(58 days)
The Trinity Biotech Captia™ Borrelia burgdorferi IgG/IgM ELISA kit is an Enzyme-Linked Immunosorbent Assay (ELISA) for the qualitative presumptive detection of total (IgG/IgM) antibodies to Borrelia burgdorferi in human serum. This ELISA should only be used for patients with signs and symptoms that are consistent with Lyme disease. Equivocal or positive results must be supplemented by testing with a standardized Western blot procedure. Positive supplemental results are supportive evidence of exposure to B. burgdorferi and can be used to support a clinical diagnosis of Lyme disease.
The Borrelia burgdorferi IgG/IgM ELISA kit is an Enzyme-Linked Immunosorbent Assay (ELISA) for the qualitative presumptive detection of total (IgG/IgM) antibodies to Borrelia burgdorferi in human serum. This ELISA should only be used for patients with signs and patients with symptoms that are consistent with Lyme disease. Equivocal or positive results should be supplemented by testing with a standardized Western blot procedure. Positive supplemental results are supportive evidence of exposure to B. burgdorferi and can be used to support a clinical diagnosis of Lyme disease.
The Borrelia burgdorferi IgG/IgM ELISA test is an enzyme linked immunosorbent assav to detect IgG/IgM antibodies to Borrelia burgdorferi. Purified Borrelia burgdorferi antigen is attached to a solid phase microtiter well. Diluted test sera is added to each well. If the antibodies are present that recognize the antigen, they will bind to the antigen in the well. After incubation, the wells are washed to remove unbound antibody. An enzyme labeled anti-human IgG/IgM is added to each well. If antibody is present, it will bind to the antibody attached to the antigen on the well. After incubation the wells are washed to remove unbound conjugate. A substrate solution is added to each well. If enzyme is present. the substrate will undergo a color change. After an incubation period the reaction is stopped and the color intensity is measured photometrically, producing and indirect measurement of specific antibody in the patient specimen.
Here's an analysis of the acceptance criteria and the study that proves the device meets them, based on the provided text:
Device: Borrelia burgdorferi IgG/IgM ELISA Test Kit (Trinity Biotech Captia™ Borrelia burgdorferi IgG/IgM ELISA)
Indications for Use: Qualitative presumptive detection of total (IgG/IgM) antibodies to Borrelia burgdorferi in human serum, for patients with signs and symptoms consistent with Lyme disease. Equivocal or positive results must be supplemented by testing with a standardized Western blot procedure.
1. Table of Acceptance Criteria and Reported Device Performance
The provided document doesn't explicitly state numerical acceptance criteria in the typical sense for assay performance (e.g., "sensitivity must be >90%"). Instead, it demonstrates performance through comparative studies and precision testing. The acceptance criteria appear to be implicitly defined by demonstrating equivalence to a predicate device (BioWhittaker's Lyme STAT test) and acceptable precision, as well as testing against a characterized CDC panel and assessing cross-reactivity.
Here's a table summarizing the performance metrics and results provided:
| Performance Characteristic | Acceptance Criteria (Implicitly Derived) | Reported Device Performance |
|---|---|---|
| Agreement with Clinical Diagnosis (CDC Panel) | Demonstrate reasonable agreement with clinical diagnosis for a characterized CDC serum panel, especially for later-stage infections. | - Overall agreement (considering equivocals as positive for 1-step) with clinical diagnosis: 71% (30/42). - Specific agreement by time after onset: - Normals: 100% (5/5) - < 1 month: 40.0% (2/5) - 1-2 months: 80.0% (8/10) - 3-12 months: 63.3% (12/19) - > 1 year: 100.0% (8/8) |
| Equivalence to Predicate Device (Study 2) | Demonstrate similar performance to the predicate device (BioWhittaker Lyme STAT) in terms of 1-step positivity/equivocality rates and 2-step positive rates. | 1-step (ELISA) Pos. or Eq.: - Trinity: 9.1% (4.8% - 13.4%) (16/176) - Lyme Stat: 7.4% (3.4% - 11.3%) (13/176) 1-step Pos. or Eq. & 2-step (WB) Pos.: - Trinity: 4% (1.0% - 6.9%) (7/176) - Lyme Stat: 2.8% (0.3% - 5.3%) (5/176) 2-step Pos. among 1-step Pos. or Eq.: - Trinity: 44% (18.9% - 68.6%) (7/16) - Lyme Stat: 39% (11.5% - ) (5/13) |
| Precision (Inter-Assay) | Achieve precision with a Coefficient of Variation (CV) <15% for appropriate technique. No positive result for negative sera, and no negative result for positive sera. | - Majority of serums (7 out of 10 measured in multi-site, multi-plate setup) showed CVs well below 15% (e.g., 7.10% to 10.34%). - Two sera (6 & 7) showed higher CVs: 40.57% and 68.93%. - Negative control (NC) showed 21.97% CV. - No false positives for negative sera or false negatives for positive sera observed in 810 determinations. |
| Cross-Reactivity | Demonstrate minimal or no cross-reactivity with commonly interfering substances and conditions (e.g., lipemic, bilirubinemic, other infections, autoimmune indicators). | - No reactivity (0 positives) observed for: Lipemic, RPR+, RF+, EBV+, RMSF+, CRP+, Elevated ESR, dsDNA+. - Limited reactivity (1 positive each) for: Bilirubinemic (1 sample out of 5), CMV+ (1 sample out of 6). |
2. Sample Size Used for the Test Set and Data Provenance
The document describes two main studies for performance evaluation:
-
Study 1 (CDC Lyme Disease Serum Panel):
- Sample Size: 47 serum samples.
- Data Provenance: The serum panel was "obtained from the CDC" and described as "masked, characterized." This suggests a retrospective panel, likely from patients previously diagnosed or classified, and potentially from diverse geographical origins within the US given CDC's role. No specific country of origin is mentioned beyond "CDC."
-
Study 2 (Fresh Sera Comparative Study):
- Sample Size: 176 fresh sera.
- Data Provenance: "fresh sera from patients of various ages and genders that were submitted to a large clinical lab for B. burgdorferi antibody testing." This indicates the data is prospective in terms of being "fresh sera" submitted for routine testing, but the source of the "large clinical lab" is not specified (likely US-based given the FDA submission).
3. Number of Experts and Qualifications for Ground Truth Establishment
The document does not explicitly state the number of experts used to establish the clinical diagnosis ground truth for the CDC panel. For the "characterized serum panel," the characterization would likely involve clinical diagnosis by medical professionals, potentially general practitioners or infectious disease specialists, supported by laboratory results (which could include Western blot). However, the specific number and qualifications of these experts are not provided.
For Study 2, the ground truth was ultimately established by Western blot (IgG and IgM Mardx Diagnostics Western Blot) for any sample found positive or equivocal by either ELISA. This implies that the Western blot itself served as the reference standard, and while expert interpretation of Western blots is often required, the document does not specify the number or qualifications of experts interpreting these Western blots.
4. Adjudication Method for the Test Set
The document does not describe a formal multi-reader adjudication method (like 2+1 or 3+1 consensus) for the test sets.
- For the CDC panel, the "agreement with clinical diagnosis" suggests that a pre-established clinical diagnosis (presumably the ground truth provided by CDC) was used as the reference against the ELISA results.
- For Study 2, the use of Western blot as the confirmatory second step implies a hierarchical diagnostic algorithm rather than an adjudication process between different readers or methods for the same result. The Western blot results, rather than a consensus of different interpretations, served as the ultimate arbiter for positive/equivocal ELISA results.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done. The study is primarily focused on the standalone performance of the device and its comparison to a predicate assay, not on how human readers' performance might improve with or without AI assistance.
6. Standalone (Algorithm Only) Performance
Yes, a standalone performance evaluation was done. The entire submission describes the performance of the Trinity Biotech Borrelia burgdorferi IgG/IgM ELISA test kit itself, as an "algorithm only" in the context of an immunoassay. The results presented in Tables 1, 2, 3, and 4 are all direct measurements of the kit's performance on various serum panels and under different conditions, without human interpretation beyond reading the photometric output and applying the assay's cutoff rules.
7. Type of Ground Truth Used
- Study 1 (CDC Panel): Clinical diagnosis (as indicated by "agreement with clinical diagnosis") and a "characterized serum panel." It is reasonable to assume this characterization includes comprehensive clinical and historical data, potentially including other laboratory tests.
- Study 2 (Comparative Study): Western blot (Mardx Diagnostics Western Blot IgG and IgM) was used as the confirmatory ground truth for samples that tested positive or equivocal by ELISA. This is a common laboratory-based reference standard for Lyme disease serology.
8. Sample Size for the Training Set
The document does not specify a separate "training set" or its sample size. This type of submission for an immunoassay typically describes the validation of the finalized assay itself, rather than the development process involving a distinct training phase for an algorithm. The reported studies (CDC panel, fresh sera, precision, cross-reactivity) are validation studies for the device.
9. How the Ground Truth for the Training Set Was Established
Since a distinct training set is not described, the method for establishing its ground truth is not provided.
{0}------------------------------------------------
NOV 26 2003
Summary of Safety and Effectiveness Information Borrelia burgdorferi IgG/IgM ELISA Test Kit
I. Trinity Biotech 2823 Girts Road Jamestown, NY 14701 Contact person: Bonnie B. DeJoy Telephone: 716-483-3851 Date of preparation: Nov. 20, 2003
II. Description of Device
burgdorferi IgG/IgM ELISA kit is an The Borrelia Enzyme-Linked ImmunosorbentAssay (ELISA) for the qualitative presumptive detection of total (IgG/IgM) antibodies to Borrelia burgdorferi in human serum. This ELISA should only be used for patients with signs and patients with symptoms that are consistent with Lyme disease. Equivocal or positive results should be supplemented by testing with a standardized Western blot procedure. Positive supplemental results are supportive evidence of exposure to B. burgdorferi and can be used to support a clinical diagnosis of Lyme disease.
The Borrelia burgdorferi IgG/IgM ELISA test is an enzyme linked immunosorbent assav to detect IgG/IgM antibodies to Borrelia burgdorferi. Purified Borrelia burgdorferi antigen is attached to a solid phase microtiter well. Diluted test sera is added to each well. If the antibodies are present that recognize the antigen, they will bind to the antigen in the well. After incubation, the wells are washed to remove unbound antibody. An enzyme labeled anti-human IgG/IgM is added to each well. If antibody is present, it will bind to the antibody attached to the antigen on the well. After incubation the wells are washed to remove unbound conjugate. A substrate solution is added to each well. If enzyme is present. the substrate will undergo a color change. After an incubation period the reaction is stopped and the color intensity is measured photometrically, producing and indirect measurement of specific antibody in the patient specimen.
III. Predicate Device
The Borrelia burgdorferi IgG/IgM ELISA test is substantially equivalent to BioWhittaker's Lyme STAT test. Equivalence is demonstrated by the following comparative results:
Performance Characteristics
The CDC Lyme Disease Serum Panel Stratified by Time After Onset
The following information is from a serum panel obtained from the CDC and tested by Trinity Biotech. The results are presented as a means to convey further information on the performance of this assay with a masked, characterized serum panel. This does not imply an endorsement of the assay by the CDC.
{1}------------------------------------------------
| Time From Onset | positive | equivocal | negative | Total | % Agreementwith ClinicalDiagnosis |
|---|---|---|---|---|---|
| normals | 0 | 0 | 5 | 5 | 100% |
| < 1 month | 2 | 0 | 3 | 5 | 40.0% |
| 1-2 months | 6 | 2 | 2 | 10 | 80.0% |
| 3-12 months | 9 | 3 | 7 | 19 | 63.3% |
| > 1yr | 8 | 0 | 0 | 8 | 100.0% |
| Total | 25 | 5 | 17 | 47 |
Table 1 Trinity Biotech B. burgdorferi IgG/IgM ELISA Results
Because the equivocals would have been tested by immunoblotting in a 2-step test system, they were considered 1-step positive for purposes of calculating % agreement. The Trinity Bitoech Borrelia burgdorferi IgG/IgM ELISA demonstrated 71% (30/42) agreement with clinical diagnosis of Lyme disease.
Study 2
One hundred seventy-six fresh sera from patients of various ages and genders that were submitted to a large clinical lab for B. burgdorferi antibody testing were tested on the Trinity Biotech B. burgdorferi IgG/IgM ELISA and BioWhittaker Lyme Stat. Any serum found positive or equivocal was tested by Mardx Diagnostics Western Blot on both IgG and IgM. The results are illustrated in Table 2.
Table 2
Western-blot
| TrinityB. burgdorferi IgG/IgM | + | 6 | - | 3 |
|---|---|---|---|---|
| eq | 1 | 6 | ||
| Lyme Stat | + | 5 | - | 3 |
| eq | 0 | 5 |
| Type of Result (95%CI) | Trinity (95%CI) | Lyme Stat (95%CI) |
|---|---|---|
| 1-step (ELISA) Pos. or Eq. | 9.1% (4.8% - 13.4%)(16/176) | 7.4% (3.4% - 11.3%)(13/176) |
| 1-step Pos. or Eq. &2-step (WB) Pos. | 4% (1.0% - 6.9%)(7/176) | 2.8% (0.3% - 5.3%)(5/176) |
| 2-step Pos. among65.4%) | 44% (18.9% - 68.6%) | 39% (11.5% - ) |
| 1-step Pos. or Eq. | (7/16) | (5/13) |
CI = Confidence Interval
{2}------------------------------------------------
Precision
Seven sera were assayed ten times each on three different plates at three different sites. An additional three sera were assayed ten times each on three different plates at two different sites. The intersite precision is shown in Table 3. With appropriate technique the user should obtain precision of <15% CV.
Table 3 Trinity Biotech Borrelia burgdorferi IgG/IgM ELISA Inter-Assay Precision Between Sites
| Inter-Assay (n=90) | |||||
|---|---|---|---|---|---|
| Serum # | X | SD | CV | n | |
| 1 | 1.18 | 0.113 | 9.58% | 90 | |
| 2 | 2.26 | 0.226 | 10.02% | 90 | |
| 3 | 3.85 | 0.278 | 7.21% | 90 | |
| 4 | 5.36 | 0.402 | 7.50% | 90 | |
| 5 | 2.04 | 0.186 | 9.11% | 90 | |
| 6 | 0.33 | 0.132 | 40.57% | 90 | |
| 7 | 0.34 | 0.234 | 68.93% | 90 | |
| 8 | 1.47 | 0.152 | 10.34% | 60 | |
| 9 | 1.47 | 0.104 | 7.10% | 60 | |
| 10 | 1.65 | 0.131 | 7.95% | 60 | |
| HPC | 5.31 | 0.314 | 5.91% | 15 | |
| LPC | 2.70 | 0.107 | 3.96% | 15 | |
| NC | 0.20 | 0.043 | 21.97% | 15 | |
| CAL | 3.34 | 0.103 | 3.08% | 45 |
A total of 810 determinations were made at the three sites. In all 810 determinations there was
not one case of a positive result for a negative serum or a negative result for a positive serum.
X=Mean ISR
SD=Standard Deviation
CV=Coefficient of Variation=SD/X x 100
The methods in NCCLS EP5 were utilized for precision parameters.
{3}------------------------------------------------
Cross-Reactivity
The following potentially cross-reactive sera were run on the Trinity Biotech Borrelia burgdorferi IgG/IgM ELISA assay to assess cross-reactivity with the assay: lipemic, bilirubinemic, RPR+, dsDNA+, RF+, EBV+, CMV+, RMS+, elevated ESR, and CRP. The data in Table 4 illustrate the amount of reactivity with the sera.
Table 4 Cross-Reactivity
| Laboratory result (Titer) positives | # of samples | # of |
|---|---|---|
| Lipemic (+ + +) | 5 | 0 |
| Bilirubinemic (1.9-16.9) | 5 | 1 |
| RPR + (1:2-1:64) | 10 | 0 |
| Rheumatoid Factor + (1:40-1:320) | 3 | 0 |
| Epstein Barr Virus Antibody + (1:40-1:2560) | 7 | 0 |
| Cytomegalovirus Antibody + (O.D. 0.718-2.308) | 6 | 1 |
| Rocky Mt Spotted Fever Antibody + (1:256-1:16,384) | 4 | 0 |
| CRP + (2.79-8.61 mg/dl) | 5 | 0 |
| Elevated ESR (40-115) | 10 | 0 |
| dsDNA + (52.3-1072 IU) | 16 | 0 |
{4}------------------------------------------------
Image /page/4/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo consists of a circular border with the text "DEPARTMENT OF HEALTH & HUMAN SERVICES • USA" arranged around the top half of the circle. Inside the circle is a stylized symbol that resembles three abstract human profiles facing right, with flowing lines suggesting movement or connection.
Food and Drug Administration 2098 Gaither Road Rockville MD 20850
NOV 26 2003
Ms. Bonnie B. DeJoy Director, Quality Systems Trinity Biotech USA P.O. Box 1059 Jamestown, NY 14702-1059
Re: K033083
Trade/Device Name: Captia Borrelia burgdorferi IgG/IgM ELISA Regulation Number: 21 CFR 866.3830 Regulation Name: Treponema pallidum treponemal test reagents Regulatory Class: Class II Product Code: LSR Dated: September 17, 2003 Received: September 29, 2003
Dear Ms. DeJoy:
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 Title 21, Code of Federal Regulations (CFR), Parts 800 to 895. 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 Parts 801 and 809); and good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820).
{5}------------------------------------------------
Page 2 -
This letter will allow you to begin marketing your device as described in your Section 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 information about the application of labeling requirements to your device, or questions on the promotion and advertising of your device, please contact the Office of In Vitro Diagnostic Device Evaluation and Safety at (301) 594-3084. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21CFR Part 807.97). You may obtain other general information on your responsibilities under the Act 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 Putman
Steven I. Gutman, M.D., M.B.A. Director Office of In Vitro Diagnostic Device Evaluation and Safety Center for Devices and Radiological Health
Enclosure
{6}------------------------------------------------
Page 1 of 1
Over-The-Counter Use
510(k) Number: K033083
Device Name: Trinity Biotech Captia™ Borrelia burgdorferi IgG/IgM ELISA
Indications For Use: The Trinity Biotech Captia™ Borrelia burgdorferi IgG/IgM ELISA kit is an Enzyme-Linked Immunosorbent Assay (ELISA) for the qualitative presumptive detection of total (IgG/IgM) antibodies to Borrelia burgdorferi in human serum. This ELISA should only be used for patients with signs and symptoms that are consistent with Lyme disease. Equivocal or positive results must be supplemented by testing with a standardized Western blot procedure. Positive supplemental results are supportive evidence of exposure to B. burgdorferi and can be used to support a clinical diagnosis of Lyme disease.
PLEASE DO NOT WRITE BELOW THIS LINE – CONTINUE ON ANQTHER PAGE IF NEEDED
Concurrence of CDRH, Office of Device Evaluation (ODE)
Prescription Use (Per 21 XFR 801.109) OR
(Optional Format 1-2-96)
Division Sign-Off for fMP
Office of In Vitro Diagnostic Device Evaluation and Safety
510(k) K033083
§ 866.3830
Treponema pallidum treponemal test reagents.(a)
Identification. Treponema pallidum treponemal test reagents are devices that consist of the antigens, antisera and all control reagents (standardized reagents with which test results are compared) which are derived from treponemal sources and that are used in the fluorescent treponemal antibody absorption test (FTA-ABS), theTreponema pallidum immobilization test (T.P.I.), and other treponemal tests used to identify antibodies toTreponema pallidum directly from infecting treponemal organisms in serum. The identification aids in the diagnosis of syphilis caused by bacteria belonging to the genusTreponema and provides epidemiological information on syphilis.(b)
Classification. Class II (performance standards).