(277 days)
The B.R.A.H.M.S.PCT LIA is an immunoluminometric assay (ILMA) used to determine the concentration of PCT (procalcitonin) in human serum and plasma.
The B.R.A.H.M.S PCT LIA is intended for use in conjunction with other laboratory findings and clinical assessments to aid in the risk assessment of critically ill patients on their first day of ICU admission for progression to severe sepsis and septic shock.
B-R A-H-S PCT LIA is an immunoluminometric assay (ILMA) used to determine the concentration of Procalcitonin (PCT) in human serum and plasma. Two antigen-specific monoclonal antibodies that bind PCT (the antigen) at two different binding sites (the calcitonin and katacalcin segments) are added in excess. One of these antibodies is luminescence labeled (the tracer), and the other is fixed to the inner walls of the tube (coated tube system). During the course of incubation, both antibodies react with PCT molecules in the sample to form "sandwich complexes". As result the luminescence labeled antibody is bound to the inner surface of the tube. Once the reaction is completed, the excess tracer is completely removed from the tube and discarded. Then, the amount of residual tracer on the test-tube wall is quantified by measuring the luminescence signal using a suitable luminometer and the B·R·A·H·M·S Basiskit LIA reagents. The intensity of the luminescence signal (RLU) is directly proportional to the PCT concentration in the sample. After a standard curve has been established using standards with known antigen concentrations (calibrated against recombinant intact human PCT), the unknown PCT concentrations in patient serum or plasma samples can then be quantitated by comparison of test values with the curve.
Here's a breakdown of the acceptance criteria and the study details for the B·R·A·H·M·S PCT LIA device, based on the provided 510(k) summary:
1. Table of Acceptance Criteria and Reported Device Performance
The document does not explicitly state "acceptance criteria" in a codified format with target values. Instead, it presents performance characteristics and clinical study results that demonstrate the device's utility for its intended use. I will present the performance characteristics provided as "reported device performance."
| Performance Characteristic | Reported Device Performance |
|---|---|
| Analytical Sensitivity | 0.1 ng/ml |
| Functional Assay Sensitivity (FAS) | 0.3 ng/ml |
| Total Precision (%CV) | 5.3 - 16.6 % CV |
| Within Run Precision (%CV) | 2.4 - 10 % CV |
| High Dose Hook Effect | Does not have an effect on patient assignment to reference ranges for PCT concentrations up to 4000 ng/ml. (If a PCT result above the highest standard is obtained, samples should be diluted and re-run.) |
| Interference | No interference from tested substances at specified concentrations (Bilirubin, Triglyceride, Hemoglobin, Protein (Albumin), Imipenem, Cefotaxim, Vancomycin, Dopamine, Noradrenaline, Dobutamine, Heparin, Furosemide, Calcitonin, Katacalcin, a-CGRP, β-CGRP, Calcitonin Salmon, Calcitonin Eel). |
| Clinical Interpretation (PCT > 2.0 ng/ml) | Represents a high risk for progression to severe sepsis and/or septic shock on the first day of ICU admission. |
| Clinical Interpretation (PCT < 0.5 ng/ml) | Represents a low risk for progression to severe sepsis and/or septic shock on the first day of ICU admission. (Does not exclude infection, especially localized or very early infections). |
| Clinical Interpretation (PCT 0.5-2.0 ng/ml) | Should be reviewed carefully considering clinical background. |
| Expected Values | In normal subjects, PCT concentrations are < 0.3 ng/ml (143 out of 144 healthy subjects had values < 0.3 ng/ml). |
2. Sample Size for the Test Set and Data Provenance
The "test set" in this context refers to the clinical study populations.
- Study 1:
- Sample Size: 101 consecutive critically ill patients.
- Data Provenance: Medical ICU in Switzerland. Retrospective or prospective is not explicitly stated in the summary itself, but the reference "Müller B. et al., Crit. Care Med. 2000; 28(4): 977-983" suggests it's a published, likely prospective, clinical study. The summary explicitly states "controlled prospective studies."
- Study 2:
- Sample Size: 78 consecutive critically ill patients.
- Data Provenance: Medical and surgical ICU in Switzerland. Prospective.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications
The document does not provide details on the number or qualifications of experts used to establish the "ground truth" for the clinical classifications (SIRS/Sepsis, Severe Sepsis, Septic Shock). The classification of patients into these categories would typically be based on established clinical criteria and diagnosis by attending physicians or critical care specialists. The referenced studies (Müller et al. and Harbarth et al.) would have detailed their methodology for patient classification.
4. Adjudication Method for the Test Set
The document does not describe a formal "adjudication method" for the clinical classifications. Patient classification into SIRS/Sepsis, Severe Sepsis, or Septic Shock was presumably done according to standard clinical diagnostic criteria at the time of the studies, likely by the clinicians managing the patients.
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done
No. This was not an MRMC comparative effectiveness study. This device is an in vitro diagnostic assay that provides a quantitative measurement (PCT concentration). The studies evaluated the diagnostic utility of this quantitative measurement in aiding risk assessment, not the performance improvement of human readers with or without AI assistance.
6. If a Standalone (i.e. algorithm only without human-in-the-loop performance) was done
Yes, in essence. The B·R·A·H·M·S PCT LIA is a standalone diagnostic assay. Its performance output is the PCT concentration, which is then interpreted by clinicians based on established thresholds and along with other clinical findings. The studies presented demonstrate the performance of the assay results in correlation with clinical outcomes (progression to severe sepsis/septic shock).
7. The Type of Ground Truth Used
The ground truth used for the clinical studies was clinical diagnosis and patient outcomes as defined by:
- SIRS (Systemic Inflammatory Response Syndrome), Sepsis, Severe Sepsis, and Septic Shock based on established clinical criteria at the time of the studies.
- Progression to severe sepsis and septic shock as observed in the critically ill patient populations.
8. The Sample Size for the Training Set
The document does not specify a separate "training set" for the clinical performance evaluation. The two studies (Study 1 with 101 patients and Study 2 with 78 patients) are presented as the clinical validation for the device's intended use.
For the assay's technical performance (e.g., sensitivity, precision, interference), these types of studies typically involve a series of laboratory experiments using controlled samples (e.g., spiked samples, known concentrations), rather than a "training set" in the machine learning sense. The "standards" (S1-S6) and "controls" (K1, K2) mentioned in the reagents section are used for calibrating and quality control of the assay itself.
9. How the Ground Truth for the Training Set was Established
As there is no distinct "training set" identified for clinical performance in the machine learning sense, this question is not fully applicable. For the technical performance aspects (e.g., calibration, linearity, precision), the ground truth is established through:
- Known concentrations of PCT (recombinant PCT used for standards S1-S6).
- Controlled spiking of interfering substances at defined concentrations.
- NCCLS testing guidelines for analytical and functional sensitivity, and precision, which involve standardized procedures and reference materials.
{0}------------------------------------------------
510(k) Premarket Notification
Page 1 of 7
510(K) SUMMARY OF SAFETY AND EFFECTIVENESS
General Information
| Submitted by: | B·R·A·H·M·S AktiengesellschaftNeuendorfstrasse 25D-16761 Hennigsdorf near BerlinGermany |
|---|---|
| Phone: +49 (0) 3302/883 0 | |
| Fax: +49 (0) 3302/883 100 | |
| Contact Person: | Jonas Leichtner |
| B·R·A·H·M·S Diagnostica, LLC | |
| 6353 Genoa Road | |
| Tracys Landing, MD 20779 USA | |
| Phone: (410) 286 0067 | |
| Fax: (410) 286 0068 | |
| Email: j.leichtner@brahms.de | |
| Date Prepared: | December 22, 2004 |
Device Name
| Trade Name: | B·R·A·H·M·S PCT LIA |
|---|---|
| Common Name: | Endotoxin Activity Assay |
| Classification Name: | Assay, Endotoxin Activity, Chemiluminescent |
Predicate Device
| Manufacturer | Product Name | 510(k) No. |
|---|---|---|
| Spectral Diagnostics, Inc. | Endotoxin Activity Assay (Eaa)Device | K021885 |
Device Description
B-R A-H-S PCT LIA is an immunoluminometric assay (ILMA) used to determine the concentration of Procalcitonin (PCT) in human serum and plasma. Two antigen-specific monoclonal antibodies that bind PCT (the antigen) at two different binding sites (the calcitonin and katacalcin segments) are added in excess. One of these antibodies is luminescence labeled (the tracer), and the other is fixed to the inner walls of the tube (coated tube system).
{1}------------------------------------------------
During the course of incubation, both antibodies react with PCT molecules in the sample to form "sandwich complexes". As result the luminescence labeled antibody is bound to the inner surface of the tube. Once the reaction is completed, the excess tracer is completely removed from the tube and discarded.
Then, the amount of residual tracer on the test-tube wall is quantified by measuring the luminescence signal using a suitable luminometer and the B·R·A·H·M·S Basiskit LIA reagents. The intensity of the luminescence signal (RLU) is directly proportional to the PCT concentration in the sample. After a standard curve has been established using standards with known antigen concentrations (calibrated against recombinant intact human PCT), the unknown PCT concentrations in patient serum or plasma samples can then be quantitated by comparison of test values with the curve.
| Reagent | Quantity for 100 det. | Contents |
|---|---|---|
| A | 1 vial lyophilized | Tracer, luminescence labeled (acridinium derivate)anti-PCT antibody (monoclonal, mouse), blue coloredsolution, 29 ml after reconstitution with buffer B. |
| B | 1 x 29 ml vial | Buffer, for reconstituting tracer A, ready for use. |
| C | 2 x 50 tubes | Coated tubes (test tubes), coated with anti-PCTantibody (monoclonal, mouse), ready for use. |
| G | 1 x 4 ml vial | Zero serum (human serum), for reconstituting thestandards resp. calibrators and controls, ready for use. |
| W | 2 x 11 ml vials | B·R·A·H·M·S Washing solution universal, concentrate,11 ml. |
| S1, S2/C1,S3, S4/C2,S5, S6 | 6 vials lyophilized | PCT standards (recombinant), reconstitute each with0.25 ml zero serum G before use. Concentrationranges: 0.08 (def.); 0.3-0.7; 1.5-2.5; 16-24; 160-240; 400 - 600 ng/ml. Precise concentrations seeleaflet enclosed. |
| K1, K2 | 2 vials lyophilized | PCT controls 1 and 2, reconstitute each with 0.25 mlzero serum G before use. Concentrations see leafletenclosed. |
The contents of the B.R.A.H.M.S.PCT LIA kit are:
Intended Use
The B.R.A.H.M.S PCT LIA is an immunoluminometric assay (ILMA) used to determine the concentration of PCT (procalcitonin) in human serum and plasma.
The B.R.A.H.M.S PCT LIA is intended for use in conjunction with other laboratory findings and clinical assessments to aid in the risk assessment of critically ill patients on their first day of ICU admission for progression to severe sepsis and septic shock.
{2}------------------------------------------------
Technological Comparison
The B.R.A.H.M.S PCT LIA immunoassay kit is similar to the Spectral Diagnostics Endotoxin Activity Assay (K021885) in the indications for use regarding risk assessment of patients for progression to severe sepsis in conjunction with other clinical information. The B R A H M S PCT LIA test differs from the Spectral Diagnostics Endotoxin Activity Assay in assay principle, using solid phase, in performance and result in the B-R-A-H-M-S PCT LIA assay, two antigen-specific monoclonal antibodies bind PCT (the antigen) at two different binding sites (the calcitonin and katacalcin segments). The intensity of the luminescence signal (RLU) is directly proportional to the PCT concentration in the sample. The Spectral Diagnostics Endotoxin Activity Assay measures the endotoxin activity in whole blood by the priming of host neutrophil respiratory burst activity via complement opsonized LPS-IgM immune complexes. The luminol reaction in the presence of immune complexes emits light energy. This light energy is measured and recorded by a luminometer. The Relative Light Units (RLU) measured by the instrument are converted by calculation into an Endotoxin Activity (EA) value which is reported as a percentage proportion of the total possible activity (0-1.0).
Performance Summary
Precision and Reproducibility
Based on NCCLS testing, the analytical sensitivity was determined to be 0.1 ng/ml and the functional assay sensitivity (FAS) was determined to be 0.3 ng/ml. In addition, the total precision ranges from 5.3 - 16.6 % CV and the within run precision ranges from 2.4 - 10 % CV.
High Dose Hook Effect
A High Dose Hook Effect occurs in immunometrical assay systems and yields erroneously low PCT results in cases of very high PCT concentrations (beyond 900 ng/ml after calibration).
Therefore, if a PCT result above the highest standard is obtained, the samples should be diluted with the dilution serum (Zero serum) contained in the assay kit and the test be re-run in order to obtain the correct PCT concentration. should PCT concentrations up to 4000 ng/ml do not have an effect on the assignment of the patient to the reference ranges described above.
{3}------------------------------------------------
Interference and Cross Reactivity
Based on NCCLS testing, the following substances were evaluated in the B·R·A·H·M·S PCT LIA at the concentrations listed and were found not to affect test performance.
| Interfering Substance | Non-InterferingConcentration |
|---|---|
| Bilirubin (conjugated) | 40 mg/dl |
| Triglyceride | 634 mg/dl |
| Hemoglobin | 500 mg/dl |
| Protein (Albumin) | 1 g/dl |
| Imipenem | 1.18 mg/ml |
| Cefotaxim | 90 mg/dl |
| Vancomycin | 3.5 mg/ml |
| Dopamine | 13 mg/dl |
| Noradrenaline | 2 µg/ml |
| Dobutamine | 11.2 µg/ml |
| Heparin | 8000 U/l |
| Furosemide | 2 mg/dl |
| Calcitonin | 8 ng/ml |
| Katacalcin | 30 ng/ml |
| a-CGRP* | 30 ng/ml |
| β-CGRP* | 30 ng/ml |
| Calcitonin Salmon | 30 µg/ml |
| Calcitonin Eel | 30 µg/ml |
*Calcitonin Gene Related Peptide
{4}------------------------------------------------
Method Comparison Summary
The clinical data for the B·R·A·H·M·S PCT LIA were obtained in two independent, controlled prospective studies performed in the ICUs of academic hospital settings
The data from the two studies is summarized in the following graph and tables. The 2x2 tables below show the PCT results for SIRS and Sepsis compared to Severe Sepsis and Septic Shock on the first day of ICU admission.
-
Study 1: Calcitonin precursors are reliable markers of sepsis in a medical intensive care unit Müller B. et al., Crit. Care Med. 2000; 28(4): 977-983.
101 consecutive critically ill patients of representative population of Patients: unselected, well-defined patients in a medical ICU in the Switzerland. The median age of the study population was 59 years (age range, 23-86 years). There were 55 men and 46 women in this study. -
Study 2: Diagnostic Value of Procalcitonin, Interleukin-6 and Interleukin-8 in Critically III Patients admitted with suspected Sepsis Harbarth S. et al., Am. J. Resp. Crit. Care Med. 2001; 164: 396-402.
-
78 consecutive critically ill patients newly admitted to a medical and surgical Patients: ICU in the Switzerland, including also neutropenic and immunosuppressed patients, with suspected diagnosis of infection. Patients had to fulfill at least 2 criteria of SIRS. Source of infection was the respiratory tract, intra-abdominal space and bloodstream infection. The mean ages were as follows: SIRS, 51 ± 18 years; sepsis, 51 ± 21 years; severe sepsis, 59 ± 18 years; and septic shock, 54 ± 15 years. There were 57 men and 21 women in this study.
| PCT ResultStudy 1 | No infection orSIRS/Sepsis | Severe Shock/Septic Shock | Totals |
|---|---|---|---|
| PCT < 0.5 | 36 | 0 | 36 |
| PCT > 0.5 | 34 | 31 | 65 |
| Totals | 70 | 31 | 101 |
| PCT ResultStudy 2 | SIRS/Sepsis | Severe Shock/Septic Shock | Totals |
| PCT < 0.5 | 8 | 0 | 8 |
| PCT > 0.5 | 24 | 46 | 70 |
| Totals | 32 | 46 | 78 |
PCT by no infection or SIRS, Sepsis versus Severe Sepsis or Septic Shock Cut Off 0.5 ng/ml
{5}------------------------------------------------
| PCT ResultStudy 1 | No infection orSIRS/Sepsis | Severe Shock/Septic Shock | Totals |
|---|---|---|---|
| PCT < 2.0 | 60 | 0 | 60 |
| PCT > 2.0 | 10 | 31 | 41 |
| Totals | 70 | 31 | 101 |
| PCT ResultStudy 2 | SIRS/Sepsis | Severe Shock/Septic Shock | Totals |
| PCT < 2.0 | 19 | 1 | 20 |
| PCT > 2.0 | 13 | 45 | 58 |
| Totals | 32 | 46 | 78 |
PCT by no infection or SIRS, Sepsis versus Severe Sepsis or Septic Shock Cut Off 2.0 ng/ml
The 4 box and whisker diagrams below summarize the individual PCT results of the 4 subgroups of patients on the first day of ICU admission.
Image /page/5/Figure/6 description: This image is a box plot comparing PCT levels in different disease conditions. The y-axis represents PCT levels in ng/ml on a logarithmic scale, ranging from 0.01 to 500. The x-axis shows the disease conditions: no infection or SIRS (n=66), Sepsis (n=36), Severe Sepsis (n=36), and Septic Shock (n=41). The plot shows an increase in PCT levels with increasing severity of the disease condition.
Summary of 2 studies: PCT by disease condition on the 1st day of admission
{6}------------------------------------------------
Interpretation of Results
The data from the two studies supports the following interpretative risk assessment criteria:
PCT > 2 ng/ml
PCT levels above 2.0 ng/ml on the first day of ICU admission represent a high risk for progression to severe sepsis and/or septic shock.
PCT < 0.5 ng/ml
PCT levels below 0.5 ng/ml on the first day of ICU admission represent a low risk for progression to severe sepsis and/or septic shock.
PCT levels below 0.5 ng/ml do not exclude an infection, because localized infections (without systemic signs) may also be associated with such low levels. If the PCT measurement is done very early after the systemic infection process has started (usually < 6 hours), these values may still be low.
As various non-infectious conditions are known to induce PCT as well, PCT levels between 0.5 ng/ml and 2.0 ng/ml should be reviewed carefully to take into account the specific clinical background and condition(s) of the individual patient.
Expected Values
In normal subjects, PCT concentrations are < 0.3 ng/ml, thus below the detection limit of the assay. In a population of 144 healthy subjects 143 had a PCT value < 0.3 ng/ml.
Specimen Collection and Handling
Serum or plasma may be used for the B·R·A·M·S PCT LIA. However, only one matrix, i.e., the same material (either serum or plasma), should be used throughout the patient's clinical course.
NCCLS guidelines should be followed for collecting, transporting, and processing patient samples. A slight difference in results was noted between the use of glass and plastic collecting tubes. For plastic tubes, a slight increase is noted if the sample remains in the collecting tube for more than 24 hours, if the filling volume is higher, or if plasma is used. B:R:A:H:M:S recommends the use of one type of collecting tube, i.e., either glass or plastic, throughout the patient's clinical course.
Samples that are not used in an assay within 24 hours following the blood draw must be frozen and stored at -20 ℃. Samples may be frozen and thawed three times.
Conclusions
The B·R·A·H·M·S PCT LIA is substantially equivalent to the legally marketed Endotoxin Activity Assays in intended use.
{7}------------------------------------------------
Image /page/7/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo features a stylized eagle with three stripes forming its body and wings. The eagle is positioned to the right of a circular seal that contains the text "DEPARTMENT OF HEALTH & HUMAN SERVICES • USA" arranged around the perimeter.
Food and Drug Administration 2098 Gaither Road Rockville MD 20850
JAN - 7 2005
Mr. Jonas Leichtner Project Manager B.R.A.H.M.S Diagnostica, LLC 6353 Genoa Road Tracys Landing, MD 20779
K040887 Re:
Trade/Device Name: B.R.A.H.M.S PCT LIA Regulation Number: 21 CFR 866.3610 Regulation Name: Endotoxin Assay Regulatory Class: Class II Product Code: NTM Dated: December 1, 2004 Received: December 1, 2004
Dear Mr. Leichtner:
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).
{8}------------------------------------------------
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 (240)276-0484. 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/industry/support/index.html
Sincerely yours.
Sale, a For
Sally A. Hojvat, M.Sc., Ph.D. Director Division of Microbiology Devices Office of In Vitro Diagnostic Device Evaluation and Safety Center for Devices and Radiological Health
Enclosure
{9}------------------------------------------------
INDICATIONS FOR USE
K040887 510(k) Number (if known):
B·R·A·H·M·S PCT LIA Device Name:
B.R.A.H.M.S Aktiengesellschaft Sponsor Name:
Indications for Use:
The B.R.A.H.M.S.PCT LIA is an immunoluminometric assay (ILMA) used to determine the concentration of PCT (procalcitonin) in human serum and plasma.
The B.R.A.H.M.S PCT LIA is intended for use in conjunction with other laboratory findings and clinical assessments to aid in the risk assessment of critically ill patients on their first day of ICU admission for progression to severe sepsis and septic shock.
Prescription Use X (21 CFR 801 Subpart D)
And/Or
Over-The-Counter Use | (21 CFR 807 Subpart C)
Do Not Write Below This Line – Continue on Another Page if Needed
Concurrence of CDRH, Office of Device Evaluation (ODE)
Luddi V. Poole
ision Sign-Off
Office of In Vitro Diagnostic Device Evaluation and Safety
510(k) K040887
§ 866.3210 Endotoxin assay.
(a)
Identification. An endotoxin assay is a device that uses serological techniques in whole blood. The device is intended for use in conjunction with other laboratory findings and clinical assessment of the patient to aid in the risk assessment of critically ill patients for progression to severe sepsis.(b)
Classification. Class II (special controls). The special control for this device is the FDA guidance entitled “Class II Special Controls Guidance Document: Endotoxin Assay.” See § 866.1(e) for the availability of this guidance document.