OSTEOMARK

{0}------------------------------------------------ ## SECTION 1: REGULATORY INFORMATION SUMMARY OF SAFETY AND EFFECTIVENESS MAR - 6 1998 280518 Osteomark® is a urinary assay that provides a quantitative measure of the excretion of cross-linked N-telopeptides of type I collagen (NTx) as an indicator of human bone resorption. Elevated levels of urinary NTx indicate elevated human bone resorption. Measurement of NTx is intended for use in: A. Predicting skeletal response (bone mineral density) to hormonal antiresorptive therapy in postmenopausal women. B. Therapeutic monitoring of: - 1. antiresorptive therapies in postmenopausal women - 2. antiresorptive therapies in individuals diagnosed with osteoporosis - 3. antiresorptive therapies in individuals diagnosed with Paget's disease of bone 4. estrogen-suppressing therapies C. Assessing the relative risk for loss of spinal bone mass after one year if not treated with hormonal antiresorptive therapy Osteomark is a competitive enzyme-linked immunosorbent assay (ELISA) which utilizes a horseradish peroxidase labeled monoclonal antibody directed against the cross-linked N-telopeptides (NTx) present in urine specimens. An Osteomark® kit is comprised of the following reagents: Antigen Coated 96-Well Plate Calibrators: 1 nM BCE 30 nM BCE 100 nM BCE 300 nM BCE 1000 nM BCE 3000 nM BCE Antibody Conjugate Concentrate Antibody Conjugate Diluent Level I and Level II Urine Controls {1}------------------------------------------------ 30X Wash Concentrate Buffered Substrate Chromogen Reagent Stopping Reagent The solid phase utilizes microwells onto which NTx has been adsorbed. NTx in the specimen or Calibrator competes with the solid phase NTx for antibody binding sites. The resulting amount of Antibody Conjugate bound to the solid phase is indirectly proportional to the amount of NTx in the specimen or Calibrator. The quantity of NTx in the specimen is determined from a standard calibration curve using reagents supplied in the kit. Assay values are standardized to an equivalent amount of bone collagen, and are expressed in nanomole bone collagen equivalents per liter (nM BCE). BCE reflects the amount of immunoreactive NTx, as measured by Osteomark, liberated from human bone collagen following digestion with bacterial collagenase, as measured by hydroxyproline by high performance liquid chromatography (HPLC). ### Expected Values #### Urine Collection: A multi-center, cross-sectional study was conducted in order to compare the results obtained with either a second morning void (SMV) spot urine collection or a 24 hour urine collection in Osteomark®. The population tested represented 186 normal premenopausal women without diseases, disorders, or currently taking medications which may affect bone metabolism or creatinine excretion. The SMV mean was 35 (+/- 15) nanomoles BCE/millimole creatinine. The 24 hour urine specimens, normalized for urinary creatinine, had a mean of 26 (+/- 13) nanomoles BCE/millimole creatinine. ### Reference Range Data: In the same study discussed above, the expected values for premenopausal women with the Osteomark® assay were determined. An additional multi-center, cross-sectional 11 {2}------------------------------------------------ study involving subjects without diseases, disorders, or currently taking medications known to affect bone metabolism or creatinine excretion was conducted to establish the expected values for postmenopausal women. The comparative results are presented in Table 1 below. | Study Group | Mean* | Std Dev | Range* | N | |----------------------------------------------------------------------------------|-------|---------|--------|-----| | Premenopausal Women<br>(mean 36 years, range 25-49) | 35 | 15 | 9-84 | 186 | | Postmenopausal Women<br>(< 3 years postmenopause,<br>mean 51 years, range 40-58) | 65 | 33 | 23-188 | 91 | Table 1 - Expected Osteomark® Values (nM BCE/millimole creatinine) # Limitations of the Procedure ### Lower Limit of Detection The lower limit of detection of the Osteomark® assay is 20 nM BCE. This value represents a concentration which is greater than the value which can be distinguished from zero, and was calculated by subtracting 3 standard deviations optical density (A450-A630) from established variability of the 1nM BCE Calibrator. Assay precision below this value is insufficient for accurate results. ### Interfering Substances Common urine components and contaminants, as well as microbiological contaminants, that are known to interfere with many laboratory urine analyses were evaluated for an interfering effect with Osteomark®. The evaluations were performed by adding normal and excessive quantities of each potential inhibitor to normal urine specimens and analyzing for an effect on the final results. Results show that specimens obviously 12 {3}------------------------------------------------ contaminated with whole blood or that have extensive hemolysis may show interference in the assay. These specimens should be avoided, and the specimen recollected. ### Performance Characteristics ### Reproducibility Assay reproducibility was evaluated for intra-assay and inter-assay variability of normal urine specimens across the range of the calibration curve. Intra-assay variability, or within assay precision, was assessed using eight urine specimens tested in replicates of 10 by each of four operators. Results demonstrate an average intra-assay variability estimate of 8% CV, with a range of 5-19% CV along the calibration curve. Inter-assay variability, or assay to assay precision, was assessed using three urine specimens tested in duplicate by one operator over 20 separate assay runs. Results demonstrate an average interassay variability estimate of 4% CV, with a range of 3-5% CV along the calibration curve. ### Antigen Recovery Antigen recovery was evaluated by adding known amounts of NTx to each of three normal urine specimens. Recovery represented the observed assay value of the "spiked" specimens, calculated as a percent of the expected urine value (baseline urine value plus added antigen value). Results demonstrate an average antigen recovery of 105%, over an assay value range of 200-2500 nM BCE. ### Dilutional Linearity Dilutional linearity was evaluated by performing serial dilutions of four urine specimens with high nM BCE values into a urine specimen with a low nM BCE value. Results {4}------------------------------------------------ demonstrated correlation coefficients of r=0.999 to r=1.000 across an assay range of 44-2940 nM BCE. ### Osteomark® (PN 9006) Quick Reference - 1. Thoroughly read the Assay Procedure before you begin. - 2. Bring kit components and specimens to room temperature. - 3. Dilute the Antibody Conjugate Concentrate into the Antibody Conjugate Diluent, using a 1:101 ratio. - 4. Pipette 25 µL samples of each Calibrator, Control, and specimen into duplicate microwells. - 5. Pipette 200 µL of diluted conjugate solution into each microwell. Gently swirl to mix. Incubate the plate at room temperature for 90± 5 minutes. - 6. Wash microwells five (5) times with the diluted wash solution, and blot dry. - 7. Dilute the Chromogen Reagent into the Buffered Substrate using a 1:101 ratio. Mix gently by inversion only. Do not mix with a stir bar or vortex. Use the Chromogen/Buffered Substrate within 30 minutes of preparation. Add 200 µL of Chromogen/Buffered Substrate to each microwell, and incubate at room temperature for 15 ± 1 minutes. - 8. Add 100 µL of Stopping Reagent to each microwell. Then gently swirl the plate for 5 -10 seconds. - 9. After five minutes, read the absorbance of each microwell at 450 nm 630 nm. Calculate the results using the standard curve. {5}------------------------------------------------ # SECTION 1: REGULATORY INFORMATION TRUTHFUL AND ACCURACY STATEMENT The information contained herein is to the best of my knowledge truthful and accurate. Harry O'Malley January 14, 1998 Date Nancy J.S. Mallinak Vice President, Regulatory and Clinical Affairs Ostex International, Inc. {6}------------------------------------------------ Image /page/6/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 three stripes forming its body and wing. The eagle faces left and is enclosed within a circular border. The text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" is arranged around the border of the circle. Food and Drug Administration 2098 Gaither Road Rockville MD 20850 MAR - 6 1998 Nancy J.S. Mallinak . Vice President, Regulatory and Clinical Affairs Ostex International, Inc. 2203 Airport Way South, Suite 400 Seattle, Washington 98134 Re : K980518 Osteomark® Regulatory Class: I Product Code: JMM Dated: January 14, 1998 Received: January 16, 1998 Dear Ms. Mallinak: 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, Drug, and Cosmetic Act (Act). You may, therefore, market the device, subject to the general controls provisions The general controls provisions of the Act of the Act. include requirements for annual reqistration, listing of devices, good manufacturing practice, labeling, and prohibitions against 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. ਸ 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 regulation (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 regulatory In addition, FDA may publish further announcements action. concerning your device in the Federal Register. 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 regulations. {7}------------------------------------------------ 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 Gutman 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 {8}------------------------------------------------ Page 1 __ 01 _1 i 10(k) Number (if known): Device Name: Indications For Use: Osteomark is a urinary assay that provides a quantitative measure of the Ostecmark is a urinary assay that provides of type I collagen (NTx) as an excretion of cross-linked N-celopeperation Revels of winds of windscate elevated human bone resorption. Masurement of NT is intenced for use in: rated human bone resorption. Measurement of this is and into A. . resorptive therapy in postmenopausal women Therapeutic monitoring of: B. - antiresorptive therapies in postmenopausal women 1. - antiresorptive therapies in individuals diagnosed uth osteoporosis antiresorptive therapies in individuals diagnosed uith 2aget's disease 2. - antiresorptive therapies in individuals diagnosed with ?aget's disease 3. of bone - estrogen-suppressing therapies বঁ Identifying the probability for a decrease in bone mineral ບ້ density after one year in postmenopausal women receiving calcium density arrer one year in pourment persuith hormonal antiresorptive therapy. The measurement range of Osteomark is 20 to 3000 nM Bone Collagen Equivalents (BCE). (PLEASE DO NOT WRITE BELOW THIS LINE - CONTINUE ON ANOTHER PAGE IF NEEDED) | Concurrence of CDRH, Office of Device Evaluation (ODE) | | |-------------------------------------------------------------|--| | Company of Children Company of Children Company of Children | | (Division Sign-Off) Division of Clinical Laboratory Devices 510(k) Number. K980518 Prescription Use Per 21 CER 801.109) OR Over-The-Counter Use (Optional Formal 1-2-96)