(78 days)
The Fujirebio Diagnostics CA 19-9™ RIA, an in vitro diagnostic test for the quantitative measurement of the CA 19-9 tumor associated antigen, in human serum or plasma, is indicated for the serial measurement of CA 19-9 to aid in the management of patients diagnosed with cancers of the exocrine pancreas. The test is useful as an aid in:
Monitoring of disease status in those patients having confirmed pancreatic cancer who have levels of serum or plasma CA 19-9 above the cutoff, at the time of diagnosis.
CA 19-9 values must be interpreted in conjunction with all other available clinical and laboratory data before a medical decision is determined.
The Fujirebio Diagnostics CA 19-9™ RIA is a solid-phase radioimmunoassay based on the forward sandwich principle. Polystyrene beads coated with a mouse monoclonal antibody against CA 19-9 are incubated with a serum or plasma specimen, or the appropriate standards or controls. During the incubation, the CA 19-9 antigen present in the specimen is specifically bound to the solid support by the mouse monoclonal antibody. Unbound material present in the specimen is removed by aspiration and washing of the beads. The same mouse monoclonal anti-CA 19-9 labeled with 1281 is then incubated with the beads and binds to the CA 19-9 antigen already bound to the beads. Unbound labeled antibody is removed by aspiration and washing. The bound radioactivity is determined by counting the beads in a gamma counter. A standard curve is obtained by plotting the CA 19-9 antigen concentration of the standards versus bound radioactivity. The CA 19-9 antigen concentrations of unknown patient specimens are determined from the standard curve and are directly proportional to the concentration of the bound tracer molecules.
The provided text describes the Fujirebio Diagnostics CA 19-9™ RIA, an in vitro diagnostic test. The acceptance criteria and supporting studies are presented across various performance characteristics.
Here's a breakdown of the requested information:
1. Table of Acceptance Criteria and Reported Device Performance
Note: Specific "acceptance criteria" are not explicitly stated as distinct pass/fail thresholds in the document, but rather "acceptable ranges" or demonstrated performance that met the manufacturer's goals for substantial equivalence. The reported performance is taken directly from the study results.
| Performance Characteristic | Acceptance Criteria (Implicit) | Reported Device Performance |
|---|---|---|
| Analytical Sensitivity | Below the established clinical cut-off of 37 U/mL. | 0.9 U/mL. |
| Interfering Substances | Minimal or no interference from common substances at tested levels. Potentially high concentrations of HAMA might interfere, but lower concentrations should not. | Only human anti-mouse antibodies (HAMA) at a high titer of 16,636 showed potential interference. HAMA at a lower titer of 1664 showed no effect. All other tested substances showed no interference at tested levels. |
| Recovery Studies | Percent recoveries should fall within calculated acceptable limits for different spike levels. (Low: 87.9 - 112.1%; Mid: 81.9 - 118%; High: 93.0 - 107.0%) | Low Spike (approx. 8 U/mL): Mean 108.34%. Individual sample recoveries ranged from 92.31% to 121.37%. One sample (Patient 4: 121.37%) slightly exceeded the upper limit. Mid Spike (approx. 29 U/mL): Mean 101.91%. Individual sample recoveries ranged from 97.75% to 103.42%. All fell within the limits. High Spike (approx. 90 U/mL): Mean 101.13%. Individual sample recoveries ranged from 96.49% to 111.58%. One sample (Patient 1: 111.58%) slightly exceeded the upper limit. |
| Linearity | Mean slope close to 1 and mean y-intercept close to 0 in regression analysis of observed vs. expected CA 19-9 values. | Mean slope: 0.96 ± 0.031. Mean y-intercept: 5.97 ± 7.65. |
| Reproducibility | Total average variability and intra-assay variation should be within acceptable limits, especially for concentrations at or above the clinical cut-off. High variability is acceptable for very low concentrations. | Total average variability ranged from 6.7% (44 U/mL) to 15.4% (8 U/mL). Day-to-day variation peaked at 14.9% CV. Maximum intra-assay variation was 18% at 8 U/mL (below first non-zero calibrator and clinical cut-off). Average intra-assay variation for 8 U/mL was 12.5% CV. For all other concentrations, average intra-assay variation did not exceed 6.5% CV. |
| Clinical Distribution | Most apparently healthy subjects should be below the 37 U/mL cut-off. Distribution in benign disease cohorts should show that a significant portion remains below the cut-off, though some may exceed it. | Healthy Subjects (N=400): 93.75% < 37 U/mL. Few individuals were > 37 U/mL (e.g., 1% of males and 0.5% of females > 100 U/mL). Benign Diseases (N=399): Genitourinary Tract: 90.9% < 37 U/mL.Gastrointestinal Tract: 88.0% < 37 U/mL.Pancreas/Pancreatitis: 94.0% < 37 U/mL.Chronic Heart Disease/Hypertension: 80.0% < 37 U/mL. |
| Monitoring Disease Status | CA 19-9 changes should correlate with changes in disease status (e.g., increase with progression, stability with no change, decrease with response). A high percentage of correlation is desired. | 57% of positive serum sets correlated with disease progression. 71% of serum sets showing no significant marker change correlated with no progression. The table provides detailed 3x3 classification. E.g., for "INC" marker change, 56.4% were progressive; for "NC" marker change, 44.1% were stable; for "DEC" marker change, 56.0% were responding. |
2. Sample sizes used for the test set and the data provenance
- Analytical Sensitivity: No specific sample size mentioned for the determination of 0.9 U/mL.
- Interfering Substances: NCCLS guideline followed. Number of samples/substances tested not explicitly stated beyond "human anti-mouse antibodies" and "all other substances."
- Recovery Studies: 10 patient samples were used, spiked at three different levels. The provenance is not explicitly stated (e.g., country of origin) but implies human patient samples from clinical settings. It also states "acceptable percent Recovery Limits calculated using the precision of the assay diluent buffer," suggesting proprietary in-house data/methods.
- Linearity: 12 individuals with elevated CA 19-9 assay values were used.
- Reproducibility: Test materials were assayed identically across each lot of reagent. Three sites performed one run per day for 13 acceptable days. No specific number of patient samples is given, but likely controls and standards were used, possibly with patient samples for different concentrations.
- Clinical Data (Apparently Healthy Subjects): 200 women and 200 men (Total N=400). Provenance is not stated (e.g., country of origin, retrospective/prospective).
- Clinical Data (Benign Disease Cohorts): 399 benign disease patient cohorts (100 for GI, 99 for Genitourinary, 100 for Pancreas/Pancreatitis, 100 for Chronic Heart Disease/Hypertension). Provenance is not stated.
- Clinical Data (Monitoring Pancreatic Cancer): 61 patients with a total of 234 observations (average 3.84 observations per patient). Provenance is not stated.
All studies appear to be retrospective analyses of collected samples, as there is no mention of prospective enrollment or follow-up for the purpose of the study itself.
3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts
- No information is provided regarding the number or qualifications of experts used to establish ground truth for any of the studies.
- For the "Monitoring of Disease Status," "disease status" (Progressing, Stable, Responding) would typically be determined by clinical experts (e.g., oncologists, radiologists) based on imaging, biopsy results, and clinical evaluation, but this is not detailed.
4. Adjudication method for the test set
- No information is provided regarding any adjudication method used for establishing ground truth for any of 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
- Not applicable. This device is an in vitro diagnostic (IVD) assay (a radioimmunoassay), not an AI-based image analysis or diagnostic support system that would involve human readers. Therefore, an MRMC study related to AI assistance for human readers was not performed.
6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done
- Yes, this entire submission describes standalone performance. The Fujirebio Diagnostics CA 19-9™ RIA is a laboratory test. Its performance characteristics (analytical sensitivity, recovery, linearity, reproducibility, and correlation with disease status from patient samples) are reported as the performance of the assay itself, without a human-in-the-loop component in the direct measurement and interpretation of the CA 19-9 values. The "intended use" explicitly states that CA 19-9 values "must be interpreted in conjunction with all other available clinical and laboratory data before a medical decision is determined," indicating the test provides quantitative data to be used by clinicians, not a definitive human-independent diagnosis.
7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.)
- Analytical Ground Truth: For analytical studies (sensitivity, recovery, linearity, reproducibility), the "ground truth" refers to known concentrations of CA 19-9 antigen (standards, spiked samples) or expected values based on dilution.
- Clinical Ground Truth:
- Healthy Subjects: Ground truth was "apparently disease free" status, likely based on medical history and general health checks.
- Benign Disease Cohorts: Ground truth was diagnosis of specific benign diseases (e.g., "Benign Diseases of the Genitourinary Tract," "Benign Diseases of the Pancreas/Pancreatitis"). These diagnoses would typically be made through standard clinical diagnostic procedures (imaging, biopsies, clinical assessment, patient history).
- Monitoring Pancreatic Cancer: Ground truth for "disease status" (Progressive, Stable, Responding) was determined from clinical assessment over time (changes in signs and symptoms). This would likely involve a combination of clinical observations, imaging studies, and possibly biopsy results overseen by treating physicians. No specific details are provided on how these states were definitively confirmed.
8. The sample size for the training set
- Not applicable. This device is a traditional RIA laboratory test, not a machine learning or AI model. Therefore, there is no "training set" in the context of AI. The methods described are part of traditional assay development and validation.
9. How the ground truth for the training set was established
- Not applicable, as there is no training set.
{0}------------------------------------------------
MAY 0 9 2002
Image /page/0/Picture/1 description: The image shows the logo for "FUJIREBIO DIAGNOSTICS, INC." The logo consists of a stylized graphic to the left of the text. To the right of the text is a handwritten number, "K020566".
510(k) SUMMARY
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.
The assigned 510(k) number is: K020566.
Submitter Information
| Address: | Fujirebio Diagnostics, Inc.201 Great Valley ParkwayMalvern, PA 19355 |
|---|---|
| Contact person: | Daniel J. O'Shannessy, Ph.D., (610) 240-3811 |
| Summary preparation date: | February 15, 2002 |
| Name of Device | |
| Trade/Proprietary Name: | Fujirebio Diagnostics CA 19-9TM RIA |
| Common/Usual Name: | Immunological test for 1116NS19-9 Antibody Defined Antigen(CA 19-9) |
| Classification Name: | 21CFR 866.6010, Class II, Tumor Associated AntigenImmunological Test System |
| Predicate Device |
Abbott Laboratories AxSYM® CEA MEIA
Device Description
The Fujirebio Diagnostics CA 19-9™ RIA is a solid-phase radioimmunoassay based on the forward sandwich principle. Polystyrene beads coated with a mouse monoclonal antibody against CA 19-9 are incubated with a serum or plasma specimen, or the appropriate standards or controls. During the incubation, the CA 19-9 antigen present in the specimen is specifically bound to the solid support by the mouse monoclonal antibody. Unbound material present in the specimen is removed by aspiration and washing of the beads. The same mouse monoclonal anti-CA 19-9 labeled with 1281 is then incubated with the beads and binds
{1}------------------------------------------------
to the CA 19-9 antigen already bound to the beads. Unbound labeled antibody is removed by aspiration and washing. The bound radioactivity is determined by counting the beads in a gamma counter. A standard curve is obtained by plotting the CA 19-9 antigen concentration of the standards versus bound radioactivity. The CA 19-9 antigen concentrations of unknown patient specimens are determined from the standard curve and are directly proportional to the concentration of the bound tracer molecules.
Intended Use
The Fujirebio Diagnostics CA 19-9™ RIA, an in vitro diagnostic test for the quantitative measurement of the CA 19-9 tumor associated antigen, in human serum or plasma, is indicated for the serial measurement of CA 19-9 to aid in the management of patients diagnosed with cancers of the exocrine pancreas. The test is useful as an aid in:
Monitoring of disease status in those patients having confirmed pancreatic cancer who have levels of serum or plasma CA 19-9 above the cutoff, at the time of diagnosis.
CA 19-9 values must be interpreted in conjunction with all other available clinical and laboratory data before a medical decision is determined.
Summary of Performance characteristics
Analytical Sensitivity (Minimal Detectable Dose)
The analytical sensitivity was determined to be 0.9 U/mL. This level of analytical sensitivity is well below the established "cut-off" of 37 U/mL.
Interfering Substances
The appropriate NCCLS guideline was followed to determine possible sources of interference with the Fujirebio Diagnostics CA 19-9™ RIA kit. Only human anti-mouse antibodies (HAMA), at a titer of 16,636, showed potential interference with the assay. This concentration of human anti-mouse antibody is extremely high. HAMA was also tested at a lower titer of 1664 and showed no effect on the assay. All other substances that were tested with the Fujirebio Diagnostics CA 19-9™ RIA kit showed no interference at the levels tested.
Recoverv Studies
Ten (10) patient samples were spiked with purified CA 19-9 antigen at three (3) different levels. Results were reported as percent recoveries (% Recovery) and compared to the acceptable percent Recovery Limits calculated using the precision of the assay diluent buffer (which was run as samples, both spiked and unspiked).
For the Low spike samples, where the values of added antigen were approximately 8 U/mL, acceptable limits of % Recovery were calculated as being 87.9 - 112.1%. For the Mid spike samples, where the values of added antigen were approximately 29 U/mL, acceptable limits of % Recovery were calculated to be 81.9 - 118%. For the High spike samples, where the values of added antigen were approximately 90 U/mL, acceptable limits of % Recovery were calculated to be 93.0 - 107.0%. These data are listed in the table below.
{2}------------------------------------------------
| PatientNumber | Low SpikePercent Recovery | Mid - SpikePercent Recovery | High SpikePercent Recovery |
|---|---|---|---|
| 1 | 110.23% | 103.42% | 111.58% |
| 2 | 112.12% | 101.87% | 96.49% |
| 3 | 114.08% | 102.35% | 99.07% |
| 4 | 121.37% | 102.30% | 107.50% |
| 5 | 112.41% | 102.89% | 100.45% |
| 6 | 92.31% | 102.18% | 99.99% |
| 7 | 117.43% | 100.93% | 98.81% |
| 8 | 101.98% | 97.75% | 99.10% |
| 9 | 99.64% | 102.43% | 98.49% |
| 10 | 101.78% | 102.96% | 99.78% |
| Mean | 108.34% | 101.91% | 101.13% |
Linearity
The linearity of the Fujirebio Diagnostics CA 19-9 RIA was tested with serial dilutions of 12 individuals with elevated CA 19-9 assay values. Dilutions were prepared in CA 19-9 0 Standard/Diluent Regression analysis comparing observed and expected CA 19-9 assay values yielded a mean slope for the twelve samples of 0.96 ± 0.031 and a mean y-intercept of 5.97 ± 7.65.
Reproducibility:
Each of three (3) sites performed one (1) run per day for thirteen (13) acceptable days with three (3) different lots of product. Test materials were assayed in random order for each run. but were tested identically across each lot of reagent under evaluation.
The total average variability ranged from 6.7% (44 U/mL) to 15.4% (8 U/mL). Day-to-day variation across sample-site-lot combinations peaked at 14.9 % CV with a nadir of 0%. The maximum intra-assay variation was 18 % at a CA 19-9 concentration of 8 U/mL, a concentration below the first non-zero calibrator and well under the clinical cut-off of 37 U/mL. The average intra-assay variation across all sites and lots for that 8 U/mL sample was 12.5 % CV. For all other concentrations tested, the average intra-assay variation did not exceed 6.5% CV.
Clinical Data
Apparently Healthy Subjects:
To determine the distribution of CA 19-9 values in apparently normal healthy individuals, and to confirm the cutoff of 37 U/mL, a sample of 200 women and 200 men who were apparently disease free were assessed.
{3}------------------------------------------------
Fujirebio Diagnostics CA 19-9™ RIA Distribution of
| Group | Total | <37U/mL | 37 - 49.9U/mL | 50 - 69.9U/mL | 70 - 99.9U/mL | >100U/mL |
|---|---|---|---|---|---|---|
| Males | 200 | 189 (94.5%) | 4 (2.0%) | 5 (2.5%) | 0 (0.0%) | 2 (1.0%) |
| Females | 200 | 186 (93.0%) | 7 (3.5%) | 4 (2.0%) | 2 (1.0%) | 1 (0.5%) |
Values of Apparently Healthy Subjects
Benign Disease Cohorts:
Three hundred and ninety-nine (399) benign disease patient cohorts were assembled to determine the distribution of serum CA 19-9 values in benign diseases that may be coexistent in patients with confirmed pancreatic cancer.
| Diagnostic Group | Total | <37U/mL | 37 - 49.9U/mL | 50 - 69.9U/mL | 70 - 99.9U/mL | ≥100U/mL |
|---|---|---|---|---|---|---|
| Benign Diseases of theGenitourinary Tract | 99 | 90 (90.9%) | 6 (6.1%) | 2 (2.0%) | 1 (1.0%) | 0 (0.0%) |
| Benign Diseases of theGastrointestinal Tract | 100 | 88 (88.0%) | 7 (7.0%) | 3 (3.0%) | 2 (2.0%) | 0 (0.0%) |
| Benign Diseases of thePancreas/Pancreatitis | 100 | 94 (94.0%) | 1 (1.0%) | 4 (4.0%) | 1 (1.0%) | 0 (0.0%) |
| Chronic Heart Disease/Hypertension | 100 | 80 (80.0%) | 10 (10.0%) | 5 (5.0%) | 5 (5.0%) | 0 (0.0%) |
Fujirebio Diagnostics CA 19-9™ RIA Distribution of Values Benign Diseases
Monitoring of Disease Status in Patients Diagnosed with Pancreatic Cancer:
The effectiveness of CA 19-9 as an aid in monitoring of disease status in patients diagnosed with pancreatic cancer was determined by assessing changes in CA 19-9 levels in serial serum sets with changes in disease status. Samples from 61 patients with a total of 234 observations were analyzed. The average number of observations per patient was 3.84. Fifty-seven percent (57%) of the positive serum sets correlated with disease progression while seventy-one (71%) of serum sets showing no significant change in the marker correlated with no progression. The Table below presents the data in a 3x3 classification scheme.
The disease states are:
- Progression from one collection to the next collection (Progressing). .
- No Change in disease status (Stable). .
- Reduction in the signs and symptoms of the disease from one collection to the next . (Responding).
Marker changes are classified as:
{4}------------------------------------------------
- A 20% or greater increase in the marker from one collection to the next (INC) .
- No significant change in the marker (|Delta CA 19-9|<20%) (NC) .
- A 20% or greater decrease in the marker value from one collection to the next (DEC) .
Expanded Distribution
| MarkerChange | Disease Status | Total | ||
|---|---|---|---|---|
| Progressive | Stable | Responding | ||
| INC | 31 | 30 | 4 | 65 |
| 56.4% (1.29) | 32.3% (.477) | 16.0% (.190) | 37.6% | |
| NC | 12 | 41 | 7 | 60 |
| 21.8% (.279) | 44.1% (.789) | 28.0% (.389) | 34.7% | |
| DEC | 12 | 22 | 14 | 48 |
| 21.8% (.279) | 23.7% (.310) | 56.0% (1.27) | 27.7% | |
| Total | 55 | 93 | 25 | 173 |
{5}------------------------------------------------
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 stylized image of an eagle with three heads, representing the department's mission to protect the health of all Americans and provide essential human services. The words "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" are arranged in a circular pattern around the eagle image.
MAY 0 9 2002
Food and Drug Administration 2098 Gaither Road Rockville MD 20850
Daniel J. O'Shannessy, Ph.D. Chief Scientific Officer Fujirebio Diagnostics, Inc. 201 Great Valley Parkway Malvern, Pennsylvania 19355-1307
Re: K020566
Trade/Device Name: Fujirebio Diagnostics CA 19-9TM RIA Regulation Number: 21 CFR § 866.6010 Regulation Name: Tumor Associated antigen Immunological Test System Regulatory Class: II Product Code: NIG Dated: April 19, 2002 Received: April 23, 2002
Dear Dr. O'Shannessy:
We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate 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) that do not require approval of a premarket approval application (PMA). 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 (PMA), 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 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.
Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
{6}------------------------------------------------
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 marketed nvellicate 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 International and Consumer 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 Butman
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}------------------------------------------------
INDICATIONS FOR USE STATEMENT
Page 1 of
510(k) Number (if known): K020566
Device Name: Fujirebio Diagnostics CA 19-9™ RIA
The Fujirebio Diagnostics CA 19-9™ RIA, an in vitro diagnostic test for the quantitative The Tullion Diagnootio Cr. To associated antigen, in human serum or plasma, is indicated measurement of the OF 10 Claims. 18-9 to aid in the management of patients diagnosed with cancers of the exocrine pancreas. The test is useful as an aid in:
Monitoring of disease status in those patients having confirmed pancreatic cancer who have levels of serum or plasma CA 19-9 above the cutoff, at the time of diagnosis.
CA 19-9 values must be interpreted in conjunction with all other available clinical and laboratory data before a medical decision is determined.
Sousan S. Altaie
(Division Sign-Off) Division of Clinical Laboratory Devices
510(k) Number K020566
(PLEASE DO NOT WRITE BELOW THIS LINE-CONTINUE ON ANOTHER PAGE OF NEEDED)
Concurence of CDRH, Office of Device Evaulation (ODE)
(Optional Format 3-10-98)
§ 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.