(164 days)
Chiron Diagnostics ACS:180 BR is an in vitro diagnostic test for the quantitative serial determination of cancer antigen CA 27.29 in human serum. The test is intended for use as an aid in the management of breast cancer patients with metastatic disease by monitoring the progression or regression of disease in response to treatment.
The Chiron Diagnostics ACS:180 BR assay is a competitive, chemiluminescent assay intended for use on the Chiron Diagnostics Automated Chemiluminescent System (ACS). One reagent, designated Lite Reagent, is composed of a mouse monoclonal antibody specific for CA 27.29, labeled with acridinium ester. The Solid Phase is composed of purified breast cancer antigen covalently coupled to paramagnetic particles (PMP). The patient serum sample is incubated with both reagents simultaneously for 7.5 minutes. An inverse relationship exists between the concentration of CA 27.29 in a sample and the relative light units (RLU) detected by the ACS:180 system. Automatic dilution is available on the ACS:180® for the ACS:180 BR assay.
Here's a breakdown of the acceptance criteria and study information for the Chiron Diagnostics ACS:180 BR device, based on the provided text:
Acceptance Criteria and Reported Device Performance
| Acceptance Criteria | Reported Device Performance |
|---|---|
| Analytical Sensitivity | < 3.5 U/mL |
| Sensitivity to Change in Disease Status | 73% |
| Specificity to Change in Disease Status | 71% |
| Positive Predictive Value to Change in Disease Status | 77% |
| Negative Predictive Value to Change in Disease Status | 67% |
| Upper Limit of Normal (ULN) | 38.6 U/mL |
| Correlation with predicate device (r) | 0.96 (for all 203 specimens) |
| Correlation with predicate device (r) | 0.96 (for 103 breast cancer patients) |
| Recovery of Interfering Substances | Range: 93.3% (Ondansetron) to 105.8% (Methotrexate) |
| Recovery of Cross-reacting Antigens | Range: 103.6% (CA 19.9) to 105.9% (CA125) |
Study Information
2. Sample size used for the test set and the data provenance:
- Test Set for Clinical Trial Results: The exact sample size for the "Clinical Trial Results" (Sensitivity, Specificity, PPV, NPV) is not explicitly stated, but it is described as a "Prospective Clinical Trial." The country of origin is not mentioned.
- Test Set for Normal Range/ULN: 314 healthy volunteer donors were tested at three laboratories. Data provenance is not specified.
- Test Set for Specificity (Non-breast Malignancies):
- Colon: 43
- Liver: 20
- Lung: 47
- Ovary: 50
- Pancreas: 45
- Prostate: 34
- Stomach: 29
- Uterus: 30
Data provenance is not specified.
- Test Set for Specificity (Other Diseases/Conditions):
- Benign Breast Disease (Breast Adenoma): 61
- Benign Breast Disease (Fibrocystic Breasts): 68
- Cirrhosis: 25
- Endometriosis: 24
- Lactating Woman: 37
- Mild Chronic Hepatitis: 28
- Ovarian Cyst: 50
- Pregnancy: 49
- Renal Impairment: 20
- Severe Chronic Hepatitis: 20
Data provenance is not specified.
- Test Set for Potentially Interfering Substances: Five serum pools containing CA 27.29 at different levels.
- Test Set for Correlation with Predicate Device: 203 specimens overall, including a subset of 103 women with histologically confirmed breast cancer. Data provenance is not specified.
3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts:
- The document does not specify the number or qualifications of experts used to establish ground truth for any of the clinical or specificity studies. For the breast cancer patients used in the correlation study, it mentions "histologically confirmed breast cancer," implying pathology involvement, but details are absent.
4. Adjudication method for the test set:
- The document does not mention any adjudication method for establishing ground truth for the test sets.
5. If a multi-reader multi-case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance:
- This device is an in vitro diagnostic test (an automated chemiluminescence system) for measuring a cancer antigen in human serum. This type of device does not involve "human readers" or "AI assistance" in the typical sense of imaging or diagnostic interpretation. Therefore, an MRMC comparative effectiveness study in the context of human readers improving with AI would not be applicable and was not performed.
6. If a standalone (i.e. algorithm only, without human-in-the-loop performance) was done:
- Yes, the entire study focuses on the standalone performance of the ACS:180 BR automated system. It is designed to perform the quantitative determination of CA 27.29 without human intervention in the assay process itself, beyond sample loading and results interpretation by a clinician.
7. The type of ground truth used:
- Clinical Trial Results (Sensitivity/Specificity to Change in Disease Status): Implied to be clinical disease progression or regression based on established clinical practice, though the exact method (e.g., imaging, clinical assessments, pathology) is not detailed.
- Specificity Studies (Non-breast Malignancies, Other Diseases/Conditions): Based on the diagnosis of the malignancy or condition (e.g., "Colon," "Liver," "Benign Breast Disease").
- Normal Range/ULN: Based on results from healthy volunteer donors.
- Correlation with Predicate Device: The ground truth for the concentration of CA 27.29 was presumably the measurement from the predicate device (Biomira TRUQUANT® BR™ RIA), against which the new device was compared. For the breast cancer patient subset, the "histologically confirmed breast cancer" provides an additional clinical ground truth for the patient population itself.
- Interfering Substances/Antigens: Based on known concentrations of spiked substances and antigens in serum pools with established CA 27.29 levels.
8. The sample size for the training set:
- The document does not explicitly mention a separate "training set" or its sample size. This is a common characteristic of in vitro diagnostics developed and evaluated prior to the widespread use of deep learning AI, where training might involve assay optimization rather than large-scale data-driven model training.
9. How the ground truth for the training set was established:
- As a training set is not explicitly mentioned, the method for establishing its ground truth is also not described. The performance characteristics discussed relate to the validation or test of the final assay.
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SUMMARY OF SAFETY AND EFFECTIVENESS
This summary of safety and effectiveness information is being submitted in accordance with the requirements of The Safe Medical Devices Act of 1990 (SMDA 1990) and 21 CFR Part 807.92.
Date of Summary Preparation: July 24, 1997
- Company Name: Chiron Diagnostics Corporation 1401 Harbor Bay Parkway Alameda, CA 94502
- Company Contact: Nancy Hombaker Regulatory Affairs Chiron Diagnostics Chiron Corporation 4560 Horton Street Emeryville, CA 94608
| Telephone Number: | 510.923.2758 |
|---|---|
| Fax: | 510.923.3344 |
- Device Name: ACS:180 BR Automated Chemiluminescence System
- Common or Usual Name: Automated Tumor Associated Antigen
- Classification: Class II device
- Predicate Device: Biomira TRUQUANT® BR™ RIA PMA P950011
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SUMMARY OF SAFETY AND EFFECTIVENESS - K970695 (continued)
Intended Use and Indications for Use:
Chiron Diagnostics ACS:180 BR is an in vitro diagnostic test for the quantitative serial determination of cancer antigen CA 27.29 in human serum. The test is intended for use as an aid in the management of breast cancer patients with metastatic disease by monitoring the progression or regression of disease in response to treatment.
Summary and Explanation of the Test:
Automatic dilution is available on the ACS:180® for the ACS:180 BR assay. Any sample initially reading with a value higher than the assay range will be rescheduled by the instrument for an automatic dilution. The ACS:180 has the capacity to aspirate as low as 5 ul of sample using the sample probe. Given the sample volume of 25 ul for ACS:180 BR, the maximum dilution that is possible is a 1:5. The instrument will aspirate 5 ul of sample and add 20 ul of diluent to maintain the 25 ul sample size. Instrument operation will then proceed as usual,
Principle of the Assay:
The Chiron Diagnostics ACS:180 BR assay is a competitive, chemiluminescent assay intended for use on the Chiron Diagnostics Automated Chemiluminescent System (ACS). One reagent, designated Lite Reagent, is composed of a mouse monoclonal antibody specific for CA 27.29, labeled with acridinium ester. The Solid Phase is composed of purified breast cancer antigen covalently coupled to paramagnetic particles (PMP). The patient serum sample is incubated with both reagents simultaneously for 7.5 minutes.
An inverse relationship exists between the concentration of CA 27.29 in a sample and the relative light units (RLU) detected by the ACS:180 system.
| Analytical Sensitivity | <3.5 U/mL |
|---|---|
| Clinical Trial Results | ProspectiveClinical Trial |
| Sensitivity to Change in Disease Status | 73% |
| Specificity to Change in Disease Status | 71% |
| Positive Predictive Value to Change in Disease Status | 77% |
| Negative Predictive Value to Change in Disease Status | 67% |
Specific Performance Characteristics:
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SUMMARY OF SAFETY AND EFFECTIVENESS - K970695 (continued)
A total of 314 healthy volunteer donors were tested at three laboratories to determine the normal range of the assay and to determine the upper limit of normal (ULN). Following good laboratory practice, each laboratory should determine its own normal range and ULN.
Upper Limit of Normal (ULN) 38.6 U/mL
Specificity of the Assay
The specificity of the assay was determined by testing serum samples from patients with active malignancies other than breast and serum from patients with other diseases and conditions. Results from the clinical study are presented below.
Patients with non breast malignancies frequently have raised levels of the CA 27,29 antigen as indicated by their specificities. CA 27.29 is normally expressed by most epithelial tissues and over-expressed by many epithelial cancers. It is not a breast specific antigen.
Specificity of the ACS180:BR in Patients with Malignancies other than Breast
| Malignancy | N | Specificity |
|---|---|---|
| Colon | 43 | 74.4% |
| Liver | 20 | 45.0% |
| Lung | 47 | 57.5% |
| Ovary | 50 | 44.0% |
| Pancreas | 45 | 53.3% |
| Prostate | 34 | 82.4% |
| Stomach | 29 | 93.1% |
| Uterus | 30 | 86.7% |
Specificity of the ACS:180 BR in Patients with Other Diseases And Conditions
| Condition | N | Specificity |
|---|---|---|
| Benign Breast Disease | ||
| Breast Adenoma | 61 | 95.08% |
| Fibrocystic Breasts | 68 | 98.53% |
| Cirrhosis | 25 | 76.00% |
| Endometriosis | 24 | 91.67% |
| Lactating Woman | 37 | 89.19% |
| Mild Chronic Hepatitis | 28 | 85.71% |
| Ovarian Cyst | 50 | 94.00% |
| Pregnancy | 49 | 97.96% |
| Renal Impairment | 20 | 85.00% |
| Severe Chronic Hepatitis | 20 | 95.00% |
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SUMMARY OF SAFETY AND EFFECTIVENESS - K970695 (continued)
Potentially Interfering Substances
There are no known cross-reactants for CA 27.29 as measured by the ACS:180 BR assay.
The potential interference of chemotherapeutic agents, therapeutic drugs, and tumor marker antigens was tested by adding these substances to five serum pools containing CA 27.29 ranging from 20.0 to 445.8 U/mL. The level of CA 27.29 in each of these pools was then determined using the ACS:180 BR assay and normalized to the level without the respective drugs or antigens.
| Substance | Mean %Recovery | Substance | Mean %Recovery |
|---|---|---|---|
| Acetaminophen (10X) | 96.3 | Granisetron HCI (10X) | 99.9 |
| Cimetidine (40X) | 100.9 | Lorazepam (10X) | 98.0 |
| Ciprofloxacin (10X) | 100.1 | Megestrol acetate (5X) | 105.2 |
| Codeine (10X) | 96.9 | Methotrexate (10X) | 105.8 |
| Cyclophosphamide (1X) | 96.2 | Morphine (10X) | 95.6 |
| Dexamethasone (10X) | 100.2 | Ondansetron (10X) | 93.3 |
| Diphenhydramine HCI (10X) | 101.8 | Paclitaxel (2X) | 101.7 |
| Doxorubicin (10X) | 95.9 | Prochlorperazine (10X) | 96.4 |
| Etopside (2X) | 99.5 | Tamoxifen (10X) | 96.6 |
| 5-Fluorouracil (10X) | 104.2 | Vinorelbine tartrate (10X) | 104.9 |
| Antigen | Mean % Recovery |
|---|---|
| Carcinoembryonic antigen(CEA) | 103.8 |
| Ovarian Cancer antigen(CA125) | 105.9 |
| GI Cancer antigen(CA 19.9) | 103.6 |
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Correlation with Predicate Device
The performance of the ACS: 180 BR assay was compared with that of the predicate device in a study of 203 specimens. These specimens had CA 27.29 levels that spanned the range from 7 to 994 U/mL, The results of the linear regression analysis indicated that the two methods were correlated. The correlation coefficient (r) was 0.96; the slope was 1.05 and y-intercept was 6 U/mL.
The CA 27.29 results from a subset of this population, 103 women with histologically confirmed breast cancer, were also highly correlated (r = 0.96). In this analysis, the slope was 1.04 and the y-intercept was 8 U/mL.
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Image /page/5/Picture/1 description: The image is a black and white logo for the U.S. Department of Health & Human Services. The logo features a circular border with the text "DEPARTMENT OF HEALTH & HUMAN SERVICES • USA" arranged around the perimeter. Inside the circle is a stylized graphic of three human profiles facing to the right, one behind the other, creating a sense of depth and unity.
Food and Drug Administration 2098 Gaither Road Rockville MD 20850
Ms. Nancy Hornbaker Requlatory Affairs Chiron Diagnostics Chiron Corporation 4560 Horton Street Emeryville, California 94608
Re : K970695/S1 Trade Name: ACS:180 BR Requlatory Class: II Product Code: MOI Dated: June 13, 1997 Received: June 16, 1997
Dear Ms. Hornbaker:
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 of the Act. The general controls provisions of the Act include requirements for annual registration, 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 Regulations, Title 21, Parts 800 to 895. A substantially equivalent determination assumes compliance with the current Good Manufacturing Practice requirement, 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 requlatory action. In addition, FDA may publish further announcements 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.
AUG - 8 1997
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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). Qther 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 at (301) 443-6597 or at its internet address "http://www.fda.gov/cdrh/dsmamain.html"
Sincerely yours,
Steven Autman
Steven I. Gutman, M.D., M.B.A. Director Division of Clinical Laboratory Devices Office of Device Evaluation Center for Devices and Radioloqical Health
Enclosure
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501(k) Number (if known):
Device Name: ACS: 180 BR
Indications For Use:
Chiron Diagnostics ACS: 180 BR is an in vitro diagnostic test for the quantitative serial determination of cancer antigen CA 27.29 in human serum. The test is intended for use as an aid in the management of breast cancer patients with metastatic disease by monitoring the progression or regression of disease in response to treatment.
Peter E. Madson
(PI.EASE DO NOT WRITE BELOW THIS LINE - CONTINUE ON ANOTHER PAGE IF NEEDED
Concurrence of CDRH, Office of Device Evaluation (ODE)
Prescription Use
Prt 21 CFR 801.109
OR
Over-the-Counter Use
§ 866.6010 Tumor-associated antigen immunological test system.
(a)
Identification. A tumor-associated antigen immunological test system is a device that consists of reagents used to qualitatively or quantitatively measure, by immunochemical techniques, tumor-associated antigens in serum, plasma, urine, or other body fluids. This device is intended as an aid in monitoring patients for disease progress or response to therapy or for the detection of recurrent or residual disease.(b)
Classification. Class II (special controls). Tumor markers must comply with the following special controls: (1) A guidance document entitled “Guidance Document for the Submission of Tumor Associated Antigen Premarket Notifications (510(k)s) to FDA,” and (2) voluntary assay performance standards issued by the National Committee on Clinical Laboratory Standards.