(675 days)
For in vitro diagnostic use with the IMMULITE® 1000 Analyzers - for the quantitative measurement of CA125 antigen in serum, as an aid in monitoring the response to therapy for patients with epithelian ovarian cancer, and in detecting residual ovarian cancer in patients who have undergone first-line therapy and would be considered for diagnostic second look procedures.
For in vitro diagnostic use with the IMMULITE® 2000 Systems Analyzers - for the quantitative measurement of CA125 antigen in serum, as an aid in monitoring the response to therapy for patients with epithelian ovarian cancer, and in detecting residual ovarian cancer in patients who have undergone first-line therapy and would be considered for diagnostic second-look procedures.
The IMMULITE®/IMMULITE 1000 OM-MA Assay is comprised of OM-MA Test Units (beads coated with murine monoclonal anti-CA125 antibody), OM-MA Cycle 1 Reagent Wedge (alkaline phosphatase conjugated to rabbit polyclonal anti-CA125 antibody in buffer), OM-MA Cycle 2 Reagent Wedge (buffer), and OM-MA Adjustors (Low and High, CA125 in a nonhuman protein/buffer matrix).
The IMMULITE® 2000 OM-MA Assay is a newer generation instrument that dispenses an individual bead from a pack into a separate reaction tube. It is comprised of OM-MA Bead Pack (beads coated with murine monoclonal anti-CA125 antibody), OM-MA Reagent Wedge (Well 1: alkaline phosphatase conjugated to rabbit polyclonal anti-CA125 antibody in buffer; Well 2: buffer), and OM-MA Adjustors (Low and High, CA125 in a nonhuman protein/buffer matrix).
Both assays are solid-phase, two-site chemiluminescent immunometric assays that measure CA125 antigen quantitatively in serum.
The Siemens Healthcare Diagnostics Products Ltd IMMULITE/IMMULITE 1000 OM-MA and IMMULITE 2000 OM-MA assays are intended for the quantitative measurement of CA125 antigen in serum. The devices aid in monitoring the response to therapy for patients with epithelial ovarian cancer and in detecting residual ovarian cancer in patients who have undergone first-line therapy.
Here's an analysis of the acceptance criteria and study proving device meets these criteria:
1. Table of Acceptance Criteria and Reported Device Performance
For IMMULITE/IMMULITE 1000 OM-MA Assay (modified):
| Acceptance Criteria | Reported Device Performance |
|---|---|
| Detection Limit (LoB) | 0.14 U/mL |
| Detection Limit (LoD) | 0.38 U/mL |
| Detection Limit (LoQ) | 2 U/mL |
| Assay Measuring Interval | 2 - 500 U/mL (confirmed by linearity with overall recovery bias ≤20%) |
| Method Comparison (Regression) | y = 0.995x - 0.199, y = 0.999x - 0.047, y = 1.022x - 0.821 (for Lot 1, 2, 3 respectively, against predicate IMMULITE 1000) |
| Precision (%CV) | Within-run: 2.9-4.5%, Within-Lab: 3.0-5.3% |
| Reproducibility (%CV) | Between-Lot: 5.25-6.45%, Total Reproducibility: 7.55-9.37% |
| Hook Effect (U/mL) | Detects >500 U/mL for concentrations as high as 84,500 U/mL |
| Biotin Interference | Specimens with biotin at 3500 ng/mL demonstrate ≤10% change in results. |
| Reference Range | 93%-94% of healthy individuals ≤ 21 U/mL (verified) |
| Shelf-life | Exceeded 365 days (estimated ty an: 665 to 30011 days) |
For IMMULITE 2000 OM-MA Assay (modified):
| Acceptance Criteria | Reported Device Performance |
|---|---|
| Detection Limit (LoB) | 0.18 U/mL |
| Detection Limit (LoD) | 0.43 U/mL |
| Detection Limit (LoQ) | 3 U/mL |
| Assay Measuring Interval | 3 - 500 U/mL (confirmed by linearity with overall recovery bias ≤15%) |
| Method Comparison (Regression) | y = 1.032x + 0.086, y = 0.955x - 0.256, y = 0.976x - 0.142 (for Lot 1, 2, 3 respectively, against predicate IMMULITE 2000) |
| Precision (%CV) | Within-run: 4.4-6.1%, Within-Lab: 5.1-7.7% |
| Reproducibility (%CV) | Lot-to-Lot: 1.89-4.94%, Total Reproducibility: 6.19-7.85% |
| Hook Effect (U/mL) | Detects >500 U/mL for concentrations as high as 80,000 U/mL |
| Biotin Interference | Specimens with biotin at 3500 ng/mL demonstrate ≤10% change in results. |
| Reference Range | 94% of healthy individuals ≤ 21 U/mL (verified) |
| Shelf-life | Exceeded 365 days (estimated ty an: 665 to 30011 days) |
2. Sample Size and Data Provenance
- Method Comparison Test Set: A total of 253 patient samples were used for method comparison studies for both the IMMULITE 1000 and IMMULITE 2000 assays. The documentation does not specify the country of origin of the data or whether it was retrospective or prospective.
- Precision Test Set: Five serum samples were tested for each assay (IMMULITE 1000 and IMMULITE 2000). The samples were tested in duplicate over 20 days, two runs per day, for a total of 80 replicates per sample level.
- Reproducibility Test Set: Five serum samples were tested for each assay (IMMULITE 1000 and IMMULITE 2000) using a 5x5x3 experimental design (5 days, 5 replicates, 3 reagent lots).
- Recovery Test Set: 19 samples were used for spike and recovery studies.
- Reference Range Verification Test Set: For each assay (IMMULITE 1000 and IMMULITE 2000), "apparently healthy female samples" were used. Specifically, for IMMULITE 1000, n=50 for Lot 1 and Lot 2, and n=45 for Lot 3. For IMMULITE 2000, n=50 for all three lots. The provenance is not explicitly stated beyond "healthy female samples."
- Stability Test Set: Native patient samples were used for accelerated stability studies, but the exact number of unique samples is not specified.
3. Number of Experts and Qualifications for Ground Truth
This device is an in vitro diagnostic (IVD) assay for quantitative measurement of a biomarker (CA125). The performance claims are based on analytical performance characteristics, not on interpretation of images or clinical outcomes by experts in the typical sense of a diagnostic imaging AI device. Therefore, the concept of "experts" to establish a ground truth for a test set, like radiologists or pathologists, is not directly applicable here. The "ground truth" for analytical performance studies is established by the assay's ability to accurately and precisely measure the analyte concentrations.
4. Adjudication Method for the Test Set
Not applicable. As an IVD assay measuring an analyte concentration, there is no adjudication process similar to that for subjective diagnostic interpretations. Performance is assessed through statistical analysis of quantitative results against established analytical methods and specifications.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
No. An MRMC study is relevant for diagnostic imaging devices where multiple human readers interpret cases. This document describes an in vitro diagnostic assay that quantitatively measures a biomarker, not a device requiring human interpretation for diagnosis. Therefore, the concept of "how much human readers improve with AI vs without AI assistance" does not apply.
6. Standalone Performance Measurement
Yes, the studies described are essentially standalone performance studies of the IMMULITE/IMMULITE 1000 OM-MA and IMMULITE 2000 OM-MA assays. The device (the assay) itself generates the quantitative measurement. The "human-in-the-loop" aspect, for this type of device, would be the clinician interpreting the numerical results in the context of a patient's treatment and disease status, a step downstream from the device's analytical performance. The studies focus on the analytical accuracy, precision, linearity, and interference of the assay itself.
7. Type of Ground Truth Used
The ground truth used for these analytical studies is primarily:
- Quantitative Reference Values / Expected Values:
- For Detection Limits (LoB, LoD, LoQ), ground truth is based on the statistical determination of the lowest measurable concentrations.
- For Linearity, ground truth is established by preparing samples with known, serially diluted concentrations (expected values).
- For Method Comparison, the predicate device's results are used as the comparative "ground truth" (or reference method) to assess equivalence.
- For Precision and Reproducibility, the ground truth is the inherent variability of the measurements around a mean dose.
- For Spike Recovery, ground truth is the "expected" concentration after spiking known amounts of analyte into samples.
- For Specificity (Cross-reactivity), ground truth is the known concentration of potentially cross-reacting substances.
- For Interference, ground truth is the known concentration of potentially interfering substances.
- For Reference Range, ground truth is derived from the established reference interval for healthy individuals (≤ 21 U/mL).
8. Sample Size for the Training Set
This document does not specify a separate "training set" or its size in the context of artificial intelligence or machine learning. The studies described are analytical performance validations for an in vitro diagnostic assay, which typically involve testing samples to verify performance against pre-defined specifications rather than training a machine learning model.
9. How the Ground Truth for the Training Set Was Established
As there is no mention of a "training set" in the context of AI/ML for this device, information on how its ground truth was established is not provided or applicable. The ground truth for the performance validation studies, as described in point 7, is based on established analytical methods and known concentrations.
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Image /page/0/Picture/0 description: The image contains the logo of the U.S. Food and 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.
September 8, 2023
Siemens Healthcare Diagnostics Products Ltd Stefani Vinkemeier Regulatory Affairs Professional Glyn Rhonwy, Llanberis Caernarfon Llanberis, Gwynedd LL55 4EL United Kingdom
Re: K213510
Trade/Device Name: IMMULITE/IMMULITE 1000 OM-MA IMMULITE 2000 OM-MA Regulation Number: 21 CFR 866.6010 Regulation Name: Tumor-Associated Antigen Immunological Test System Regulatory Class: Class II Product Code: LTK Dated: February 24, 2023 Received: February 27, 2023
Dear Stefani Vinkemeier:
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.
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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 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 (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).
Sincerely,
Ying Mao -S
Ying Mao, Ph.D. Branch Chief Division of Immunology and Hematology Devices OHT7: Office of In Vitro Diagnostics 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) K213510
Device Name IMMULITE/IMMULITE 1000 OM-MA IMMULITE 2000 OM-MA
Indications for Use (Describe)
I
For in vitro diagnostic use with the IMMULITE® 1000 Analyzers - for the quantitative measurement of CA125 antigen in serum, as an aid in monitoring the response to therapy for patients with epithelian ovarian cancer, and in detecting residual ovarian cancer in patients who have undergone first-line therapy and would be considered for diagnostic second look procedures.
For in vitro diagnostic use with the IMMULITE® 2000 Systems Analyzers - for the quantitative measurement of CA125 antigen in serum, as an aid in monitoring the response to therapy for patients with epithelian ovarian cancer, and in detecting residual ovarian cancer in patients who have undergone first-line therapy and would be considered for diagnostic second-look procedures.
| 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
This 510(k) summary of safety and effectiveness information is submitted in accordance with the requirements of 21 CFR 807.92 and SMDA 1990.
The assigned 510(k) number is: K213510____________________________________________________________________________________________________________________________
5.1 Submitter
| Contact Person: | Stefani Vinkemeier |
|---|---|
| Address: | Siemens Healthcare Diagnostics Products LtdGlyn Rhonwy, Llanberis Caernarfon, Llanberis,Gwynedd LL55 4EL GBR |
| E-mail: | stefani.vinkemeier@siemens-healthineers.com |
| Phone: | 302-489-9232 |
| Date of Preparation: | May 11, 2023 |
5.2 Device
Regulatory Information
| Trade Name: | IMMULITE®/IMMULITE 1000 OM-MA, |
|---|---|
| IMMULITE® 2000 OM-MA | |
| Common Name: | Test, Epithelial Ovarian Tumor-associated Antigen (Ca125) |
| Classification Name: | Tumor-associated antigen immunological test system |
| Regulation Number: | 21 CFR 866.6010 |
| Classification: | Class II |
| Product Code: | LTK |
| Review Panel: | Immunology (82) |
Design and Use of the Device
| Question | Yes | No |
|---|---|---|
| Is the device intended for prescription use (21 CFR 801 subpart D)? | X | |
| Is the device intended for over-the-counter use (21 CFR 801 subpart C)? | X | |
| Does the device contain components derived from a tissue or other biologic source? | X | |
| Is the device provided sterile? | X | |
| Is the device intended for single use? | X | |
| Is the device a reprocessed single use device? | X | |
| Does the device contain a drug? | X | |
| Does the device contain a biologic? | X | |
| Does the device use software? | X | |
| Does the submission include clinical information? | X | |
| Is the device implanted? | X |
5.3 Predicate Device
The predicate devices, IMMULITE 1000 OM-MA and IMMULITE 2000 OM-MA, manufactured by Siemens Healthcare Diagnostics Products Ltd, Glyn Rhonwy, Llanberis, Wales, United Kingdom, were cleared by the FDA under K981297 and K983391.
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5.4 Device Description
The IMMULITE®/IMMULITE 1000 OM-MA Assay is comprised of the following components:
| Component | Volume | Ingredients |
|---|---|---|
| OM-MA Test Units (LOP1) | 1 bead / test unit | murine monoclonal anti-CA125antibody |
| OM-MA Cycle 1 Reagent Wedge(LOPA) | 7.5 mL | alkaline phosphatase (bovinecalf intestine) conjugated torabbit polyclonal anti-CA125antibody in buffer, withpreservative |
| OM-MA Cycle 2 Reagent Wedge(LOPB) | 5 mL | buffer, with preservative |
| OM-MA Adjustors (Low andHigh, LOPL, LOPH) | 3 mL each | CA125 in a nonhumanprotein/buffer matrix, withpreservative. |
The IMMULITE® 2000 OM-MA Assay is a newer generation of the instrument. Rather than conducting the reactions in pre-packaged individual test units, this instrument dispenses an individual bead from a pack into a separate reaction tube. The IMMULITE® 2000 OM-MA Assay is comprised of the following components:
| Component | Volume | Ingredients |
|---|---|---|
| OM-MA Bead Pack (L2KOP) | 200 beads | murine monoclonal anti-CA125antibody |
| OM-MA Reagent Wedge (L2OPA2) | Well 1 - 11.5 mL | alkaline phosphatase (bovine calf intestine) conjugated to rabbit polyclonal anti-CA125antibody in buffer, with preservative |
| Well 2 – 6.5 mL | buffer, with preservative | |
| OM-MA Adjustors (Low and High, LOPL, LOPH) | 3 mL each | CA125 in a nonhuman protein/buffer matrix, withpreservative. |
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5.5 Test Principle
The IMMULITE/IMMULITE 1000 and IMMULITE 2000 OM-MA are solid-phase, two-site chemiluminescent immunometric assays. There are two incubation cycles of 30 minutes each.
During the initial 30-minute cycle, the patient sample is incubated with biotinylated antibody coated bead and alkaline phosphatase antibody conjugate. This cycle creates a bead pair immunocomplex sandwich consisting of capture Ab-antiqen-detection Ab. During the second 30-minute cycle, buffer is added to remove unbound conjugate, which is then removed by centrifugal wash.
The amount of alkaline phosphate bound is directly proportional to the analyte in the patient sample. Following the two 30-minute incubation periods, IMMULITE chemiluminescent substrate (LSUBX or L2SUBM) is added for a further 10-minute incubation period to generate the luminogenic reaction.
The chemiluminescent substrate underqoes hydrolysis in the presence of the alkaline phosphatase to yield an unstable intermediate, which then emits photons. The sustained emissions are measured by the luminometer. The resulting relative light units (RLU) are proportional to the concentration of CA 125 in the sample, which is expressed as U/mL.
5.6 Intended Use / Indications for Use
IMMULITE/IMMULITE® 1000 OM-MA Assay
For in vitro diagnostic use with the IMMULITE® and IMMULITE® 1000 Analyzers — for the quantitative measurement of CA125 antigen in serum, as an aid in monitoring the resoonse to therapy for patients with epithelian ovarian cancer, and in detecting residual ovarian cancer in patients who have undergone first-line therapy and would be considered for diagnostic second look procedures.
IMMULITE® 2000 OM-MA Assay
For in vitro diagnostic use with the IMMULITE® 2000 Systems Analyzers — for the quantitative measurement of CA125 antigen in serum, as an aid in monitoring the response to therapy for patients with epithelian ovarian cancer, and in detecting residual ovarian cancer in patients who have undergone first-line therapy and would be considered for diagnostic second-look procedures.
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5.7 Comparison to Predicate Device
| Attribute | Candidate Device:IMMULITE®/IMMULITE 1000 OM-MAAssay, modified | Predicate Device:IMMULITE®/IMMULITE 1000 OM-MA Assay, K981297 |
|---|---|---|
| Intended Use /Indications for Use | For in vitro diagnostic use with theIMMULITE® and IMMULITE® 1000Analyzers — for thequantitative measurement of CA125antigen in serum, as an aid inmonitoring the response to therapyfor patients with epithelial ovariancancer, and in detecting residualovarian cancer in patients who haveundergone first-line therapy andwould be considered for diagnosticsecond look procedures. | Same |
| Analyte | Cancer Antigen 125 | Same |
| Automated | Automated assay | Same |
| Measurement | Quantitative | Same |
| Sample Type | Human serum | Same |
| Detection Limit | LoB: 0.14 U/mLLoD: 0.38 U/mLLoQ: 2 U/mL | Analytical Sensitivity: 1 U/mL |
| Assay MeasuringInterval | 2 - 500 U/mL | 1 - 500 U/mL |
| Operating Principle | Immunologic sandwich | Same |
| Technology | Direct chemiluminescent | Same |
| Instrument | IMMULITE® 1000 systems | Same |
| Sample Volume | 50 μL | Same |
| Calibrator(Adjustors) | CA125 in a nonhuman protein/buffermatrix, withpreservative. | Same |
| Controls | Commercially available, minimum of 2levels | Same |
| Detection Antibody | alkaline phosphatase (bovine calfintestine) conjugated to rabbitpolyclonal anti-CA125 antibody | Same |
| Capture Antibody | monoclonal mouse anti-CA125 | Same |
| Biotin interference | Specimens that contain biotin at aconcentration of 3500 ng/mLdemonstrate a less than or equal to10% change in results. Biotinconcentrations greater than this maylead to incorrect results for patient | Specimens that contain biotin at aconcentration of 2 ng/mLdemonstration less than of equal to10% change in results. Biotinconcentrations greater than thismay lead to falsely elevated results. |
Comparison Table of Technological Characteristics for IMMULITE/IMMULITE 1000
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| Candidate Device: | Predicate Device: | |
|---|---|---|
| IMMULITE® 2000 OM-MA Assay,modified | IMMULITE® 2000 OM-MA Assay,K983391 | |
| Attribute | ||
| Intended Use /Indications for Use | For in vitro diagnostic use withthe IMMULITE® 2000 SystemsAnalyzers — for the quantitativemeasurement of CA125 antigenin serum, as an aid in monitoringthe response to therapy forpatients with epithelian ovariancancer, and in detecting residualovarian cancer in patients whohave undergone first-linetherapy and would beconsidered for diagnosticsecond-look procedures. | Same |
| Analyte | Cancer Antigen 125 | Same |
| Automated | Automated assay | Same |
| Measurement | Quantitative | Same |
| Sample Type | Human serum | Same |
| Detection Limit | LoB: 0.18 U/mLLoD: 0.43 U/mLLoQ: 3 U/mL | Analytical Sensitivity: 1 U/mL |
| Assay MeasuringInterval | 3 - 500 U/mL | 1 - 500 U/mL |
| Operating Principle | Immunologic sandwich | Same |
| Technology | Direct chemiluminescent | Same |
| Instrument | IMMULITE® 2000 andIMMULITE® 2000 XPi systems | Same |
| Sample Volume | 50 μL | Same |
| Calibrator(Adjustors) | CA125 in a nonhumanprotein/buffer matrix, withpreservative. | Same |
| Controls | Commercially available,minimum of 2 levels | Same |
| Detection Antibody | alkaline phosphatase (bovine calfintestine) conjugated to rabbitpolyclonal anti-CA125 antibody | Same |
| Capture Antibody | monoclonal mouse anti-CA125 | Same |
| Biotin interference | Specimens that contain biotin ata concentration of 3500 ng/mLdemonstrate a less than or equalto 10% change in results. Biotinconcentrations greater than thismay lead to incorrect results forpatient samples. | Specimens that contain biotin at aconcentration of 2 ng/mLdemonstration less than of equal to10% change in results. Biotinconcentrations greater than this maylead to falsely elevated results. |
Comparison Table of Technological Characteristics for IMMULITE 2000
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5.8 Summary of Performance Testing
Substantial equivalence of the modified IMMULITE®/IMMULITE 1000 OM-MA Assay and IMMULITE® 2000 OM-MA Assay were demonstrated by testing performance characteristics including detection capability, linearity, method comparison, precision, spike recovery, hook effect and interference.
The resulting performance data are provided in support of a substantial equivalence determination.
5.8.1 Detection Limits
LoB. LoD, and LoO were determined in accordance with Clinical and Laboratory Standards Institute (CLSI) EP17-A2: Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures: Approved Guideline - Second Edition. The LoB/LoD/LoQ estimates are summarized below:
| IMMULITE 1000 (U/mL) | IMMULITE 2000 (U/mL) | |
|---|---|---|
| Limit of Blank (LoB) | 0.14 | 0.18 |
| Limit of Detection (LoD) | 0.38 | 0.43 |
| Limit of Quantitation (LoQ) | 2 | 3 |
5.8.2 Measuring Interval / Linearity
Linearity was verified by testing samples spanning the assay range prepared by combining a high serum pool with a low serum sample to produce nine different levels.
For the IMMULITE 1000 OM-MA assay, linearity was confirmed across the assay range by acceptable bias of ≤20% at each individual level. Linear regression analysis of expected versus observed values confirm an overall recovery bias of ≤20% and supports the measuring interval of 2 U/mL to 500 U/mL.
For the IMMULITE 2000 OM-MA assay, linearity was confirmed across the assay range by acceptable bias of ≤15% at each individual level. Linear regression analysis of expected versus observed values confirm an overall recovery bias of ≤15% and supports the measuring interval of 3 U/mL to 500 U/mL.
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5.8.3 Method Comparison: Quantitative Assay
Method comparison studies were performed comparing the modified devices to the currently-marketed predicate devices (IMMULITE 1000 and IMMULITE 2000). A total of 253 patient samples covering the full range of the assay were analyzed on both methods.
A single replicate was processed for each sample. Passing-Bablok regression was used to compare the methods.
| Lot | SpecimenType | ComparisonAssay (x) | N | RegressionEquation | Sample Range(U/mL) |
|---|---|---|---|---|---|
| 1 | Serum | IMMULITE 1000 | 246 | $y = 0.995x - 0.199$ | 1.03 - 466 |
| 2 | Serum | IMMULITE 1000 | 246 | $y = 0.999x - 0.047$ | 1.68 - 455 |
| 3 | Serum | IMMULITE 1000 | 247 | $y = 1.022x - 0.821$ | 1.27 - 471 |
IMMULITE 1000
IMMULITE 2000
| Lot | SpecimenType | ComparisonAssay (x) | N | RegressionEquation | Sample Range(U/mL) |
|---|---|---|---|---|---|
| 1 | Serum | IMMULITE 2000 | 246 | $y = 1.032x + 0.086$ | 2.47 - 511 |
| 2 | Serum | IMMULITE 2000 | 246 | $y = 0.955x - 0.256$ | 2.11 - 525 |
| 3 | Serum | IMMULITE 2000 | 246 | $y = 0.976x - 0.142$ | 2.29 - 489 |
5.8.4 Verification of Assay Precision
Precision studies were conducted on one reagent lot per platform in accordance with CLSI EP05-A3 Evaluation of Precision of Quantitative Measurement Procedures. For each assay, testing was performed on five serum samples spanning the range of the assays. Each sample was tested in duplicate over a period of 20 days, two runs per day, for a total of 40 runs and 80 replicates. The results are given in the following tables.
Results for Within Run and Total precision for IMMULITE
| Mean Dose(U/mL) | Repeatability | Within-LabImprecision | |||
|---|---|---|---|---|---|
| S.D. | %CV | S.D. | %CV | ||
| Level 1 | 9.17 | 0.41 | 4.5 | 0.49 | 5.3 |
| Level 2 | 19.21 | 0.86 | 4.5 | 0.95 | 5.0 |
| Level 3 | 41.36 | 1.38 | 3.3 | 1.77 | 4.3 |
| Level 4 | 225.95 | 8.87 | 3.9 | 9.41 | 4.2 |
| Level 5 | 427.48 | 12.40 | 2.9 | 12.86 | 3.0 |
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| PrecisionSample | MeanDose(U/mL) | Repeatability | Within-LabImprecision | ||
|---|---|---|---|---|---|
| S.D. | %CV | S.D. | %CV | ||
| Level 1 | 11.23 | 0.59 | 5.2 | 0.68 | 6.0 |
| Level 2 | 23.69 | 1.45 | 6.1 | 1.82 | 7.7 |
| Level 3 | 42.59 | 1.86 | 4.4 | 2.19 | 5.1 |
| Level 4 | 226.17 | 10.57 | 4.7 | 11.66 | 5.2 |
| Level 5 | 451.54 | 22.58 | 5.0 | 26.82 | 5.9 |
Results for Within Run and Total precision for IMMULITE 2000
5.8.5 Verification of Assay Reproducibility
Reproducibility studies were conducted on three reagents lot per platform in accordance with CLSI EP05-A3 Evaluation of Precision of Quantitative Measurement Procedures, using the 5 x 5 x 3 experimental design. For each assay, testing was performed on five serum samples spanning the range of the assays. Each sample was tested in over a period of five days, with five replicates per sample. The results are given in the following tables.
| Sample | Mean Dose(U/mL) | Between-Lot | TotalReproducibility | ||
|---|---|---|---|---|---|
| SD | %CV | SD | %CV | ||
| 1 | 9.41 | 0.54 | 5.73 | 0.78 | 8.33 |
| 2 | 18.72 | 1.21 | 6.45 | 1.75 | 9.37 |
| 3 | 39.68 | 2.53 | 6.38 | 3.64 | 9.18 |
| 4 | 215.20 | 11.30 | 5.25 | 16.24 | 7.55 |
| 5 | 420.97 | 25.32 | 6.02 | 37.57 | 8.93 |
Reproducibility Results for IMMULITE
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| ReproducibilitySample | Mean Dose(U/mL) | Lot-to-Lot | TotalReproducibility | ||
|---|---|---|---|---|---|
| SD | %CV | SD | %CV | ||
| 1 | 11.26 | 0.53 | 4.66 | 0.81 | 7.15 |
| 2 | 22.94 | 1.13 | 4.94 | 1.76 | 7.66 |
| 3 | 40.49 | 1.34 | 3.30 | 2.64 | 6.52 |
| 4 | 213.03 | 4.02 | 1.89 | 13.18 | 6.19 |
| 5 | 425.82 | 18.49 | 4.34 | 33.43 | 7.85 |
Reproducibility Results for IMMULITE 2000
5.8.6 Recovery
Spike and recovery studies were performed by spiking samples 1 to 19 with three CA 125 solutions of differing concentrations.
| Solution | Observed | Expected | %O/E | |
|---|---|---|---|---|
| 1 | - | 2.7 | - | - |
| A | 32 | 33 | 97% | |
| B | 55 | 63 | 87% | |
| C | 106 | 125 | 85% | |
| 2 | - | 4.3 | - | - |
| A | 37 | 34 | 109% | |
| B | 63 | 65 | 97% | |
| C | 128 | 127 | 101% | |
| 3 | - | 2.9 | - | - |
| A | 32 | 33 | 97% | |
| B | 53 | 64 | 83% | |
| C | 108 | 125 | 86% | |
| 4 | - | 8.7 | - | - |
| A | 38 | 38 | 100% | |
| B | 66 | 69 | 96% | |
| C | 126 | 131 | 96% |
IMMULITE – Spiking solutions 602, 1218 and 2450 U/mL
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| Solution | Observed | Expected | %O/E | |
|---|---|---|---|---|
| 1 | - | 16 | - | - |
| A | 56 | 62 | 90% | |
| B | 88 | 104 | 85% | |
| C | 151 | 201 | 75% | |
| 2 | - | 28 | - | - |
| A | 63 | 73 | 86% | |
| B | 86 | 115 | 75% | |
| C | 165 | 212 | 78% | |
| 3 | - | 63 | - | - |
| A | 107 | 107 | 100% | |
| B | 135 | 149 | 91% | |
| C | 222 | 246 | 90% | |
| 4 | - | 95 | - | - |
| A | 119 | 137 | 87% | |
| B | 169 | 179 | 94% | |
| C | 247 | 276 | 89% |
IMMULITE 2000 - Spiking solutions 933, 1776 and 3716 U/mL
5.8.7 Hook Effect
CA 125 concentrations as high as 84,500 U/mL for the IMMULITE and 80,000 U/mL for the IMMULITE 2000 will report as >500 U/mL. The high-dose hook effect information provided in the Instructions for Use for the modified IMMULITE OM-MA and IMMULITE 2000 OM-MA was confirmed and remain as presented in K981297 and K983391, respectively.
5.8.8 Specificity (Cross-reactivity)
Specificity (cross-reactivity) of the modified OM-MA assays to compounds with structural similarities to the CA 125 tumor marker were evaluated. Cross-reactant solutions were prepared by dissolving each potential cross-reactant into an appropriate solvent. The resulting solutions were spiked into patient sample pools to produce final concentrations approximately equal to the concentrations listed in the labeling. The samples were compared to the appropriate level patient sample pool that was mixed with an equal volume of solvent to determine a percent cross-reactivity. The specificity information provided in the Instructions for Use for the modified IMMULITE OM-MA and IMMULITE 2000 OM-MA was confirmed and remains as presented in K981297 and K983391, respectively.
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IMMULITE Specificity
| Compound | Amount Added | Apparent U/mL | % Cross- reactivity |
|---|---|---|---|
| AFP | 10,000 IU/mL | ND | ND |
| CA15-3 | 1753 U/mL | 7.1 | 0.41% |
| CA19-9 | 4000 U/mL | ND | ND |
| CEA | 10,000 ng/mL | 4.8 | 0.05% |
ND: not detectable
IMMULITE 2000 Specificity
| Compound | Amount Added | Apparent U/mL | % Cross- reactivity |
|---|---|---|---|
| AFP | 10,000 IU/mL | ND | ND |
| CA15-3 | 1753 U/mL | 7.1 | 0.41% |
| CA19-9 | 4000 U/mL | ND | ND |
| CEA | 10,000 ng/mL | 4.8 | 0.05% |
ND: not detectable
5.8.9 Interference
Verification of the assay interference was conducted in accordance with CLSI EP07-ED3, Interference Testing in Clinical Chemistry. The tested substances were determined to have no substantial interference.
IMMULITE Interfering Substances
| Interfering Substance | Amount Added | % Bias |
|---|---|---|
| Conjugated Bilirubin | 200 mg/L | ≤10% |
| Unconjugated Bilirubin | 200 mg/L | ≤10% |
| Haemoglobin | 381 mg/dL | ≤10% |
| Intralipid (Triglycerides) | 3000 mg/dL | ≤10% |
| Biotin | 3500 mg/mL | ≤10% |
IMMULITE 2000 Interfering Substances
| Interfering Substance | Amount Added | % Bias |
|---|---|---|
| Conjugated Bilirubin | 200 mg/L | ≤10% |
| Unconjugated Bilirubin | 200 mg/L | ≤10% |
| Haemoglobin | 192 mg/dL | ≤10% |
| Intralipid (Triglycerides) | 3000 mg/dL | ≤10% |
| Biotin | 3500 ng/mL | ≤10% |
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5.8.10 Reference Range
The reference range was verified by assaying apparently healthy female samples according to CLSI EP28-A3, Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory, to verify the existing healthy Reference Interval (Healthy Individuals ≤ 21 U/mL).
IMMULITE Reference Range Results
| Lot 1 | Lot 2 | Lot 3 | |
|---|---|---|---|
| n | 50 | 50 | 45 |
| n < 21 U/mL | 47 | 47 | 42 |
| % < 21U/mL | 94% | 94% | 93% |
IMMULITE 2000 Reference Range Results
| Lot 1 | Lot 2 | Lot 3 | |
|---|---|---|---|
| n | 50 | 50 | 50 |
| n < 21 U/mL | 47 | 47 | 47 |
| % < 21U/mL | 94% | 94% | 94% |
Siemens provides this information for reference. As with all in vitro diagnostic assays, each laboratory should determine its own reference ranges for the diagnostic evaluation of patient results. Consider these values as a guideline only.
5.8.11 Stability
Siemens conducted an accelerated stability study using native patient samples, following CLSI EP25-A Evaluation of Stability of In Vitro Diagnostic Reagents. The shelf-life estimation (tyan) derived from each sample exceeded the kit shelf-life of 365 days for three kit lots tested.
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Shelf-life Estimation (tstab) in Days
| Sample | Lot 1 | Lot 2 | Lot 3 |
|---|---|---|---|
| Low-Dose (~11 U/mL) | 4165 | 884 | 30011 |
| MDL-Dose (~21 U/mL) | 3175 | 16257 | 7623 |
| High-Dose (~110 U/mL) | 1092 | 665 | 3582 |
5.9 Conclusion
These performance studies support that the modified IMMULITE®/IMMULITE 1000 OM-MA Assay and IMMULITE® 2000 OM-MA Assay are substantially equivalent to the IMMULITE 1000 OM-MA Assay and IMMULITE® 2000 OM-MA Assay that are currently marketed, with the exception of biotin interference.
§ 866.6010 Tumor-associated antigen immunological test system.
(a)
Identification. A tumor-associated antigen immunological test system is a device that consists of reagents used to qualitatively or quantitatively measure, by immunochemical techniques, tumor-associated antigens in serum, plasma, urine, or other body fluids. This device is intended as an aid in monitoring patients for disease progress or response to therapy or for the detection of recurrent or residual disease.(b)
Classification. Class II (special controls). Tumor markers must comply with the following special controls: (1) A guidance document entitled “Guidance Document for the Submission of Tumor Associated Antigen Premarket Notifications (510(k)s) to FDA,” and (2) voluntary assay performance standards issued by the National Committee on Clinical Laboratory Standards.