DIMENSION MYCOPHENOLIC ACID (MPAT) FLEX REAGENT CARTRIDGE, DIMENSION MYCOPHENOLIC ACID CALIBRATOR (MPAT CAL)

{0} 1 # 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY ASSAY ONLY TEMPLATE A. 510(k) Number: k102772 B. Purpose for Submission: New Device C. Measurand: Mycophenolic Acid D. Type of Test: Quantitative homogenous particle enhanced turbidimetric inhibition immunoassay (PETINIA) E. Applicant: Siemens Healthcare Diagnostics Inc. F. Proprietary and Established Names: Siemens Dimension® Mycophenolic Acid Flex® reagent cartridge Siemens Dimension® Mycophenolic Acid Calibrator G. Regulatory Information: | Product Code | Classification | Regulation Section | Panel | | --- | --- | --- | --- | | OAV | II, Sirolimus Test System (Classification Name) | 862.3840 | Toxicology | | DLJ | II, Clinical Toxicology Calibrator | 862.3200 | Toxicology | {1} H. Intended Use: 1. Intended use(s): See indication(s) for use below. 2. Indication(s) for use: The Dimension® Mycophenolic Acid Flex® reagent cartridge is an in vitro diagnostic test for the quantitative measurement of Mycophenolic acid (MPA) in human plasma on the Dimension® clinical chemistry system. Measurements of MPA are used as an aid in the management of mycophenolic acid therapy in renal, hepatic, and cardiac transplant patients. The Dimension® Mycophenolic Acid Calibrator is an in vitro diagnostic product for the calibration of the Mycophenolic Acid method on the Dimension® clinical chemistry system. 3. Special conditions for use statement(s): For prescription use only. 4. Special instrument requirements: For use with the Dimension RxL Max clinical chemistry system. I. Device Description: The Siemens Mycophenolic Acid assay consists of three in vitro diagnostic liquid reagents that are contained within the flex cartridge: Particle Reagent: 5.0 mg/mL plus stabilizers and preservatives; Antibody Reagent: 0.100 mg/mL (mouse monoclonal) plus stabilizers and preservatives, and buffer The MPAT calibrator is an aqueous bovine serum albumin (BSA) matrix product containing Mycophenolic acid. J. Substantial Equivalence Information: 1. Predicate device name (s): Roche Total MPA assay for the COBAS INTEGRA system Roche Total MPA Calibrators for the COBAS INTEGRA system {2} 2. Predicate 510(k) number(s): k063520 3. Comparison with predicate: | Similarities - Reagent | | | | --- | --- | --- | | Item | Proposed Device | Predicate | | Feature | Dimension® Mycophenolic Acid Flex® Reagent Cartridge | Roche Total MPA assay for the COBAS INTEGRA system | | Intended Use | Same | in vitro diagnostic use; quantitative measurement of Mycophenolic Acid as an aid in the management of MPA therapy in renal and cardiac transplant patients. | | Differences - Reagent | | | | --- | --- | --- | | Item | Proposed Device | Predicate | | Feature | Dimension® Mycophenolic Acid Flex® Reagent Cartridge | Roche Total MPA assay for the COBAS INTEGRA system | | Sample Type | EDTA Plasma only | Serum, EDTA Plasma | | Assay Range | 0.2 – 30.0 μg/mL | 0.4 - 15 μg/mL, extendable with post-dilution to 50 μg/mL | | Technology | Homogenous particle enhanced turbidimetric inhibition immunoassay (PETINIA) technique with the MPA rate of aggregation inversely proportional to the MPA concentration in the sample. | Enzyme-mimicking assay with MPA concentration inversely proportional to the formation of NADH. | | Detection | Bichromatic turbidimetric readings at 340 nm and 700 nm. | Spectrophotometric readings | | Sample Size | 5 μL | 3 μL | | Binding Protein | monoclonal mycophenolic acid specific antibody | None present | {3} | Similarities – Calibrator | | | | --- | --- | --- | | Item | Proposed Device | Predicate | | Feature | Dimension® Mycophenolic Acid Calibrator | Roche Total MPA Calibrators for the COBAS INTEGRA system | | Intended Use | for the calibration of the Mycophenolic Acid assay | Same | | Analytes | MPA | Same | | Traceable to: | Gravimetric preparation | Same | | Form | Liquid, stored at 2-8°C | Same | | Differences – Calibrator | | | | --- | --- | --- | | Item | Proposed Device | Predicate | | Matrix | Bovine Serum Albumin | Human Serum | | Volume | Vial containing Level 1 with 5.0 mL and Levels 2-5 have 2.0 mL per vial. | Levels A - F with 5.0 mL each and one vial of diluents (10.0 mL) | | Levels | 5 levels (0, 0.7, 2.3, 6.7, and 30.0 μg/mL) | 6 levels (0, 1, 3, 5, 10, 15 μg/mL) | # K. Standard/Guidance Document Referenced (if applicable): CLSI EP09-A2: Method Comparison and Bias Estimation Using Patient Samples; Approved Guideline CLSI EP5-A: Evaluation of Precision Performance of Clinical Chemistry Devices; Approved Guideline CLSI EP17-A: Protocols for Determination of Limits of Detection and Limits of Quantitation # L. Test Principle: The methodology for the MPAT assay is based on a homogeneous particle enhanced turbidimetric inhibition immunoassay (PETINIA) technique, which uses a synthetic {4} particle-mycophenolic acid conjugate (PR) and monoclonal mycophenolic acid specific antibody (Ab). Mycophenolic acid present in the sample competes with mycophenolic acid on the particles for available antibody, thereby decreasing the rate of aggregation. Hence, the rate of aggregation is inversely proportional to the concentration of mycophenolic acid in the sample. The rate of aggregation is measured using bichromatic turbidimetric readings at 340 nm and 700 nm. The reaction can be represented as follows: $$ \text{Mycophenolic acid} + PR + Ab \longrightarrow PR-Ab\ complex + \text{mycophenolic acid-Ab} $$ (scatter light at 340 nm) ## M. Performance Characteristics (if/when applicable): ### 1. Analytical performance: #### a. Precision/Reproducibility: Precision performance was evaluated at two external sites and at the manufacturer's facility. At the external sites, three EDTA plasma pools were analyzed in duplicate, twice a day, for 20 non-consecutive days. Testing was conducted on two Dimension RxL Max instruments (one instrument/site) by two operators (one operator/site) and one reagent lot. Results were as follows: External Site 1 Level 1 for n = 20 Plasma Pool L1 | Grand mean | | SD | % CV | | --- | --- | --- | --- | | 1.0 | Repeatability | 0.05 | 4.9 | | | Between Run | 0.03 | 3.3 | | | Between Day | 0.02 | 2.1 | | | Within-Lab | 0.06 | 6.2 | External Site 1 Level 2 for n = 20 Plasma Pool L2 | Grand mean | | SD | % CV | | --- | --- | --- | --- | | 7.9 | Repeatability | 0.2 | 2.2 | | | Between Run | 0.3 | 3.5 | | | Between Day | 0.0 | 0.0 | | | Within-Lab | 0.3 | 3.9 | {5} External Site 2 Level 1 for n = 20 Plasma Pool L1 | Grand mean | | SD | % CV | | --- | --- | --- | --- | | 0.9 | Repeatability | 0.05 | 5.5 | | | Between Run | 0.00 | 0.0 | | | Between Day | 0.03 | 3.0 | | | Within-Lab | 0.05 | 6.0 | External Site 2 Level 2 for n = 20 Plasma Pool L2 | Grand mean | | SD | % CV | | --- | --- | --- | --- | | 7.4 | Repeatability | 0.19 | 2.5 | | | Between Run | 0.20 | 2.7 | | | Between Day | 0.00 | 0.0 | | | Within-Lab | 0.27 | 3.6 | External Site 2 Level 3 for n = 20 Plasma Pool L3 | Grand mean | | SD | % CV | | --- | --- | --- | --- | | 25.52 | Repeatability | 0.82 | 3.2 | | | Between Run | 0.10 | 0.4 | | | Between Day | 0.30 | 1.2 | | | Within-Lab | 0.88 | 3.4 | At the internal sites, plasma pools and a commercial control were analyzed in duplicate, twice a day, for 20 non-consecutive days. Testing was conducted on one instrument by one operator on one reagent lot. The reagent lot was different than that used at the external sites. Results were as follows: Internal site plasma pool 1 | Grand mean | | SD | % CV | | --- | --- | --- | --- | | 0.44 | Repeatability | 0.04 | 10.2 | | | Between Run | 0.03 | 5.7 | | | Between Day | 0.00 | 0.0 | | | Within-Lab | 0.05 | 11.7 | Internal site plasma pool 2 | Grand mean | | SD | % CV | | --- | --- | --- | --- | | 1.02 | Repeatability | 0.03 | 3.3 | | | Between Run | 0.03 | 2.5 | | | Between Day | 0.02 | 2.0 | | | Within-Lab | 0.05 | 4.6 | {6} Internal site plasma pool 3 | Grand mean | | SD | % CV | | --- | --- | --- | --- | | 7.48 | Repeatability | 0.14 | 1.9 | | | Between Run | 0.04 | 0.5 | | | Between Day | 0.02 | 0.2 | | | Within-Lab | 0.15 | 2.0 | Commercial Control | Grand mean | | SD | % CV | | --- | --- | --- | --- | | 11.70 | Repeatability | 0.21 | 1.8 | | | Between Run | 0.12 | 1.0 | | | Between Day | 0.15 | 1.3 | | | Within-Lab | 0.29 | 2.5 | Internal Site Plasma Pool 4 | Grand mean | | SD | % CV | | --- | --- | --- | --- | | 25.41 | Repeatability | 0.66 | 2.6 | | | Between Run | 0.13 | 0.5 | | | Between Day | 0.00 | 0.0 | | | Within-Lab | 0.68 | 2.7 | # b. Linearity/assay reportable range: The claimed reportable range of the assay is $0.2 - 30.0~\mu \mathrm{g / mL}$ . Linearity was determined across the range of the assay by diluting a high MPAT plasma pool with a low MPAT plasma pool to yield 13 concentrations covering and extending slightly above and below the assay measuring range. The initial low starting concentration was an EDTA plasma sample not containing MPAT and the initial high starting concentration was determined by spiking in a known amount of MPAT. Theoretical values below are based on the gravimetrically-determined spiked concentrations and the dilution factors. The mean of 5 measurements was compared to the theoretical values according to the dilution scheme. All recoveries were within $\pm 9\%$ as follows: | Sample Pool | Observed Mean (μg/mL) | Theoretical Value (μg/mL) | Bias μg/mL | (%) Recovery | | --- | --- | --- | --- | --- | | 1 | 0.02 | n/a | n/a | n/a | | 2 | 0.22 | 0.22 | 0 | 100 | | 3 | 0.49 | 0.53 | -0.04 | 92.4 | | 4 | 0.99 | 1.03 | -0.04 | 96.1 | | 5 | 1.98 | 2.03 | -0.05 | 97.5 | | 6 | 3.68 | 4.04 | -0.36 | 91.1 | {7} | 7 | 8.1 | 8.05 | 0.05 | 100.6 | | --- | --- | --- | --- | --- | | 8 | 12.24 | 12.06 | 0.18 | 101.5 | | 9 | 16.74 | 16.07 | 0.67 | 104.2 | | 10 | 20.56 | 20.09 | 0.47 | 102.3 | | 11 | 24.08 | 24.1 | -0.02 | 99.9 | | 12 | 27.76 | 28.11 | -0.35 | 98.8 | | 13 | 32.12 | n/a | n/a | n/a | Simple linear regression produced the following equation: $y = 1.00x + 0.00$ . c. Traceability, Stability, Expected values (controls, calibrators, or methods): # Calibrator Traceability and Value Assignment Calibrators are provided at 0, 0.7, 2.3, 6.7, and $30.0~\mu \mathrm{g / mL}$ and are prepared in an aqueous bovine serum albumin (BSA) matrix. Each commercial lot of calibrator is traceable to a five-level Anchor Pool of MPA. The Anchor Pool is traceable to a gravimetric measurement of MPA (Pharmaceutical grade raw material). The sponsor estimates the uncertainty of assigned values of lot calibrators relative to the pharmaceutical grade material to be $< 4\%$ . Commercial lot values for each level are assigned from Dimension instruments calibrated with Anchor Pool. # Calibrator Stability The claimed shelf life (closed vial) for the calibrator is 12 months at $2 - 8^{\circ}\mathrm{C}$ . Shelf life is determined by comparing multiple replicates of the calibrator stored at $2 - 8^{\circ}\mathrm{C}$ with the same material stored at $< -20^{\circ}\mathrm{C}$ . The method is calibrated each month with calibrator stored at $< -20^{\circ}\mathrm{C}$ . The $2 - 8^{\circ}\mathrm{C}$ material values are recovered (as unknowns) versus the calibration. Recovery versus time is monitored and percent change over time is determined. The sponsor's protocols and acceptance criteria were reviewed and found to be acceptable. The claimed open vial stability for the calibrator is 60 days at $2 - 8^{\circ}\mathrm{C}$ . Opened vial stability is determined as follows: Vials are opened on day zero. A quantity sufficient for a calibration is removed and the vials are recapped and stored at $2 - 8^{\circ}\mathrm{C}$ . These vials are tested on days 0, 33 and 61. Freshly opened vials are tested on days 33 and 61 for comparison. The sponsor's protocols and acceptance criteria were reviewed and found to be acceptable. d. Detection limit: Five samples were gravimetrically spiked to $0.2\mu \mathrm{g / mL}$ MPA analyte for analysis. Two instruments were used, with a different reagent lot on each {8} instrument. The five samples were processed in triplicate during each run. Three runs were performed on each instrument system over three days. The sponsor analyzed LoQ data consistent with CLSI EP17-A. Results were as follows: ## Instrument 1 Bias of individual measurements relative to LC-MS ranged from - 0.07 µg/mL to + 0.07 µg/mL CV: 12.5% at 0.2 µg/mL ## Instrument 2 Bias of individual measurements relative to LC-MS ranged from - 0.07 µg/mL to + 0.05 µg/mL. CV: 16.4% at 0.20 µg/mL The LoQ was determined to be 0.2 µg/mL. ## e. Analytical specificity: Specificity studies were conducted for two MPA metabolites, MPA-acyl glucuronide (MPA-ag) and 7-O-MPA-β-glucuronide (MPAG), in addition to the pro-drug Mycophenolate Mofetil (MMF). The percent cross-reactivity was calculated as follows: % Cross Reactivity = ((Measured Analyte - Control Analyte) / (Metabolite concentration) X 100. | Plasma Pool [MPA] (μg/mL) | Compound Added | Quantity Added (μg/mL) | MPAT Result (μg/mL) | % Cross-Reactivity | | --- | --- | --- | --- | --- | | 0.0 | MMF | 5 | 2.6 | 53% | | 0.0 | MMF | 25 | 13.2 | 53% | {9} | Plasma Pool [MPA] (μg/mL) | Compound Added | Quantity Added (μg/mL) | MPAT Result (μg/mL) | % Cross-Reactivity | | --- | --- | --- | --- | --- | | 0.0 | MMF | 50 | 25.9 | 52% | | 5.0 | MMF | 5 | 7.8 | 62% | | 5.0 | MMF | 25 | 18.2 | 54% | | 5.0 | MMF | 50 | 33.96 | 58% | | 0.0 | MPAG | 50 | 0.26 | 0.5% | | 0.0 | MPAG | 100 | 0.70 | 0.7% | | 0.0 | MPAG | 1000 | 6.32 | 0.6% | | 5.0 | MPAG | 50 | 5.28 | 0.4% | | 5.0 | MPAG | 100 | 5.66 | 0.8% | | 5.0 | MPAG | 1000 | 12.48 | 0.8% | | 0.0 | MPA-ag | 1.0 | 0.71 | 59.3% | | 0.0 | MPA-ag | 5.0 | 3.29 | 64.5% | | 0.0 | MPA-ag | 25.0 | 13.34 | 53.1% | | 5.0 | MPA-ag | 1.0 | 5.51 | 36.8% | | 5.0 | MPA-ag | 5.0 | 7.04 | 42.0% | | 5.0 | MPA-ag | 25.0 | 16.45 | 46.1% | Ninety-five exogenous substances and co-administered drugs and four endogenous substances were tested to the highest concentration expected. Test substances, in duplicate, were spiked into aliquots of EDTA plasma pools containing MPA (2 μg/mL and 5μg/mL) and analyzed by calculating the mean and percent recovery of MPA. These results are compared to control samples prepared without the test substance. The manufacturer defined interference as bias greater than 10%. None of the substances in the list below caused significant interference at the concentrations tested. | Substance | Test Concentration | SI Units | | --- | --- | --- | | Acetaminophen | 20 mg/dL | 1324 μmol/L | | Acyclovir | 1000 μg/mL | 4.44 mmol/L | | Albuterol | 1.0 mg/mL | 4.18 mmol/L | | Amikacin | 8.0 mg/dL | 137 μmol/L | | Amphotericin B | 100 μg/mL | 108.2 μmol/L | | Ampicillin | 5.3 mg/dL | 152 μmol/L | | Ascorbic Acid | 6.0 mg/dL | 341 μmol/L | | Azathioprine | 1.0 mg/mL | 10.8 μmol/L | | Caffeine | 6.0 mg/dL | 309 μmol/L | | Carbamazepine | 3.0 mg/dL | 127 μmol/L | | Cefaclor | 1.0 mg/mL | 2.59 mmol/L | | Cefazolin | 1.2 mg/mL | 2.6 mmol/L | | Chloramphenicol | 5.0 mg/dL | 155 μmol/L | | Chlordiazepoxide | 1.0 mg/dL | 33.3 μmol/L | {10} 11 | Chlorpromazine | 0.2 mg/dL | 6.27 μmol/L | | --- | --- | --- | | Cholesterol | 500 mg/dL | 12.9 mmol/L | | Cimetidine | 2 mg/dL | 79.4 μmol/L | | Ciprofloxacin | 40 μg/mL | 121 μmol/L | | Clofibrate | 0.25 mg/mL | 1.03 mmol/L | | Clonidine | 0.5 mg/mL | 1.88 mmol/L | | Creatinine | 30 mg/dL | 2.65 mmol/L | | Cyclophosphamide | 1.0 mg/mL | 3.58 mmol/L | | Cyclosporine | 0.005 mg/mL | 4.16 μmol/L | | Dextran 40 | 6000 mg/dL | 1500 μmol/L | | Diazepam | 0.5 mg/dL | 18 μmol/L | | Digoxin | 6.1 ng/mL | 7.8 nmol/L | | Diphenhydramine | 1.0 mg/mL | 3.92 mmol/L | | Disopyramide | 1.0 mg/mL | 2.94 mmol/L | | Ephedrine | 1.0 mg/mL | 6.05 mmol/L | | Erythromycin | 6.0 mg/dL | 81.7 μmol/L | | Ethanol | 400 mg/dL | 86.8 mmol/L | | Ethosuximide | 25.0 mg/dL | 1.77 mmol/L | | Everolimus | 9.0 μg/mL | 9.39 μmol/L | | Fluconazole | 100 μg/mL | 326.8 μmol/L | | Flucytosine | 301 μg/mL | 2.33 mmol/L | | 5-Fluorouracil | 1.0 mg/mL | 7.69 mmol/L | | Furosemide | 6.0 mg/dL | 181 μmol/L | | Gancyclovir | 1100 μg/mL | 3.97 mmol/L | | Gentamicin | 1.0 mg/dL | 21 μmol/L | | Griseofulvin | 0.5 mg/mL | 1.42 mmol/L | | Heparin | 3.0 U/mL | 3000 U/L | | Hydralazine | 1.0 mg/mL | 6.2 mmol/L | | Hydrochlorothiazide | 0.25 mg/mL | 839 μmol/L | | Ibuprofen | 50.0 mg/dL | 2.43 mmol/L | | Immunoglobulin G | 5 g/dL | 50 g/L | | Indomethacin | 0.2 mg/mL | 559 μmol/L | | Isoniazid | 1.0 mg/mL | 7.30 mmol/L | | Isoproterenol | 0.25 mg/mL | 1.18 mmol/L | | Itraconazole | 50 μg/mL | 70.82 μmol/L | | Kanamycin | 1.0 mg/mL | 1.72 mmol/L | | Ketoconazole | 100 μg/mL | 188.2 μmol/L | | Lidocaine | 1.2 mg/dL | 51.3 μmol/L | | Lithium | 2.2 mg/dL | 3.2 mmol/L | | Methicillin | 0.5 mg/mL | 1.24 mmol/L | | Methotrexate | 1.0 mg/mL | 2.20 mmol/L | | Methylprednisolone | 1.0 mg/mL | 2.67 mmol/L | | Metoclopramide | 1.0 mg/mL | 2.97 mmol/L | | Metoprolol | 1.0 mg/mL | 3.74 mmol/L | | Miconazole | 1.0 mg/mL | 2.09 mmol/L | | Nadolol | 1.0 mg/mL | 3.24 mmol/L | {11} | Naproxen | 1.0 mg/mL | 4.34 mmol/L | | --- | --- | --- | | Neomycin | 1.0 mg/mL | 1.63 mmol/L | | Niacin | 1.0 mg/mL | 8.13 mmol/L | | Nicotine | 0.10 mg/dL | 6.2 μmol/L | | Nifedipine | 0.25 mg/mL | 722 μmol/L | | OKT3 | 6.0 μg/mL | 6.0 mg/L | | Penicillin G | 25 U/mL | 25,000 U/L | | Pentobarbital | 8.0 mg/dL | 354 μmol/L | | Phenobarbital | 10.0 mg/dL | 431 μmol/L | | Phenylephrine | 0.82 mg/mL | 4.90 mmol/L | | Phenytoin | 5.0 mg/dL | 198 μmol/L | | Piperacillin | 1.0 mg/mL | 1.85 mmol/L | | Prednisolone | 0.25 mg/mL | 693 μmol/L | | Prednisone | 0.25 mg/mL | 697 μmol/L | | Primidone | 4.0 mg/dL | 183 μmol/L | | Probucol | 0.2 mg/mL | 387 μmol/L | | Procainamide | 1.0 mg/mL | 3.67 mmol/L | | Promethazine | 1.0 mg/mL | 3.12 mmol/L | | Propanolol | 0.22 mg/mL | 845 μmol/L | | Propoxyphene | 0.16 mg/dL | 4.91 μmol/L | | Protein (Albumin) | 4.7 g/dL | 47 g/L | | Protein (Total) | 10.0 g/dL | 100 g/L | | Ranitidine | 1.0 mg/mL | 2.85 mmol/L | | Rheumatoid Factor | 489 IU/mL | 489,000 IU/L | | Rifampin | 100 μg/mL | 121.5 μmol/L | | Salicylic Acid | 60 mg/dL | 4.34 mmol/L | | Sirolimus | 50 μg/mL | 55.0 μmol/L | | Streptomycin | 1.0 mg/mL | 1.7 mmol/L | | Sulfaquinoxaline | 1.0 mg/mL | 3.10 mmol/L | | Tacrolimus | 0.0005 mg/mL | 622 nmol/L | | Theophylline | 4.0 mg/dL | 222 μmol/L | | Tobramycin | 100 μg/mL | 213.9 μmol/L | | Triamterene | 1.0 mg/mL | 3.95 mmol/L | | Triglycerides | 1000 mg/dL | 11.3 mmol/L | | Urea | 500 mg/dL | 83.3 mmol/L | | Uric Acid | 25 mg/dL | 1.5 mmol/L | | Valproic Acid | 50 mg/dL | 3.47 mmol/L | | Vancomycin | 614 μg/mL | 424 μmol/L | A separate study was performed to assess the effect of hemoglobin, conjugated and unconjugated bilirubin, and triglycerides (through the use of Intralipid). Test substances were prepared in duplicate; the interferent was added to EDTA plasma pools containing $2\mu \mathrm{g} / \mathrm{mL}$ and $5\mathrm{ug / mL}$ of MPA. The samples were analyzed and the calculated mean of replicates and percent recovery of MPA were compared to the "negative control" (EDTA plasma pool with 2 {12} $\mu \mathrm{g} / \mathrm{mL}$ and $5\mathrm{ug / mL}$ of MPA without interferent). No interference was observed from these substances at the following levels: | Interferent | Concentration Tested | | --- | --- | | Hemoglobin | 1000 mg/dL | | Bilirubin (unconjugated) | 80 mg/dL | | Bilirubin (conjugated) | 80 mg/dL | | Triglycerides (Intralipid) | 1000 mg/dL | f. Assay cut-off: Not applicable. ## 2. Comparison studies: a. Method comparison with predicate device: The sponsor analyzed 109 EDTA plasma samples on the MPAT assay and on the HPLC reference method. These included 33 samples from liver transplant patients, 42 samples from kidney transplant patients, and 34 samples from heart transplant patients. All were clinical trough samples from adults. The concentration range of the samples was $0.2 - 29.7\mu \mathrm{g / mL}$ . Deming regression including all sample types produced the following (with $95\%$ Confidence Intervals): slope: 1.04 (0.99 - 1.09) y-int: -0.02 (-0.09 - 0.04) r: 0.98 sy/x: 0.35 Deming regression for the individual sample types was as follows: Heart slope: 1.01 (0.93 to 1.10) y-int: 0.0 (-0.03 to 0.04) r: 0.97 sy/x: 0.21 Kidney slope: 0.99 (0.92 to 1.06) y-int: 0.17 (0.06 to 0.27) r: 0.98 sy/x: 0.18 {13} Liver slope: 1.10 (0.91 to 1.29) y-int: -0.07 (-0.17 to 0.03) r: 0.99 sy/x: 0.59 b. Matrix comparison: Not applicable. This assay is intended to be used with serum samples only. 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. 5. Expected values/Reference range: The optimal concentration range for mycophenolic acid in plasma or serum using this assay has not been established. Therefore in the labeling the sponsor states the following: "Optimal concentration ranges vary according to the specific assay used, and therefore should be established for each specific assay. Values obtained with different assay methods should not be used interchangeably due to differences in cross-reactivity with metabolites, nor should correction factors be applied. Laboratories should include identification of the assay used in order to aid in interpretation of results. Each institution should establish the optimal ranges based on the specific assay used and other factors relevant to their patient population. 14 {14} Optimal ranges depend upon the patient’s clinical state, individual differences in sensitivity to immunosuppressive and nephrotoxic effects of mycophenolic acid, co-administration of other immunosuppressants, time post-transplant and a number of other factors. Therefore, individual mycophenolic acid values cannot be used as the sole indicator for making changes in treatment regimen and each patient should be thoroughly evaluated clinically before changes in treatment regimens are made. Decreased incidence of rejection in the early months after transplantation have been reported in renal transplant patients with trough level MPA concentrations (measured by HPLC) of ≥ 1.3 μg/mL [4.1 μmol/L] with co-administration of cyclosporine and ≥ 1.9 μg/mL [5.9 μmol/L] with co-administration of tacrolimus. An upper therapeutic limit based on development of toxicity has not been clearly established”. 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. 15