ONLINE TDM Vancomycin Gen.3

{0} 1 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY ASSAY ONLY TEMPLATE A. 510(k) Number: k152245 B. Purpose for Submission: New device C. Measurand: Vancomycin D. Type of Test: Quantitative Immunoassay E. Applicant: Roche Diagnostics Operations Inc. F. Proprietary and Established Names: ONLINE TDM Vancomycin Gen.3 G. Regulatory Information: 1. Regulation section: 21 CFR 862.3950; Vancomycin test system 2. Classification: Class II 3. Product code: LEH 4. Panel: Toxicology (91) H. Intended Use: 1. Intended use(s): See Indications for Use below 2. Indication(s) for use: In vitro test for the quantitative determination of vancomycin in serum and plasma on Roche/Hitachi cobas c systems. A vancomycin test system is a device intended to measure vancomycin, an antibiotic {1} drug, in serum and plasma. Measurements obtained by this device are used in the diagnosis and treatment of vancomycin overdose and in monitoring the level of vancomycin to ensure appropriate therapy 3. Special conditions for use statement(s): For in vitro diagnostic use only. 4. Special instrument requirements: Roche/Hitachi cobas c 501 analyzer I. Device Description: The ONLINE TDM Vancomycin Gen.3 is a two reagent assay for the in vitro quantitative determination of vancomycin in human serum or plasma on automated clinical chemistry analyzers. The assay consists of 2 wet reagents, one of which contains a Vancomycin conjugate, piperazine- N,N'-bis (2 ethanesulfonic acid) (PIPES) buffer, preservative and a stabilizer; the other reagent contains an Anti-Vancomycin antibody (mouse Mono-clonal); latex microparticles, 3-(Nmorpholino) propane sulfonic acid (MOPS) buffer, and a stabilizer. The two reagents are sold together and available in kits of either 100 or 200 tests. Calibrators for this assay include the Preciset TDM 1 Calibrator (k031856). The recommended control material for this assay is the TDM Control Set (k070200) or other commercially available suitable control material. J. Substantial Equivalence Information: 1. Predicate device name(s): ONLINE TDM Vancomycin 2. Predicate 510(k) number(s): k060586 3. Comparison with predicate: | Similarities | | | | --- | --- | --- | | Item | Candidate Device ONLINE TDM Vancomycin Gen.3 (K152245) | Predicate Device ONLINE TDM Vancomycin (k060586) | | Intended Use | Intended for the quantitative determination of vancomycin in serum and plasma for the diagnosis and treatment of vancomycin overdose and in monitoring levels of vancomycin to ensure appropriate therapy | Same | | Controls | TDM Control Set | Same | | Calibrator | Preciset TDM 1 Calibrator | Same | | Reagent Shelf Life | 2-8 °C until expiration date | Same | {2} | Similarities | | | | --- | --- | --- | | Item | Candidate Device ONLINE TDM Vancomycin Gen.3 (K152245) | Predicate Device ONLINE TDM Vancomycin (k060586) | | Traceability | Traceable to USP reference standards | Same | | Differences | | | | --- | --- | --- | | Item | Candidate Device ONLINE TDM Vancomycin Gen.3 (K152245) | Predicate Device ONLINE TDM Vancomycin (k060586) | | Methodology | Competitive interaction of microparticles in solution immunoassay | Homogeneous enzyme immunoassay | | Instrumentation | Roche/ Hitachi cobas c 501 | Roche/Hitachi 911, 912, 917, and MODULAR P analyzers | | Specimen Type | Serum, plasma collected in K2- or K3-EDTA, or lithium heparin | Serum, plasma collected in K2- or K3-EDTA, sodium citrate, or fluoride oxalate | | Reagent Composition | Reagent 1: Vancomycin conjugate, piperazine- N,N'-bis (2 ethanesulfonic acid) (PIPES) buffer, pH 7.2; preservative; stabilizer Reagent 2: Anti-Vancomycin antibody (mouse Mono-clonal); latex microparticle; 3-(Nmorpholino) propane sulfonic acid (MOPS) buffer, pH 7.2; stabilizer | Reagent 1: G6PHDH-labeled Vancomycin in buffer Reagent 2: Anti-vancomycin antibody (mouse monoclonal), G6P and NAD in buffer | | Lower Limits of Measurement | LoB = 1.0 μg/mL (0.69 μmol/L) LoD = 1.5 μg/mL (1.04 μmol/L) LoQ = 4.0 μg/mL (2.76 μmol/L) | Lower Detection Limit = 1.7 μg/mL (1.2 μmol/L) | | Reagent On-Board Stability | 12 weeks on-board in use and refrigerated on the analyzer | 60 days opened and refrigerated on the analyzer | | Measuring Range | 4.0 to 80 μg/mL | 1.7 to 80 μg/mL | | Calibration Frequency | After lot change, after 6 weeks, and as required following quality control procedures | After reagent bottle change, after reagent lot change, and as required following quality control procedures | K. Standard/Guidance Document Referenced (if applicable): - CLSI EP5-A2: Evaluation of Precision Performance of Quantitative Measurement Methods; Approved Guideline- Second Edition - CLSI EP6-A: Evaluation of the Linearity of Quantitative Measurement Procedures: A {3} Statistical Approach; Approved Guideline. - CLSI EP17-A: Protocol for Determination of Limits of Detection and Limits of Quantitation; Approved Guideline. - CLSI EP7-A2: Interference Testing in Clinical Chemistry: Approved Guideline-Second Edition - CLSI EP9-A2: Method Comparison and Bias Estimation Using Patient Samples: Approved Guideline- Second Edition # L. Test Principle: This is a two reagent assay for the in vitro quantitative determination of vancomycin in human serum or plasma on automated clinical chemistry analyzers. One reagent comprises vancomycin antibody covalently coupled to microparticles. The second reagent comprises a drug (vancomycin) conjugate linked to a macromolecule. The kinetic interaction (aggregation) of antibody-coupled microparticles in solution is induced by binding of the drug conjugate to the antibody and is inhibited by the presence of Vancomycin in the sample. The resulting kinetic interaction is measured by absorbance and is indirectly proportional to the amount of drug present in the sample. # M. Performance Characteristics (if/when applicable): # 1. Analytical performance: # a. Precision/Reproducibility: Precision (within-run precision) and intermediate precision (between-day precision) were assessed in accordance with CLSI Guideline EP5-A2 using three levels of control solutions (TDM Control set, k070200) and human serum spiked to five different Vancomycin levels. Samples were run in duplicate, twice per day per day, for 21 days, on a single analyzer using 3 lots of reagent. The within-run precision data are summarized in the table below. | Specimen | Reagent Lot | N | Mean (μg/mL) | SD (μg/mL) | CV (%) | | --- | --- | --- | --- | --- | --- | | Control 1 | 1 | 84 | 7.85 | 0.28 | 3.5 | | | 2 | 84 | 7.45 | 0.39 | 5.2 | | | 3 | 84 | 7.68 | 0.33 | 4.2 | | Control 2 | 1 | 84 | 22.1 | 0.4 | 1.7 | | | 2 | 84 | 21.5 | 0.5 | 2.3 | | | 3 | 84 | 21.3 | 0.4 | 2.1 | | Control 3 | 1 | 84 | 35.9 | 0.6 | 1.8 | | | 2 | 84 | 36.2 | 0.9 | 2.4 | | | 3 | 84 | 35.5 | 0.8 | 2.3 | | Serum 1 | 1 | 84 | 5.33 | 0.26 | 4.8 | | | 2 | 84 | 4.82 | 0.40 | 8.2 | | | 3 | 84 | 4.93 | 0.32 | 6.5 | | Serum 2 | 1 | 84 | 8.49 | 0.23 | 2.7 | | | 2 | 84 | 7.95 | 0.41 | 5.2 | | | 3 | 84 | 8.17 | 0.33 | 4.0 | | Serum 3 | 1 | 84 | 31.8 | 0.6 | 1.8 | | | 2 | 84 | 32.1 | 0.8 | 2.5 | {4} The intermediate precision (between-day) precision data are summarized in the table below: | Specimen | Reagent Lot | N | Mean (μg/mL) | SD (μg/mL) | CV (%) | | --- | --- | --- | --- | --- | --- | | Control 1 | 1 | 84 | 7.85 | 0.31 | 3.9 | | | 2 | 84 | 7.45 | 0.46 | 6.2 | | | 3 | 84 | 7.68 | 0.39 | 5.1 | | Control 2 | 1 | 84 | 22.1 | 0.4 | 2.0 | | | 2 | 84 | 21.5 | 0.8 | 3.7 | | | 3 | 84 | 21.3 | 0.8 | 3.5 | | Control 3 | 1 | 84 | 35.9 | 0.8 | 2.3 | | | 2 | 84 | 36.2 | 1.1 | 3.0 | | | 3 | 84 | 35.5 | 1.1 | 3.2 | | Serum 1 | 1 | 84 | 5.33 | 0.29 | 5.4 | | | 2 | 84 | 4.82 | 0.51 | 10.6 | | | 3 | 84 | 4.93 | 0.52 | 10.5 | | Serum 2 | 1 | 84 | 8.49 | 0.27 | 3.1 | | | 2 | 84 | 7.95 | 0.47 | 5.9 | | | 3 | 84 | 8.17 | 0.46 | 5.6 | | Serum 3 | 1 | 84 | 31.8 | 0.7 | 2.1 | | | 2 | 84 | 32.1 | 1.1 | 3.4 | | | 3 | 84 | 31.1 | 1.0 | 3.2 | | Serum 4 | 1 | 84 | 40.0 | 1.1 | 2.8 | | | 2 | 84 | 39.5 | 1.1 | 2.9 | | | 3 | 84 | 38.5 | 1.1 | 2.9 | | Serum 5 | 1 | 84 | 72.5 | 2.0 | 2.8 | | | 2 | 84 | 71.4 | 2.2 | 3.1 | | | 3 | 84 | 72.9 | 1.9 | 2.7 | # b. Linearity/assay reportable range: To assess linearity of the assay, the sponsor conducted a linearity study according to CLSI EP-6A. A sixteen level dilution series was prepared for serum and plasma samples using spiked human serum and plasma pools. Concentrations of each sample in the dilution series (serum: 0, 2.97, 3.96, 4.95, 5.94, 6.93, 7.92, 8.91, 9.90, 19.80, 29.70, 39.6, 49.5, 59.4, 69.3, 79.2, 89.1, $99.0~\mu \mathrm{g / mL}$ ; plasma: 0, 3.07, 4.09, 5.11, 6.14, 7.16, 8.18, 9.2, 0, 10.2, 20.5, 30.7, 40.9, 51.1, 61.4, 71.6, 81.8, 92.0, 102.3 $\mu \mathrm{g / mL}$ ) were calculated based on measurement of a sample at the mid-point of the claimed measuring range. Each sample was measured in triplicate, measured results were compared to calculated sample concentrations, and percent relative recovery calculated. {5} Percent recovery for serum samples ranged from 85.6 to 109.2%. Percent recovery for plasma samples ranged from 80.8 to 105.6%. The results support the claimed measuring range of 4.0 to 80.0 µg/mL vancomycin in serum and plasma. c. Traceability, Stability, Expected values (controls, calibrators, or methods): **Controls and Calibrators** The Preciset TDM 1 Calibrators contain known quantities of vancomycin in normal human serum and are traceable to primary master calibrators; these calibrators were cleared under k031856. The TDM Control Set contains liquid controls based on human serum and is traceable to USP reference standards; the controls were cleared under k070200. Protocols and acceptance criteria for stability and value assignment of calibrators and controls were previously reviewed in k031856 and k070200 and found acceptable. **Reagent Stability – closed vial** Protocols and acceptance criteria for ongoing real-time closed-vial (shelf life) stability studies were reviewed and found acceptable to support storage of reagents between 2-8°C until the expiration date printed on the bottle. Real time closed-vial stability studies are ongoing. **Reagent Stability – on board** Protocols and acceptance criteria for on-board reagent stability were reviewed and found acceptable to support the claim that reagents are stable when refrigerated in use on board the analyzer for up to 12 weeks. d. Detection limits: Limit of Blank (LoB), Limit of Detection (LoD), and Limit of Quantitation (LoQ) studies were performed based on CLSI EP17-A2 and as described below: **Limit of Blank (LoB):** To determine LoB, 5 analyte-free samples was measured in duplicate on two instruments, with two runs per day, using three lots of reagent, over three days, for a total of 180 measurements. The sponsor defined LoB as the concentration below which analyte-free samples could be found with a probability of 95%. Results of the study support the sponsor’s claimed LoB of 1.0 µg/mL. **Limit of Detection (LOD):** To determine LoD, 5 low-analyte samples were measured in duplicate on two instruments, using three lots of reagent, over three days, for a total of 180 measurements. The sponsor defined LoD as the lowest analyte concentration which could be detected, with a value above the LoB, with a probability of 95%. Results of the study support the sponsor’s claimed LoB of 1.5 µg/mL. **Limit of Quantitation (LoQ)** To determine LoQ, fifteen human serum samples were spiked with vancomycin to cover the analyte concentration range between LoB and 2x the expected LoQ. These 6 {6} samples were measured in duplicate in six runs over four days using three lots of reagent and one analyzer, for a total of 36 measurements per sample. Expected values for each sample were determined using LCMS/MS. Total Error (TE) was calculated based on precision and accuracy for each sample using the formula $\mathrm{TE} = \sqrt{\left(\mathrm{s}^2 + \mathrm{Bias}^2\right)}$ where $\mathrm{s} =$ standard deviation. LoQ was defined as the lowest vancomycin concentration with a total error less than $20\%$, and above which all samples also had a total error less than $20\%$. Results of the study support the sponsor's claimed LoQ of $4.0~\mu \mathrm{g / mL}$. e. Analytical specificity: Endogenous interferents The sponsor evaluated the effects of known potential endogenous interferents (hemoglobin, triglycerides, bilirubin, rheumatoid factor, protein, and HAMA) on the ONLINE TDM Vancomycin Gen.3 assay using human serum pools prepared with low $(\approx 7.5\mu \mathrm{g} / \mathrm{mL})$ or intermediate $(\approx 30\mu \mathrm{g} / \mathrm{mL})$ vancomycin levels. The test ranges were: hemoglobin $>1000~\mathrm{mg / dL}$, triglycerides $\geq 1000~\mathrm{mg / dL}$, conjugated bilirubin $>60~\mathrm{mg / dL}$, unconjugated bilirubin $>60~\mathrm{mg / dL}$, rheumatoid factor $>1200~\mathrm{IU / mL}$, total protein 2-12 g/dL. The sponsor tested potential interference from IgA, IgG, IgM and albumin using human serum samples spiked with low $(\approx 7.5\mu \mathrm{g} / \mathrm{mL})$, intermediate $(\approx 30\mu \mathrm{g} / \mathrm{mL})$ and high $(\approx 60\mu \mathrm{g} / \mathrm{mL})$ vancomycin levels. Measurements from samples containing potential endogenous interferents were compared to measurements from sample containing no potential interferent and the percent recovery was calculated. The results demonstrated no interference from these potential endogenous interferents at the concentrations shown below: Hemoglobin up to $1000\mathrm{mg / dL}$ Conjugated bilirubin up to $60~\mathrm{mg / dL}$ Unconjugated bilirubin up to $60~\mathrm{mg / dL}$ Triglycerides up to $1000\mathrm{mg / dL}$ Total Protein up to $12\mathrm{g / dL}$ Rheumatoid Factor up to 1200 IU/mL IgA up to $16\mathrm{g / L}$ IgG up to $70~\mathrm{g / L}$ IgM up to $10~\mathrm{g / L}$ Albumin up to $70\mathrm{g / L}$ The sponsor included the following statements in their labeling regarding human anti-mouse antibodies (HAMA) and IgM interference: As with any assay employing mouse antibodies, the possibility exists for interference by human anti-mouse antibodies (HAMA) in the sample, which could cause falsely lowered results. In very rare cases, gammopathy, in particular type IgM (Waldenström's {7} macroglobulinemia), may cause unreliable results. ## Interference from common therapeutic substances The sponsor evaluated interference from therapeutic substances using human serum pools prepared to low (≈7.5 μg/mL) or intermediate (≈30μg/mL) vancomycin levels and spiked with concentrations of potential therapeutic interferents at concentrations identified in CLSI EP7-A2 or higher. Measurements from samples containing potential interferent were compared to measurements from sample containing no potential interferent. The sponsor defined significant interference as recovery relative to the no-interferent sample of within ±1.0μg/mL for the low vancomycin concentration and within ±10% for the intermediate vancomycin concentration. These criteria were met for the following substances at the concentrations indicated in the table below: | Therapeutic Substance | Highest concentration tested at which no significant interference was observed. | | --- | --- | | Acetylsalicylic acid | 1000 mg/L | | Acetaminophen | 200 mg/L | | Acetylcysteine | 1660 mg/L | | Ampicillin-sodium | 1000 mg/L | | Ascorbic acid | 300 mg/L | | Cefoxitin | 2500 mg/L | | Cyclosporine | 5 mg/L | | Doxycycline | 50 mg/L | | Heparin | 5000 U/L | | Ibuprofen | 500 mg/L | | Levodopa | 20 mg/L | | Methotrexate | 455 μg/mL | | Methyldopa | 20 mg/L | | Metronidazole | 200 μg/mL | | Phenylbutazone | 400 mg/L | | Rifampicin | 60 mg/L | | Theophylline | 100 mg/L | ## Cross Reactivity The sponsor tested for cross reactivity using human serum pools prepared to low (≈7.5 μg/mL) or intermediate (≈30μg/mL) vancomycin levels and spiked with concentrations of potential cross-reacting substance at typical or higher than expected therapeutic serum concentrations. Measurements from samples containing potential cross reactant were compared to measurements from samples containing no potential cross reactant. Absolute difference in measured vancomycin levels between samples with and without cross reactant and percent cross reactivity (100x absolute difference / concentration of cross reactant) were calculated. The following potential cross-reacting substances showed no significant cross reaction, defined by the sponsor as a difference of <1.5μg/mL in the presence and absence of potential cross reactant at the {8} indicated levels: | Drug | Highest concentration tested at which no significant cross-reaction was observed | | --- | --- | | CDP-I (crystallization degradation product) | 20 μg/mL | | Acyclovir | 50 μg/mL | | Amikacin | 100 μg/mL | | Amphotericin B | 10 μg/mL | | Aztreonam | 450 μg/mL | | Caffeine | 60 μg/mL | | Cefazolin | 500 μg/mL | | Cefotaxine | 300 μg/mL | | Chloramphenicol | 60 μg/mL | | Ciprofloxacin | 12 μg/mL | | Cisplatin | 15 μg/mL | | Clindamycin | 50 μg/mL | | Cyclosporine | 50 μg/mL | | Digoxin | 50 μg/mL | | Epinephrine | 25 μg/mL | | Erythromycin | 60 μg/mL | | Ethacrynic acid | 50 μg/mL | | Flucytosine | 300 μg/mL | | Furosemide | 60 μg/mL | | Fusidic acid | 600 μg/mL | | Gentamicin | 30 μg/mL | | Imipenem | 250 μg/mL | | Methicillin | 250 μg/mL | | Metronidazole | 150 μg/mL | | Netilmicin | 30 μg/mL | | Nitroprusside | 90 μg/mL | | Penicillin G | 36 μg/mL | | Pentamidine | 50 μg/mL | | Phenobarbital | 150 μg/mL | | Rifampin | 60 μg/mL | | Salicylate | 750 μg/mL | | Sulfamethoxazol | 400 μg/mL | | Theophylline | 60 μg/mL | | Tobramycin | 30 μg/mL | | Trimethoprim | 40 μg/mL | f. Assay cut-off: Not applicable. {9} 10 2. Comparison studies: a. Method comparison with predicate device: The sponsor tested 125 native human serum samples from patients taking Vancomycin, ranging in concentration from 4.8 to 76 µg/mL as measured with the candidate device. Eight samples were altered at the upper end of the measuring range (above ≈60 µg/mL vancomycin). The samples were tested in singlicate using the candidate and predicate device and analyzed using Passing Bablok regression which yielded the following regression equation: y = 0.993x + 0.641, r = 0.994. A mean bias of 4.4% was observed across all data points. The sponsor conducted an additional method comparison of 134 native human serum samples from patients taking Vancomycin, ranging from 4.1 to 76 µg/mL as measured with the candidate device. Thirty four samples were altered across the measuring range. The samples were tested in singlicate using the candidate device and by liquid-chromatography/mass-spectrometry (LC/MS) and analyzed using weighted Deming regression, with a weighting of 1/concentration². This analysis yielded the following regression equation: y = 0.992 x + 0.841, r = 0.991. A mean bias of 5.7% was observed across all data points. b. Matrix comparison: A matrix comparison study was performed using 77 or 78 matched samples (serum and K₂-EDTA, serum and K₃-EDTA, serum and Li-Heparin). Each sample set comprised 67 full tubes and 9 or 10 half-filled tubes. Only samples within the measuring range of 4-80 µg/mL were used. In each case, serum was used as the comparator matrix. Results of linear regression analyses are summarized below: 1. K₂-EDTA plasma vs. serum: y = 0.998x + 0.00194, r = 0.996 2. K₃-EDTA vs. serum: y = 0.995x - 0.128, r = 0.995 3. Li-Heparin plasma vs. serum: y = 1.01x - 0.224, r = 0.996 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: Not applicable. {10} 5. Expected values/Reference range: In the labeling, the sponsor states: The practice of routine monitoring and adjustment of serum vancomycin concentrations has been the subject of intense debate for many years.¹ Historically trough concentrations between 5 to 10 µg/mL and peak concentrations between 20 to 40 µg/mL were generally accepted for therapeutic effectiveness.¹⁻³ The increased prevalence of resistant organisms, increasing vancomycin minimum inhibitory concentrations in target pathogens (particularly MRSA) and vancomycin failures have prompted more aggressive vancomycin dosing practices and recommendations.¹,⁴ Therefore, current guidelines recommend higher trough concentrations in the range of 10–15 µg/mL for uncomplicated MRSA bacteremia and even 15–20 µg/mL in cases of sustained MRSA bacteremia or endocarditis and other severe invasive MRSA infections (i.e. prosthetic joint infections, hospital-acquired pneumonia or central nervous system infections).¹,⁵ However, higher doses of vancomycin used have been associated with significantly higher vancomycin trough levels, resulting in acute renal failure and ototoxicity.⁴,⁶⁻⁸ The decision to target increased vancomycin trough concentrations should be based on an assessment of the severity of the infection and must consider the toxic risk associated with increased vancomycin levels. Each laboratory should investigate the transferability of the expected values to its own patient population and if necessary determine its own reference ranges. ¹ Rybak M, Lomaestro B, Rotschafer JC, et al. Therapeutic monitoring of vancomycin in adult patients: a consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Am J Health Syst Pharm 2009;66(1):82-98. ² Hammett-Stabler CA, Johns T. Laboratory guidelines for monitoring of antimicrobial drugs. Clin Chem 1998;44(5):1129-1140. ³ Burtis CA, Ashwood ER, Bruns DE, eds. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics, 5th edition (Elsevier) 2006;2186. ⁴ Pritchard L, Baker C, Leggett J, et al. Increasing Vancomycin in Serum Trough Concentrations and Incidence of Nephrotoxicity. Am J Med 2010;123:1143-1149. ⁵ Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis 2011;52(3):285-292. ⁶ Hidayat LK, Hsu DI, Quist R, et al. High-dose vancomycin therapy for methicillin-resistant Staphylococcus aureus infections: efficacy and toxicity. Arch Intern Med 2006;166(19):2138-2144. ⁷ Jeffres MN, Isakow W, Doherty JA, et al. A retrospective analysis of possible renal toxicity associated with vancomycin in patients with health care-associated methicillin-resistant Staphylococcus aureus 11 {11} pneumonia. Clin Ther 2007;29(6):1107-1115. 8 Lodise TP, Lomaestro B, Graves J, et al. Larger vancomycin does (at least four grams per day) are associated with an increased incidence of nephrotoxicity. Antimicrob Agents Chemother 2008;52(4):1330-1336. 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. 12