DIMENSION VISTA SYSTEM A2MAC FLEX REAGENT CARTRIDGE, DIMENSION VISTA SYSTEM PROTEIN 1 CALIBRATOR, DIMENSION VISTA SYSYEM

{0} 1 # 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY A. 510(k) Number: k081249 B. Purpose for Submission: New analyte, controls, and calibrator C. Measurand: Alpha 2 macroglobulin D. Type of Test: Quantitative, Nephelometric E. Applicant: Dade Behring, Inc. F. Proprietary and Established Names: Dimension Vista System A2mac Flex Reagent Cartridge, Dimension Vista System Protein 1 Calibrator, Dimension Vista System. G. Regulatory Information: | Regulation Section | Classification | Product Code | Panel | | --- | --- | --- | --- | | 21 CFR 866.5620, Alpha-2-macroglobulin immunological test system. | Class II | Alpha-2-Macroglobulin, Antigen, Antiserum, Control (DEB) | 82 Immunology (IM) | | 21 CFR 862.1660, Quality control material (assayed and unassayed). | Class I | Multi-Analyte Controls, All Kinds (Assayed) (JJY) | 75 Clinical Chemistry (CH) | | 21 CFR 862.1150, Calibrator. | Class II | Calibrator, Multi-Analyte Mixture (JIX) | 75 Clinical Chemistry (CH) | H. Intended Use: 1. Intended use(s): Dimension Vista® System A2MAC Flex® Reagent Cartridge The A2MAC assay is an in vitro diagnostic test for the quantitative measurement of alpha2-macroglobulin in human serum and heparinized and EDTA plasma on the Dimension Vista® Systems. Measurements of a2-macroglobulin aid in the diagnosis of blood clotting or blood lysis disorders. Dimension Vista® Protein 1 Calibrator Dimension Vista® Protein 1 Calibrator is an in vitro diagnostic product for the calibration of the Dimension Vista® System for: α1-Acid Glycoprotein (A1AG), α1-Antitrypsin (A1AT), α2-Macroglobulin (A2MAC), β2-Microglobulin (B2MIC), C3 Complement (C3), C4 Complement (C4), Ceruloplasmin (CER), Haptoglobin (HAPT), Hemopexin (HPX), Homocysteine (HCYS), Immunoglobulin A (IGA), Immunoglobulin E (IGE), Immunoglobulin G (IGG, IGG-C*), Immunoglobulin G Subclass 1, (IGG1), Immunoglobulin G Subclass 2 (IGG2), Immunoglobulin G {1} Subclass 3 (IGG3), Immunoglobulin Subclass 4 (IGG4), Immunoglobulin M (IGM), Prealbumin (PREALB), Retinol Binding Protein (RBP), soluble Transferrin Receptor (sTFR) and Transferring (TRF). *for cerebrospinal fluid ## Dimension Vista® Protein 1 Control L Dimension Vista® Protein 1 Control L is an assayed, low level, intra-laboratory control for the assessment of precision and analytical bias on the Dimension Vista® System in the quantitative measurement of: α1-Acid Glycoprotein (A1AG), α1-Antitrypsin (A1AT), α2-Macroglobulin (A2MAC), C3 Complement (C3), C4 Complement (C4), Ceruloplasmin (CER), Haptoglobin (HAPT), Hemopexin (HPX), Homocysteine (HCYS), Immunoglobulin A (IGA), Immunoglobulin E (IGE), Immunoglobulin G (IGG), Immunoglobulin G Subclass 1 (IGG1), Immunoglobulin G Subclass 2 (IGG2), Immunoglobulin G Subclass 3 (IGG3), Immunoglobulin Subclass 4 (IGG4), Immunoglobulin M (IGM), Prealbumin (PREALB), Retinol Binding Protein (RBP), soluble Transferrin Receptor (sTFR), specialty Albumin (sALB*) and Transferring (TRF). *for serum and plasma ## Dimension Vista® Protein 1 Control M Dimension Vista® Protein 1 Control M is an assayed, mid level, intralaboratory control for the assessment of precision and analytical bias on the Dimension Vista® System in the quantitative measurement of: α1-Acid Glycoprotein (A1AG), α1-Antitrypsin (A1AT), α2-Macroglobulin (A2MAC), β2-Microglobulin (B2MIC), C3 Complement (C3), C4 Complement (C4), Ceruloplasmin (CER), Haptoglobin (HAPT), Hemopexin (HPX), Homocysteine (HCYS), Immunoglobulin A (IGA), Immunoglobulin E (IGE), Immunoglobulin G (IGG), Immunoglobulin G Subclass 1 (IGG1), Immunoglobulin G Subclass 2 (IGG2), Immunoglobulin G Subclass 3 (IGG3), Immunoglobulin Subclass 4 (IGG4), Immunoglobulin M (IGM), Prealbumin (PREALB), Retinol Binding Protein (RBP), soluble Transferrin Receptor (sTFR), specialty Albumin (sALB*) and Transferrin (TRF). *for serum and plasma ## Dimension Vista® Protein 1 Control H Dimension Vista® Protein 1 Control H is an assayed, high level, intralaboratory control for the assessment of precision and analytical bias on the Dimension Vista® System in the quantitative measurement of: α1-Acid Glycoprotein (A1AG), α1-Antitrypsin (A1AT), α2-Macroglobulin (A2MAC), β2-Microglobulin (B2MIC), C3 Complement (C3), C4 Complement (C4), Ceruloplasmin (CER), Haptoglobin (HAPT), Hemopexin (HPX), Homocysteine (HCYS), Immunoglobulin A (IGA), Immunoglobulin E (IGE), Immunoglobulin G (IGG), Immunoglobulin G Subclass 1 (IGG1), Immunoglobulin G Subclass 2 (IGG2), Immunoglobulin G Subclass 3 (IGG3), Immunoglobulin Subclass 4 (IGG4), Immunoglobulin M (IGM), Prealbumin (PREALB), Retinol Binding Protein (RBP), soluble Transferrin Receptor (sTFR), specialty Albumin (sALB*) and Transferring (TRF). {2} *for serum and plasma 2. Indication(s) for use: Same as Intended use 3. Special conditions for use statement(s): For Prescription use only. 4. Special instrument requirements: The Dimension Vista® A2MAC Flex® Reagent Cartridge, the Dimension Vista Protein 1 Calibrator, and Dimension Vista Protein 1 Control L, M, and H are for use on the Dimension Vista System, previously cleared under k051087, and its family member, Dimension Vista System 3000T. I. Device Description: The assay is supplied as a liquid, ready-to-use single reagent kit containing Arsenazo-III dye at a concentration of 0.2 mmol/L. Reagents are contained in 12 segregated wells in a plastic cartridge. Wells 1 - 8 contain buffers and polyethylene glycol. Wells 9 - 12 contain liquid rabbit antiserum to human α2-macroglobulin. There are two Flex® reagent cartridges per carton. PROT1 CAL is a multi-analyte, liquid human based product. PROT1 CON L, M and H are multi-analyte liquid human serum based product with low, medium and high levels respectively. All human materials included in the calibrators and controls were tested by FDA approved methods and found to be negative for the presence of antibodies to HIV-1, HIV-2, HBsAg, and HCV. J. Substantial Equivalence Information: 1. Predicate device name(s): N Antiserum to Human alpha 2 Macroglobulin N Protein Standard SL N/T Protein Controls SL L, M, and H 2. Predicate 510(k) number(s): k053073, k860894 k012470 k012468 3. Comparison with predicate: | Feature | N Antisera to Human α2-Macroglobulin (Predicate) | Dimension Vista® A2MAC Assay (New assay) | | --- | --- | --- | | Similarities: | | | | Intended Use: | In vitro diagnostic reagents for the quantitative determination of α2-macroglobulin in human plasma and serum | Same. | | Technology: | Nephelometry | Same | | Antibody: | Rabbit Polyclonal | Same | | Reagents | Reagents are liquid and ready for use | Same | {3} Differences: Analyzer: BN™ Systems Dimension Vista® System | Feature | N Protein Standard SL | Dimension Vista® PROT 1 CAL | | --- | --- | --- | | Similarities: | | | | Intended Use: | For the calibration of the α2-macroglobulin method. | Same | | Form: | Liquid human serum based. | Same | | Traceability | All analytes in N Protein Standard SL are traceable to recognized standards or highly purified proteins for all components. Values for α2-macroglobulin are traceable to ERM®DA 470 (CRM470). | Same | | Differences: | | | | Instruments: | BN™ Systems. | Dimension Vista® System. | | Constituents: | N Protein Standard SL contains: α1-acid glycoprotein, α1-antrypsin, albumin, α2-macroglobulin, β2-microglobulin, C3 Complement, C4 complement, ceruloplasmin, ferritin, haptoglobin, hemopexin, homocysteine, IgA, IgE, IgG, IgG1, IgG2, IgG3, IgG4, immunoglobulin light chains kappa, immunoglobulin light chains lambda, IgM, prealbumin, retinol binding protein, total protein, soluble transferrin receptor and transferrin. | Dimension Vista® PROT 1 CAL contains: α1-acid glycoprotein, α1-antrypsin, α2-macroglobulin, β2-microglobulin, C3 complement, C4 complement, ceruloplasmin, haptoglobin, hemopexin, homocysteine, IgA, IgE, IgG, IgG1, IgG2, IgG3, IgG4, IgM, prealbumin, retinol binding protein, soluble transferrin receptor and transferrin. | | Feature | N/T Protein Controls SL | Dimension Vista® PROT 1 CON | | --- | --- | --- | | Similarities: | | | | Intended Use: | Assayed interlaboratory controls for the assessment of precision and analytical bias on automated systems. | Same | | Form: | Liquid, human based material ready for use. | Same | | Differences: | | | | Instruments: | BN™ Systems. | Dimension Vista Systems. | | Constituents | N Protein Controls SL L, M and H are low, mid and high level controls respectively. They are multianalyte controls containing α1-acid glycoprotein, α1-antrypsin, α2-macroglobulin, albumin, β2-microglobulin, C3 Complement, C4 complement, ceruloplasmin, haptoglobin, hemopexin, ferritin, IgA, IgE, IgG, IgG1, 2, 3 and 4 immunoglobulin/light chains kappa, immunoglobulin/light chains lambda, | Dimension Vista® PROT 1 CON L, is a low level multianalyte control containing: α1-antrypsin, α2-macroglobulin, albumin, C3 Complement, C4 complement, ceruloplasmin, haptoglobin, hemopexin, homocysteine, IgA, IgE, IgG, IgG1, 2, 3 and 4, IgM, prealbumin, retinol binding protein, soluble transferrin receptor and transferrin. | {4} | Feature | N/T Protein Controls SL | Dimension Vista® PROT 1 CON | | --- | --- | --- | | | IgM, prealbumin, retinol binding protein, soluble transferrin receptor, total protein and transferrin. | Dimension Vista® PROT 1 CON M and H are mid and high level controls respectively containing: α1-acid glycoprotein, α1-antrypsin, α2-macroglobulin, albumin, β2-microglobulin, C3 Complement, C4 complement, ceruloplasmin, haptoglobin, hemopexin, IgA, IgE, IgG, IgG1, 2, 3 and 4, immunoglobulin/ light chains kappa, immunoglobulin/light chains lambda, IgM, prealbumin, retinol binding protein, soluble transferrin receptor and transferrin. | # K. Standard/Guidance Document Referenced (if applicable): | GUIDANCE | | | | | --- | --- | --- | --- | | Document Title | Office | Division | Web Page | | Guidance for Industry and FDA Staff - Assayed and Unassayed Quality Control Material | | | http://www.fda.gov/cdrh/oivd/guidance/2231. | # L. Test Principle: The Dimension Vista® A2MAC method is based on the principle of nephelometry. Proteins contained in human body fluids form immune complexes in an immunochemical reaction with specific antibodies. These complexes scatter a beam of light passed through the sample and the scattered light is measured. The intensity of the scattered light is proportional to the concentration of the respective protein in the sample. The result is evaluated by comparison with a standard of known concentration. The principle of nephelometry is used by the device as well as the predicate. The Dimension Vista® A2MAC method uses antisera to human $\mathbf{a}_2$ -macroglobulin which is produced by immunization of rabbits with highly purified human $\mathbf{a}_2$ -macroglobulin. # M. Performance Characteristics (if/when applicable): 1. Analytical performance: a. Precision/Reproducibility: This study was done over twenty days according to CLSI/NCCLS EP5-A2, at a single site using a single instrument, a single reagent lot and two operators. On each day of testing, each sample was run in duplicate, in two separate runs. The test samples consisted of three levels of Dimension Vista® Protein 1 Controls, two serum samples and two plasma samples. {5} The pools were established at levels below the expected range, at low and high points in the expected range and at a level at the upper portion of the analytical measuring range. The serum and plasma pools with high concentrations were prepared by spiking a native pool with purified analyte. Analysis of variance (ANOVA) was used to evaluate the data consistent with the recommendations of EP5-A2. | Material | Mean | | Standard Deviation mg/dL [g/L] (% CV) | | | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | mg/dL [g/L] | | Repeatability Within-Lab | | | | | | | PROT1 CON L | 123 | [1.23] | 2 | [0.02] | (1.8) | 3 | [0.03] | (2.6) | | PROT1 CON M | 142 | [1.42] | 2 | [0.02] | (1.7) | 3 | [0.03] | (2.4) | | PROT1 CON H | 224 | [2.24] | 5 | [0.05] | (2.0) | 7 | [0.07] | (3.0) | | Serum pool | 103 | [1.03] | 2 | [0.02] | (1.6) | 3 | [0.03] | (2.9) | | Serum pool | 591 | [5.91] | 12 | [0.12] | (2.1) | 18 | [0.18] | (3.1) | | Plasma pool | 151 | [1.51] | 2 | [0.02] | (1.5) | 4 | [0.04] | (2.5) | | Plasma pool | 271 | [2.71] | 5 | [0.05] | (1.9) | 7 | [0.07] | (2.5) | b. Linearity/assay reportable range: The A2MAC measuring range is 27 - 640 mg/dL (0.27 - 6.4 g/L). The linear range was determined according to CLSI, EP06-A. The linearity study covered a range of 20.2 to 685 mg/dL (0.202 - 6.85 g/L). The linearity studies were performed using a high serum sample (685 mg/dL). Serial dilutions were prepared using System Diluent. Based on the results of this testing and that from the Limit of Quantitation Study, the measuring range was established.  c. Traceability, Stability, Expected values (controls, calibrators, or methods): The calibrator and Protein 1 Control L, M, and H are traceable to ERM®-DA470 (CRM470). {6} 7 d. Detection limit: Three human serum samples were spiked with ERM® -DA470 with a known concentration of α2-macroglobulin. Two concentrations were tested, 270 mg/dL (0.27 g/L) and 70 mg/dL (0.07 g/L). These levels were chosen to challenge the low end of the analytical measuring range (1:20) and extended low range (1:5) of the assay. Five runs of triplicate determinations on each of three human serum samples were tested on one day with a single reagent and calibrator lot and a single instrument and operator. The Limit of Quantitation was determined to be 6.8 mg/dL (0.068 g/L) using the calculations described in CLSA Guideline EP17-A. e. Analytical specificity: Test samples were prepared by spiking the potential interferent into serum except for rheumatoid factors. CLSI/NCCLS EP7-A2 was followed to select the intereferent level. The concentration of α2-macroglobulin in the serum samples tested ranged from 118 mg/dL - 392 mg/dL (1.18 g/L - 3.92 g/L). Ten replicates of each serum sample with interferent were tested. All samples that were tested for interference, except RF, were compared to a negative control or baseline samples without the spiking material. Interference was defined as "recovery" of a2-macroglobulin greater than ±10% of the baseline sample. Recovery of a2-macroglobulin was in the range of 97 - 110% when compared to the sample without the interfering compound. The acceptance criterion for the bias (<= 10%) was met in all cases. | Substance | Test Concentration | SI Units | | --- | --- | --- | | Acetaminophen | 20 mg/dL | 1328 μmol/L | | Amikacin | 15 mg/dL | 256 μmol/L | | Ammonium heparin | 3 U/mL | 3000 U/L | | Ampicillin | 5.3 mg/dL | 152 μmol/L | | Ascorbic acid | 5 mg/dL | 284 μmol/L | | Caffeine | 6 mg/dL | 308 μmol/L | | Carbamazepine | 3 mg/dL | 127 μmol/L | | Chloramphenicol | 5 mg/dL | 155 μmol/L | | Chlordiazepoxide | 1 mg/dL | 33.3 μmol/L | | Chlorpromazine | 0.2 mg/dL | 6.27 μmol/L | | Cholesterol | 500 mg/dL | 12.9 mmol/L | | Cimetidine | 2 mg/dL | 79.2 μmol/L | | Creatinine | 30 mg/dL | 2652 μmol/L | {7} | Substance | Test Concentration | SI Units | | --- | --- | --- | | Dextran | 6000 mg/dL | 1500 μmol/L | | Diazepam | 0.5 mg/dL | 17.6 μmol/L | | Digoxin | 5 ng/mL | 6.15 nmol/L | | Erythromycin | 6 mg/dL | 81.6 μmol/L | | Ethanol | 400 mg/dL | 86.8 mmol/L | | Ethosuximide | 25 mg/dL | 1770 μmol/L | | Furosemide | 6 mg/dL | 181 μmol/L | | Gentamicin | 12 mg/dL | 151 μmol/L | | Ibuprofen | 50 mg/dL | 2425 μmol/L | | Immunoglobulin G (IgG) | 5 g/dL | 50 g/L | | Lidocaine | 1.2 mg/dL | 51.2 μmol/L | | Lithium chloride | 2.3 mg/dL | 3.2 mmol/L | | Lithium heparin | 3 U/mL | 3000 U/L | | Nicotine | 0.1 mg/dL | 6.2 μmol/L | | Penicillin | 25 U/mL | 25000 U/L | | Pentobarbital | 8 mg/dL | 354 μmol/L | | Phenobarbital | 10 mg/dL | 431 μmol/L | | Phenytoin | 5 mg/dL | 198 μmol/L | | Primidone | 4 mg/dL | 183 μmol/L | | Propoxyphene | 0.2 mg/dL | 4.91 μmol/L | | Protein, Albumin | 6 g/dL | 60 g/L | | Rheumatoid Factors | 906 IU/mL | 906 IU/mL | | Salicylic acid | 60 mg/dL | 4.34 mmol/L | | Sodium heparin | 3 U/mL | 3000 U/L | | Theophylline | 4 mg/dL | 95 μmol/L | | Urea | 500 mg/dL | 83.3 mmol/L | | Uric acid | 20 mg/dL | 1190 μmol/L | | Valproic acid | 50 mg/dL | 3467 μmol/L | To evaluate possible interference from rheumatoid factors, 1:1 dilutions of samples with RF concentrations in the range of 978 - 1812 IU/mL and samples with no detectable RF were made and tested. The range of α2-macroglobulin in the samples used for this study was 1.52 - 4.42 g/L. Recovery of α2-macroglobulin was in the range of -2.7% to +0.7% for these samples. The acceptance criterion for the bias was ± 10%. f. Assay cut-off: Not applicable. 2. Comparison studies: a. Method comparison with predicate device: De-identified serum and plasma samples containing measurable amounts of α2-macroglobulin were used in this study. The only additional requirement was a sufficient sample volume for testing. The samples were obtained from external sources. The samples were frozen within 24 hours of collection and {8} stored frozen $(-20^{\circ}\mathrm{C})$ for up to 3 months without exposure to repeated freeze-thaw cycles until tested for both the predicate and the proposed device. Sample stability studies were performed on samples stored at $2 - 8^{\circ}\mathrm{C}$ for seven days and frozen at $-20^{\circ}\mathrm{C}$ for three months to validate storage conditions. There were a total of 143 samples consisting of 64 serum samples and 79 heparin (lithium and sodium) plasma samples in the method comparison study. A single determination was run for each sample following CLSI/NCCLS EP9-A2. Passing-Bablok regression analysis was used to analyze the data for the initial measuring range. The regression statistics as follows: Serum: Slope = 1.028, Intercept = +5.7 (0.057) mg/dL (g/L) Correlation Coefficient (r) = 0.996, n = 64 Plasma: Slope = 1.050, Intercept = +6.0 (0.060) mg/dL (g/L) Correlation Coefficient (r) = 0.990, n = 79 Combined: Slope = 1.042, Intercept = +6.3 (0.063) mg/dL (g/L) Correlation Coefficient (r) = 0.993, n = 143 # b. Matrix comparison: In addition to the method comparison studies, a separate study was done using matched serum and plasma samples on the Dimension Vista® System. In this study, matched samples of serum, lithium heparin, sodium heparin and EDTA were tested on the Dimension Vista® System. The % recovery of α2-macroglobulin for each plasma type was determined versus serum and a regression analysis was done for each plasma type versus serum. The acceptance criteria were for a correlation coefficient of $\geq 0.950$ and for a median of the normalized differences $\geq 7\%$ . All samples met the acceptance criterion. | | Linear Regression vs. Serum | | | % Recovery Statistics | | | | --- | --- | --- | --- | --- | --- | --- | | | Li Hep | Na Hep | EDTA | Li Hep | Na Hep | EDTA | | Slope | 0.99 | 1.00 | 0.98 | | | | | Y-int | 0.03 | -0.03 | -0.04 | Mean: 0.5% | -1.4% | -4.7% | | r | 0.997 | 0.999 | 1.000 | Min: -6.9% | -6.0% | -8.0% | | Syx | 0.14 | 0.09 | 0.05 | Max: 8.2% | 3.9% | -1.7% | | Low 95% CI Slope | 0.953 | 0.976 | 0.963 | | | | | High 95% CI Slope | 1.03 | 1.03 | 0.99 | | | | # 3. Clinical studies: a. Clinical Sensitivity: Not applicable. b. Clinical specificity: Not applicable. c. Other clinical supportive data (when a. and b. are not applicable): Not applicable. # 4. Clinical cut-off: {9} Not Applicable. 5. Expected values/Reference range: A literature reference was used for the expected range. The expected range interval is 130 - 300 mg/dL (1.30 - 3.0 g/L) for serum and plasma. N. Proposed Labeling: The labeling is sufficient and it satisfies the requirements of 21 CFR Part 809.10. O. Conclusion: The submitted information in this premarket notification is complete and supports a substantial equivalence decision. 10