BIOCIRCUITS IOS FREE THYROXINE (FT4) TEST CARTRIDGES BIOCIRCUITS IOS CONTROLS

{0}------------------------------------------------ 510(k) Summary APR - 3 1998 This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of SMDA 1990 and 21 CFR 807.92. K980819 The assigned 510(k) number is: __ - A. Submitter: Biocircuits Corporation 1324 Chesapeake Terrace Sunnyvale, CA 94089 phone: (408) 745-1961 (408) 752-8765 fax: Contact: Sheila Ramerman Date Prepared: March 27, 1998 | Device Names: | | |----------------------|----------------------------------------------------------------------------------------------| | Proprietary Name: | Biocircuits IOS® Free Thyroxine Test Cartridges<br>Biocircuits IOS® Controls | | Common names: | Reagents for free thyroxine measurement<br>Quality control materials (assayed and unassayed) | | Classification Name: | Free thyroxine test system<br>Quality control materials (assayed and unassayed) | C. Legally Marketed Device: B The IOS Free Thyroxine Test Cartridges are substantially equivalent to the Dade Stratus Free Thyroxine Fluorometric Enzyme Immunoassay, currently manufactured and distributed by Dade International, Inc. #### Device Description: D. Free Thyroxine Test Cartridges: Thyroxine (T4) is a small molecular weight hormone that is synthesized in the thyroid gland and secreted into the blood stream, and which plays an important role in regulating metabolism. The secreted hormone is reversibly bound to three plasma proteins in the serum: thyroxine binding globulin (TBG), thyroxine binding prealbumin (TBPA), and albumin (1). Greater than 99,5 % of thyroxine is bound by these plasma proteins, with 80% bound to TBG (2,3). The remaining T4 circulates as the free form in the serum. The free hormone is generally accepted to be the physiologically active hormone (4,5), and is believed to induce/control metabolism and to control thyroid hormone secretion by a feed-back loop through the thyroid gland, pituitary gland, and hypothalamus (8,9). B-1 {1}------------------------------------------------ FAX NO: IOS FT4 510(k) Summary page 2 The bound T4 hormone fraction can be changed due to alterations or abnormalities in the properties of the binding proteins, or by malfunction of the thyroid gland. The free form of T4 remains at constant equilibrium compared to bound hormone, however, since it is not affected by variations in thyroxine binding proteins. The concentration of free T4, therefore, reflects thyroid function more closely than does the total T4 concentration (6,7). Measurement of free T4 levels is useful when altered total T4 concentrations occur as a result of changes in T4 binding proteins, especially in TBG, and can differentiate true hyperthyroid and hypothyroid status from pseudo-hyperthyroxinemias and hypothyroxinemias in these cases (10). TBG levels remain relatively constant in healthy individuals, but normal pregnancy, steroid therapy, and oral contraceptive use can change the levels of TBG, changing the diagnosis from euthyroid to hypothyroid or hyperthyroid status (11,12, 13). In these conditions, the free T4 concentration remains constant while the total T4 level will fluctuate in parallel to TBG concentration changes. Free T4 levels have been reported to be altered due to treatment with drugs which can displace the bound T4, such as phenytoin, phenylbutazone, salicylates and diphenylhydantoin (14,15,16). ## Principle of the Test The IOS Free T4 assay is a sequential immunoassay in which free T4 in the patient serum sample first binds to a monoclonal anti-T4 antibody; this free T4:anti-T4 complex is then captured by polyclonal goat-anti-mouse immobilized on the plastic surface. Excess ('uncomplexed') anti-T4 antibody also binds to the surface. After an incubation period, any excess sample and unbound anti-T4 antibody are removed. In the second step, alkaline phosphatase-labeled T4 ('conjugate') is added, and the conjugate binds to T4 binding sites on the uncomplexed anti-T4 antibody. After another incubation period, excess conjugate is washed away and substrate is added. The substrate reacts with the conjugate bound to uncomplexed anti-T4 antibody and produces a fluorescent signal. The level of fluorescence is directly proportional to the amount of conjugate bound to the uncomplexed anti-T4 antibody and inversely proportional to the amount of free T4:T4 antibody complex, and thus inversely proportional to the amount of free T4 present in the serum sample. All the reagents necessary to perform the test are dried in the IOS Free T4 Test Cartridge, and are rehydrated by addition of patient sample by the operator or by the addition of buffer by the instrument. To perform a test , the operator inserts an IOS Free T4 Test Cartridge into the IOS instrument. When prompted, the operator adds sample to the sample well and starts the test sequence. The instrument draws the cartridge inside and adds buffer to dilute the serum. The diluted serum rehydrates the dried reagent (mouse anti-T4 antibody) in the sample well. A short incubation period allows the serum and reagents to react. This mixture then flows into the incubation/ reaction chamber, where binding to the solid phase occurs. At the end of the incubation time, excess mixture is aspirated out of the incubation/reaction chamber by the instrument. Buffer is used to rehydrate conjugate in a separate chamber; rehydrated conjugate is allowed to enter the reaction chamber to bind to uncomplexed T4 antibody. At the end of this incubation time, excess conjugate is washed away by buffer dispensed by the instrument. Buffer is also used to rehydrate the substrate necessary for signal generation and quantitation in a third chamber: {2}------------------------------------------------ FAX NO: IOS FT4 510(k) Summary page 3 rehydrated substrate is then allowed to enter the incubation/reaction chamber. The signal produced is read as a rate by front-surface fluorometry, compared to the signal produced by a series of calibrators stored in instrument memory, and the amount of free T4 present in the patient sample is calculated from the stored calibration curve. IOS Controls: The use of materials derived from human blood to monitor quality control of clinical chemistry testing in the clinical laboratory has been widely established over the past several years. The Biocircuits IOS Controls are two levels of blood-based material for use with Biocircuits IOS Test Cartridges. To run a control, the operator inserts the Control Cartridge (packaged with the controls) into the IOS instrument. The instrument reads the lot number and ranges of acceptable values for the control solutions from the Control Cartidge barcode, and then ejects the Control Cartidge. The operator then inserts a test cartridge and follows the instrument prompts to identify the control level, apply control solutions, and begin the test sequence. The IOS instrument performs the required buffer additions to rehydrate assay reagents and perform wash steps as necessary, reads the fluorescence signal generated, and calculates and prints the control result just as it would if the cartridge were used to test a patient sample. #### Intended Use: E. The IOS Free Thyroxine Test Cartridges are to be used for the quantitative determination of free thyroxine levels in serum for the diagnosis and treatment of thyroid diseases. They are intended to be used with the IOS instrument in clinical laboratories, physicians' office laboratories, and other alternate sites of use close to the point of patient care. The IOS Controls are to be used to assist in monitoring accuracy and precision in the IOS immunoassay test cartridges. F. Companson with the Predicate Device: Table I summarizes the comparative features of the IOS and Stratus assays. #### Performance Data: G. ## Free Thyroxine Test Cartridges: Non-clinical testing performed in the manufacturer's laboratories gave the following results: - 1. Precision: | Control Level | 1 | 2 | 3 | |--------------------------|--------|--------|--------| | Mean (ng/dL) | 1.21 | 3.59 | 0.56 | | SD, overall (ng/dL) | 0.14 | 0.30 | 0.14 | | % CV, within-day (n=10) | 11.3 % | 8.2% | 25.4% | | % CV, between-day (n=40) | 8.4% | 13.1% | 14.9% | | % CV, total | 13.12% | 14.53% | 28.08% | 12 {3}------------------------------------------------ IOS FT4 510(k) Summary page 4 #### 2. Accuracy: A comparison of methods obtained by testing 119 patient samples in the manufacturer's laboratories using the IOS Free Thyroxine assay and a commercially available fluorescent enzyme immunoassay gave a correlation coefficient ('r') of 0.96, with the line of regression described by the equation y = - 0.05 + 0.98x. Samples tested ranged from 0.2 to 4.6 ng/dL, and included pooled human serum spiked with T4 to obtain high concentrations of free T4. Clinical testing performed in a typical physicians' office laboratory gave the following results: - 1. Precision: | Control Level | 1 | 2 | |----------------------|-------|-------| | number of replicates | 44 | 40 | | Mean (ng/dL) | 1.12 | 3.95 | | SD, overall (ng/dL) | 0.14 | 0.56 | | % CV, total | 12.58 | 14.22 | ## 2. Accuracy: A comparison of methods was also performed by users in a typical physician's office laboratory. A total of 68 patient samples were tested using the IOS Free Thyroxine assay in the office laboratory; the samples were split and sent to the manufacturer's laboratory for testing by both the IOS and a commercially available fluorescent enzyme immunoassay. These studies gave a correlation with the commercially available assay of 0.962, with the line of regression described by the equation y = - 0.14 + 1.10x. The samples tested ranged from 0.4 ng/dL to 4.9 ng/dL, and included pooled human serum spiked with T4 to obtain high concentrations of free T4. ### IOS Controls: The following ranges for the Free Thyroxine analyte in IOS Controls were determined in studies in the manufacturer's laboratories. To establish the ranges, each control level was tested in 80 cartridges, over at least 3 days, using several IOS instruments. These values only apply to this lot of JOS Controls. Different lots of IOS Controls will likely have slightly different ranges. Each laboratory should establish its own range for these controls over time. | | Control Level 1<br>lot # (to be assigned) | Control Level 2<br>lot # (to be assigned) | |-------------|-------------------------------------------|-------------------------------------------| | FT4 (ng/dL) | 0.7 - 1.5 | 2.3 - 4.6 | It is self-evident from the data and information presented here that the Biocircuits IOS Free Thyroxine Test Cartridges are as safe, effective, and perform as well as the Dade Stratus Free Thyroxine Fluorometric Immunoassay manufactured and distributed by Dade International, Inc. Attachment: Table I: Assay Comparison B-t {4}------------------------------------------------ # TABLE 1 Dade STRATUS vs. Biocircuits IOS® Assay Comparison and the comments of the comments of the comments of | ATTRIBUTE | STRATUS FT4 | IOS FT4 | |-----------------------|---------------------------------------------------------------------|------------------------------------------------------------------------| | Technology | Fluorometric enzyme immunoassay | Fluorometric enzyme immunoassay | | Assay format | Sequential | Sequential | | Enzyme label | Alkaline phosphatase | Alkaline phosphatase | | Substrate | Methylumbelliferyl phosphate | Methylumbelliferyl phosphate | | Reagents | | | | Immobilization Medium | Reaction tab | Plastic cartridge | | Dry | Polyclonal anti-T4 | Polyclonal anti-mouse, monoclonal anti-T4,<br>T4-conjugate, substrate | | Wet | 3 (assay-specific), loaded by operator at start<br>of each run | 1 (diluent, used for all assays), continuously on board | | Delivery | Fully automated | Fully automated | | Calibration | User-generated | Factory-generated | | Calibration Stability | 14 days (minimum) | 120 days (minimum) | | Storage | Refrigerated (2-8°C) | Room Temperature (15-30°C) | | Sample | | | | Type | Serum or plasma | Serum | | Volume | 0.2 ml (minimum) | 0.033mL | | Measurement Needed | Non-precision | Precision | | Operating environment | 22°-32° C | 15°-30° C | | Data analysis | Microprocessor-controlled<br>Stored standard curves, user-generated | Microprocessor-controlled<br>Stored standard curves, factory-generated | | Data output | LCD display<br>Printed alphanumeric hard copy | LCD display<br>Printed alphanumeric hard copy | {5}------------------------------------------------ Image /page/5/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo features the department's name arranged in a circular fashion around a stylized symbol. The symbol is a representation of people, with three figures connected and flowing together, suggesting unity and collaboration. Public Health Service Food and Drug Administration 2098 Gaither Road Rockville MD 20850 APR - 3 1998 Sheila J. Ramerman Manager, Regulatory and Clinical Affairs Biocircuits Corporation 1324 Chesapeake Terrace 94089 Sunnyvale, California Re : K980819 Biocircuits IOS® (In-Office-System) Free Thyroxine (Free T4, FT4) Test Cartridges and IOS Controls Requlatory Class: I & II Product Code: JJY, CEC Dated: March 2, 1998 Received: March 3, 1998 Dear Ms. Ramerman: We have reviewed your Section 510(k) notification of intent to market the device referenced above and we have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to 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, Druq, and Cosmetic Act (Act). 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 aqainst misbranding and adulteration. If your device is classified (see above) into either class II (Special Controls) or class III (Premarket Approval), it may be subject to such additional controls. Existing major regulations affecting your device can be found in the Code of Federal Requlations, Title 21, Parts 800 to 895. A substantially equivalent determination assumes compliance with the Current Good Manufacturing Practice requirements, as set forth in the Quality System Regulation (QS) for Medical Devices: General requlation (21 CFR Part 820) and that, through periodic QS inspections, the Food and Drug Administration (FDA) will verify such assumptions. Failure to comply with the GMP regulation may result in requlatory action. In addition, FDA may publish further announcements concerning your device in the Federal Reqister. Please note: this response to your premarket notification submission does not affect any obligation you might have under sections 531 through 542 of the Act for devices under the Electronic Product Radiation Control provisions, or other Federal laws or requlations. {6}------------------------------------------------ Page 2 Under the Clinical Laboratory Improvement Amendments of 1988 (CLIA-88), this device may require a CLIA complexity categorization. To determine if it does, you should contact the Centers for Disease Control and Prevention (CDC) at (770) 488-7655. This letter will allow you to begin marketing your device as described in your 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 Part 801 and additionally 809.10 for in vitro diagnostic devices), please contact the Office of Compliance at (301) 594-4588. Additionally, for questions on the promotion and advertising of your device, please contact the Office of Compliance at (301) 594-4639. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR 807.97). Other general information on your responsibilities under the Act may be obtained from the Division of Small Manufacturers Assistance at its toll-free number (800) 638-2041 or (301) 443-6597 or at its internet address "http://www.fda.gov/cdrh/dsmamain.html". sincerely yours, Steven Litman Steven I. Gutman, M.D., M.B.A. Director Division of Clinical Laboratory Devices Office of Device Evaluation Center for Devices and Radiological Health Enclosure {7}------------------------------------------------ 510(k) Number: K980819 Device Name: _ Biocircuits IOS® Free Thyroxine Test Cartridges and IOS Controls Indications for Use: The IOS Free Thyroxine Test Cartridges are intended to be used for the quantitative determination of free (not protein bound) thyroxine (thyroid hormone) in serum for the diagnosis and treatment of thyroid diseases. They are intended to be used with the Biocircuits IOS® instrument in clinical laboratories, physician office laboratories, and other alternate sites of use close to the point of patient care. The IOS Controls are to be used to assist in monitoring accuracy and precision in the IOS immunoassay test cartridges. ## PLEASE DO NOT WRITE BELOW THIS LINE - CONTINUE ON ANOTHER PAGE IF NEEDED | Concurrence of CDRH, Office of Device Evaluation (ODE) | | |--------------------------------------------------------|----------------------------------------------------------------| | | (Division Sign-Off)<br>Division of Clinical Laboratory Devices | | 510(k) Number | K980819 | Prescription Use (Per 21 CFR 801.109) OR Over-The-Counter Use (Optional Format 1-2-96)