(456 days)
The BioPlex® 2200 APLS IgG and IgA kits are multiplex flow immunoassays intended for the semi-quantitative detection of IgG and IgA antibodies to Cardiolipin (CL) and Beta-2 Glycoprotein I (ß2GPI) in human serum and plasma (lithium heparin, sodium heparin, and sodium citrate). In conjunction with other clinical findings, the test systems are used as an aid in the diagnosis of primary Antiphospholipid Syndrome (APS) and those secondary to systemic lupus erythematosus (SLE) or SLE-like disorders.
The BioPlex 2200 APLS IgG and IgA kits are intended for use with the Bio-Rad BioPlex 2200 System
The BioPlex® 2200 APLS IgG and IgA IgG kit uses multiplex flow immunoassay, a methodology that greatly resembles traditional EIA, but permits simultaneous detection and identification of many antibodies in a single tube. "APLS" is an acronym for Anti-Phospholipid Syndrome.
Two (2) different populations of dyed beads are coated with the antigens associated with Cardiolipin (CL) and Beta-2-Glycoprpotein I (ß2GPI), respectively. The BioPlex 2200 System combines an aliquot of patient sample, sample diluent, and bead reagent into a reaction vessel. The mixture is incubated at 37°C. After a wash cycle, anti-human IgG or IgA antibody, conjugated to phycoerythrin (PE) is added to the dyed beads and this mixture is incubated at 37℃. The excess conjugate is removed in another wash cycle, and the beads are re-suspended in wash buffer. The bead mixture then passes through the detector. The identity of the dyed beads is determined by the fluorescence of the dyes, and the amount of analyte captured is determined by the fluorescence of the attached PE. Raw data is calculated in relative fluorescence intensity (RFI).
Three additional dyed beads, an Internal Standard Bead (ISB), a Serum Verification Bead (SVB) and a Reagent Blank Bead (RBB) are present in each reaction mixture to normalize detector response, to verify the addition of serum to the reaction vessel and the absence of significant non-specific binding in serum or plasma. Refer to the BioPlex 2200 System Operation Manual for more information.
The instrument is calibrated using a set of seven (7) distinct calibrator vials for APLS IgG kit and a set of three (3) distinct calibrator vials for the APLS IgA kit, all supplied separately by Bio-Rad Laboratories. For each aCL IgG and aß2GPI IgG, four (4) vials representing four (4) different antibody concentrations are used for semi-quantitative calibration. For each aCL IgA and aß2GPI IgA assay, two (2) vials representing two (2) different antibody concentrations are used for semi-quantitative calibration. The cut-off value and assignment of the calibrators are determined by performing concordance testing and Receiver Operator Characteristic (ROC) analysis, using clinical diagnosis as the standard. The results for aCL IgG and aCL IgA are expressed in GPL-U/mL and APL-U/mL units, respectively. The results for aß2GPI IgG and aß2GPI IgA are each expressed in U/mL units.
The APLS IgG and APLS IgA Control Sets are intended for use as an assayed quality control to monitor the overall performance of the BioPlex® 2200 instrument and BioPlex 2200 APLS IgG and IgA reagent packs in the clinical laboratory.
Each of the APLS IgG and APLS IgA Control Sets includes a negative control and a positive control for each aCL IgG or IgA and aß2GPI IgG or IgA in a human serum matrix made from defibrinated plasma, containing antibodies present for analytes within the APLS IgG or IgA kit. The positive controls are manufactured to give positive results. with values above the cutoff for each specific bead. The negative control is manufactured to give negative results, with values below the cutoff for each specific bead. The negative control must have a negative result, and the positive control must have a positive result.
Here's an analysis of the provided text regarding the BioPlex® 2200 Anti-Phospholipid Syndrome (APLS) IgG and IgA kits, structured according to your requested points:
Acceptance Criteria and Study for BioPlex® 2200 APLS IgG and IgA Kits
1. Table of Acceptance Criteria and Reported Device Performance
The acceptance criteria are generally established by the performance metrics shown to be acceptable for the predicate devices and the clinical utility of the test. The document emphasizes achieving clinical accuracy through concordance testing and Receiver Operator Characteristic (ROC) analysis to establish cutoffs, which then dictate sensitivity and specificity. The specific numerical acceptance criteria (e.g., minimum sensitivity/specificity percentages) are not explicitly stated as "acceptance criteria" but are demonstrated by the comparative performance results deemed sufficient for substantial equivalence.
Based on the "Clinical Sensitivity and Specificity" section, the reported device performance is as follows:
| Performance Metric | Target/Acceptance Criteria (Implied by Predicate & Clinical Utility) | Reported Device Performance (BioPlex 2200 APLS kit) |
|---|---|---|
| For aCL IgG | (No explicit numerical target stated, but performance needs to be comparable to predicate and clinically useful) | Sensitivity: 65.7% (95% CI: 60.1–71.0%) |
| Specificity: 98.5% (95% CI: 95.7–99.5%) | ||
| For aβ2GPI IgG | (No explicit numerical target stated) | Sensitivity: 65.0% (95% CI: 59.3–70.3%) |
| Specificity: 99.0% (95% CI: 96.4–99.7%) | ||
| For aCL IgA | (No explicit numerical target stated) | Sensitivity: 55.3% (95% CI: 49.7–60.8%) |
| Specificity: 96.5% (95% CI: 93.0–98.3%) | ||
| For aβ2GPI IgA | (No explicit numerical target stated) | Sensitivity: 52.0% (95% CI: 46.4–57.6%) |
| Specificity: 97.0% (95% CI: 93.7–98.6%) | ||
| Precision/Reproducibility | Based on CLSI EP15-A2 guidelines (implicitly good precision) | Within-run %CV: 1.3-8.9% (Min-Max across assays) |
| Total %CV: 1.7-9.2% (Min-Max across assays) | ||
| Linearity/Reportable Range | Based on CLSI EP06-A guidelines (implicitly linear performance) | High R^2 values (e.g., 0.9999 for aCL IgG) indicating linearity across tested ranges |
| Limit of Detection (LoD) | Based on CLSI EP17-A guidelines (implicitly low detection limits) | aCL IgG: 1.6 GPL-U/mL, aβ2GPI IgG: 1.4 U/mL, aCL IgA: 0.5 APL-U/mL, aβ2GPI IgA: 0.6 U/mL |
| Interfering Substances | No interference observed at specified concentrations | No interference observed for listed substances |
| Cross-Reactivity | No significant cross-reactivity observed with listed disease states | Low positivity rates (e.g., typically 0-10%) in samples with other disease states. |
2. Sample Size for Test Set and Data Provenance
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Sample Size for Clinical Performance (Comparative Testing & Sensitivity/Specificity):
- Total Specimens: 804 specimens
- 300 apparently healthy blood donors
- 302 patients previously diagnosed with primary or secondary APS
- 202 patients with other rheumatic or non-APS diseases
- For the Clinical Sensitivity and Specificity section (which excluded 17 samples due to instrument errors): 487 samples for IgG assays (286 Diagnosed APS + 201 Non-APS Control) and 504 samples for IgA assays (302 Diagnosed APS + 202 Non-APS Control).
- Total Specimens: 804 specimens
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Sample Size for Analytical Performance (Precision/Reproducibility): 8 human samples (4 panels of serum/plasma containing aCL IgG & IgA, aß2GPI IgG & IgA) tested in quadruplicate over five days (20 replicates per panel member).
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**Sample Size for Linearity: ** 3 APLS-positive patient samples for each analyte tested.
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Sample Size for Limit of Detection (LoD): Low negative and blank samples in 50 replicates.
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Sample Size for Interfering Substances: Samples prepared by blending negative human serum with positive samples and interferent/blank. Specific count not given but refers to multiple concentrations tested.
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Sample Size for Cross-Reactivity: Varies by disease state, ranging from 3 (CREST) to 34 (Systemic Lupus Erythematosus) samples per disease state.
-
**Sample Size for Expected Values/Reference Range: ** 300 samples from apparently healthy donors (132 males, 168 females).
-
Data Provenance:
- "Patient specimens were purchased from commercial suppliers or rheumatology clinic labs and were frozen serum."
- A clinical trial site performed the reproducibility study.
- Healthy donor samples were used for prevalence and reference range.
- The document implies the data is from retrospective samples (patients previously diagnosed with APS, purchased samples, etc.). The country of origin is not explicitly stated.
3. Number of Experts and Qualifications for Ground Truth
The document does not explicitly state the number or qualifications of experts used to establish the ground truth for the test set.
- For the clinical sensitivity and specificity study, the ground truth for APS patients is based on a "diagnosed APS" status. For controls, it's either "non-APS disease control patients" or "apparently healthy blood donors." The method by which these diagnoses were confirmed or by how many experts is not detailed.
- For the assay cut-off determination, it mentions "using clinical diagnosis as the standard" and later "103 samples from patients diagnosed as primary and secondary APS and 208 from normal healthy and 123 from non-APS cardiac donors."
- There's no mention of a panel of experts reviewing the cases used for ground truth.
4. Adjudication Method for the Test Set
The document does not describe any specific adjudication method (such as 2+1, 3+1, or other consensus methods) for establishing the ground truth of the test set. The clinical diagnosis appears to be a pre-existing classification of the samples.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study and Effect Size
This device is an in vitro diagnostic (IVD) assay, not an AI-assisted diagnostic tool for human readers. Therefore, an MRMC comparative effectiveness study involving human readers with and without AI assistance is not applicable and was not performed. The comparative effectiveness study performed was against predicate IVD devices.
6. Standalone (Algorithm Only) Performance
Yes, a standalone performance study was done. The entire study described for the BioPlex® 2200 APLS IgG and IgA kits (analytical performance, comparative performance, clinical sensitivity and specificity, linearity, precision, LoD, etc.) represents the standalone performance of the algorithm/device system. There is no "human-in-the-loop" component described for the device's function or evaluation. The system automatically measures specific antibodies and reports semi-quantitative results.
7. Type of Ground Truth Used
The primary type of ground truth used is clinical diagnosis (e.g., "patients diagnosed with primary or secondary APS," "normal healthy donors," "non-APS disease control patients").
8. Sample Size for the Training Set
The document does not explicitly describe a separate "training set" in the context of machine learning or AI algorithm development because the device is a multiplex flow immunoassay providing semi-quantitative results, not a machine learning model that is "trained."
However, the "Calibrator assignment" section describes a process that functionally serves a role akin to parameter tuning or establishing operational reference points:
- "Calibrator assignment is established for matched lots of BioPlex 2200 APLS IgG or IgA kit and calibrators using a master set of calibrators as reference and replicate analyses on multiple BioPlex 2200 instruments."
- The "cut-off value and assignment of the calibrators are determined by performing concordance testing and Receiver Operator Characteristic (ROC) analysis, using clinical diagnosis as the standard." This ROC analysis would involve a dataset to determine optimal cutoffs, which could be considered part of an initial "training" or optimization phase. The size of this specific dataset is partially revealed: "one clinical cohort has 103 samples from patients diagnosed as primary and secondary APS and 208 from normal healthy and 123 from non-APS cardiac donors." (Total 434 samples for cutoff determination.)
9. How Ground Truth for the Training Set Was Established
As noted above, there isn't a traditional "training set" for an AI model. For the calibrator assignment and cutoff determination, the ground truth was established by clinical diagnosis. The cut-off value was established by "optimizing for clinical accuracy" using ROC analysis against existing clinical diagnoses of APS (primary and secondary) and control groups (normal healthy, non-APS cardiac donors).
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510(k) Summary Report
BioPlex® 2200 Anti-Phospholipid Syndrome (APLS) IgG and IgA kits
510(k) Number: K103834
Date Prepared: March 28, 2012
Bio-Rad Laboratories hereby submits this Special 510(k) in accordance with the requirements of SMDA 1990 and 21 CFR 807.92. This summary of 510(k) safety and effectiveness information provides detail as a basis for a determination of substantial equivalence for the BioPlex® 2200 APLS IgG and IgA.
1. Applicant/Sponsor
| Submitter | Contact Person |
|---|---|
| Bio-Rad Laboratories, Inc | Juang Wang |
| BioPlex Division | Regulatory Affairs Representative |
| 5500 E. Second Street | Phone: (510)741-4609 |
| Benicia, CA 94510 | Fax: (510)741-3941 |
2. Device Name
BioPlex® 2200 APLS IgG Kit Proprietary Name: BioPlex® 2200 APLS IgG Calibrator Set BioPlex® 2200 APLS IgG Control Set BioPlex® 2200 APLS IgA Kit BioPlex® 2200 APLS IgA Calibrator Set BioPlex® 2200 APLS IgA Control Set
Common/Usual Name: Multi-Analyte Detection System: APLS IgG and IgA IgG
Classification Name:
system, test, anticardiolipin immunological system test,antibodies,b2 - glycoprotein I (b2 - gpi) calibrator, multi-analyte mixture single-analyte controls, all kinds (assayed and unassayed)
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3. Regulatory Information
| Product Code | Classification | Regulation Section | Panel |
|---|---|---|---|
| system, test,anticardiolipinimmunological(MID) | Class II | 21 CFR § 866.5660,Multiple autoantibodiesimmunological testsystem. | Immunology |
| system, test, antibodies, b2- glycoprotein I (b2 - gpi)(MSV) | Class II | 21 CFR § 866.5660,Multiple autoantibodiesimmunological testsystem. | Immunology |
| Calibrator, multi-analytemixture (JIX) | Class II | 21 CFR § 862.1150 -Calibrator | Clinical Chemistry |
| single (specified) analytecontrols (assayed andunassayed) (JJX) | Class I | 21 CFR § 862.1660 –Quality control Material(Assayed and Unassayed) | Clinical Chemistry |
Predicate Devices 4.
K022992 REAADS anti-Cardiolipin IgG/IgM Semi-Quantitative Test Kit (2 assays) K022990 REAADS IgA anti-Cardiolipin Semi-Quantitative Test Kit K013080 REAADS anti-Beta 2 Glycoprotein I IgG Test Kit K013079 REAADS anti-Beta 2 Glycoprotein I IgA Test Kit
5. Device Description
The BioPlex® 2200 APLS IgG and IgA IgG kit uses multiplex flow immunoassay, a methodology that greatly resembles traditional EIA, but permits simultaneous detection and identification of many antibodies in a single tube. "APLS" is an acronym for Anti-Phospholipid Syndrome.
Two (2) different populations of dyed beads are coated with the antigens associated with Cardiolipin (CL) and Beta-2-Glycoprpotein I (ß2GPI), respectively. The BioPlex 2200 System combines an aliquot of patient sample, sample diluent, and bead reagent into a reaction vessel. The mixture is incubated at 37°C. After a wash cycle, anti-human IgG or IgA antibody, conjugated to phycoerythrin (PE) is added to the dyed beads and this mixture is incubated at 37℃. The excess conjugate is removed in another wash cycle, and the beads are re-suspended in wash buffer. The bead mixture then passes through the detector. The identity of the dyed beads is determined by the fluorescence of the dyes, and the amount of analyte captured is determined by the fluorescence of the attached PE. Raw data is calculated in relative fluorescence intensity (RFI).
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Three additional dyed beads, an Internal Standard Bead (ISB), a Serum Verification Bead (SVB) and a Reagent Blank Bead (RBB) are present in each reaction mixture to normalize detector response, to verify the addition of serum to the reaction vessel and the absence of significant non-specific binding in serum or plasma. Refer to the BioPlex 2200 System Operation Manual for more information.
The instrument is calibrated using a set of seven (7) distinct calibrator vials for APLS IgG kit and a set of three (3) distinct calibrator vials for the APLS IgA kit, all supplied separately by Bio-Rad Laboratories. For each aCL IgG and aß2GPI IgG, four (4) vials representing four (4) different antibody concentrations are used for semi-quantitative calibration. For each aCL IgA and aß2GPI IgA assay, two (2) vials representing two (2) different antibody concentrations are used for semi-quantitative calibration. The cut-off value and assignment of the calibrators are determined by performing concordance testing and Receiver Operator Characteristic (ROC) analysis, using clinical diagnosis as the standard. The results for aCL IgG and aCL IgA are expressed in GPL-U/mL and APL-U/mL units, respectively. The results for aß2GPI IgG and aß2GPI IgA are each expressed in U/mL units.
The APLS IgG and APLS IgA Control Sets are intended for use as an assayed quality control to monitor the overall performance of the BioPlex® 2200 instrument and BioPlex 2200 APLS IgG and IgA reagent packs in the clinical laboratory.
Each of the APLS IgG and APLS IgA Control Sets includes a negative control and a positive control for each aCL IgG or IgA and aß2GPI IgG or IgA in a human serum matrix made from defibrinated plasma, containing antibodies present for analytes within the APLS IgG or IgA kit. The positive controls are manufactured to give positive results. with values above the cutoff for each specific bead. The negative control is manufactured to give negative results, with values below the cutoff for each specific bead. The negative control must have a negative result, and the positive control must have a positive result.
BioPlex® 2200 APLS IgG and IgA Kit Components 6.
The BioPlex 2200® APLS IgG(665-1950) and IgA (665-2150) kit contains supplies sufficient for 100 tests.
| Vial | Description |
|---|---|
| Bead Set | One (1) 10 mL vial, containing dyed beads coatedwith CL and β2GPI; an Internal Standard bead (ISB),a Serum Verification bead (SVB), and a ReagentBlank bead (RBB) in a MOPS (3-[N-Morpholino]propanesulfonic acid) buffer supplemented withglycerol and protein stabilizers (porcine). ProClin300 (≤0.3%), sodium benzoate (≤0.1%) and sodiumazide (<0.1%) as preservatives. |
| Conjugate | One (1) 5 mL vial, containing phycoerythrinconjugated murine monoclonal anti-human IgG or |
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| IgA antibody and phycoerythrin conjugated murinemonoclonal anti-human FXIII antibody in MOPS (3-[N-Morpholino] propanesulfonic acid) buffersupplemented with protein stabilizers (bovine).ProClin 300 (≤ 0.3%), sodium benzoate (≤ 0.1%) andsodium azide (<0.1%) as preservatives. | |
|---|---|
| Sample Diluent | One (1) 10 mL vial, containing buffer with proteinstabilizers (bovine and murine). ProClin 300 (0.3%),sodium benzoate (<0.1%) and sodium azide (<0.1%) as preservatives. |
Additional Required Items, Available from Bio-Rad:
| Catalog # | Description |
|---|---|
| 663-1900 | BioPlex 2200 APLS IgG Calibrator Set: Seven 0.5 mL vials, each containing human antibodies to CL and/or B2GPI, in a human serum matrix made from defibrinated plasma. All calibrators contain ProClin 300 (≤0.3%), sodium benzoate (≤ 0.1%) and sodium azide (<0.1%) as preservatives. |
| 663-2100 | BioPlex 2200 APLS IgA Calibrator Set: Three 0.5 mL vials, each containing human antibodies to CL and/or ẞ2GPI, in a human serum matrix made from defibrinated plasma. All calibrators contain ProClin 300 (≤0.3%), sodium benzoate (≤0.1%) and sodium azide (<0.1%) as preservatives. |
| 663-1930 | BioPlex 2200 APLS IgG Control Set: Four 1.5 mL Positive Control serum vials, each containing human antibodies to CL or ẞ2GPI, in a human serum matrix made from defibrinated plasma; and two Negative Control serum vials, in a human serum matrix made from defibrinated plasma. All controls contain ProClin 300 (≤0.3%), sodium benzoate (≤0.1%) and sodium azide (<0.1%) as preservatives. |
| 663-2130 | BioPlex 2200 APLS IgA Control Set: Four 1.5 mL Positive Control serum vials, each containing human antibodies to CL or ẞ2GPI, in a human serum matrix made from defibrinated plasma; and two Negative Control serum vials, in a human serum matrix made from defibrinated plasma. All controls contain ProClin 300 (≤ 0.3%), sodium benzoate (≤0.1%) and sodium azide (<0.1%) as preservatives. |
| 660-0817 | BioPlex 2200 Sheath Fluid: Two 4 L bottles containing Phosphate Buffered Saline (PBS). ProClin® 300 (0.03%) and sodium azide (<0.1%) as preservatives. |
| 660-0818 | BioPlex 2200 Wash Solution: One 10 L bottle |
| Catalog # | Description |
| containing Phosphate Buffered Saline (PBS) andTween 20. ProClin® 300 (≤0.03%) and sodiumazide (<0.1%) as preservatives. | |
| 660-0000 | BioPlex 2200 Instrument and Software System. |
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7. Intended Use
BioPlex® 2200 APLS IgG and IgA Kits
The BioPlex® 2200 APLS IgG and IgA kits are multiplex flow immunoassays intended for the semi-quantitative detection of IgG and IgA antibodies to Cardiolipin (CL) and Beta-2 Glycoprotein I (ß2GPI) in human serum and plasma (lithium heparin, sodium heparin, and sodium citrate). In conjunction with other clinical findings, the test systems are used as an aid in the diagnosis of primary Antiphospholipid Syndrome (APS) and those secondary to systemic lupus erythematosus (SLE) or SLE-like disorders.
The BioPlex 2200 APLS IgG and IgA kits are intended for use with the Bio-Rad BioPlex 2200 System
BioPlex® 2200 APLS IgG and IgA Calibrator Sets
The BioPlex® 2200 APLS IgG and IgA Calibrator Sets are intended for the calibration of the corresponding BioPlex® 2200 APLS IgG and IgA Reagent Packs.
BioPlex® 2200 APLS IgG and IgA Control Sets
The BioPlex® 2200 APLS IgG and IgA Control Sets are intended for use as an assayed quality control to monitor the overall performance of the BioPlex 2200 instrument and the corresponding BioPlex 2200 APLS IgG and IgA Reagent Packs in the clinical laboratory. The performance of the BioPlex 2200 APLS IgG and IgA Control Sets has not been established with any other anti-Cardiolipin and anti- Beta-2 Glycoprotein I IgG or IQA APS assays.
ထ Technological Characteristics and Substantial Equivalence
The following tables summarize the similarities and differences between the BioPlex 2200 APLS IgG and IgA kit and the predicate devices used in comparative studies with the BioPlex® 2200 APLS IgG and IgA kits.
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| SimilaritiesbetweenComponents /Materials | BioPlex® 2200 APLS IgG and IgAKits | REAADS Anti-Cardiolipin IgG and IgASemi-Quantitative TestKits(K022992 IgG, K022990IgA) | REAADS Anti- ẞ2Glycoprotein I IgG andIgA Semi-QuantitativeTest Kits(K013080, K013077,K013079) |
|---|---|---|---|
| Intended Use | The BioPlex® 2200 APLSIgG and IgA kits aremultiplex flowimmunoassays intended forthe semi-quantitativedetection of IgG and IgAantibodies to Cardiolipin(CL) and Beta-2Glycoprotein I (ß2GPI) inhuman serum and plasma(lithium heparin, sodiumheparin, and sodiumcitrate). In conjunction withother clinical findings, thetest systems are used as anaid in the diagnosis ofprimary AntiphospholipidSyndrome (APS) and thosesecondary to systemic lupuserythematosus (SLE) orSLE-like disorders.The BioPlex 2200 APLSIgG and IgA kits areintended for use with theBio-Rad BioPlex 2200System. | An enzyme-linkedimmunosorbent assay(ELISA) for the semi-quantitative determinationof anti-cardiolipin IgG,and IgA antibodies inhuman serum or plasma inindividuals with systemiclupus erythematosus(SLE) and lupus-likedisorders (anti-phospholipid syndrome) | An enzyme-linkedimmunosorbent assay(ELISA) for the semi-quantitative determinationof anti-ß2 Glycoprotein I(ß2GPI) IgG and IgAantibodies in humanserum or citrated plasmain individuals withsystemic lupuserythematosus (SLE) andlupus-like disorders (anti-phospholipid syndrome) |
| Capture Antigen | Cardiolipin and ß2Glycoprotein I | Same | Same |
| Assay Type | Semi-Quantitativedetection | Same | Same |
| Analyte Detected | Human IgG or IgAantibodiesto Cardiolipin and ß2Glycoprotein I | Same | Same |
| Specimen Type | Serum and plasma | Same | Same |
| SimilaritiesbetweenComponents /Materials | BioPlex® 2200APLS IgG and IgAKits | REAADS Anti-Cardiolipin IgG and IgASemi-Quantitative TestKits(K022992 IgG, K022990IgA) | REAADS Anti--β2Glycoprotein I IgG andIgA Semi-QuantitativeTest Kits(K013080, K013077,K013079) |
| Controls | Negative and PositiveControls | Same | Same |
| Calibrator(s) | Multiple Calibrators | Same | Same |
BioPlex 2200® APLS IgG and IgA Kits vs. Predicate Devices - Similarities
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BioPlex 2200® APLS IgG and IgA Kits vs. Predicate Device - Differences
| DifferencesbetweenComponents/Materials | BioPlex® 2200APLS IgG and IgA Kits | REAADS Anti-Cardiolipin IgG and IgASemi-Quantitative TestKits(K022992 IgG, K022990IgA) | REAADS Anti-β2Glycoprotein I IgG and IgASemi-Quantitative Test Kits(K013080, K013077,K013079) |
|---|---|---|---|
| AssayTechnology | Automated Multiplex flowimmunoassay | Manual, microtitre plateformat, Enzyme-linkedImmunosorbent assay(ELISA) | Manual, microtitre plateformat, Enzyme-linkedImmunosorbent assay(ELISA) |
| ConjugateAntibody | Phycoerythrin conjugatedmurine monoclonal anti-human IgG or IgA. | Goat anti-human IgG, orIgA HRP-conjugatedantibody solution | Goat anti-human IgG or IgAHRP-conjugated antibodysolution |
| Substrate | None | Tetramethylbenzidine(TMB) and hydrogenperoxide (H2O2) | Tetramethylbenzidine(TMB) and hydrogenperoxide (H2O2) |
| Specimen Type | Serum and plasma (citratedand heparin) | Serum and plasma (exceptheparin) | Serum and plasma (citrated) |
| Signal Detection | Fluorescence | Color, read at 450nm | Color, read at 450nm |
| Solid Phase | Antigen-coatedparamagnetic microbeadreagent. Microbeads areinfused with red andinfrared fluorescent dyesfor bead classification.Green fluorescence fromthe immunoassay label isused for analytemeasurement. | Antigen-coated solid phasemicrotitre wells | Antigen-coated solid phasemicrotitre wells |
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| DifferencesbetweenComponents /Materials | BioPlex® 2200-APLS IgG and IgA Kits | REAADS Anti-Cardiolipin IgG and IgASemi-Quantitative TestKits(K022992 IgG, K022990IgA) | REAADS Anti-β2Glycoprotein I IgG and IgASemi-Quantitative Test Kits(K013080, K013077,K013079) |
|---|---|---|---|
| Calibrator(s) | 4 levels of Calibrator forIgG2 levels of Calibrator forIgA | 3 levels of Calibrator forIgG and IgA | 3 levels of Calibrator forIgG and IgA |
| Calibrator Range | Anti-Cardiolipin :IgG : 1.6 - 112 GPL U/mLIgA : 0.5 - 28 APL U/mLAnti-Beta-2 GlycoproteinI:IgG: 1.4 - 112 U/mLIgA : 0.6-28 U/mL | Anti-Cardiolipin :IgG :0 - 100 GPL- U/mLIgA : 0-80 APL U/mL | Anti-Beta-2 Glycoprotein I :IgG : 0 - 200 U//mLIgA : 0- 200 U/mL |
| Calibrators andControls | Sold separately | Kit components | Kit components |
| Quantitation | Results are determinedfrom a standard calibrationcurve utilizing a point-to-point calculation | Results are derived from alinear regression analysis | Results are derived from alinear regression analysis |
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Performance Characteristics ഗ
A. Analytical Performance
i. Precision/Reproducibility
EP15-A2 reproducibility studies were conducted to evaluate the reproducibility of the BioPlex 2200 APLS IgG and IgA kits on the BioPlex 2200 instrument. Reproducibility studies were based on the principles described in Clinical and Laboratory Standards Institute (CLSI) EP15-A2, User Verification of Performance for Precision and Trueness.
The study was performed at one clinical trial site. One lot each of BioPlex 200 APLS IgG and IgA reagent packs, Calibrator Sets and Control Sets was evaluated. Four panels were made from serum and plasma (lithium heparin, sodium heparin and sodium citrate) plus controls. Each panel of 8 samples covering the assay measuring range was tested in quadruplicate over five days (4 replicates x 1 run x 5 days x 1 testing site = 20 replicates per panel member) according to CLSI EP15-A2 guideline.
The data were analyzed for within-run, between-day, and total precision and the standard deviation (SD) and percent coefficient of variation ( %CV) were calculated.
The within-run precision and total precision in %CV for positive samples near the cut-off for anti-Cardiolipin IgG and IgA (20 GPL-U/mL, MPL-U/mL, and APL-U/mL) and for anti-Beta-2 Glycoprotein I IgG and IgA (20 U/mL) in all sample matrices are shown below.
| BioPlex 2200 | Within run (%CV) | Total (%CV) | ||
|---|---|---|---|---|
| APLS Assay | Min | Max | Min | Max |
| aCL IgG | 1.4 | 8.9 | 2.3 | 9.2 |
| aß2GPI IgG | 1.3 | 6.2 | 1.7 | 7.0 |
| aCL IgA | 2.2 | 4.3 | 2.5 | 4.3 |
| aß2GPI IgA | 2.0 | 4.2 | 2.0 | 4.5 |
ii. Linearity/Assay Reportable Ranges
Three (3) APLS anti-Cardiolipin and anti- ß2GPI IgG and IgA positive patient samples were tested to demonstrate linearity. These samples were diluted with immunodepleted serum according to CLSI EP06-A, Evaluation of the Linearity of Quantitative Measurement Procedures: A Statistical Approach.
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Each sample and dilution was evaluated in replicates of four using one APLS IgG and IgA IgG lot on one instrument. Linear and polynomial regression analysis of APLS IgG and IgA IgG recovery vs. sample dilution was performed to determine if the dilution curves exhibit statistically significant non-linear regression based on the CLSI guideline EP06-A.
The regression parameters (slope, intercept and r2) of the observed values vs. predicted values are show below. The BioPlex 2200 APLS IgG and IgA IgG assay demonstrated linearity from 0 to 112 GPL-U/mL for aCL IgG and, 0 to 28 APL-U/mL for aCL IgA and 0 to 112 U/mL for.aB2GPI IgG and 0 to 28 U/mL for aß2GPI IgA.
| APLSAssays | Sample ID | Conc. | Slope | Intercept | r2 |
|---|---|---|---|---|---|
| aCL IgG(GPL-U/mL) | APS0471A | 50.8 | 0.9998 | 0.0056 | 0.9999 |
| APS0882 | 56.1 | 1.0001 | 0.0105 | 0.9994 | |
| APS0893 | 43.3 | 1.0009 | -0.0182 | 0.9964 | |
| APS0471B | 104.5 | 1.0004 | -0.0033 | 0.9991 | |
| APS0486 | 89.3 | 1.0008 | -0.0307 | 0.9982 | |
| 791227A4 | 92.7 | 1.0003 | -0.0112 | 0.9999 | |
| aB2GPIIgG(U/mL) | APS0882 | 56.8 | 0.9996 | 0.0104 | 0.9999 |
| APS0893 | 45.3 | 0.9995 | 0.0104 | 0.9978 | |
| 791250G | 54.9 | 1.0000 | 0.0010 | 0.9758 | |
| APS0471 | 95.1 | 1.0003 | -0.0113 | 0.9991 | |
| APS0486 | 98.4 | 1.0001 | -0.0038 | 0.9958 | |
| 791227G4 | 100.4 | 1.0008 | -0.0049 | 0.9997 | |
| aCL IgA(APL-U/mL) | APS0485 | 26.4 | 0.9999 | 0.0012 | 0.9932 |
| APS0885 | 27.1 | 1.0014 | 0.0102 | 0.9958 | |
| APS0891 | 30.2 | 1.0011 | -0.0169 | 0.9836 | |
| aB2GPIIgA(U/mL) | APS0485 | 33.2 | 1.0001 | 0.0009 | 0.9900 |
| APS0885 | 33.9 | 1.0022 | -0.0356 | 0.9937 | |
| APS0891 | 28.1 | 1.0017 | -0.0251 | 0.9758 |
The BioPlex 2200 system does not support an on-board dilution feature for testing over-range samples.
iii. Traceability of Calibrators/Controls
There is no international or certified reference material available for APLS aCL and aB2GPI IgG and IgA assays.
The BioPlex 2200 APLS IgG or IgA Calibrator Set is intended for the calibration of the BioPlex 2200 APLS IgG or IgA Reagent Pack, respectively.
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The BioPlex 2200 APLS IgG or IgA Reagent Kit is calibrated using a set of four distinct serum based calibrators for IgG ; a set of two distinct serum based calibrators for IgA, which are used to establish points of reference for determining the presence of IgG or IgA in human specimens. The calibrators are made in human serum matrix derived from defibrinated plasma depleted of IgG plus known concentrations of anti-Beta-2Glycoprotein I (aB2GPI) IgG or IgA or anti-Cardiolipin (aCL) IgG or IgA derived from defibrinated human plasma. The Calibrators are manufactured independently from the controls, and are stabilized with <0.3% ProClin® 300. <0.1% sodium benzoate, and <0.1% sodium azide.
Calibrator assignment is established for matched lots of BioPlex 2200 APLS IgG or IgA kit and calibrators using a master set of calibrators as reference and replicate analyses on multiple BioPlex 2200 instruments.
For the aCL IgG, and aCL IgA assays, the assays are calibrated in units of GPL-U/mL and APL-U/mL, respectively. For aß2GPI IgG ,and aß2GPI IgA, the assays are calibrated in units of U/mL.
The BioPlex 2200 APLS IgG or IgA Control Set is intended for use as an assayed quality control to monitor the overall performance of the BioPlex 2200 Instrument and BioPlex 2200 APLS IgG or IgA Kit in the clinical laboratory, respectively. The performance of the BioPlex 2200 APLS IgG or IgA Control Set has not been established with any other Antiphospholipid assay.
The controls are provided in liquid form in a human serum matrix made from defibrinated plasma stabilized with <0.3% ProClin® 300, 0.1% sodium benzoate and <0.1% sodium azide. The positive control contains known concentrations of anti-Beta-2 Glycoprotein I (aB2GPI) IgG or IgA and anti-Cardiolipin (aCL) IgG or IgA derived from human plasma.
The negative control is provided as a human serum matrix made from defibrinated plasma that has been tested to give results with values below the cut-off for each assay. The positive control is prepared by blending human disease state serum with negative serum matrix and is manufactured to give results with values above the assay cut-off. The blending formulation for a specific lot of positive control is derived by a theoretical calculation. Based on this calculation, a pilot blend is prepared and tested. The results are used to adjust the spike volumes until an optimized manufacturing formulation that meets the target control values is achieved.
iv. Limit of Detection
The Limit of Detection (LoD) of BioPlex 2200 APLS IgG and IgA was determined by assaying low negative and blank samples in replicates of
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| BioPlex 2200APLS Assay | LoD |
|---|---|
| aCL IgG | 1.6 GPL-U/mL |
| aβ2GPI IgG | 1.4 U/mL |
fifty (50). The LoD was calculated according to CLSI EP17-A, Protocols for Determination of Limits of Detection and Limits of Quantitation. The calculated LoD for the APLS IgG and IgA assay is listed below..
0.5 APL-U/mL
0.6 U/mL
v. Analytical Specificity
Interfering Substances
aCL IgA aß2GPI IgA
An interfering substances study was conducted to evaluate the potential interference of specific endogenous and exogenous substances with the BioPlex 2200 APLS IgG and IgA assay.
Samples were prepared by blending a pool of negative human serum with samples positive for anti-Cardiolipin (aCL) IgG or IgA and anti-Beta-2Glycoprotein I (aß2GPI) IgG or IgA to achieve approximate values of 10, 20, 60 and 100 GPL for aCL IgG and 10, 20, 60 , 100 U/mL for aB2GPI IgG and 10, 20 APL-U/mL and U/mL for aCL and aB2GPI IgA with interferent or blank.
The study was conducted based on the principles described in Clinical and Laboratory Standards Institute (CLSI) EP7-A2, Interference Testing in Clinical Chemistry. No interference was observed with any of the substances tested. The substances and the maximum levels tested are shown in the table below.
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Interfering Substances
| Substance | Concentration |
|---|---|
| Hemoglobin | ≤ 500 mg/dL |
| Bilirubin, Unconjugated | ≤ 20 mg/dL |
| Bilirubin, Conjugated | ≤ 30 mg/dL |
| Cholesterol | ≤ 500 mg/dL |
| Red Blood Cells | ≤ 0.4% (v/v) |
| Gamma Globulin | ≤ 6 g/dL |
| Triglycerides | ≤ 3300 mg/dL |
| Protein (total) | ≤ 12 g/dL |
| Beta-Carotene | ≤ 0.6 mg/dL |
| Ascorbic Acid | ≤ 3 mg/dL |
| Lithium Heparin | ≤ 8000 units/dL |
| Sodium Heparin | ≤ 8000 units/dL |
| Sodium Citrate | ≤ 1000 mg/dL |
| EDTA | < 800 mg/dL |
Cross-Reactivity
A cross-reactivity study was performed to determine if samples from individuals with various disease states and other potentially interfering factors interfere with test results from the BioPlex 2200 APLS IgG or IgA kit. Samples from individual with known disease states for potential cross reactivity listed in the table below were evaluated with the BioPlex 2200 APLS IgG, or IgA kit.
Table below shows the number (N) of samples containing potential cross reactants as disease state evaluated by the BioPlex APLS IgG and IgA. The cross reactivity was obtained as the positivity rate from the ratio of the number of samples scored positive by the BioPlex APLS IgG or IgA assays to the total number of cross reactant samples evaluated.
No significant cross reactivity for these potential cross reactants was observed.
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| Cross ReactantDisease State | N | aCL IgG | aB2GPI IgG | aCL IgA | aB2GPI IgA | ||||
|---|---|---|---|---|---|---|---|---|---|
| # Pos | PositivityRate | # Pos | PositivityRate | # Pos | PositivityRate | # Pos | PositivityRate | ||
| Systemic LupusErythematosus | 34 | 2 | 5.9% | 2 | 5.9% | 2 | 5.9% | 2 | 5.9% |
| Scleroderma | 20 | 0 | 0.0% | 0 | 0.0% | 1 | 5.0% | 2 | 10.0% |
| Sjogrens | 22 | 0 | 0.0% | 0 | 0.0% | 0 | 0.0% | 0 | 0.0% |
| Crohn's Disease | 21 | 1 | 4.8% | 0 | 0.0% | 1 | 4.8% | 1 | 4.8% |
| Ulcerative Colitis | 20 | 0 | 0.0% | 0 | 0.0% | 0 | 0.0% | 0 | 0.0% |
| RheumatoidArthritis | 12 | 0 | 0.0% | 0 | 0.0% | 1 | 8.3% | 0 | 0.0% |
| Syphilis | 15 | 1 | 6.7% | 1 | 6.7% | 0 | 0.0% | 0 | 0.0% |
Cross Reactivity - APLS IgG and IgA
vi. Assay Cut-off
The cutoff value and assignment of the calibrators are determined by performing concordance testing and Receiver Operator Characteristic (ROC) analysis. The study to determine the APLS IgG or IgA assay cutoff is comprised of two sample groups - one clinical cohort has 103 samples from patients diagnosed as primary and secondary APS and 208 from normal healthy and 123 from non-APS cardiac donors.
A cutoff of 20.0 GPL- or APL-U/mL for aCL IgG or IgA and 20 U/mL for aß2GPI IgG, or IgA was established by optimizing for clinical accuracy.
The second cohort was comprised of the 208 samples from normal healthy donors plus 250 samples that were purchased based on vendor testing by aCL or aB2GPI IgG and IgA assay. This cohort was used for determining predicate agreement using the cutoff established by clinical accuracy.
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B. Comparative Performance
i. Comparative Testing
Method Comparison
Performance of the BioPlex 2200 APLS IgG, and IgA kits was evaluated against predicate device immunoassay.
The performance of the BioPlex 2200 APLS IgG and IgA kits was evaluated using a total of 804 specimens: 300 apparently healthy blood donors, 302 patients previously diagnosed with primary or secondary APS and 202 patients with other rheumatic or non-APS diseases that were tested at one clinical site. Patient specimens were purchased from commercial suppliers or rheumatology clinic labs and were frozen serum. Each sample was unique and was unlinked to patient identity and not individually identifiable. The study was evaluated for the clinical samples within the measuring range. The comparison results are presented in the tables below.
| Healthy, Diagnosed APSand Non-APS | Predicate Immunoassay | |||||
|---|---|---|---|---|---|---|
| Positive | Negative | Total | Positive% Agreement(95% CI) | Negative% Agreement(95%CI) | ||
| BioPlex APLS IgGaCL IgG | Positive | 99 | 14 | 113 | 75.6% | 88.9% |
| Negative | 32 | 112 | 144 | (99/131) | (112/126) | |
| Total | 131 | 126 | 257 | (67.6 - 82.1%) | (82.2% - 93.3%) | |
| BioPlex APLS IgGaβ2GPI IgG | Positive | 109 | 7 | 116 | 89.3% | 94.9% |
| Negative | 13 | 130 | 143 | (109/122) | (130/137) | |
| Total | 122 | 137 | 259 | (82.6 - 93.7%) | (89.8 - 97.5%) |
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| Healthy, Diagnosed APSand Non-APSN=804 | Predicate Immunoassay | ||||||
|---|---|---|---|---|---|---|---|
| Positive | Negative | Total | Positive % Agreement(95% CI) | Negative % Agreement(95%CI) | |||
| aCL IgA | Positive | 39 | 24 | 63 | 88.6% | 94.5% | |
| BioPlex APLS IgA | Negative | 5 | 416 | 421 | (39/44) | (416/440) | |
| Total | 44 | 440 | 484 | (76.0 – 95.0%) | (92.0 – 96.3%) | ||
| aβ2GPI IgA | Positive | 57 | 1 | 58 | 40.1% | 99.6% | |
| Negative | 85 | 271 | 356 | (57/142) | (271/272) | ||
| Total | 142 | 272 | 414 | (32.4 – 48.4%) | (97.9 – 99.9%) |
Matrix Comparison
Testing for matrix effects was conducted in accordance with CLSI EP9-A2 (Vol. 22, No. 19). More than 30 matched sets of serum and sodium citrate, lithium heparin, and sodium heparin plasma samples drawn from the same donor were acquired from a commercial source. The samples were spiked with aCL IgG or IgA and aB2GPI IgG or IgA positive sera as necessary in order to assemble a panel of samples to cover the measuring range of the assay. All samples were evaluated in replicates of two. Plasma values were . compared to matched serum values. The regression correlation parameters for the slopes, intercepts and correlation coefficient (r) are shown below.
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| MatrixComparison | N | BioPlexAPLS Assay | Slope(95% CI) | Intercept(95% CI) | Correlation ( r ) |
|---|---|---|---|---|---|
| Lithium Heparinvs. Serum | 32 | aCL IgG | 0.9720(0.9457, 0.9984) | 0.3788(-1.0552, 1.8128) | 0.9974 |
| 32 | aβ2GPI IgG | 0.9756(0.9488, 1.0023) | 0.4377(-1.1789, 2.0543) | 0.9973 | |
| 36 | aCL IgA | 0.9767(0.9090, 1.0445) | 0.6309(-0.3103, 1.5721) | 0.9808 | |
| 36 | aβ2GPI IgA | 0.9865(0.9249, 1.0480) | 0.4698(-0.2643, 1.2039) | 0.9844 | |
| Sodium Heparinvs. Serum | 32 | aCL IgG | 0.9885(0.9531, 1.0239) | 0.1921(-1.7335, 2.1177) | 0.9954 |
| 32 | aβ2GPI IgG | 0.9889(0.9555, 1.0222) | 0.3559(-1.6615, 2.3732) | 0.9959 | |
| 36 | aCL IgA | 1.0244(0.9641, 1.0847) | 0.0753(-0.7627, 0.9134) | 0.9860 | |
| 36 | aβ2GPI IgA | 1.0150(0.9520, 1.0779) | 0.1714(-0.5799, 0.9228) | 0.9845 | |
| Sodium Citratevs. Serum | 32 | aCL IgG | 0.9398(0.8757, 1.0039) | 0.8087(-2.6816, 4.2990) | 0.9837 |
| 32 | aβ2GPI IgG | 0.9351(0.8730, 0.9972) | 1.1299(-2.6264, 4.8862) | 0.9845 | |
| 36 | aCL IgA | 1.0096(0.9480, 1.0713) | 0.1181(-0.7384, 0.9746) | 0.9850 | |
| 36 | aβ2GPI IgA | 1.0061(0.9500, 1.0622) | 0.1801(-0.4895, 0.8497) | 0.9874 |
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CONFIDENTIAL
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ii. Clinical Sensitivity and Specificity
The clinical studies involved testing 504 specimens including 302 diagnosed primary or secondary APS patients and 202 non-APS disease control patients. . The BioPlex 2200 APLS IgG and IgA Sensitivity and Specificity are shown below.
| BioPlex APLS IgG | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| ClinicalSensitivity andSpecificity | aCL IgG | aβ2GPI IgG | ||||||||
| Pos | Neg | Total | Sensitivity(95% CI) | Specificity(95% CI) | Pos | Neg | Total | Sensitivity(95% CI) | Specificity(95% CI) | |
| DiagnosedAPS Patients | 188 | 98 | 286 | 65.7%(188/286) | 98.5%(198/201) | 186 | 100 | 286 | 65.0%(186/286) | 99.0%(199/201) |
| Non-APSDiseaseControl | 3 | 198 | 201 | 60.1 –71.0% | 95.7 –99.5% | 2 | 199 | 201 | 59.3 –70.3% | 96.4–99.7% |
| Total | 191 | 296 | 487* | 188 | 299 | 487* |
- 17 samples exhibiting repeated instrument errors were excluded from the data analysis.
| BioPlex APLS IgA | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| ClinicalSensitivity andSpecificity | aCL IgA | Sensitivity(95% CI) | Specificity(95% CI) | aβ2GPI IgA | Sensitivity(95% CI) | Specificity(95% CI) | ||||
| Pos | Neg | Total | Pos | Neg | Total | |||||
| DiagnosedAPS Patients | 167 | 135 | 302 | 55.3%(167/302) | 96.5%(195/202) | 157 | 145 | 302 | 52.0%(157/302) | 97.0%(196/202) |
| Non-APSDiseaseControl | 7 | 195 | 202 | 49.7 –60.8% | 93.0 –98.3% | 6 | 196 | 202 | 46.4 –57.6% | 93.7 –98.6% |
| Total | 174 | 330 | 504 | 163 | 341 | 504 |
The results of the BioPlex APLS IgG and IgA in each of disease category are shown below.
.
{18}------------------------------------------------
| Disease Category | NumberEnrolled | aCL IgG | aβ2GPI IgG | aCL IgA | aβ2GPI IgA |
|---|---|---|---|---|---|
| Primary APS (PAPS) | 207* | 119 (61%) | 119 (61%) | 108 (52%) | 104 (50%) |
| Secondary APS (SAPS) | 95* | 67 (74%) | 67 (74%) | 59 (62%) | 53 (56%) |
| Apparently HealthySubjects | 300 | 0 (0%) | 0 (0%) | 2 (1%) | 2 (1%) |
| Systemic LupusErythrematosus | 34 | 2 (6%) | 2 (6%) | 2 (6%) | 2 (6%) |
| CREST | 3 | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Crohn's Disease | 21 | 1 (5%) | 0 (0%) | 1 (5%) | 1 (5%) |
| Fibromyalgia | 20 | 0 (0%) | 0 (0%) | 1 (5%) | 0 (0%) |
| Gout | 14 | 0 (0%) | 0 (0%) | 1 (7%) | 1 (7%) |
| InflammatoryArthritis | 4 | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Osteoarthritis | 12 | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Scleroderma | 20 | 0 (0%) | 0 (0%) | 1 (5%) | 2 (10%) |
| Sjogrens | 22 | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Ulcerative Colitis | 20 | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| WegenersGranulomatosis. | 5 | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Rheumatoid Arthritis | 12 | 0 (0%) | 0 (0%) | 1 (8%) | 0 (0%) |
| Syphilis | 15* | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
- 195 PAPS, 91 SAPS and 14 Syphilis patient sample results were included in the data analysis for APLS IgG.
iii. Expected Values
Expected Values/Reference Range:
300 samples from apparently healthy donors including 132 males ranging in age from 7 to 85 and 168 females ranging in age from 14 to 83 were tested with BioPlex 2200 APLS IgG and IgA kits. The number of positive, mean value and 99th percentile of the BioPlex APLS IgG and IgA results are shown below. Results of <20.0 GPL- or APL-U/mL for aCL IgG or IgA and < 20.0 U/mL for aß2GPI IgG, or IgA are reported as negative and results ≥ 20.0
{19}------------------------------------------------
| APLS | N (%Positive) | Mean | 99th percentile |
|---|---|---|---|
| Assay | |||
| aCL IgG | 0 (0.0%) | <1.6 GPL -U/mL | 8.5 GPL-U/mL |
| aβ2GPI IgG | 0 (0.0%) | <1.4 U/mL | 6.0 U/mL |
| aCL IgA | 2 (0.7%) | 1.4 APL- U/mL | 14.5 APL-U/mL |
| aβ2GPI IgA | 2 (0.7%) | 1.3 U/mL | 12.1 U/mL |
GPL- or APL-U/mL for aCL IgG or IgA and ≥ 20.0 U/mL for aß2GPI IgG or IgA are reported as positive.
Note: Each laboratory should establish its own reference range pertinent to their specific patient populations.
Prevalence:
The observed prevalence for the APLS IgG and IgA assay was determined using samples collected from apparently healthy blood donors (N=300) including 132 males ranging in age from 7 to 85 and 168 females ranging in age from 14 to 83 The results by gender and age are presented in the tables below.
Note: Each laboratory should establish frequency distributions for their specific patient populations.
{20}------------------------------------------------
| aCL IgG | aβ2GPI IgG | ||||
|---|---|---|---|---|---|
| Age | Gender | Pos/Total | % Prevalence | Pos/Total | % Prevalence |
| ≤20 | F | 0/14 | 0.0% | 0/14 | 0.0% |
| M | 0/5 | 0.0% | 0/5 | 0.0% | |
| 21-30 | F | 0/13 | 0.0% | 0/13 | 0.0% |
| M | 0/23 | 0.0% | 0/23 | 0.0% | |
| 31-40 | F | 0/53 | 0.0% | 0/53 | 0.0% |
| M | 0/24 | 0.0% | 0/24 | 0.0% | |
| 41-50 | F | 0/32 | 0.0% | 0/32 | 0.0% |
| M | 0/12 | 0.0% | 0/12 | 0.0% | |
| 51-60 | F | 0/33 | 0.0% | 0/33 | 0.0% |
| M | 0/35 | 0.0% | 0/35 | 0.0% | |
| 61-70 | F | 0/15 | 0.0% | 0/15 | 0.0% |
| M | 0/14 | 0.0% | 0/14 | 0.0% | |
| 71+ | F | 0/8 | 0.0% | 0/8 | 0.0% |
| M | 0/19 | 0.0% | 0/19 | 0.0% | |
| Total | 0/300 | 0.0% | 0/300 | 0.0% |
Samples from Apparently Healthy Blood Donors . BioPlex2200 APLS IgG Prevalence Results by Age and Gender
Page 21/22
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| aCL IgA | aβ2GPI IgA | ||||
|---|---|---|---|---|---|
| Age | Gender | Pos/Total | % Prevalence | Pos/Total | % Prevalence |
| ≤20 | F | 0/14 | 0.0% | 0/14 | 0.0% |
| M | 0/5 | 0.0% | 0/5 | 0.0% | |
| 21-30 | F | 0/13 | 0.0% | 0/13 | 0.0% |
| M | 0/23 | 0.0% | 0/23 | 0.0% | |
| 31-40 | F | 0/53 | 0.0% | 0/53 | 0.0% |
| M | 0/24 | 0.0% | 0/24 | 0.0% | |
| 41-50 | F | 0/32 | 0.0% | 0/32 | 0.0% |
| M | 0/12 | 0.0% | 0/12 | 0.0% | |
| 51-60 | F | 1/33 | 3.0% | 1/33 | 3.0% |
| M | 1/35 | 2.9% | 1/35 | 2.9% | |
| 61-70 | F | 0/15 | 0.0% | 0/15 | 0.0% |
| M | 0/14 | 0.0% | 0/14 | 0.0% | |
| 71+ | F | 0/8 | 0.0% | 0/8 | 0.0% |
| M | 0/19 | 0.0% | 0/19 | 0.0% | |
| Total | 2/300 | 0.7% | 2/300 | 0.7% |
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・・ Samples from Apparently Healthy Blood Donors BioPlex2200 APLS IgA Prevalence Results by Age and Gender
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Image /page/22/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo consists of a stylized eagle with its head turned to the left and its wings outstretched. The eagle is positioned to the right of the text "DEPARTMENT OF HEALTH & HUMAN SERVICES • USA", which is arranged in a circular fashion around the eagle.
Public Health Service
Food and Drug Administration 10903 New Hampshire Avenue Silver Spring, MD 20993
Bio-Rad Laboratories, Inc. c/o Dr. Juang Wang Regulatory Affairs Representative 5500 East Second St. Benicia, CA 94510
MAR 3 0 2012
Re: K103834
Trade/Device Name: BioPlex® 2200 IgG and IgA Kit, Calibrator and Control Regulation Number: 21 CFR §866.5660 Regulation Name: Multiple autoantibodies immunological test system Regulatory Class: Class II Product Code: MID, MSV, JIX, JJX Dated: March 16, 2012 Received: March 19, 2012
Dear Dr. Wang:
We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration.
If your device is classified (see above) into class II (Special Controls), it may be subject to such additional controls. Existing major regulations affecting your device can be found in Title 21, Code of Federal Regulations (CFR), Parts 800 to 895. 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 Parts 801 and 809); medical device reporting (reporting of medical device-related adverse events) (21 CFR 803); and good manufacturing practice
{23}------------------------------------------------
Page 2 - Dr. Juang Wang
requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820). This letter will allow you to begin marketing your device as described in your Section 510(k) premarket notification. The FDA finding of substantial equivalence of your device to a legally marketed predicate device results in a classification for your device and thus, permits your device to proceed to the market.
If you desire specific advice for your device on our labeling regulation (21 CFR Parts 801 and 809), please contact the Office of In Vitro Diagnostic Device Evaluation and Safety at (301) 796-5450. 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
http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm for the CDRH's Office of Surveillance and Biometrics/Division of Postmarket Surveillance.
You may obtain other general information on your responsibilities under the Act from the Division of Small Manufacturers, International and Consumer Assistance at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address http://www.fda.gov/cdrh/industry/support/index.html.
Sincerely yours.
Mama Mchan
Maria M. Chan, Ph.D. Director
Division Immunology and Hematology Devices Office of In Vitro Diagnostic Device Evaluation and Safety Center for Devices and Radiological Health
Enclosure
{24}------------------------------------------------
Indication(s) for use
510(k) Number (if known): K103834
Device Name: BioPlex® 2200 Antiphospholipid Syndrome IgG and IgA Kits on the BioPlex® 2200 Multi Analyte Detection System
BioPlex® 2200 Antiphospholipid Syndrome IgG and IgA Calibrator Sets BioPlex® 2200 Antiphospholipid Syndrome IgG and IgA Control Sets
Indications for Use:
The BioPlex® Antiphospholipid Syndrome (APLS) IgG and IgA Kits
The BioPlex® 2200 APLS IgG and IgA kits are multiplex flow immunoassays intended for the semi-quantitative detection of IgG and IgA antibodies to Cardiolipin (CL) and Beta-2 Glycoprotein I (ß2GPI) in human serum and plasma (lithium heparin, sodium heparin, and sodium citrate). In conjunction with other clinical findings, the test systems are used as an aid in the diagnosis of primary Antiphospholipid Syndrome (APS) and those secondary to systemic lupus erythematosus (SLE) or SLE-like disorders.
The BioPlex 2200 APLS IgG and IgA kits are intended for use with the Bio-Rad BioPlex 2200 System
BioPlex® 2200 Antiphospholipid Syndrome (APLS) IgG and IgA Calibrator Sets The BioPlex® 2200 APLS IgG and IgA Calibrator Sets are intended for the calibration of the corresponding BioPlex® 2200 APLS IgG and IgA Reagent Packs.
BioPlex® 2200 Antiphospholipid Syndrome (APLS) IgG and IgA Control Sets
The BioPlex® 2200 APLS IgG and IgA Control Sets are intended for use as an assayed quality control to monitor the overall performance of the BioPlex 2200 instrument and the corresponding BioPlex 2200 APLS IgG and IgA Reagent Packs in the clinical laboratory. The performance of the BioPlex 2200 APLS IgG and IgA Control Sets has not been established with any other anti-Cardiolipin and anti- Beta-2 Glycoprotein I IgG or IgA APS assays.
Prescription Use X AND/OR Over-the-Counter Use (21 CFR 801 Subpart C) (Part 21 CFR 801 Subpart D)
(Please do not write below this line-Continue on another page if needed)
Concurrence of CDRH, Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD)
Marie In Chan
Division Sign-Off Office of In Vitro Diagnostic Device Evaluation and Safety
510(k) K103834
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§ 866.5660 Multiple autoantibodies immunological test system.
(a)
Identification. A multiple autoantibodies immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the autoantibodies (antibodies produced against the body's own tissues) in serum and other body fluids. Measurement of multiple autoantibodies aids in the diagnosis of autoimmune disorders (disease produced when the body's own tissues are injured by autoantibodies).(b)
Classification. Class II (performance standards).