------|---------------------------------------------------------------------|
| Common Name: | Chemiluminescence Immunoassay, for the<br>determination of Cortisol |
| Classification Name: | Cortisol Test System |
| FDA Classification: | Class II |
| Review Panel: | Clinical Chemistry |
| Product Code: | CRG |
| Requlation Number: | 21 CFR 862.1205 |

#### G. Predicate Device:

Device Name: IMMULITE® 2000 Cortisol

510(k) Number: K931409

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## Healthine

#### H. Intended Use:

Same as Indication for Use

#### -Indications for Use:

For in vitro diagnostic use with the IMMULITE® 2000 Systems Analyzers — for the quantitative measurement of cortisol (hydrocortisone, Compound F) in serum, as an aid in the clinical assessment of adrenal status.

#### J. Special Conditions for Use statement(s):

For Prescription Use Only

#### K. Special Instrument Requirements

For use with IMMULITE® 2000

#### L. Device Description

The IMMULITE 2000 Cortisol assay is comprised of the following components:

| Component | Volume | Ingredients |
|---------------------------------------------|-----------|---------------------------------------------------------------------------------------------------------|
| Cortisol Bead Pack<br>(solid phase) | 200 beads | Polyclonal rabbit anti-cortisol antibody. |
| Cortisol Reagent<br>Wedge (liquid<br>phase) | 11.5 mL | Alkaline phosphatase (bovine calf<br>intestine) conjugated to cortisol in buffer,<br>with preservative. |
| Cortisol Adjustors<br>(Low and High) | 3 mL | Cortisol in processed human serum, with<br>preservative. |

#### M. Substantial Equivalence Information

The following table demonstrates substantial equivalence between the IMMULITE 2000 Cortisol (Candidate Device) with an antibody from a new supplier and the currently marketed IMMULITE 2000 (Predicate Device) that was cleared under 510 (k) K931409.

| Trade name | Candidate Device (Modified)<br>IMMULITE® 2000 Cortisol | Predicate device<br>(Unmodified)<br>IMMULITE® 2000 Cortisol |
|--------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Intended Use | For in vitro diagnostic use<br>with the IMMULITE® 2000<br>Systems Analyzers — for<br>the quantitative<br>measurement of cortisol<br>(hydrocortisone, Compound<br>F) in serum, as an aid in the<br>clinical assessment of<br>adrenal status. | For in vitro diagnostic use<br>with the IMMULITE® 2000<br>Systems Analyzers — for<br>the quantitative<br>measurement of cortisol<br>(hydrocortisone, Compound<br>F) in serum, as an aid in the<br>clinical assessment of<br>adrenal status. |
| Analyte | Cortisol | Same |
| Automated | Automated Assay | Same |

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| Trade name | Candidate Device (Modified) | Predicate device<br>(Unmodified) |
|----------------------------------|---------------------------------------------------------------------------|-------------------------------------------------|
| | IMMULITE® 2000 Cortisol | IMMULITE® 2000 Cortisol |
| Measurement | Quantitative | Same |
| Sample Type | Human serum | Same |
| Detection<br>Limit | LoB: 0.014 µg/dL<br>(0.39 nmol/L) | Analytical Sensitivity: 0.20 µg/dL (5.5 nmol/L) |
| | LoD: 0.07 µg/dL<br>(1.9 nmol/L) | Not Applicable |
| | LoQ: 0.25 µg/dL<br>(6.9 nmol/L) | Not Applicable |
| Calibration<br>Range | 1-50 µg/dL (28 to 1380 nmol/L) | Same |
| Operating<br>Principle | Competitive | Same |
| Technology | Chemiluminescent enzyme<br>immunoassay | Same |
| Instrument | IMMULITE 2000 | Same |
| Sample<br>Volume | 10 µL | 10 µL |
| Calibrator | Two levels (low & high)<br>cortisol adjustor | Same |
| Controls | Commercial | Commercial |
| Detection<br>Enzyme<br>conjugate | Alkaline phosphatase<br>(bovine calf intestine)<br>conjugated to cortisol | Same |
| Capture<br>Antibody | Polyclonal rabbit anti-cortisol | Same |

#### N. Test Principle

IMMULITE 2000 Cortisol is a solid-phase, enzyme-labeled chemiluminescent competitive immunoassay. The solid phase (bead) is coated with polyclonal rabbit anti-cortisol antibody. The liquid phase consists of alkaline phosphatase (bovine calf intestine) conjugated to cortisol. The patient sample and the reagent are incubated together with the coated bead for 30 minutes. During this time, cortisol in the sample competes with enzyme-conjugated cortisol in the reagent for a limited number of antibody binding sites on the bead. Unbound patient sample and enzyme conjugate are then removed by centrifugal washes. Finally, chemiluminescent substrate is added to the test unit containing the bead and the signal is generated inversely proportional to the bound enzyme.

#### O. Performance Characteristics

The assay principle, design and reagent formulation has not changed from the original device. Substantial equivalence was demonstrated by testing several

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# Healthineer

performance characteristics including detection limits, linearity, precision, spike recovery, method comparison, interfering and cross-reactive substances. All the studies evaluated produced acceptable results when compared to the Predicate device and were deemed verified.

### 1. Detection Limits

LoB, LoD, and LoQ were determined in accordance with Clinical and Laboratory Standards Institute (CLSI) Section 008, p. 17-A2. The LoB/LoD/LoQ estimates are summarized below:

| Limit of Blank (LoB) | 0.014 µg/dL (0.39 nmol/L) |
|-----------------------------|---------------------------|
| Limit of Detection (LoD) | 0.07 µg/dL (1.9 nmol/L) |
| Limit of Quantitation (LoQ) | 0.25 µg/dL (6.9nmol/L) |

The reportable range of the IMMULITE 2000 Cortisol assay is 1 to 50 µg/dL (28 to 1380 nmol/L).

#### 2. Linearity

The Linearity study was conducted in accordance with the principles described in CLSI EP06-A: Evaluation of the Linearity of Quantitative Measurement Procedures: A Statistical Approach; Approved Guideline. Samples spanning the assay range were prepared by combining a high human serum pool with a low human serum pool for a total of 9 levels of dilutions prepared by mixing the high and low serum pools. The high serum pool consisted of a human serum pool sample spiked with cortisol to obtain a desired cortisol concentration at the upper end of the working range of the assay (observed concentration: 54.7ug/dL). The low serum pool consisted of a low-level human serum pool diluted with charcoal-adsorbed human serum in order to achieve a cortisol concentration at the approximate LoQ (observed concentration: 0.2 µg/dL).The modified IMMULITE 2000 Cortisol assay has been shown to be linear from 0.19 - 54.7 µg/dL. The Linearity information provided in the Instruction for Use for modified IMMULITE 2000 Cortisol has not changed and are as per K931409.

#### 3. Repeatability and Within-Lab Precision

The repeatability and within-lab precision information provided in the Instruction for Use for modified IMMULITE 2000 Cortisol has not changed and are as per K931409.

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#### 4. Spike Recovery

The spike and recovery information provided in the Instruction for Use for modified IMMULITE 2000 Cortisol has not changed and are as per K931409.

#### 5. Method Comparison with predicate device

A method comparison study was performed by comparing the modified device to the currently-marketed predicate device (unmodified IMMULITE 2000 Cortisol Assay) in accordance with CLSI EP09c Measurement Procedure Comparison and Bias Estimation Using Patient Samples, 3rd Edition. A total of 149 native patient samples covering the full range of the assay were assayed in duplicate split across 4 runs, with each run on a different instrument (40 patients on instrument 1-3, and 30 patients on instrument 4).

| Sample<br>Category | N | Range | Regression equation |
|--------------------|-----|----------------------|--------------------------------------------------------------------------|
| Serum | 149 | 1.97 – 48.7<br>µg/dL | IMM 2000 = 0.996 (IMMULITE 2000 commercial) -<br>0.0766 µg/dL. r = 0.981 |

#### 6. Specificity (Cross-Reactivity)

Specificity (cross-reactivity) of the modified IMMULITE 2000 Cortisol assay to the various compounds listed in the Table below were evaluated. Crossreactant solutions were prepared by dissolving each cross-reactant into an appropriate solvent (ethanol, methanol or NaOH). Each cross-reactant was then spiked at a ratio of 1:19 into an aliquot of a blank sample (charcoalabsorbed human serum) such that the final concentration in the sample was equal to that outlined in Table below. Blank samples were also prepared which consisted of charcoal-adsorbed human serum spiked 1:19 with the solvents used to prepare the cross-reactants. In addition to the cross reactants evaluated in K931409 following cross reactants were evaluated: Allotetrahydrocortisol, α-Cortol, α-Cortolone, β-Cortol' β-Cortolone, Dehydrocorticosterone 20a-Dihydrocortisol, 20ß-Dihydrocortisol, 20a-Dihydrocortisone, Estradiol, Fludrocortisone. Complete summary of the results are summarized below.

| Compound | Cross-<br>Reactant<br>added<br>concentration<br>(ug/dL) | % Cross-<br>Reactivity |
|------------------------------|---------------------------------------------------------|------------------------|
| Aldosterone | 1000 | ND |
| Androstenedione | 10000 | ND |
| Betamethasone | 1000 | ND |
| Corticosterone | 400 | 0.90% |
| Cortisone | 400 | 1.60% |
| 11-Deoxycorticosterone | 400 | ND |
| Compound | Cross-<br>Reactant<br>added<br>concentration<br>(µg/dL) | % Cross-<br>Reactivity |
| 11-Deoxycortisol | 100 | 4.70% |
| 21-Deoxycortisone | 500 | ND |
| Dexamethasone | 500 | ND |
| DHEA-SO4 | 10000 | ND |
| Estriol | 100 | ND |
| Estrone | 500 | ND |
| Fluticasone | 22 | ND |
| 17α-<br>Hydroxyprogesterone | 400 | ND |
| Methotrexate | 100 | ND |
| Methylprednisolone | 200 | 1.00% |
| Prednisolone | 8 | 23.80% |
| Prednisone | 16 | ND |
| Pregnanediol | 2000 | ND |
| Progesterone | 400 | ND |
| Spironolactone | 1000 | ND |
| Tetrahydrocortisone | 400 | ND |
| Triamcinolone | 5000 | ND |
| Allotetrahydrocortisol | 100 | 2.41% |
| α-Cortolone | 1000 | ND |
| α-Cortol | 1000 | ND |
| β-Cortol | 1000 | ND |
| β-Cortolone | 1000 | ND |
| 11-<br>Dehydrocorticosterone | 1000 | ND |
| 20α-dihydrocortisol | 1000 | 0.368% |
| 20β-dihydrocortisol | 1000 | ND |
| 20α-dihydrocortisone | 1000 | ND |
| Fludrocortisone | 1000 | ND |
| Estradiol | 1000 | ND |

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#### 7. Interference

Interference with the modified IMMULITE 2000 Cortisol assay was determined for the following substances: conjugated and unconjugated bilirubin, hemoglobin, intralipid and biotin. The paired difference approach was employed for this study as per CLSI EP07: Interference Testing in Clinical Chemistry, 3rd Edition. Working stock solutions of the interfering substance were prepared and spiked into 5 patient samples such that the final interferent

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concentration in the sample was equal to that found in Table below. The 5 patient samples ranged from 3.6 – 22.1 µg/dL. The interference information for Bilirubin, Hemolysis and Lipemia provided in the Instruction for Use for modified IMMULITE 2000 Cortisol has not changed and are as per K931409. Information regarding Biotin interference are summarized below:

| Interfering<br>Substance | Interfering<br>substance<br>spiking<br>concentration | Observed<br>Mean %<br>Recovery |
|--------------------------|------------------------------------------------------|--------------------------------|
| Biotin | 3500ng/mL | 108% |

#### 8. Clinical Evaluation

Not applicable

#### P. Conclusion

Based on the results of comparative testing, the modified IMMULITE® 2000 Cortisol is substantially equivalent to the currently marketed predicate device, IMMULITE® 2000 Cortisol.