LIAISON® Folate

K192586 · DiaSorin, Inc. · CGN · May 6, 2020 · Clinical Chemistry

Device Facts

• Record ID: K192586
• Device Name: LIAISON® Folate
• Applicant: DiaSorin, Inc.
• Product Code: CGN · Clinical Chemistry
• Decision Date: May 6, 2020
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 862.1295
• Device Class: Class 2

Indications for Use

The DiaSorin LIAISON® Folate assay uses chemiluminescent immunoassay (CLIA) technology for the quantitative determination of Folic acid in human serum. Folic acid measurements are used in the diagnosis and treatment of anemias. Assay results should be used in conjunction with other clinical or laboratory data to assist the clinician in making individual patient management decisions. The assay must be performed on the LIAISON® XL Analyzer.

Device Story

The LIAISON® Folate assay is a competitive chemiluminescence immunoassay (CLIA) performed on the LIAISON® XL Analyzer. It measures Folic acid in human serum samples. The process involves dissociating Folic acid from its binding protein using a high pH buffer, followed by competitive binding of Folic acid to a Folate Binding Protein on magnetic particles and a Folic acid-isoluminol derivative conjugate. After washing, starter reagents initiate a flash chemiluminescent reaction. A photomultiplier measures the light signal (relative light units), which is inversely proportional to the Folic acid concentration. The device is used in clinical laboratory settings by trained personnel. Results are provided to clinicians to aid in the diagnosis and management of anemias, such as megaloblastic anemia, in conjunction with other clinical data.

Clinical Evidence

Bench testing only. Method comparison study (n=157) against a commercially available method showed Passing & Bablok regression y = 0.96x - 0.61 (R=0.948). Precision studies (n=160) across 20 days showed total %CV ranging from 4.3% to 7.0%. Linearity (R=0.999) and recovery (97.6%–110.4%) were verified. Analytical specificity and interference testing (including hemoglobin, bilirubin, triglycerides, biotin, and various drugs) showed no significant interference. LoQ is 1.6 ng/mL.

Technological Characteristics

Competitive CLIA; solid phase: magnetic particles coated with bovine folate binding protein; conjugate: Folic acid-isoluminol derivative; energy source: chemiluminescent reaction; platform: LIAISON® XL Analyzer; sample type: human serum; storage: 2-8°C; traceability: WHO IS 03/178.

Indications for Use

Indicated for the quantitative determination of Folic acid in human serum to assist in the diagnosis and treatment of anemias in adult patients. For prescription use only.

Regulatory Classification

Identification

A folic acid test system is a device intended to measure the vitamin folic acid in plasma and serum. Folic acid measurements are used in the diagnosis and treatment of megaloblastic anemia, which is characterized by the presence of megaloblasts (an abnormal red blood cell series) in the bone marrow.

Predicate Devices

• Abbott Laboratories, ARCHITECT Folate (K092740)

Submission Summary (Full Text)

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Image /page/0/Picture/0 description: The image contains the logo of the U.S. Food & Drug Administration (FDA). On the left is the Department of Health & Human Services logo. To the right of that is the FDA logo, which is a blue square with the letters "FDA" in white. To the right of the blue square is the text "U.S. FOOD & DRUG ADMINISTRATION" in blue.

May 6, 2020

DiaSorin Inc. Mari Meyer Vice President of Regulatory & Clinical Affairs 1951 Northwestern Ave Stillwater, MN 55082-0285

### Re: K192586

Trade/Device Name: Liaison® Folate Regulation Number: 21 CFR 862.1295 Regulation Name: Folic Acid Test System Regulatory Class: Class II Product Code: CGN Dated: May 1, 2020 Received: May 4, 2020

## Dear Mari Meyer:

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 requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part

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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 (QS) 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 medical devices and radiation-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,

Marianela Perez-Torres, Ph.D. Acting Deputy 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) K192586

Device Name LIAISON® Folate

Indications for Use (Describe)

The DiaSorin LIAISON® Folate assay uses chemiluminescent immunoassay (CLIA) technology for the quantitative determination of Folic acid in human serum. Folic acid measurements are used in the diagnosis and treatment of anemias. Assay results should be used in conjunction with other clinical or laboratory data to assist the clinician in making individual patient management decisions.

The assay must be performed on the LIAISON® XL Analyzer.

| Type of Use (Select one or both, as applicable) | |
|--------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------|
| <span style="font-size: 10pt;"> <input checked="true" type="checkbox"/> Prescription Use (Part 21 CFR 801 Subpart D) </span> | <span style="font-size: 10pt;"> <input type="checkbox"/> Over-The-Counter Use (21 CFR 801 Subpart C) </span> |

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## 510(k) Summary

## LIAISON® Folate

This summary of 510(k) safety and effectiveness information is submitted in accordance with the requirements of SMDA 1990 and 21 CFR 807.92.

## 1. 510(k) Number: K192586

## 2. Applicant:

Mari Meyer Vice President of Regulatory and Clinical Affairs DiaSorin Inc. 1951 Northwestern Avenue, P.O. Box 285, Stillwater, MN 55082-0285 Office Number: 651-351-9710; Fax Number: 651-351-5669 Email: [e-mail]

### 3. Date: May 5, 2020

## 4. Proprietary and Established Names:

LIAISON® Folate

## 5. Regulatory Information:

Classification Name: Folic acid test system Trade Name: LIAISON® Folate Common Name: Folate Regulation: 21 CFR 862.1295 Classification: Class II Panel: Clinical Chemistry (75) Product Code: CGN

### 6. Predicate Devices:

The predicate device used to demonstrate substantial equivalence to the LIAISON® Folate Assay is the Abbott Laboratories, ARCHITECT Folate, (K092740).

## 7. Device Description:

The LIAISON® Folate assay is a competitive chemiluminescence immunoassay (CLIA) for quantitative determination of Folic acid in serum. During the first incubation, Folic acid is dissociated from its binding protein. After five (5) minutes, a high pH buffer is added to prevent re-association to the binding protein. After five (5) minutes, Folic acid binds to a Folate Binding Protein on the solid phase, which competes with a Folic acid linked to an isoluminol derivative. After a third incubation, the unbound material is removed with a wash cycle. Subsequently, the starter reagents are added to initiate a flash chemiluminescent reaction. The light signal is measured by a photomultiplier as relative light units (RLU) and is inversely proportional to the concentration of Folic acid present in calibrators, controls, or samples.

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# 8. Intended Use:

The DiaSorin LIAISON® Folate Assay uses chemiluminescent immunoassay (CLIA) technology for the quantitative determination of Folic acid in human serum. Folic acid measurements are used in the diagnosis and treatment of anemias. Assay results should be used in conjunction with other clinical or laboratory data to assist the clinician in making individual patient management decisions.

The assay must be performed on the LIAISON® XL Analyzer.

# 9. Indication(s) for Use:

Same as Intended Use

## 10. Substantial Equivalence Information:

A comparison of the similarities and differences between the LIAISON® Folate and the predicate is provided below:

| Assay - Similarities and Differences | | |
|--------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Characteristic | Candidate Device | Predicate Device |
| | LIAISON® Folate | Abbott Laboratories, ARCHITECT Folate (K092740) |
| Intended Use | The DiaSorin LIAISON® Folate assay uses chemiluminescent immunoassay (CLIA) technology for the quantitative determination of Folic acid in human serum. Folic acid measurements are used in the diagnosis and treatment of anemias. Assay results should be used in conjunction with other clinical or laboratory data to assist the clinician in making individual patient management decisions.<br><br>The assay must be performed on the LIAISON® XL Analyzer. | The ARCHITECT Folate assay is a chemiluminescent microparticle Folate Binding Protein assay for the quantitative determination of folate in human serum and plasma on the ARCHITECT iSystem.<br><br>Folate measurements are used in the diagnosis and treatment of megaloblastic anemia. |
| Measured Analyte | Folate | Same |
| Assay Type | Chemiluminescence Immunoassay | Same |
| Results | Quantitative | Same |
| Sample Type | Human Serum | Human Serum & Plasma |
| Sample size | 50 μL | 150 μL |
| Storage | 2-8°C | Same |
| Operating Principle | Automated Chemiluminescence Immunoassay (CLIA) | Same |
| Solid Phase | Magnetic particles coated with bovine folate binding protein | Microparticles coated with mouse monoclonal antibodies bound to bovine folate binding protein |

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| Assay - Similarities and Differences | | |
|--------------------------------------|-------------------------------------------------------------------------|---------------------------------------------------------------------------------------|
| Characteristic | Candidate Device | Predicate Device |
| Conjugate | LIAISON® Folate<br>Folic acid conjugated to an<br>isoluminol derivative | Abbott Laboratories,<br>ARCHITECT Folate (K092740)<br>Acridinium labeled pteroic acid |
| Analytical<br>Measuring Range | 1.6 ng/mL - 20 ng/mL | Same |

#### Standard/quidance Document Reference: 11.

- CLSI Guideline EP5-A3, Evaluation of Precision of Quantitative Measurement o Procedures; Approved Guideline.
- CLSI Guideline EP15-A3, User Verification of Precision and Estimation of Bias; O Approved Guideline.
- CLSI Guideline EP07-A2. Interference Testing in Clinical Chemistry. Approved O Guideline.
- CLSI Guideline EP06-A, Evaluation of the Linearity of Quantitative Measurement o Procedures: A Statistical Approach: Approved Guideline.
- CLSI Guideline EP 17-A2, Evaluation of Detection Capability for Clinical O Laboratory Measurement Procedures; Approved Guideline.
- CLSI EP37-A: Supplemental Tables for Interference Testing in Clinical o Chemistry; First Edition, April 2018.
- CLSI Guideline EP09-A3, Measurement Procedure Comparison and Bias O Estimation Using Patient Samples; Approved Guideline.
- CLSI Guideline EP28-A3C, Defining, Establishing and Verifying Reference o Intervals in the Clinical Laboratory; Approved Guideline.

## 12. Performance Characteristics:

## Method Comparison

A total of 157 human serum samples spanning the assay range, were tested by the LIAISON® Folate and by another commercially available method following CLSI EP9-A3. The study yielded the following Passing & Bablok regression analysis: LIAISON® Folate = (y = 0.96x - 0.61); R = 0.948

| Medical Decision<br>level | Bias | 95% confidence interval |
|---------------------------|--------------|-------------------------|
| 4.41 ng/mL | -0.772 ng/mL | -1.550 to -0.130 ng/mL |

# Bias at the medical decision level:

## Expected Values

It is recommended that each laboratory establish its own range of expected values for the population taken into consideration.

To assess the expected reference range for the LIAISON® Folate assay, a study was performed with prospectively collected serum samples from 166 apparently healthy Section 5 Page 3 of 6

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adults 21 - 59 years of age from mixed ethnic backgrounds (30% Caucasian, 32% African Americans and 38% Hispanics) who were fasting for at least eight (8) hrs. Apparently healthy status was determined by subjects who had no history of anemias, Folic acid or B12 deficiency, IBD or suspected IBD, celiac disease, gastrointestinal malabsorption disorders, or eating disorders. No oral contraceptive use within three (3) months and no alcohol within 48 hours of blood draw. No pregnant women or anyone taking folic acid supplementation were included in the study population.

Based on the 95% Confidence Interval the following values were established according to CLSI guideline C28-A3.

| Observed Reference Ranges | | | |
|---------------------------|--------------|----------------------------------------|-------|
| Population (n=166) | Median | Observed<br>2.5th to 97.5th Percentile | Range |
| United States | 8.22 (ng/mL) | 3.96 ng/mL – 16.70 (ng/mL) | |

#### Precision

Two (2) kit controls and six (6) samples containing concentrations of analyte prepared to span the range of the assay were assaved twice per day in duplicate, over 20 operating days using two (2) reagent lots, to determine repeatability and reproducibility of the LIAISON® Folate assay.

Results Table for Combined Lots

| | | mean | Repeatability<br>(Between-Lot) | | Reproducibility<br>(Total Across Lots) | |
|-------------------|-----|---------|--------------------------------|------|----------------------------------------|------|
| Sample ID | n | (ng/mL) | SD | %CV | SD | %CV |
| Kit Control 1 | 160 | 4.79 | 0.14 | 2.9% | 0.25 | 5.3% |
| Kit Control 2 | 160 | 12.33 | 0.23 | 1.8% | 0.52 | 4.3% |
| Precision Serum 1 | 160 | 2.90 | 0.18 | 6.4% | 0.20 | 7.0% |
| Precision Serum 2 | 160 | 4.57 | 0.18 | 3.9% | 0.27 | 5.8% |
| Precision Serum 3 | 160 | 7.87 | 0.14 | 1.8% | 0.40 | 5.1% |
| Precision Serum 4 | 160 | 10.2 | 0.04 | 0.4% | 0.50 | 4.9% |
| Precision Serum 5 | 160 | 12.1 | 0.08 | 0.7% | 0.64 | 5.3% |
| Precision Serum 6 | 160 | 14.1 | 0.22 | 1.6% | 0.72 | 5.1% |

### Results Table for Single Lot

| Sample<br>ID | n | mean<br>(ng/mL) | Within-Run | | Run-to-Run | | Day-to-Day | | TOTAL<br>(Within-lot) | |
|--------------|----|-----------------|------------|------|------------|------|------------|------|-----------------------|------|
| | | | SD | %CV | SD | %CV | SD | %CV | SD | %CV |
| Control 1 | 80 | 4.69 | 0.22 | 4.7% | 0.05 | 1.0% | 0.13 | 2.9% | 0.26 | 5.6% |
| Control 2 | 80 | 12.49 | 0.29 | 2.3% | 0.29 | 2.3% | 0.40 | 3.2% | 0.57 | 4.6% |
| Serum 1 | 80 | 2.77 | 0.11 | 4.1% | 0.14 | 5.2% | 0.10 | 3.7% | 0.21 | 7.6% |
| Serum 2 | 80 | 4.44 | 0.13 | 3.0% | 0.21 | 4.7% | 0.10 | 2.3% | 0.27 | 6.0% |
| Serum 3 | 80 | 7.77 | 0.20 | 2.6% | 0.20 | 2.5% | 0.35 | 4.5% | 0.45 | 5.8% |
| Serum 4 | 80 | 10.24 | 0.26 | 2.5% | 0.16 | 1.6% | 0.50 | 4.9% | 0.58 | 5.7% |
| Serum 5 | 80 | 12.10 | 0.30 | 2.5% | 0.46 | 3.8% | 0.53 | 4.4% | 0.76 | 6.3% |
| Serum 6 | 80 | 14.24 | 0.33 | 2.3% | 0.32 | 2.2% | 0.73 | 5.1% | 0.84 | 6.1% |

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## Linearity

One neat high serum sample containing endogenous Folate, above the measuring range of the assay at 20 ng/mL, was diluted with a contrived low serum sample for preparing the dilution series. The dilution series was analyzed by the LIAISON® Folate assay following CLSI EP6-A. The results were analyzed by regression of observed concentration versus expected concentration.

The resulting equation is: Serum: Observed Folate = 1.011 (Expected) - 0.147; R = 0.999

## Recovery

Seven (7) neat high concentration serum samples were analyzed with the LIAISON Folate assay. Recovery samples were then prepared by diluting the samples with the LIAISON Endocrinology Diluent according to the IFU. The results are provided in the following table.

| Sample | Neat (ng/mL) | Calculated dilution 1:3<br>(ng/mL) | Diluted 1:3<br>(ng/mL) | % recovery |
|--------|--------------|------------------------------------|------------------------|------------|
| S1 | 22.9 | 5.73 | 5.83 | 101.8% |
| S2 | 30.6 | 7.65 | 7.71 | 100.8% |
| S3 | *18.5 | 4.63 | 4.95 | 107.0% |
| S4 | *19.6 | 4.90 | 4.86 | 99.2% |
| S5 | 38.4 | 9.60 | 10.6 | 110.4% |
| S6 | 27.9 | 6.98 | 6.81 | 97.6% |
| S7 | 23.4 | 5.85 | 5.87 | 100.3% |

### Analytical Specificity

### Cross-Reactivity

Controlled Studies of potentially cross-reacting substances were performed on the LIAISON® Folate assay at the concentrations listed below. The testing was based on CLSI-EP7-A2.

| Cross-Reactant | Spiked<br>Concentration | % Cross<br>Reactivity |
|--------------------------------|-------------------------|-----------------------|
| Aminopterin | 490 ng/mL | 0.488% |
| Phenytoin | 201,400 ng/mL | 0.000% |
| Methotrexate<br>(Amethopterin) | 1,000 ng/mL | 0.781% |
| Folinic Acid (Leucovorin) | 500 ng/mL | 1.730% |

### Interfering Substances

Controlled studies of potentially interfering substances performed serum at 2 levels showed no interference in the LIAISON® Folate at the highest concentration for each substance listed below. The testing was based on CLSI-EP7-A2.

| Drug/Substance | Concentration Tested |
|----------------|----------------------|
|----------------|----------------------|

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| Hemoglobin | 30 mg/dL |
|--------------------------|-------------|
| Bilirubin (conjugated) | 35 mg/dL |
| Bilirubin (unconjugated) | 40 mg/dL |
| Triglycerides | 3,000 mg/dL |
| Cholesterol | 500 mg/dL |
| Albumin | 9 g/dL |
| Human IgG | 7.5 g/dL |
| HAMA | 807 ng/mL |
| Rheumatoid Factor | 1000 IU/mL |
| Acetaminophen | 20 mg/dL |
| Acetylsalicylic Acid | 65 mg/dL |
| Ibuprofen | 50 mg/dL |
| Biotin | 2.5 mg/mL |
| Acetylcysteine | 283 mg/dL |
| Ampicillin Na | 1000 mg/dL |
| Cefoxitin | 660 mg/dL |
| Cyclosporin | 5 mg/dL |
| Doxycycline hyclate | 6.25 mg/dL |
| Levodopa | 20 mg/dL |
| Methyldopa | 20 mg/dL |
| Metronidazole | 25 mg/dL |
| Phenylbutazone | 40 mg/dL |
| Rifampicin | 7.5 mg/dL |
| Theophylline | 5 mg/dL |
| Ascorbic Acid | 44 mg/dL |

Limit of Blank, Limit of Detection and Limit of Quantitation

The Limit of Blank, Limit of Detection and Limit of Quantitation were determined according to CLSI EP17-A2: Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures; Approved Guideline June 2012- Second Edition.

The following limits were determined with the LIAISON® Folate assay:

The limits are reported in the following table:

| LoB | LoD | LoQ |
|------------|-----------|-----------|
| ≤1.2 ng/mL | 1.4 ng/mL | 1.6 ng/mL |

Stability

| Product | Storage Conditions | | Claimed stability |
|-------------------|--------------------|-------|-------------------|
| Reagent Integral | Open vial | 2-8°C | 6 weeks |
| Calibration curve | N/A | N/A | 21 days |

Traceability

The LIAISON® Folate Calibrators are traceable to the WHO IS 03/178 (pg/mL).

#### 13. Conclusion:

The LIAISON® Folate assay is substantially equivalent in principle and performance to the Abbott Laboratories, ARCHITECT Folate.