(506 days)
ACL TOP 970 CL: The ACL TOP 970 CL is a bench top, fully automated, random access analyzer designed specifically for in vitro diagnostic use by health care professionals in a clinical laboratory. The system provides results for both direct measurements and calculated parameters.
HemosIL CL Anti-Cardiolipin IgM: HemosIL CL Anti-Cardiolipin IgM is a fully automated chemiluminescent immunoassay for the semi-quantitative measurement of anti-cardiolipin (aCL) IgM antibodies in human 3.2% or 3.8% citrated plasma on the ACL TOP 970 CL in the laboratory setting by a healthcare professional, as an aid in the diagnosis of Antiphospholipid Syndrome (APS) when used in conjunction with other laboratory and clinical findings. For use with adult population. For prescription use only.
HemosIL CL Anti-ß2 Glycoprotein-I IgM: HemosIL CL Anti-B2 Glycoprotein-I IgM is a fully automated chemiluminescent immunoassay for the semi-quantitative measurement of anti-B2 Glycoprotein-I (anti-B2GPI) IgM antibodies in human 3.2% or 3.8% citrated plasma on the ACL TOP 970 CL in the laboratory setting by a healthcare professional, as an aid in the diagnosis of Antiphospholipid Syndrome (APS) when used in conjunction with other laboratory and clinical findings. For use with adult population. For prescription use only.
ACL TOP 970 CL Instrument: The ACL TOP 970 CL is an instrument that integrates new chemiluminescent test capability similar to the ACL AcuStar, K083518.
HemosIL CL Anti-Cardiolipin IgM: HemosIL CL Anti-Cardiolipin IgM is a chemiluminescent two-step immunoassay consisting of magnetic particles coated with cardiolipin and human purified ß2GPI, which capture, if present, the aCL antibodies from the sample. After incubation, magnetic separation, and a wash step, a tracer consisting of an isoluminol-labeled anti-human IgM antibody is added and may bind with the captured aCL IgM on the particles. After a second incubation, magnetic separation, and wash step, reagents that trigger the luminescent reaction are added, and the emitted light is measured as relative light units (RLU) by the ACL TOP 970 CL optical system. RLUs are directly proportional to the aCL IgM concentration in the sample.
HemosIL CL Anti-ß2 Glycoprotein-I IgM: HemosIL CL Anti-ß2 Glycoprotein-I IgM is a chemiluminescent two-step immunoassay consisting of magnetic particles coated with human purified ß2GPI, which capture, if present, the aß2GPI antibodies from the sample. After incubation, magnetic separation, and a wash step, a tracer consisting of an isoluminol-labeled anti-human IgM antibody is added and may bind with the captured aß2GPI IgM on the particles. After a second incubation, magnetic separation, and wash step, reagents that trigger the luminescent reaction are added, and the emitted light is measured as relative light units (RLUs) by the ACL TOP 970 CL optical system. RLUs are directly proportional to the aß2GPI IgM concentration in the sample.
The provided text describes the 510(k) summary for the ACL TOP 970 CL instrument and two associated immunoassays, HemosIL CL Anti-Cardiolipin IgM and HemosIL CL Anti-β2 Glycoprotein-I IgM. The studies presented focus on analytical performance and comparability to predicate devices, rather than AI model performance or human-in-the-loop studies. Therefore, many of the requested elements pertaining to AI-driven diagnostic devices (such as expert adjudication, MRMC studies, or training set details for AI) are not applicable or cannot be extracted from this document.
However, I can extract information related to the acceptance criteria for the analytical performance of the assays and how that performance was demonstrated.
Here's a breakdown of the available information:
1. Acceptance Criteria and Reported Device Performance
The acceptance criteria for these in vitro diagnostic devices are demonstrated through various analytical performance studies, focusing on precision, linearity, analytical sensitivity (LoD/LoQ), analytical specificity, and method comparison to predicate devices. The document does not explicitly state pre-defined acceptance thresholds for each parameter (e.g., minimum CV for precision, minimum slope for linearity). Instead, it presents the results of these studies, implying that the observed performance met internal or regulatory acceptance.
HemosIL CL Anti-Cardiolipin IgM
| Acceptance Criteria (Implied) | Reported Device Performance |
|---|---|
| Precision (Low Lot-to-Lot Variability) | Lot-to-Lot Variability (% CV):- Low Multi-Ab Control: 1.6%- High Multi-Ab Control: 1.2%- Plasma Samples A-E: 1.6% - 9.6% |
| Reproducibility (Low CV across sites/runs) | Reproducibility (% CV):- Low Multi-Ab Control: 7.0%- High Multi-Ab Control: 7.4%- Clinical Samples 1-4: 4.5% - 9.5% |
| Analytical Sensitivity (LoD/LoQ) | LoD: 1.0 U/mLLoQ: 1.0 U/mL |
| Linearity Range | 2.7 - 500.0 U/mL |
| Analytical Specificity (No interference) | No interference for: Hemoglobin, Bilirubin, Triglycerides, Heparin (LMW/UF), Rheumatoid Factor, Acetylsalicylic acid, Atorvastatin, Warfarin, Prednisone, Acid Citric Dextrose, Hydroxychloroquine, Rituximab at specified concentrations. |
| Method Comparison (Strong correlation to predicate) | Slope (95% CI): 1.00 (0.98 - 1.01)r: 1.00 |
| Diagnostic Performance (Sensitivity/Specificity vs. APS Classification - provided for context, not a direct "acceptance criterion" in the same way as analytical measures) | Sensitivity: 40.5% (33.8% - 47.6%)Specificity: 91.9% (88.4% - 94.5%) |
HemosIL CL Anti-β2 Glycoprotein-I IgM
| Acceptance Criteria (Implied) | Reported Device Performance |
|---|---|
| Precision (Low Lot-to-Lot Variability) | Lot-to-Lot Variability (% CV):- Low Multi-Ab Control: 12.8%- High Multi-Ab Control: 11.5%- Plasma Samples A-E: 3.6% - 7.2% |
| Reproducibility (Low CV across sites/runs) | Reproducibility (% CV):- Low Multi-Ab Control: 8.3%- High Multi-Ab Control: 7.7%- Clinical Samples 1-4: 4.8% - 8.3% |
| Analytical Sensitivity (LoD/LoQ) | LoD: 2.0 U/mLLoQ: 2.0 U/mL |
| Linearity Range | 1.9 - 400.0 U/mL |
| Analytical Specificity (No interference) | No interference for: Hemoglobin, Bilirubin, Triglycerides, Heparin (LMW/UF), Rheumatoid Factor, Acetylsalicylic acid, Atorvastatin, Warfarin, Prednisone, Acid Citric Dextrose, Hydroxychloroquine, Rituximab at specified concentrations. |
| Method Comparison (Strong correlation to predicate) | Slope (95% CI): 0.94 (0.92 – 0.96)r: 0.99 |
| Diagnostic Performance (Sensitivity/Specificity vs. APS Classification - provided for context, not a direct "acceptance criterion" in the same way as analytical measures) | Sensitivity: 33.0% (26.7% - 39.9%)Specificity: 94.6% (91.4% - 96.6%) |
2. Sample Sizes Used for the Test Set and Data Provenance
- Precision Study (Test Set):
- HemosIL CL Anti-Cardiolipin IgM & Anti-β2 Glycoprotein-I IgM: 5 plasma samples (3 positive, 2 negative) and 2 levels of controls. Each material was run in duplicate, twice per day over 20 days.
- Reproducibility Study (Test Set):
- HemosIL CL Anti-Cardiolipin IgM & Anti-β2 Glycoprotein-I IgM: 4 plasma samples (3 positive, 1 negative for Anti-Cardiolipin IgM; 3 positive for Anti-β2 Glycoprotein-I IgM) and 2 levels of controls. Each material tested in triplicate, twice a day for 5 days, totaling 30 replicates per level.
- Analytical Sensitivity (LoD/LoQ):
- Specific sample numbers for LoD/LoQ for new reagent lots are not detailed, but samples prepared by combining Ab-positive and normal donor plasma were used.
- Linearity:
- For each assay, samples were prepared by diluting a high antibody plasma sample with a negative antibody plasma sample to create required concentrations. Each level was measured in seven replicates.
- Normal Reference Range:
- 100 citrated plasma normal donor samples.
- Method Comparison:
- HemosIL CL Anti-Cardiolipin IgM: N = 131 samples.
- HemosIL CL Anti-β2 Glycoprotein-I IgM: N = 123 samples.
- APS Outcome Study (Diagnostic Performance):
- HemosIL CL Anti-Cardiolipin IgM: N = 500 samples.
- HemosIL CL Anti-β2 Glycoprotein-I IgM: N = 503 samples (indicated by the sum of Positive/Negative categories: 63+17+128+295=503).
Data Provenance: The document does not specify the country of origin for the data or whether the studies were retrospective or prospective, though typical clinical performance studies for diagnostic devices are usually prospective or utilize carefully curated samples. Reproducibility studies were conducted at "3 external sites."
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications
This information is not provided. For these in vitro diagnostic immunoassays, the "ground truth" for the analytical performance studies (precision, linearity, etc.) is the quantitative measurement itself, validated against established laboratory methods or reference materials. For the "APS Outcome Study," the ground truth is "APS disease classification per 2006 International Consensus Statement from Miyakis et al." This classification is typically based on a combination of clinical and laboratory findings, interpreted by clinicians, but the specific number and qualifications of experts involved in this classification for the study samples are not detailed.
4. Adjudication Method (e.g., 2+1, 3+1, none) for the Test Set
Not applicable, as this is an in vitro diagnostic device measuring analyte concentrations, not an imaging AI relying on expert interpretations or adjudications. The diagnostic performance (sensitivity/specificity) is compared against pre-defined clinical classification criteria (Miyakis et al. 2006).
5. If a multi reader multi case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance
Not applicable. This document describes an in vitro diagnostic device (immunoassay and analyzer), not an AI-driven imaging diagnostic device. There is no mention of human readers or AI assistance in diagnostic interpretation.
6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done
The performance data provided (precision, linearity, sensitivity, specificity, method comparison) is the standalone performance of the device (instrument + assay). The device provides a semi-quantitative measurement of antibodies, which then aids in diagnosis when used "in conjunction with other laboratory and clinical findings." There is no "human-in-the-loop" component in the assay's direct operation or result generation as described beyond the healthcare professional performing the test.
7. The Type of Ground Truth Used
- Analytical Studies (Precision, Linearity, LoD/LoQ, Specificity): The ground truth is inherent to the nature of these highly controlled analytical tests. For example, for linearity, serially diluted samples with known concentrations are used. For interference, samples spiked with known interferents are used.
- Method Comparison: The ground truth is established by the measurements obtained from the predicate (reference) devices: HemosIL AcuStar Anti-Cardiolipin IgM (K092181) and HemosIL AcuStar Anti-β2 Glycoprotein-I IgM (K091556) on the ACL AcuStar (K083518).
- Normal Reference Range: Established by testing 100 samples from "normal donors."
- APS Outcome Study: "APS disease classification per 2006 International Consensus Statement from Miyakis et al." This is a consensus-based clinical classification criteria.
8. The Sample Size for the Training Set
Not applicable, as this is not an AI/machine learning device that requires a distinct training set. The "development" of the assays would involve internal R&D, but not a "training set" in the context of AI.
9. How the Ground Truth for the Training Set Was Established
Not applicable, as there is no training set mentioned for an AI model. For the development/validation of the immunoassay itself, the "ground truth" for calibrators and controls would be established through careful analytical procedures, often traceable to international standards or reference materials, under strict quality control.
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Image /page/0/Picture/0 description: The image shows 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, with the letters "FDA" in a blue square. To the right of the blue square is the text "U.S. FOOD & DRUG ADMINISTRATION" in blue.
September 29, 2023
Instrumentation Laboratory Co. Nikita Malladi Principal Regulatory Affairs Specialist 180 Hartwell Road Bedford, Massachusetts 01730
Re: K221359
Trade/Device Name: ACL TOP 970 CL, HemosIL CL Anti-Cardiolipin IgM, HemosIL CL Anti-R2 Glycoprotein-I IgM Regulation Number: 21 CFR 864.5425 Regulation Name: Multipurpose System For In Vitro Coagulation Studies Regulatory Class: Class II Product Code: JPA, MID, MSV Dated: May 10, 2022 Received: May 11, 2022
Dear Nikita Malladi:
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 (the 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 available 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.
Additional information about changes that may require a new premarket notification are provided in the FDA guidance documents entitled "Deciding When to Submit a 510(k) for a Change to an Existing Device"
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(https://www.fda.gov/media/99812/download) and "Deciding When to Submit a 510(k) for a Software Change to an Existing Device" (https://www.fda.gov/media/99785/download).
Your device is also subject to, among other requirements, the Quality System (QS) regulation (21 CFR Part 820), which includes, but is not limited to, 21 CFR 820.30. Design controls; 21 CFR 820.90. Nonconforming product; and 21 CFR 820.100, Corrective and preventive action. Please note that regardless of whether a change requires premarket review. the OS regulation requires device manufacturers to review and approve changes to device design and production (21 CFR 820.30 and 21 CFR 820.70) and document changes and approvals in the device master record (21 CFR 820.181).
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 Part 803) for devices or postmarketing safety reporting (21 CFR Part 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safetyreporting-combination-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 Part 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR Parts 1000-1050.
Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR 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 (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).
Sincerely. Min Wu -S
Min Wu. 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
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Indications for Use
510(k) Number (if known) K221359
Device Name
ACL TOP 970 CL, HemosIL CL Anti-Cardiolipin IgM and HemosIL CL Anti-B2 Glycoprotein-I IgM
Indications for Use (Describe)
ACL TOP 970 CL
The ACL TOP 970 CL is a bench top, fully automated, random access analyzer designed specifically for in vitro diagnostic use by health care professionals in a clinical laboratory. The system provides results for both direct measurements and calculated parameters.
HemosIL CL Anti-Cardiolipin IgM
HemosIL CL Anti-Cardiolipin IgM is a fully automated chemiluminescent immunoassay for the semi-quantitative measurement of anti-cardiolipin (aCL) IgM antibodies in human 3.2% or 3.8% citrated plasma on the ACL TOP 970 CL in the laboratory setting by a healthcare professional, as an aid in the diagnosis of Antiphospholipid Syndrome (APS) when used in conjunction with other laboratory and clinical findings. For use with adult population. For prescription use only.
HemosIL CL Anti-ß2 Glycoprotein-I IgM
HemosIL CL Anti-B2 Glycoprotein-I IgM is a fully automated chemiluminescent immunoassay for the semi-quantitative measurement of anti-B2 Glycoprotein-I (anti-B2GPI) IgM antibodies in human 3.2% or 3.8% citrated plasma on the ACL TOP 970 CL in the laboratory setting by a healthcare professional, as an aid in the diagnosis of Antiphospholipid Syndrome (APS) when used in conjunction with other laboratory and clinical findings. For use with adult population. For prescription use only.
| Type of Use (Select one or both, as applicable) | |
|---|---|
| ☑ Prescription Use (Part 21 CFR 801 Subpart D) | ☐ Over-The-Counter Use (21 CFR 801 Subpart C) |
[X] Prescription Use (Part 21 CFR 801 Subpart DI Counter Use (21 CFR 801 Subbart C)
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Image /page/3/Picture/0 description: The image shows the word "werfen" in a sans-serif font. The word is written in a dark blue color. The letters are evenly spaced and the word is horizontally aligned.
510(k) Summary
This 510(k) Summary of Safety and Effectiveness is being submitted in accordance with the requirements of 21 CFR 807.92.
| Submitter's Information | Instrumentation Laboratory (IL) Co.180 Hartwell RoadBedford, MA 01730, USA |
|---|---|
| Contact 1 (Primary) | Nikita Malladi, Regulatory Affairs Manager IPhone: 781-353-1486Fax: 781-861-4207Email: nmalladi@werfen.com |
| Preparation Date | September 28, 2023 |
| Device Trade Names | ACL TOP 970 CL |
|---|---|
| HemosIL CL Anti-Cardiolipin IgM | |
| HemosIL CL Anti-β2 Glycoprotein-I IgM |
| Predicate Devicesand 510(k) Numbers | Instrument | ACL AcuStar | K083518 | |
|---|---|---|---|---|
| Assays | HemosIL AcuStar Anti-Cardiolipin IgM | K092181 | ||
| HemosIL AcuStar Anti-β₂ Glycoprotein-I IgM | K091556 |
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| Regulatory Information | |
|---|---|
| ACL TOP 970 CL | Instrument |
| Regulation Section No. | 21 CFR 864.5425 |
| Regulation Description | Multipurpose system for in vitro coagulation studies |
| Classification | Class II |
| Product Code | JPA |
| Panel | Hematology (81) |
| Chemiluminescent Assays | |
| HemosIL CLAnti-Cardiolipin IgM | |
| Regulation Section No. | 21 CFR 866.5660 |
| Regulation Description | System, Test, Anti-cardiolipin Immunological |
| Classification | Class II |
| Product Code | MID |
| Panel | Immunology (82) |
| HemosIL CLAnti-β2 Glycoprotein-I IgM | |
| Regulation Section No. | 21 CFR 866.5660 |
| Regulation Description | System, Test, Antibodies, β2 - Glycoprotein I (β2 - Gpi) |
| Classification | Class II |
| Product Code | MSV |
| Panel | Immunology (82) |
Reasons for Submission
This Traditional 510(k) is submitted by Instrumentation Laboratory Co. for the following reasons:
- To obtain FDA clearance for the ACL TOP 970 CL instrument ●
- To obtain FDA clearance for two new immunoassays (HemosIL CL Anti-Cardiolipin IgM and HemosIL CL . Anti-ß2 Glycoprotein-I IgM)
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| Device Description | Intended Use / Indications for Use | ||
|---|---|---|---|
| Instrument | Instrument | ||
| ACL TOP 970 CLInstrument | The ACL TOP 970 CL is an instrument that integrates new chemiluminescenttest capability similar to the ACL AcuStar, K083518. | ACL TOP 970 CL | The ACL TOP 970 CL is a bench top, fully automated, random access analyzerdesigned specifically for in vitro diagnostic use by health care professionals in aclinical laboratory.The system provides results for both direct measurements and calculatedparameters. |
| Chemiluminescent Assays | Chemiluminescent Assays | ||
| HemosIL CLAnti-Cardiolipin IgM | HemosIL CL Anti-Cardiolipin IgM is a chemiluminescent two-stepimmunoassay consisting of magnetic particles coated with cardiolipin andhuman purified \u03b22GPI, which capture, if present, the aCL antibodies from thesample. After incubation, magnetic separation, and a wash step, a tracerconsisting of an isoluminol-labeled anti-human IgM antibody is added andmay bind with the captured aCL IgM on the particles. After a secondincubation, magnetic separation, and wash step, reagents that trigger theluminescent reaction are added, and the emitted light is measured as relativelight units (RLU) by the ACL TOP 970 CL optical system. RLUs are directlyproportional to the aCL IgM concentration in the sample. | HemosIL CLAnti-Cardiolipin IgM | HemosIL CL Anti-Cardiolipin IgM is a fully automated chemiluminescentimmunoassay for the semi-quantitative measurement of anti-cardiolipin (aCL)IgM antibodies in human 3.2% or 3.8% citrated plasma on the ACL TOP® 970CL in the laboratory setting by a healthcare professional, as an aid in thediagnosis of Antiphospholipid Syndrome (APS) when used in conjunction withother laboratory and clinical findings.For use with adult population. For prescription use only. |
| HemosIL CLAnti-\u03b22 Glycoprotein-I IgM | HemosIL CL Anti-\u03b22 Glycoprotein-I IgM is a chemiluminescent two-stepimmunoassay consisting of magnetic particles coated with human purified\u03b22GPI, which capture, if present, the a\u03b22GPI antibodies from the sample. Afterincubation, magnetic separation, and a wash step, a tracer consisting of anisoluminol-labeled anti-human IgM antibody is added and may bind with thecaptured a\u03b22GPI IgM on the particles. After a second incubation, magneticseparation, and wash step, reagents that trigger the luminescent reaction areadded, and the emitted light is measured as relative light units (RLUs) by theACL TOP 970 CL optical system. RLUs are directly proportional to thea\u03b22GPI IgM concentration in the sample. | HemosIL CLAnti-ß2 Glycoprotein-I IgM | HemosIL CL Anti-ß2 Glycoprotein-I IgM is a fully automated chemiluminescentimmunoassay for the semi-quantitative measurement of anti-ß2 Glycoprotein-I(anti-ß2GPI) IgM antibodies in human 3.2% or 3.8% citrated plasma on the ACLTOP® 970 CL in the laboratory setting by a healthcare professional, as an aid inthe diagnosis of Antiphospholipid Syndrome (APS) when used in conjunctionwith other laboratory and clinical findings.For use with adult population. For prescription use only. |
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| ACL TOP 970 CL Instrument Comparison to Predicate Device | |||
|---|---|---|---|
| Item | Predicate Device No .: K083518 | Subject Device | |
| Trade Names | ACL AcuStar | ACL TOP 970 CL | |
| Intended Use/Indications for Use | The ACL AcuStar is an automatedimmunoassay analyzer designedspecifically for in vitro diagnostic use in aclinical laboratory. The assay analysis isbased on chemiluminescent technology.The system provides results for both directmeasurements and calculated parameters. | The ACL TOP 970 CL is a bench top, fullyautomated, random access analyzer designedspecifically for in vitro diagnostic use by healthcare professionals in a clinical laboratory.The system provides results for both directmeasurements and calculated parameters. | |
| Quality Control | Automated QC | Automated QC | |
| Methodology | Chemiluminescence reading unit and photomultiplier tube (PMT) | Similar chemiluminescence reading unit and PhotoMultiplier Tube (PMT) to the ACL AcuStar. | |
| Interface | Windows 7 Operating System | Windows 10 Operating System | |
| Item | Predicate Device: K092181 | Subject Device | |
| Trade Name | HemosIL AcuStar Anti-Cardiolipin IgM | HemosIL CL Anti-Cardiolipin IgM | |
| Intended Use/Indications for Use | HemosIL AcuStar Anti-Cardiolipin IgM is afully automated chemiluminescent assay for thesemi-quantitative measurement of anti-cardiolipin (aCL) IgM antibodies in humancitrated plasma and serum on the ACL AcuStar,as an aid in the diagnosis of thrombotic disordersrelated to primary and secondaryAntiphospholipid Syndrome (APS) when used inconjunction with other laboratory and clinicalfindings. | HemosIL CL Anti-Cardiolipin IgM is a fullyautomated chemiluminescent immunoassay forthe semi-quantitative measurement of anti-cardiolipin (aCL) IgM antibodies in human 3.2%or 3.8% citrated plasma on the ACL TOP® 970CL in the laboratory setting by a healthcareprofessional, as an aid in the diagnosis ofAntiphospholipid Syndrome (APS) when used inconjunction with other laboratory and clinicalfindings.For use with adult population. For prescriptionuse only. | |
| Type of Test | Semi-quantitative | Same | |
| Technology | Two-step chemiluminescent immunoassay | Same | |
| Clinical Cut-off | 20.0 U/mL | Same | |
| Calibrator | Calibrator 1: 1 x 1 mL barcoded tube of a solutionwith aCL IgM in saline solution containing bovinefetal serum, stabilizers, and preservative.Calibrator 2: 1 x 1 mL barcoded tube of a solutionwith aCL IgM in saline solution containing bovinefetal serum, stabilizers, and preservative. | Calibrator 1: 1 x 1.2 mL barcoded vial of asolution with aCL IgM in saline solutioncontaining bovine fetal serum, stabilizers, andpreservative.Calibrator 2: 1 x 1.2 mL barcoded vial of asolution with aCL IgM in saline solutioncontaining bovine fetal serum, stabilizers, andpreservative. | |
| Composition | 1 cartridge containing 1 vial of magnetic particlesuspension coated with bovine cardiolipin andhuman purified β2GPI, 1 vial of assay buffer, 1 vialof tracer consisting of an anti-human IgM antibodylabeled with isoluminol, and 1 vial of samplediluent used for the regular predilution of thesample and automated dilution in the rerun. Thereagents are in a phosphate or borate buffercontaining bovine serum albumin, bovinecardiolipin, human β2GPI, mouse monoclonal IgM,stabilizers, and preservative. | 1 cartridge containing 1 vial of magnetic particlesuspension coated with bovine cardiolipin andhuman purified β2GPI, 1 vial of assay buffer, 1vial of tracer consisting of an anti-human IgMantibody labeled with isoluminol, and 1 vial ofsample diluent. The reagents are in a phosphateor borate buffer containing bovine serumalbumin, bovine cardiolipin, human β2GPI,mouse monoclonal IgM, stabilizers, andpreservative. | |
| HemosIL CL Anti-Cardiolipin IgM Comparison to Predicate Device (Cont.) | |||
| Item | Predicate Device: K092181 | Subject Device | |
| Trade Name | HemosIL AcuStar Anti-Cardiolipin IgM | HemosIL CL Anti-Cardiolipin IgM | |
| Sample Type | Serum or Citrated Plasma | Human 3.2% or 3.8% citrated plasma | |
| Quality Control | Low and high controls (sold separately) | Different control material, with two levels at ornear cut-off and at abnormal level | |
| Detection Limit | 1.0 U/mL | 2.0 U/mL | |
| Linearity | 1.0 - 774 U/mL | 2.7 - 500.0 U/mL | |
| When the rerun capability of the instrument isactivated, the instrument makes an automaticdilution and corrects the final result for the dilutionfactor (20x), thereby expanding the test range to15,480 U/mL. | The assay is not affected by prozone effect. Theassay protocol has a washing step after the sampleincubation that precludes the prozone effect. | ||
| Item | Predicate Device: K091556 | Subject Device | |
| Trade Name | HemosIL AcuStar Anti-β2 Glycoprotein-I IgM | HemosIL CL Anti-β2 Glycoprotein-I IgM | |
| Intended Use/Indications for Use | HemosIL AcuStar Anti-β2 Glycoprotein-I IgM is a fully automated chemiluminescent immunoassay for the semi-quantitative measurement of anti-β2 Glycoprotein-I (anti-β2GPI) IgM antibodies in human citrated plasma and serum on the ACL AcuStar, as an aid in the diagnosis of thrombotic disorders related to primary and secondary Antiphospholipid Syndrome (APS) when used in conjunction with other laboratory and clinical findings. | HemosIL CL Anti-β2 Glycoprotein-I IgM is a fully automated chemiluminescent immunoassay for the semi-quantitative measurement of anti-β2 Glycoprotein-I (anti-β2GPI) IgM antibodies in human 3.2% or 3.8% citrated plasma on the ACL TOP® 970 CL in the laboratory setting by a healthcare professional, as an aid in the diagnosis of Antiphospholipid Syndrome (APS) when used in conjunction with other laboratory and clinical findings.For use with adult population. For prescription use only. | |
| Type of Test | Semi-quantitative | Same | |
| Technology | Two-step chemiluminescent immunoassay | Same | |
| Clinical Cut-off | 20.0 U/mL | Same | |
| Calibrator | Calibrator 1: 1 x 1 mL barcoded tube of a solution with aβ2GPI IgM in a phosphate buffer containing bovine serum albumin, stabilizers, and preservative.Calibrator 2: 1 x 1 mL barcoded tube of a solution with aβ2GPI IgM in a phosphate buffer containing bovine serum albumin, stabilizers, and preservative. | Calibrator 1: 1 x 1.2 mL barcoded vial of a solution with aβ2GPI IgM in a phosphate buffer containing bovine serum albumin, stabilizers, and preservative.Calibrator 2: 1 x 1.2 mL barcoded vial of a solution with aβ2GPI IgM in a phosphate buffer containing bovine serum albumin, stabilizers, and preservative. | |
| Composition | 1 cartridge containing 1 vial of a magnetic particle suspension coated with human purified β2GPI, 1 vial of assay buffer, 1 vial of tracer consisting of an anti-human IgM antibody labeled with isoluminol, and 1 vial of sample diluent used for the regular predilution of the sample and automatic dilution in rerun. The reagents are in a phosphate buffer containing bovine serum albumin, human β2GPI, mouse monoclonal IgM, stabilizers, and preservative. | 1 cartridge containing 1 vial of a magnetic particle suspension coated with human purified β2GPI, 1 vial of assay buffer, 1 vial of tracer consisting of an anti-human IgM antibody labeled with isoluminol, and 1 vial of sample diluent. The reagents are in a phosphate buffer containing bovine serum albumin, human β2GPI, mouse monoclonal IgM, stabilizers, and preservative. | |
| HemosIL CL Anti-B2 Glycoprotein-I IgM Comparison to Predicate Device (Cont.) | |||
| Item | Predicate Device: K091556 | Subject Device | |
| Trade Name | HemosIL AcuStar Anti-β2 Glycoprotein-I IgM | HemosIL CL Anti-β2 Glycoprotein-I IgM | |
| Sample Type | Serum or Citrated Plasma | Human 3.2% or 3.8% citrated plasma | |
| Quality Control | Low and high controls (sold separately) | Different control material with two levels at ornear cut-off and at abnormal level | |
| Detection Limit | 1.1 U/mL | 1.0 U/mL | |
| Linearity | 1.1 - 841 U/mL | 1.9 - 400.0 U/mL | |
| When the rerun capability of the instrument isactivated, the instrument makes an automaticdilution and corrects the final result for the dilutionfactor (20x), thereby expanding the test range to16,820 U/mL. | The assay is not affected by prozone effect. Theassay protocol has a washing step after thesample incubation that precludes the prozoneeffect. |
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HemosIL CL Anti-Cardiolipin IgM Comparison to Predicate Device
This table provides a comparative description of the similarities and differences between the subject device, HemosIL CL Anti-Cardiolipin IgM, and its predicate device, the currently marketed HemosIL AcuStar Anti-Cardiolipin IgM (K092181).
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HemosIL CL Anti-ß2 Glycoprotein-I IgM Comparison to Predicate Device
This table provides a comparative description of the similarities and differences between the subject device, HemosIL CL Anti-13 Glycoprotein-I IgM, and its predicate device, the currently marketed HemosIL AcuStar Anti-ß2 Glycoprotein-I I IgM (K091556).
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Precision
HemosIL CL Anti-Cardiolipin IgM
A precision study was performed in accordance with CLSI Edition), using three lots of HemosIL CL Anti-Cardiolipin IgM reagents. Repeatability and within laboratory precision were assessed. To span the study tested 5 plasma samples (3 positive; 2 negative), and 3 lots of Hemos!L CL Multi-Ab Controls (low and high). Each material was run in duplicate, twice per day over 20 days on an ACL TOP 970 CL.
The table below shows the aggregated data for the 3 reagent lots.
| Material | Mean (U/mL) | Lot-to-Lot Variability (% CV) |
|---|---|---|
| Low Multi-Ab Control | 8.4 | 1.6 |
| High Multi-Ab Control | 86.1 | 1.2 |
| Plasma Sample A | 5.5 | 9.6 |
| Plasma Sample B | 15.7 | 5.2 |
| Plasma Sample C | 24.3 | 2.7 |
| Plasma Sample D | 107.5 | 1.6 |
| Plasma Sample E | 396.4 | 2.3 |
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Precision (Cont.)
HemosIL CL Anti-ß2 Glycoprotein-I IgM
A precision study was performed in accordance with CLSI Edition), using three lots of HemosIL CL Ant-1» Glycoprotein-I Igh reagens. Repeatability and within laboratory precision were assay range, the study tested 5 plasma samples (3 positive; 2 regative), and 3 lots of HemosIL CL Multi-Ab Controls (low and high). Each material was run in duplicate, twice per day over 20 days on an ACL TOP 970 CL.
The table below shows aggregated data for the 3 reagent lots.
| Material | Mean (U/mL) | Lot-to-Lot Variability (% CV) |
|---|---|---|
| Low Multi-Ab Control | 4.1 | 12.8 |
| High Multi-Ab Control | 51.5 | 11.5 |
| Plasma Sample A | 8.4 | 5.6 |
| Plasma Sample B | 15.0 | 4.4 |
| Plasma Sample C | 21.7 | 3.6 |
| Plasma Sample D | 96.9 | 7.2 |
| Plasma Sample E | 297.3 | 7.1 |
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Reproducibility
HemosIL CL Anti-Cardiolipin IgM
Reproducibility studies were conducted at 3 external sith CLSI EP05-A3 (3" Edition), using different operators (1 operator per site), on 3 different ACL TOP 970 CL systems (1 system per site), using 3 lots of HemosIL CL Anti-Cardiolipin IgM and 1 lot of HemosIL CL Multi-Ab Controls. To span the assay range, 4 plasma samples (3 positive and 1 negative) were also tested across the 3 sites.
Each material was tested in triplicate, twice a day for 5 days, for a total of 30 replicates per level.
The pooled data for a representative reagent lot is presented below.
| Level | Mean(U/mL) | N | Repeatability | Between-run | Between-day | Between-site | Reproducibility | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| SD | % CV | SD | % CV | SD | % CV | SD | % CV | SD | % CV | |||
| Low Multi-Ab Control | 8.6 | 90 | 0.40 | 4.6 | 0.28 | 3.3 | 0.00 | 0.0 | 0.36 | 4.2 | 0.61 | 7.0 |
| HighMulti-AbControl | 100.3 | 90 | 3.86 | 3.8 | 5.24 | 5.2 | 0.00 | 0.0 | 3.47 | 3.5 | 7.37 | 7.4 |
| ClinicalSample 1(pool) | 5.5 | 90 | 0.22 | 3.9 | 0.38 | 6.9 | 0.16 | 2.9 | 0.24 | 4.4 | 0.52 | 9.5 |
| ClinicalSample 2(pool) | 30.0 | 90 | 1.01 | 3.4 | 0.70 | 2.3 | 0.00 | 0.0 | 0.58 | 1.9 | 1.36 | 4.5 |
| ClinicalSample 3(unadulterated) | 97.7 | 90 | 4.49 | 4.6 | 2.82 | 2.9 | 0.00 | 0.0 | 3.67 | 3.8 | 6.45 | 6.6 |
| ClinicalSample 4(pool) | 402.9 | 90 | 12.42 | 3.1 | 24.89 | 6.2 | 10.12 | 2.5 | 9.47 | 2.3 | 31.08 | 7.7 |
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Reproducibility (Cont.)
HemosIL CL Anti-ß2 Glycoprotein-I IgM
Reproducibility studies were conducted at 3 external sites, in accordance with CLSI EPO5-A3 (3ª Edition), using different operator (1 operator per site), on 3 different ACL TOP 970 CL systems (1 system per site), using 3 lots of Hemos!L CL Anti-19 Glycoprotein-I IgM and 1 lot of Hemos!L CL Multi-Ab Low and High Controls. To span the assay range, 4 plasma samples (3 positive) were also tested across the 3 sites.
Each material was tested in triplicate, twice a day for 5 days, for a total of 30 replicates per level.
The pooled data for a representative reagent lot is presented below.
| Level | Mean(U/ML) | N | Repeatability | Between-run | Between-day | Between-site | Reproducibility | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| SD | % CV | SD | % CV | SD | % CV | SD | % CV | SD | % CV | |||
| LowMulti-AbControl | 9.9 | 90 | 0.42 | 4.2 | 0.58 | 5.9 | 0.00 | 0.0 | 0.40 | 4.1 | 0.82 | 8.3 |
| HighMulti-AbControl | 125.3 | 90 | 4.72 | 3.8 | 6.45 | 5.1 | 0.00 | 0.0 | 5.36 | 4.3 | 9.62 | 7.7 |
| ClinicalSample 1(pool) | 8.5 | 90 | 0.24 | 2.8 | 0.41 | 4.8 | 0.00 | 0.0 | 0.52 | 6.1 | 0.71 | 8.3 |
| ClinicalSample 2(pool) | 27.9 | 90 | 0.70 | 2.5 | 0.78 | 2.8 | 0.37 | 1.3 | 1.20 | 4.3 | 1.64 | 5.9 |
| ClinicalSample 3(unadulterated) | 94.4 | 90 | 2.57 | 2.7 | 3.12 | 3.3 | 1.59 | 1.7 | 4.98 | 5.3 | 6.61 | 7.0 |
| ClinicalSample 4(unadulterated) | 288.1 | 90 | 5.65 | 2.0 | 8.93 | 3.1 | 3.76 | 1.3 | 8.16 | 2.8 | 13.87 | 4.8 |
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Analytical Sensitivity
Limit of detection (LoD) was assessed per CLSI EP17-A2 (2nd Edition) using three different lots of HemosIL CL Anti-Cardiolipin IgM and three different lots of HemosIL CL Anti-ß2 Glycoprotein-I IgM reagent cartridges. LoD samples were prepared by combining Ab-positive donor plasma and normal donor plasma per protocol. Based on the results, following are the limits of detection (LoDs) for the two assays:
| HemosIL CL Anti-Cardiolipin IgM | HemosIL CL Anti-β2 Glycoprotein-I IgM |
|---|---|
| LoD | 1.0 U/mL |
| LoQ | 1.0 U/mL |
| LoD | 2.0 U/mL |
| LoQ | 2.0 U/mL |
Linearity
Linearity was assessed per CLSI EP06 (2nd Edition) using three different lots of HemosIL CL Anti-Cardiolipin IgM and three different lots of HemosIL CL Anti-ß2 Glycoprotein-I IgM reagent cartridges. For each assay, a set of linearity samples were prepared by diluting a high antibody plasma sample with a negative antibody plasma sample to create the required sample concentrations. Each level was measured in seven replicates with the three lots for each assay. The linearity range was determined such that all acceptance criteria were met.
Based on the results, following are the linear ranges for the two assays:
| HemosIL CL Anti-Cardiolipin IgM | HemosIL CL Anti-β2 Glycoprotein-I IgM |
|---|---|
| Linearity Range2.7 - 500.0 U/mL | Linearity Range1.9 - 400.0 U/mL |
| The assay is not affected by prozone effect. The assay protocol has a washing step after the sample incubation that precludes the prozone effect. | The assay is not affected by prozone effect. The assay protocol has a washing step after the sample incubation that precludes the prozone effect. |
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Analytical Specificity
Interference testing was performed in accordance with CLSI EP07 (3rd Edition) using HemosIL CL Anti-Cardiolipin IgM and HemosIL CL Anti-ß2 Glycoprotein-I IgM reagent cartridges.
Based on the results, following are the interference claims for the two assays:
| HemosIL CL Anti-Cardiolipin IgM | HemosIL CL Anti-β₂ Glycoprotein-I IgM |
|---|---|
| No interference for: | No interference for: |
| • Hemoglobin up to 1000 mg/dL | • Hemoglobin up to 1000 mg/dL |
| • Bilirubin up to 40 mg/dL | • Bilirubin up to 40 mg/dL |
| • Triglycerides up to 1500 mg/dL | • Triglycerides up to 1500 mg/dL |
| • Heparin (LMW and UF) up to 3.3 IU/mL | • Heparin (LMW and UF) up to 3.3 IU/mL |
| • Rheumatoid Factor up to 500 IU/mL | • Rheumatoid Factor up to 500 IU/mL |
| • Acetylsalicylic acid up to 3 mg/dL | • Acetylsalicylic acid up to 3 mg/dL |
| • Atorvastatin up to 0.075 mg/dL | • Atorvastatin up to 0.075 mg/dL |
| • Warfarin up to 7.5 mg/dL | • Warfarin up to 7.5 mg/dL |
| • Prednisone up to 9.90E-03 mg/dL | • Prednisone up to 9.90E-03 mg/dL |
| • Acid Citric Dextrose up to 4.5 g/dL | • Acid Citric Dextrose up to 4.5 g/dL |
| • Hydroxychloroquine up to 777.6 ng/mL | • Hydroxychloroquine up to 777.6 ng/mL |
| • Rituximab up to 318 mcg/mL | • Rituximab up to 318 mcg/mL |
| The possible interference of cryoglobulins should be considered in the interpretation of the results.¹ |
- Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006; 4: 295-306.
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Normal Reference Range
A normal range study was performed in accordance with CLSI EP28-A3c (3d Edition) using one lot of HemosIL CL Anti-Cardiolipin IgM and one lot of HemosIL CL Anti-B2 Glycoprotein-I IgM reagent cartridges. The normal range was verified on the ACL TOP 970 CL using 100 citrated plasma normal donor samples. The threshold for positive aCL IgM and positive aß2GPI IgM antibodies were established in the 99th percentile.
Following are the resultant upper limits of the normal range for the two assays:
| HemosIL CL Anti-Cardiolipin IgM | HemosIL CL Anti-β2 Glycoprotein-I IgM |
|---|---|
| Upper Limit20.0 U/mL | Upper Limit20.0 U/mL |
Due to many variables which may impact results, each laboratory should determine its own normal range.
Method Comparison
A method comparison study was performed, comparing the performance of HemosIL CL Anti-Cardiolipin IgM and HemosIL CL Anti-ß2 Glycoprotein-I IgM reagent cartridges with the respective predicate devices.
HemosIL CL Anti-Cardiolipin IgM
A method comparison was performed comparing HemosIL CL Anti-Cardiolipin IgM with a commercially available chemiluminescence assay.
| System | N | Slope (95% CI) | r | Reference Method |
|---|---|---|---|---|
| ACL TOP 970 CL | 131 | 1.00 (0.98 - 1.01) | 1.00 | ACL AcuStar |
HemosIL CL Anti-ß2 Glycoprotein-I IgM
A method comparison was performed comparing HemosIL CL Anti-l2 Glycoprotem-1 IgM with a commercially available chemiluminescence assay.
| System | N | Slope (95% CI) | r | Reference Method |
|---|---|---|---|---|
| ACL TOP 970 CL | 123 | 0.94 (0.92 – 0.96) | 0.99 | ACL AcuStar |
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APS Outcome Study
HemosIL CL Anti-Cardiolipin IgM
A diagnostic clinical performance study was performed comparing HemosIL CL Anti-Cardiolipin IgM with APS disease classification per 2006 International Consensus Statement from Miyakis et al.'
| APS Classification | ||
|---|---|---|
| HemosIL CLAnti-Cardiolipin IgM | Positive | Negative |
| Positive | 77 | 25 |
| Negative | 113 | 285 |
| Predicate Device | N | Sensitivity(95% CI) | Specificity(95% CI) |
|---|---|---|---|
| APS Classification | 500 | 40.5%(33.8% - 47.6%) | 91.9%(88.4% - 94.5%) |
HemosIL CL Anti-ß2 Glycoprotein-I IgM
A diagnostic clinical performance study was performed comparing HemosIL CL Anti-l2_Glycoprotein-1 IgM with APS disease classification per 2006 International Consensus Statement from Miyakis et al.1
| APS Classification | ||
|---|---|---|
| HemosIL CLAnti-β2 Glycoprotein-I IgM | Positive | Negative |
| Positive | 63 | 17 |
| Negative | 128 | 295 |
| Predicate Device | N | Sensitivitv(95% CI) | Specificity(95% CI) |
|---|---|---|---|
| APS Classification | રે રેણવાડી તેમ જ દૂધની ડેરી જેવી સવલતો પ્રાપ્ય થયેલી છે. આ ગામનાં લોકોનો મુખ્ય વ્યવસાય ખેતી, ખેતમજૂરી તેમ જ પશુપાલન છે. આ ગામનાં મુખ્યત્વે ખેતી, ખેતમજૂરી તેમ જ પશુપાલન છે. આ | 33.0%(26.7% - 39.9%) | 94.6%(91.4% - 96.6%) |
- Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006; 4: 295-306.
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Conclusion
Based on the substantial equivalence comparison and the results of the conducted performance evaluations, the HemosIL CL Anti-Cardiolipin IgM and the HemosIL CL Anti-B2 Glycoprotein-I IgM assays on the ACL TOP 970 CL were shown to be substantially equivalent to the cleared and currently marketed devices, HemosIL AcuStar Anti-Cardiolipin IgM (K092181) and HemosIL AcuStar Anti-B2 Glycoprotein-I IgM assays (K091556) on the ACL AcuStar (K083518). The differences between the subject and predicate devices do not impact safety and effectiveness.
§ 864.5425 Multipurpose system for in vitro coagulation studies.
(a)
Identification. A multipurpose system for in vitro coagulation studies is a device consisting of one automated or semiautomated instrument and its associated reagents and controls. The system is used to perform a series of coagulation studies and coagulation factor assays.(b)
Classification. Class II (special controls). A control intended for use with a multipurpose system for in vitro coagulation studies is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9.