BARD AND BTA TEST

{0} K964151 APR 16 1997 # 510(k) SUMMARY INFORMATION This 510(k) summary information is being submitted in accordance with the requirements of SMDA 1990 and 21 CFR 807.92. The following information provides sufficient detail to understand the basis for a determination of substantial equivalence. ## A. Submitter's Information: Submitter's Name: Bard Diagnostic Sciences, Inc. Address: 12277 134th Ct., NE Contact Person: Glen Paul Freiberg Contact Person's Phone: (206) 814-1520 Contact Person's Fax: (206) 814-1521 Date of Preparation: September 11, 1996 ## B. Device Name: Trade Name: Bard® BTA stat™ Test Common / Usual Name: BTA stat™ Test Classification Name: Tumor Associated Antigen Immunological Test System ## C. Predicate Device Name: Trade Name: Bard® BTA® Test P940018 - Reclassified to Class II Bard Diagnostic Sciences, Inc., claims substantial equivalence to the above mentioned test. {1} 510(k) SUMMARY INFORMATION Bard BTA stat Test Page 2 D. Device Description: The BTA stat test for bladder tumor associated antigen is an immunochromatographic assay utilizing monoclonal antibodies to specifically detect the presence of bladder tumor associated antigen in urine. Patient urine is added to the sample well and allowed to react with a colloidal gold-conjugated antibody. If the antigen is present in the sample, an antigen conjugate complex is formed and a line in the patient (P) test zone appears. E. Intended Use: The BTA stat test is an in vitro diagnostic immunoassay indicated for the qualitative detection of bladder tumor associated antigen in urine of persons diagnosed with bladder cancer. This test is indicated for use as an aid in the management of bladder cancer patients in conjunction with cystoscopy. F. Indications for Use: The BTA stat test is a qualitative test indicated for use as an aid in the management of bladder cancer patients in conjunction with cystoscopy. G. Substantial Equivalence & Technological Characteristics Summary: The Bard BTA stat Test and the Bard BTA Test are both rapid format qualitative assays. The Bard BTA stat test is a lateral flow assay which detects antigen though antigen-specific antibodies. The Bard BTA Test is a test strip assay which detects "bladder tumor associated analytes" through an agglutination interaction with IgG coated latex particles. Both assays are intended for management of bladder cancer patients, but they detect different substances. {2} # EXPECTED RESULTS ## CLINICAL SENSITIVITY BTA stat test sensitivity (Table I) was determined using urine samples from 220 patients with biopsy confirmed bladder tumor recurrence. Samples were collected from 5 different geographic locations throughout the United States and stored frozen until tested. Testing of samples for this study was performed at Bard Diagnostic Sciences, Inc. The average patient age was 68 years, 78% were males, 67% Caucasian, 1% African American, 4% Asian, Hispanic or other, and 27% of unknown ethnicity. Results are presented below by stage and by grade of the tumor. Table I. BTA stat TEST SENSITIVITY BY STAGE AND GRADE* | STAGE | N | SENSITIVITY (%) | | --- | --- | --- | | Ta | 111 | 51 | | T1 | 36 | 90 | | ≥T2 | 50 | 86 | | Tis | 15 | 61 | | GRADE | N | SENSITIVITY (%) | | 1 | 57 | 42 | | 2 | 56 | 66 | | 3 | 96 | 83 | *3 patients without stage and 12 without grade determinations. A subset of the patients studied (181) also had the Bard BTA test performed on the same sample as the BTA stat test. In this study the Bard BTA test had a sensitivity of 59% while the BTA stat test had a sensitivity of 66% (p=0.233). Table II. COMPARISON OF BTA stat TEST TO BARD BTA TEST | | BARD BTA TEST | | | | | --- | --- | --- | --- | --- | | | | POSITIVE | NEGATIVE | TOTAL | | BTA stat TEST | POSITIVE | 67 | 32 | 119 | | | NEGATIVE | 20 | 42 | 62 | | | TOTAL | 107 | 74 | 161 | Table III presents the overall sensitivity in 220 patients with histologically confirmed bladder cancer recurrence (Table I), as well as the specificity in 107 patients who were being monitored for recurrence of bladder cancer and determined by cystoscopy and/or biopsy to have no evidence of disease (NED) at the time of the BTA stat determination. Table III. BTA stat TEST RESULTS FROM PATIENTS WITH A HISTORY OF BLADDER CANCER | | BTA stat TEST | | | | | --- | --- | --- | --- | --- | | | | POSITIVE | NEGATIVE | TOTAL | | HISTOLOGY/CYSTOSCOPY RESULT | POSITIVE | 147 | 73 | 220 | | | NEGATIVE | 32 | 75 | 107 | | | TOTAL | 179 | 146 | 327 | Monitoring sensitivity = 67% (60 - 79, 95% confidence interval) Monitoring specificity = 70% (61 - 79, 95% confidence interval) Using the data in Table III and a 10%, 20%, and 30% hypothetical prevalence of bladder cancer recurrence, the positive predictive values and negative predictive values of the BTA stat test are presented in Table IV. Due to the possibility that bladder cancer may have been present in some of the NED individuals in this study, yet missed by cystoscopy, the true specificity in these patients and the positive and negative predictive values are likely to be higher. Table IV. HYPOTHETICAL POSITIVE PREDICTIVE VALUES (PPV) AND NEGATIVE PREDICTIVE VALUES (NPV) OF THE BTA stat TEST | BLADDER CANCER RECURRENCE PREVALENCE | PPV | NPV | | --- | --- | --- | | 10% | 19.8 | 95.0 | | 20% | 35.8 | 69.4 | | 30% | 48.8 | 63.1 | {3} A subset of the patients with histologically confirmed bladder cancer (131) also had voided urine cytology (VUC) performed on the same sample as the BTA stat test (Table V). The BTA stat test was shown to be more sensitive than VUC in all categories except for Tis (tumor in situ). Table V. BTA stat TEST AND VUC SENSITIVITIES | STAGE | N | SENSITIVITY BTA stat (%) | SENSITIVITY VUC (%) | SENSITIVITY BTA stat + VUC (%) | | --- | --- | --- | --- | --- | | Ta | 73 | 45 | 7 | 49 | | T1 | 27 | 85 | 41 | 85 | | ≥T2 | 16 | 75 | 38 | 81 | | Tis | 15 | 53 | 60 | 80 | In a subset of patients (99) with a history of bladder cancer and no evidence of disease the specificity of the BTA stat test was 69% compared to VUC with a specificity of 97%. ## CLINICAL SPECIFICITY BTA stat test specificity (Table VI) was determined using urine samples from 555 individuals with no history of bladder cancer. Samples were collected from 5 different geographic locations throughout the United States and stored frozen (-80°C) until tested. Testing of samples for this study was performed at Bard Diagnostic Sciences, Inc. The average age was 55 years, 52% were females, 66% were caucasian, 8% African American, 4% Asian, Hispanic or other, and 3% of unknown ethnicity. The normal healthy population consisted of 60% non-smokers. The non-genitourinary (GU) diseases and cancers (71% of samples provided by females) included diabetes, arthritis, lupus erythematosus and other collagen degenerative diseases, as well as leukemia, lymphomas, breast, lung and gastrointestinal cancers. The non-bladder genitourinary cancers category (69% of samples provided by males) consisted of prostate, renal cell, renal TCC, endometrial, ovarian and other GU carcinomas. The GU disease category (52% of samples provided by females) consisted of patients with benign prostatic hyperplasia (BPH), prostatitis, urethritis, renal stones and disease, urinary tract infections (UTI), incontinence, sexually transmitted diseases (STD) and other disorders. The results indicated that in healthy individuals and individuals without GU diseases and malignancies, the BTA stat test negative rate was 86% and 95%, respectively. Positive BTA stat test results may occur in patients with renal disease such as stones and nephritis and patients with renal cancer including upper tract TCC. Expected results may vary depending on the patient population tested. Table VI. BTA stat TEST SPECIFICITY RESULTS | PATIENT TYPE | NUMBER OF SUBJECTS | TEST NEGATIVE (%) | | --- | --- | --- | | Healthy Subjects | 167 | 95 | | Non-smokers | 100 | 93 | | Smokers | 67 | 97 | | Non-Genitourinary Benign Diseases and Cancers | 105 | 93 | | Non-Genitourinary Benign Diseases | 52 | 96 | | Non-Genitourinary Cancers | 53 | 59 | | Genitourinary Diseases | 152 | 72 | | BPH | 26 | 88 | | Benign Renal Disease | 32 | 50 | | Misc. GU Disease | 94 | 76 | | UTI/cystitis | 30 | 60 | | STD | 24 | 79 | | Other | 40 | 85 | | Genitourinary Cancers | 77 | 73 | | Prostate Cancers | 45 | 78 | | Renal Cancers | 7 | 29 | | Renal TCC | 1 | 0 | | Renal Cell Carcinoma | 6 | 33 | | Other Cancers | 25 | 76 | | Genitourinary Trauma | 54 | 33 | | TOTAL* | 555 | NA | | History of Bladder Cancer - No Evidence of Disease* | 107 | 70 | * total of subjects with no history of bladder cancer * No evidence of disease confirmed by cystoscopy and/or biopsy; 78% of patients in this category were males. {4} # PERFORMANCE CHARACTERISTICS ## HIGH DOSE HOOK EFFECT High dose hook (prozone) effect tests were conducted to determine if the BTA stat test is free from interference from high concentration positive patient samples. Results showed that there was no prozone effect up to 12,400 U/mL bladder tumor associated antigen in a patient's urine sample, which was the highest concentration available for testing. ## REPRODUCIBILITY Three lots of BTA stat devices were used for the reproducibility studies to determine day-to-day, reader-to-reader and lot-to-lot variability. These studies were conducted by testing 10 replicates of 4 blinded samples per day for 5 days using three independent readers for each lot of devices. Between laboratory reproducibility studies were conducted at three laboratories by testing 10 replicates of 4 blinded samples on one lot of BTA stat devices. All reproducibility studies showed nearly total agreement with the exception of samples near the limit of detection, which is to be expected for qualitative tests. # INTERFERING SUBSTANCES Normal and TCC positive urine pools containing the substances listed below were tested in the BTA stat test. Table VII. INTERFERING SUBSTANCES | SUBSTANCE | HIGHEST LEVEL TESTED WITH NO INTERFERENCE | LEVEL AT WHICH SUBSTANCE INTERFERED | | --- | --- | --- | | Possible Urine Constituents | | | | Hemoglobin | 100 mg/dL | No interference at MLTa | | White Blood Cells | 10^{6} cells/mL | No interference at MLT | | Red Blood Cells | 10^{6} cells/mL | No interference at MLT | | Albumin | 1 g/dL | No interference at MLT | | Bilirubin (unconjugated) | 0.4 mg/dL | 0.8 mg/dLa | | IgG | 10 mg/dL | No interference at MLT | | Uric Acid | 250 mg/dL | No interference at MLT | | Ascorbic Acid | 5 g/dL | No interference at MLT | | Caffeine | 58.3 mg/dL | 117 mg/dLa | | Nicotine | 14 mg/dL | 28 mg/dLa | | Sodium chloride | 365 mg/dL | 730 mg/dLa | | Ethanol | 1% (v/v) | No interference at MLT | | Possible Microbial Contaminants | | | | Candida albicans | 1.25 x 10^{10} CFU/mL | 2.5 x 10^{10} CFU/mLa | | Escherichia coli | 2.5 x 10^{10} CFU/mL | No interference at MLT° | | Pseudomonas aeruginosa | 2.5 x 10^{10} CFU/mL | No interference at MLT° | | Therapeutic Agents | | | | Ampicillin | 600 mg/dL | No interference at MLT | | Acetaminophen | 520 mg/dL | 5.2 g/dLa | | Acetyl Salicylic Acid | 520 mg/dL | 5.2 g/dLa | | Doxorubicin-HCI | 10 mg/dL | No interference at MLT | | Mitomycin C | 10 mg/dL | No interference at MLT | | Nitrofurantoin | 50 mg/dL | No interference at MLT | | Phenazopyridine-HCI | 80 mg/dL | 100 mg/dLa | | Thiotepa | 10 mg/dL | No interference at MLT | | Trimethoprim | 50 mg/dL | No interference at MLT | | Bacillus Calmette Guerin | 20 mg/dL | No interference at MLT | | Finasteride | 2.5 mg/dL | No interference at MLT | | Flutamide | 100 mg/dL | No interference at MLT | | loversol, 74% (imaging contrast agent) | 1% | 5%a | | Urised | 17.5 mg/dL | 35 mg/dLa | a MLT - maximum level tested b Negative interference: substance decreased the intensity of a TCC positive urine test result c Subjecting samples to one freeze/thaw cycle resulted in no interference at 1.25 x 10¹⁰ CFU/mL, the MLT. o Results of interference studies unchanged by subjecting samples to one freeze/thaw cycle ° Substance's coloration caused results for both normal and TCC positive urine to be difficult to interpret In conclusion, the Bard BTA stat Test is substantially equivalent to the predicate device referenced in this submission.