(120 days)
The Bayer Diagnostics PSA Immunoassay is for the quantitative serial determination of prostate specific antigen in human serum and to aid in the managenent (monitoring) of patients with prostate cancer
The ACS:180 and ADVIA Centaur PSA assays are a two-site sandwich immunoassay using direct chemiluminometric technology, which uses constant amounts of two antibodies. The direct offermilammomotio to a polyclonal anti-goat antibody labeled with acridinium not ankibody, in the Solid Phase, is a monoclonal anti-mouse antibody, which is covalently coupled to paramagnetic particles.
A direct relationship exists between the amount of PSA present in the patient sample and the amount of relative light units (RLUs) detected by the system
Here's an analysis of the provided text, focusing on acceptance criteria and the study data, organized by your requested points:
Bayer Diagnostics ACS: 180/ADVIA Centaur PSA Assay Performance Data
This document describes the performance of the Bayer Diagnostics ACS: 180 and ADVIA Centaur PSA assays, which are immunoassays for the quantitative determination of prostate-specific antigen (PSA) in human serum.
1. Table of Acceptance Criteria and Reported Device Performance
The document does not explicitly state "acceptance criteria" as pass/fail thresholds for specific metrics. However, it presents various performance characteristics intended to demonstrate the device's analytical capabilities and equivalence to a predicate device. For this table, I will present the reported performance data for key metrics.
| Performance Metric | Acceptance Criteria (Implied/Reference) | Reported Device Performance (ACS: 180) | Reported Device Performance (ADVIA Centaur) |
|---|---|---|---|
| Analytical Sensitivity | Not explicitly stated but expected to be precise at low concentrations | 0.06 ng/mL (minimum detectable concentration) at 2 SD above mean zero standard | 0.06 ng/mL (minimum detectable concentration) at 2 SD above mean zero standard |
| Assay Range | Not explicitly stated (standard for PSA assays) | Up to 100 ng/mL | Up to 100 ng/mL |
| Accuracy (Method Comparison with Alternate Method) | Strong correlation (e.g., r > 0.95, slope ~1, intercept ~0) | ACS: 180 PSA = 0.98 (alternate method) + 0.0118 ng/mL; r = 0.986 (for 629 samples, 0.06-100 ng/mL) | Not directly compared to "alternate method" in this section |
| Accuracy (Method Comparison with ACS: 180) | Strong correlation (e.g., r > 0.95, slope ~1, intercept ~0) | N/A | ADVIA Centaur PSA = 0.99 (ACS: 180 PSA) - 0.09 ng/mL; r = 0.990 (for 661 samples, 0.06-100 ng/mL) |
| Precision (Total % CV) at specific PSA levels | Not explicitly stated (typically <10% for clinical assays, often lower for R&D/manufacturing targets) | See table below | See table below |
| Examples (ACS: 180) | 0.70 ng/mL: 5.9% CV | 0.44 ng/mL: 5.97% CV | |
| 1.83 ng/mL: 5.0% CV | 1.831 ng/mL: 5.12% CV | ||
| 76.25 ng/mL: 6.3% CV | 17.706 ng/mL: 3.31% CV |
ACS: 180 Precision Summary Table (Total % CV)
| Mean (ng/mL) | Total % CV |
|---|---|
| 0.70 | 5.9 |
| 0.91 | 5.3 |
| 1.83 | 5.0 |
| 17.55 | 4.2 |
| 18.23 | 4.6 |
| 29.73 | 5.1 |
| 54.34 | 5.3 |
| 76.25 | 6.3 |
ADVIA Centaur Precision Summary Table (Total % CV)
| Mean (ng/mL) | Total % CV |
|---|---|
| 0.44 | 5.97 |
| 0.708 | 3.71 |
| 1.831 | 5.12 |
| 1.934 | 2.60 |
| 11.308 | 4.68 |
| 17.706 | 3.31 |
2. Sample size used for the test set and the data provenance
-
Accuracy and Method Comparison:
- ACS: 180 vs. Alternate Method: 629 samples
- ADVIA Centaur vs. ACS: 180: 661 samples
- Data Provenance: Not specified in the provided text. It does not mention country of origin or if the data was retrospective or prospective.
-
Expected Results (Distribution of PSA by Diagnostic Category): This can be considered a test set for assessing the clinical utility of the assay against expected population distributions.
- Total Patients: 100 (Healthy Female) + 283 (Healthy Male) + 191 (Prostate Cancer) + 152 (BPH) + 50 (GU) + 18 (Prostatitis) + 5 (Rheumatoid Factor) + 10 (Breast Cancer) + 6 (Renal Cancer) + 10 (Pulmonary Cancer) + 39 (Misc. GU) + 12 (Gastrointestinal) + 18 (Other) = 814 samples
- Data Provenance: Not specified. It refers to "serum samples from healthy subjects and patients with various malignant diseases." No mention of country or retrospective/prospective nature.
-
Precision:
- ACS: 180: 8 samples, each assayed 3 times in 6 assays, on each of 4 systems (n = 72 for each sample). This implies 8 x 72 = 576 data points for calculation, but the samples are typically controls or pooled patient samples run multiple times, not unique patient samples.
- ADVIA Centaur: 6 samples, each assayed 3 times in 8 runs, on each of 4 systems, over 3 days (n = 24 for each sample). This implies 6 x 24 = 144 data points for calculation.
- Data Provenance: Not specified.
3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts
The provided text describes analytical performance studies and clinical distribution studies for a PSA immunoassay. For immunoassay performance studies (like accuracy and precision), ground truth is typically established by the reference measurement procedure or the assigned value of calibrators/control materials, not by experts adjudicating images or clinical cases.
For the "Expected Results" section, which stratifies PSA levels by patient diagnosis, the diagnoses (Prostate Cancer, BPH, etc.) would represent the "ground truth." The document does not specify the number or qualifications of experts used to establish these diagnoses for the patients whose samples were included in the study. These diagnoses would have been established by standard clinical practices (e.g., biopsy results, imaging, clinical examination, and physician judgment) at the time of sample collection.
4. Adjudication method for the test set
Not applicable. As noted above, this study evaluates an immunoassay's analytical performance and the distribution of a biomarker in various clinical populations. There is no multi-reader or image interpretation component requiring an adjudication method like 2+1 or 3+1. The "ground truth" for patient diagnoses (in the "Expected Results" section) would have been based on established clinical diagnostic criteria, not expert adjudication in the context of this document.
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
Not applicable. This document describes an in vitro diagnostic (IVD) immunoassay for measuring PSA levels in blood. It is not an AI-assisted diagnostic device, nor does it involve human readers interpreting cases (like imaging diagnostics). Therefore, an MRMC comparative effectiveness study involving AI assistance is not relevant to this submission.
6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done
Yes, the studies presented are standalone performance studies of the immunoassay devices themselves. The devices (ACS: 180 and ADVIA Centaur) are automated systems that measure PSA levels. Their performance is described analytically (sensitivity, range, accuracy, precision) as the algorithm/device only, without human interpretation of the assay results as a primary variable in these specific performance metrics. The end-user (clinician) then interprets the quantitative PSA result in the context of a patient's clinical picture.
7. The type of ground truth used
- Analytical Sensitivity, Assay Range, Precision: The ground truth for these metrics usually comes from reference materials, certified calibrators, and control samples with known, assigned values. Analytical sensitivity is based on statistical deviation from a zero standard.
- Accuracy (Method Comparison): The "ground truth" is typically the result from a methodologically equivalent or predicate device (e.g., "alternate method" or the ACS: 180 assay when evaluating the ADVIA Centaur). This establishes agreement between the new device and an already accepted method.
- Expected Results (Distribution of PSA by Diagnostic Category): The ground truth for these categories (e.g., "Prostate Cancer," "Benign Prostatic Hypertrophy") is the clinical diagnosis of the patients. This diagnosis would be based on a combination of clinical findings, imaging, and often, histopathology (pathology results) from biopsies for cancer diagnoses. "Outcomes data" could also contribute to confirming disease status over time.
8. The sample size for the training set
The document does not explicitly describe a "training set" in the context of machine learning or AI. This is a submission for an immunoassay, which is a chemical and biological measurement system, not a software algorithm that is "trained" in the conventional AI sense.
The development of such an immunoassay involves extensive research and development, including:
- Selection and optimization of antibodies and reagents.
- Optimization of assay protocols (incubation times, temperatures).
- Calibration curve development.
- Internal validation studies to refine the assay before formal performance testing.
The samples used during these developmental and optimization phases would informally serve a "training" function for the assay design, but they are not referred to as a "training set" in this type of regulatory submission. The performance data presented are from validation studies intended to demonstrate the final product's performance.
9. How the ground truth for the training set was established
As there is no "training set" in the AI sense for this immunoassay, this question is not directly applicable. For the developmental and optimization phases, the "ground truth" would be established through a combination of:
- Known concentrations of PSA in spiked samples.
- Characterized reference materials and patient samples whose PSA levels have been reliably measured by established reference methods or predicate devices.
- Clinical diagnoses (including pathology) for patient samples used to understand the relationship between PSA levels and disease states during method development.
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Image /page/0/Picture/0 description: The image shows the date "APR 13 2000" in a bold, sans-serif font. The letters and numbers are printed in black ink. The date is likely extracted from a document or photograph, and it represents April 13, 2000.
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Summary of Safety and Effectiveness
As required by 21 CFR 807.92, the following 510(k) Summary is provided:
1. Submitter Information
| Contact person: | William J. Pignato |
|---|---|
| Address:63 North StreetMedfield, MA 02052 | Bayer Diagnostics Corporation |
| Phone:FAX:e-mail: | (508) 359-3825(508) 359-3356william.pignato.b@bayer.com |
| Date Summary Prepared: | April 5, 2000 |
| Device Information | |
| Proprietary Name:Common Name:Classification Name: | ADVIA: Centaur and ACS: 180 ePSA AssayPSA ImmunoassayReclassified to Class II, classification numbers |
3. Predicate Device Information
| Name: | Immuno I PSA Immunoassay |
|---|---|
| Manufacturer: | Bayer Diagnostics |
The Immuno 1 PSA Immunoassay was approved by FDA as PMA #P950021 and downclassified to class II by 21 CFR 866.6010, Tumor Associated AntigenImmunological Test System on Dec 17, 1997.
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4. Device Description
PSA is detected in the serum of males with normal, benignhypertrophic, and malignant prostate tissue. PSA is not detected in the serum of males without prostate tissue (because of radical prostatectomy or cystoprostatectomy) or in the serum of most females. The fact that PSA is unique to prostate tissue makes it a suitable marker for monitoring men with cancer of the prostate. PSA is also useful for determining possible recurrence after therapy when used in conjunction with other diagnostic indices.
Measurement of serum PSA levels is not recommended as a screening procedure for the diagnosis of cancer because elevated PSA levels also are observed in patients with benign prostatic hypertrophy. However, studies suggest that the measurement of PSA in conjunction with digital rectal examination (DRE) and ultrasound provide a better method of detecting prostate cancer than DRE alone.
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PSA levels increase in men with cancer of the prostate, and after radicalprostatectomy PSA r SA levels increase in firen with cance. If prostatic tissue remains after surgery or levels routinely fall to the and course to be useful in detecting residual and early metastals nas oboured, to read PSA levels can help determine the success of recurrence of turner. Therefore, ourther treatment, such as radiation, endocrine or prostatootonly, and in the monitoring of the effectiveness of therapy.
5. Statement of Intended Use
The Bayer Diagnostics PSA Immunoassay is for the quantitative determination of prostate The Bayer Diagnostial PDA minutioused) to formalitoring) of patients prostate cancer specific antigen in seram to alle in the management ADVIA Automated Chemiluminescence Systems.
6. Summary of Technological Characteristics
The ACS:180 and ADVIA Centaur PSA assays are a two-site sandwich immunoassay using direct chemiluminometric technology, which uses constant amounts of two antibodies. The direct offermilammomotio to a polyclonal anti-goat antibody labeled with acridinium not ankibody, in the Solid Phase, is a monoclonal anti-mouse antibody, which is covalently coupled to paramagnetic particles.
A direct relationship exists between the amount of PSA present in the patient sample and the amount of relative light units (RLUs) detected by the system
7. Performance Data
Sensitivity and Assay Range
The ACS: 180 PSA and ADVIA Centaur PSA assays measure total PSA concentrations up to 100 ng/mL (100 µg/L) with a minimum detectable concentration (analytical sensitivity) of 0.06 ng/mL (0.06 [g/L). Analytical sensitivity is defined as the concentration of PSA that corresponds to the RLUs that are two standard deviations greater than the mean RLUs of 20 replicate determinations of the PSA zero standard.
Accuracy and Method Comparison
For 629 samples in the range of 0.06 to 100 ng/mL (0.06 to 100 رو/L), the relationship between the ACS: 180 PSA assay and an alternate method is described by the equation:
ACS: 180 PSA = 0.98 (alternate method) + 0.0.118 ng/mL
Correlation coefficient (r) = 0.986
For 661 samples in the range of 0.06 to 100 ng/mL (0.06 to 100 ¡q/L), the relationship between the ADVIA Centaur PSA assay and the ACS: 180 PSA assay is described by the equation:
ADVIA Centaur PSA = 0.99 (ACS: 180 PSA) - 0.09 ng/mL
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Correlation coefficient (r) = 0.990
Expected Results
To confirm the distribution of total PSA in patients, as shown below, serum samples from healthy subjects and patients with various malignant diseases were analyzed using the ACS: 180 PSA reagents. The patients included in this study represent a variety of disease states from active, progressive malignancy to no clinical evidence of disease. The frequency of positive PSA results is significantly lower in patients with no evidence of active disease compared to those with active disease.
| PatientDiagnosis | N | 0.0-4.0ng/mL | 4.1-10ng/mL | 10.1-40ng/mL | >40ng/mL | MedianPSA(ng/mL) |
|---|---|---|---|---|---|---|
| ApparentlyHealthy | ||||||
| Female | 100 | 100.0 | 0.0 | 0.0 | 0.0 | < 0.06 |
| Male < 40 | 71 | 100.0 | 0.0 | 0.0 | 0.0 | 0.73 |
| Male 40-50 | 50 | 100.0 | 0.0 | 0.0 | 0.0 | 0.53 |
| Male 50-60 | 54 | 100.0 | 0.0 | 0.0 | 0.0 | 0.61 |
| Male 60-70 | 50 | 100.0 | 0.0 | 0.0 | 0.0 | 0.85 |
| Male > 70 | 58 | 100.0 | 0.0 | 0.0 | 0.0 | 0.77 |
| Total Males | 283 | 100.0 | 0.0 | 0.0 | 0.0 | 0.71 |
| ProstateCancer | ||||||
| Stage A | 42 | 69.0 | 26.2 | 4.8 | 0.0 | 3.92 |
| Stage B | 50 | 60.0 | 32.0 | 8.0 | 0.0 | 3.52 |
| Stage C | 43 | 20.9 | 72.1 | 4.7 | 2.3 | 5.25 |
| Stage D* | 46 | 56.5 | 21.7 | 19.6 | 2.2 | 3.48 |
| Total Prostate | 191 | 51.6 | 38.0 | 9.3 | 1.1 | 4.04 |
| BenignDiseases | ||||||
| ProstateHypertrophy(BPH) | 152 | 46.7 | 32.9 | 20.4 | 0.0 | 4.37 |
| Genitourinary(GU)a | 50 | 90.0 | 8.0 | 2.0 | 0.0 | 1.38 |
| Prostatitis | 18 | 27.8 | 5.6 | 5.6 | 61.1 | 125.9 |
| RheumatoidFactor | 5 | 100.0 | 0.0 | 0.0 | 0.0 | 0.58 |
% Distribution of PSA by Diagnostic Category
- Six of the these samples were from untreated patients, the remaining samples were patients under treatment
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% Distribution of PSA by Diagnostic Category
| Patient | 0.0-4.0 | 4.1-10 | 10.1-40 | >40 | MedianPSA | |
|---|---|---|---|---|---|---|
| Diagnosis | N | ng/mL | ng/mL | ng/mL | ng/mL | (ng/mL) |
| Other Cancers | ||||||
| Breast | 10 | 100.0 | 0.0 | 0.0 | 0.0 | 0.08 |
| Renal | 6 | 100.0 | 0.0 | 0.0 | 0.0 | 0.37 |
| Pulmonary | 10 | 100.0 | 0.0 | 0.0 | 0.0 | 0.08 |
| Misc. GU | 39 | 92.3 | 5.1 | 2 6 | 0.0 | 0.42 |
| Gastrointestinal | 12 | 91.7 | 0.0 | 0 0 | 8.3 | 0.90 |
| Other | 18 | 100.0 | 0.0 | 0 0 | 0.0 | 0.45 |
Precision
,
:
For the ACS: 180 eight samples were assayed 3 times in 6 assays, on each of 4 systems (n = 72 for each samples were abouted of the following results were
shteined; obtained:
| Mean(ng/mL) | Mean(ug/L) | Within-run% CV | Run-to-run% CV | Total% CV |
|---|---|---|---|---|
| 0.70 | 0.70 | 3.4 | 3.2 | 5.9 |
| 0.91 | 0.91 | 3.4 | 3.6 | 5.3 |
| 1.83 | 1.83 | 2.8 | 3.3 | 5.0 |
| 17.55 | 17.55 | 2.8 | 2.7 | 4.2 |
| 18.23 | 18.23 | 2.9 | 3.1 | 4.6 |
| 29.73 | 29.73 | 3.2 | 3.0 | 5.1 |
| 54.34 | 54.34 | 3.5 | 3.3 | 5.3 |
| 76.25 | 76.25 | 3.7 | 3.4 | 6.3 |
For the ADVIA Centaur six samples were assayed 3 times in 8 runs, on each of 4 systems (n = 24 for each sample), over a period of 3 days. The following results were obtained
| Mean(ng/mL) | Mean(µg/L) | Within-run% CV | Run-to-run% CV | Total% CV |
|---|---|---|---|---|
| 0.44 | 0.44 | 4.8 | 4.05 | 5.97 |
| .708 | .708 | 3.08 | 2.07 | 3.71 |
| 1.831 | 1.831 | 2.09 | 4.67 | 5.12 |
| 1.934 | 1.934 | 2.08 | 1.56 | 2.60 |
| 11.308 | 11.308 | 2.97 | 3.61 | 4.68 |
| 17.706 | 17.706 | 2.29 | 2.40 | 3.31 |
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DEPARTMENT OF HEALTH & HUMAN SERVICES
Image /page/4/Picture/1 description: The image shows the seal of the Department of Health & Human Services (HHS). The seal features an abstract eagle design with three stylized lines representing the bird's body and wings. The words "DEPARTMENT OF HEALTH & HUMAN SERVICES USA" are arranged in a circular pattern around the eagle, indicating the department's name and national affiliation.
APR 1 3 2000
Food and Drug Administration 2098 Gaither Road Rockville MD 20850
Mr. William J. Pignato Director or Regulatory Affairs Bayer Diagnostics Corporation 63 North Street Medfield, Massachusetts 02052
Re: K994221
Trade Name: Bayer Diagnostics Corporation ACS: 180/ADVIA Centaur PSA Assay Regulatory Class: II Product Code: LTJ Dated: March 10, 2000 Received: March 15, 2000
Dear Mr. Pignato:
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 legally marketed predical (or the multiple) for the multiplish for use prior to May 28, 1976, the enactment date of the Medical Innersiale United States 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 Kegulations, 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 regulation (21 CFR Part 820) and that, through periodic QS inspections, the Food and Drug Administration (FTA) will verify such assumptions. Failure to comply with the GMP regulation may result in regulatory 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.
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Page 2
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 parketed 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" (21CFR 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/dsma/dsmamain.html".
Sincerely yours,
Steven Putman
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
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Page _______ of __
510(k) Number (if known): K994221
Device Name: Bayer Diagnostics ACS:180 and ADVIA Centaur PSA Assay
Indications for Use:
The Bayer Diagnostics PSA Immunoassay is for the quantitative serial determination of prostate specific antigen in human serum and to aid in the managenent (monitoring) of patients with prostate cancer
Qine E. Macher
(Division Sign-Off) Division of Clinical Laboratory Devi 510(k) Number -
(PLEASE DO NOT WRITE BELOW THIS LINE--CONTINUE ON ANOTHER PAGE, IF NEEDED)
Concurrence of CDRH, Office of Device Evaluation (ODE)
| Prescription Use | |
|---|---|
| Counter Use | |
| (Per 21 CFR 801.109) | |
| Format 1-2-96) |
OR
Over-The-
(Optional
§ 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.