(160 days)
Immunoassay for the in vitro quantitative determination of PCT (procalcitonin) in human serum and plasma (K2 –EDTA, K3-EDTA and Li-Heparin).
The electrochemiluminescence immunoassay "ECLIA" is intended for use on Elecsys and cobas e immunoassay analyzers.
Used in conjunction with other laboratory findings and clinical assessments, Elecsys B R A - H M S PCT is intended for use as follows:
· 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,
· to determine the change in PCT level over time as an aid in assessing the cumulative 28-day risk of all-cause mortality for patients diagnosed with severe sepsis or septic shock in the ICU or when obtained in the emergency department or other medical wards prior to ICU admission,
· to aid in decision making on antibiotic therapy, for inpatients in the emergency department with suspected or confirmed lower respiratory tract infections (LRT) - defined as community-acquired pneumonia (CAP), acute bronchitis, and acute exacerbation of chronic obstructive pulmonary disease (AECOPD),
· to aid in decision making on antibiotic discontinuation for patients with suspected or confirmed sepsis.
The Elecsys BRAHMS PCT assay is a two-step sandwich immunoassay with streptavidin microparticles, biotinylated antibody and antibody labeled with ruthenium as well as an electrochemiluminescence detection system. Procalcitonin (PCT) in the sample reacts with these labeled antibodies to form a sandwich complex. This complex binds to streptavidin coated magnetic microparticles, which are magnetically captured onto an electrode. Application of voltage to the electrode induces chemiluminescence which is measured by a photomultiplier tube. Results are determined via a calibration curve which is instrument-specifically generated by 2-point calibration and a master curve provided via the reagent barcode. An optional Procalcitonin CalCheck product is also available.
The provided text describes the performance evaluation of the Elecsys BRAHMS PCT device. Here's a breakdown of the acceptance criteria and study details based on the information provided:
1. Table of Acceptance Criteria and Reported Device Performance
The document doesn't explicitly state "acceptance criteria" for all performance parameters in a singular table. However, it presents claims and then demonstrates performance against those claims, implying these are the acceptance criteria.
| Performance Characteristic | Acceptance Criteria (Implied from claims) | Reported Device Performance and Remarks |
|---|---|---|
| Precision | Not explicitly stated with numerical values, but implies acceptable within-run and intermediate precision. Expects reasonable %CV and % Total Error. | Repeatability (Within Run CV%): Ranges from 1.0% to 13.2% across different PCT concentrations. Intermediate Precision (Within Lab CV%): Ranges from 3.1% to 16.1% across different PCT concentrations. % Total Error: Ranges from 7.38% to 39.9% across different PCT concentrations. (Calculated using TE = 1.65 * CV + %bias, with %CV taken from intermediate precision). |
| Sample Matrix Comparison | Values obtained from different sample types (serum, Li-Heparin, K2-EDTA, K3-EDTA plasma) should be comparable. | Data evaluated using Passing/Bablok regression analysis; curves for method comparison are shown, but specific numeric agreement or non-inferiority limits are not explicitly stated in this section. |
| Endogenous Interferences | Recovery should be within ±15% of the initial value for PCT concentrations > 0.1 ng/mL, and within 0.015 ng/mL for concentrations < 0.1 ng/mL, at specified interferent levels. | Intralipid: 1500 mg/dL - met criteria. Biotin: 1200 ng/mL - met criteria. Bilirubin: 25 mg/dL - met criteria. Hemoglobin: 900 mg/dL - met criteria. Rheumatic Factor: 1500 IU/mL - met criteria. |
| Exogenous Interferences (Drugs) | Recovery should be within ±10% of the reference value at the tested concentrations. | 34 pharmaceutical compounds tested at specified concentrations (e.g., Acetylcysteine 150 mg/L, Ampicillin 75 mg/L, etc.) - all met criteria. |
| Analytical Specificity/Cross-reactivity | Recovery within ±15% of the initial value at PCT concentrations of ~0.5 ng/mL and ~2 ng/mL for specified cross-reactant concentrations. | Human katacalcin (30 ng/mL): Met criteria. Human calcitonin (10 ng/mL): Met criteria. Human alpha-CGRP (10000 ng/mL): Met criteria. Human beta-CGRP (10000 ng/mL): Met criteria. Calcitonin Salmon (30000 ng/mL): Met criteria. Calcitonin Eel (30000 ng/mL): Met criteria. |
| Reagent On-Board Stability | Reagent kits can be kept on board for up to 4 weeks (28 days), with re-calibration recommended every 7 days. Mean recovery values for each sample range should be acceptable (specific quantitative target not provided for recovery). | Demonstrated stability for up to 4 weeks (28 days) with re-calibration every 7 days, as assessed by mean recovery values across target decision levels and measuring range. |
| Calibration Stability | 8 weeks lot calibration stability when using the same reagent kit lot, with recovery compared to reference within acceptable limits (specific quantitative target not provided for recovery). | Demonstrated stability for 9 weeks using the calibration curve established on Day 0 for the same reagent kit lot, supporting the 8-week claim. Recovery for 14 human serum samples (across decision levels and measuring range) was acceptable. |
| LoQ (Limit of Quantitation) | LoQ claim of 0.06 ng/mL. It represents the lowest amount of analyte that can be quantified with an intermediate precision of no more than 20%. | Determined LoQ of 0.025 ng/mL using CLSI EP17-A2, which is better than the claimed 0.06 ng/mL. The sample with a mean of 0.025 ng/mL had an intermediate precision (CV%) of 18.0%, which is within the ≤ 20% specification. |
| Clinical Performance Evaluation (Method Comparison to Predicate) | > 96% total agreement between the Elecsys BRAHMS PCT and the predicate device at the medical decision points 0.1, 0.25, 0.5 and 2.0 ng/mL. Regression slopes within +/- 10% of identity in Passing-Bablok and Weighted Deming Analysis. | Total Agreement: 0.1 ng/mL: 98.4% 0.25 ng/mL: 98.6% 0.5 ng/mL: 99.2% 2.0 ng/mL: 99.0% All met the >96% criteria. Passing Bablok Slope: 0.990 (95% CI: 0.984; 0.994) – within +/- 10% of 1. Weighted Deming Slope: 0.969 (95% CI: 0.963; 0.975) – within +/- 10% of 1. Pearson Correlation Coefficient: 1.000 for both. |
2. Sample Size and Data Provenance for Test Set
- Precision: Seven (7) human serum samples and two (2) QC samples.
- Sample Matrix Comparison: A minimum of 40 serum/plasma pairs per sample material (serum, Li-Heparin plasma, K2-EDTA plasma, K3-EDTA plasma).
- Endogenous Interferences: Spiked serum pools.
- Exogenous Interferences (Drugs): Two human serum samples, spiked.
- Analytical Specificity/Cross-reactivity: Native human serum samples, spiked.
- Reagent On-Board Stability: Eight (8) human serum (HS) sample pools.
- Calibration Stability: Fourteen (14) human serum samples.
- LoQ: Seven native human serum (HS) samples. Total of 150 measuring points collected (7 samples measured in five-fold determination for each of 5 days).
- Clinical Performance Evaluation (Method Comparison to Predicate): 496 native human clinical samples.
- Data Provenance: The document states "human serum" and "human clinical samples" without specifying the country of origin. The assays are for "in vitro quantitative determination" using patient samples, implying retrospective collection for these performance studies.
3. Number of Experts and Qualifications for Ground Truth
This information is not provided in the document. The studies primarily involve analytical performance and method comparison against a predicate device and established laboratory guidelines rather than clinical interpretation by experts for ground truth establishment.
4. Adjudication Method for Test Set
This information is not applicable as the studies are analytical and method comparison, not involving expert adjudication of diagnostic outcomes or images.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
This information is not provided and is not applicable. This device is an in-vitro diagnostic (IVD) assay that quantitatively measures procalcitonin levels, not an AI-assisted diagnostic imaging device requiring human reader interaction.
6. Standalone (Algorithm Only Without Human-in-the-Loop Performance) Study
This is an IVD assay, meaning its performance is inherently standalone (algorithm only, or rather, assay-only). The results are quantitative measurements. Human interpretation comes after the device generates the PCT value, in conjunction with other clinical assessments, as indicated in the "Indications for Use." The data presented here (e.g., precision, interference, method comparison) reflects the standalone analytical performance of the assay.
7. Type of Ground Truth Used
- For precision, interference, stability, LoQ, and analytic specificity, the ground truth is based on known spiked concentrations or the reference value/measurement of the analyte in the samples.
- For the method comparison study, the "ground truth" for comparison is the results obtained from the legally marketed predicate device (Elecsys BRAHMS PCT cleared under K173927). This establishes substantial equivalence.
8. Sample Size for the Training Set
This information is not provided. The document describes performance evaluation (testing) of the device. It does not detail the development or training process for the assay's reagents or calibration, which would involve a "training set." For an immunoassay, the "training" equivalent would typically involve assay development and optimization using various known samples and controls, rather than a distinct "training set" as understood in machine learning. Calibration data also serves a role similar to training in defining the dose-response curve.
9. How the Ground Truth for the Training Set Was Established
This information is not provided as the document does not discuss a "training set" in the context of this IVD device. For an immunoassay, ground truth for development (e.g., calibrators) is typically established through careful gravimetric or volumetric preparations, reference methods, and standardization to an international reference material where available (as indicated by "This method has been standardized against the BRAHMS PCT LIA assay" and "Traceability/ Standardization").
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Build Correspondence
Image /page/0/Picture/2 description: The image contains the logo of the U.S. Food and Drug Administration (FDA). The logo consists of two parts: the Department of Health & Human Services logo on the left and the FDA acronym with the full name of the agency on the right. The FDA part of the logo is in blue, with the acronym in a square and the full name written out to the right of the square. The full name of the agency is "U.S. Food & Drug Administration".
March 9, 2020
Roche Diagnostics Wes Gerbig Regulatory Affairs Principal 9115 Hague Road Indianapolis, Indiana 46250
Re: K192815
Trade/Device Name: Elecsys BRAHMS PCT Regulation Number: 21 CFR 866.3215 Regulation Name: Device to detect and measure non-microbial analyte(s) in human clinical specimens to aid in assessment of patients with suspected sepsis Regulatory Class: Class II Product Code: PRI, PMT, NTM Dated: September 27, 2019 Received: October 1, 2019
Dear Wes Gerbig:
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. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database located at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. 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. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.
If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to 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
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requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR 803) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-products); good manufacturing practice requirements as set forth in the quality systems (OS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.
For comprehensive regulatory information about mediation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).
Sincerely,
Kristian Roth, Ph.D. Chief Bacterial Multiplex and Medical Counter Measures Branch Division of Microbiology OHT7: Office of In Vitro Diagnostics and Radiological Health Office of Product Evaluation and Ouality Center for Devices and Radiological Health
Enclosure
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Indications for Use
510(k) Number (if known) K192815
Device Name Elecsys BRAHMS PCT
Indications for Use (Describe) Elecsys BRAHMS PCT
Immunoassay for the in vitro quantitative determination of PCT (procalcitonin) in human serum and plasma (K2 –EDTA, K3-EDTA and Li-Heparin).
The electrochemiluminescence immunoassay "ECLIA" is intended for use on Elecsys and cobas e immunoassay analyzers.
Used in conjunction with other laboratory findings and clinical assessments, Elecsys B R A - H M S PCT is intended for use as follows:
· 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,
· to determine the change in PCT level over time as an aid in assessing the cumulative 28-day risk of all-cause mortality for patients diagnosed with severe sepsis or septic shock in the ICU or when obtained in the emergency department or other medical wards prior to ICU admission,
· to aid in decision making on antibiotic therapy, for inpatients in the emergency department with suspected or confirmed lower respiratory tract infections (LRT) - defined as community-acquired pneumonia (CAP), acute bronchitis, and acute exacerbation of chronic obstructive pulmonary disease (AECOPD),
· to aid in decision making on antibiotic discontinuation for patients with suspected or confirmed sepsis.
Type of Use (Select one or both, as applicable)
| ☑ Prescription Use (Part 21 CFR 801 Subpart D) |
|---|
| ☐ Over-The-Counter Use (21 CFR 801 Subpart C) |
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Elecsys BRAHMS PCT
510(k) Summary
This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of 21 CFR 807.92.
In accordance with 21 CFR 807.87, Roche Diagnostics hereby submits official notification as required by Section 510(k) of the Federal Food, Drug and Cosmetics Act of our intention to market the device described in this Premarket Notification 510(k).
The purpose of this Traditional 510(k) Premarket Notification is to obtain FDA review and clearance for the Elecsys BRAHMS PCT Test System.
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| Submitter Name | Roche Diagnostics |
|---|---|
| Address | 9115 Hague RoadP.O. Box 50416Indianapolis, IN 46250-0457 |
| Contact | Wes GerbigPhone: (317) 521-3743FAX: (317) 521-2324Email: wes.gerbig@roche.com |
| Secondary Contact NameTammy DeanPhone: 317-521-3978FAX: (317) 521-2324Email: tammy.dean@roche.com | |
| Date Prepared | September 30, 2019 |
| Proprietary Name | Elecsys BRAHMS PCT |
| Common Name | Procalcitonin |
| Classification Name | Device to detect and measure non-microbial analyte(s) in human clinicalspecimens to aid in assessment of patients with suspected sepsis |
| Product Codes,Regulation Numbers | PRI, PMT, NTM, 866.3215 |
| Predicate Devices | Elecsys BRAHMS PCT cleared under K173927. |
| Establishment Registration | For the Elecsys BRAHMS PCT Test System the establishment registrationnumber for Roche Diagnostics GmbH in Mannheim, Germany is 9610126, andfor Penzberg, Germany, 9610529. The establishment registration number forRoche Diagnostics in the United States is 1823260. |
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1. Device Description
The Elecsys BRAHMS PCT assay is a two-step sandwich immunoassay with streptavidin microparticles, biotinylated antibody and antibody labeled with ruthenium as well as an electrochemiluminescence detection system. Procalcitonin (PCT) in the sample reacts with these labeled antibodies to form a sandwich complex. This complex binds to streptavidin coated magnetic microparticles, which are magnetically captured onto an electrode. Application of voltage to the electrode induces chemiluminescence which is measured by a photomultiplier tube. Results are determined via a calibration curve which is instrument-specifically generated by 2-point calibration and a master curve provided via the reagent barcode. An optional Procalcitonin CalCheck product is also available.
1.1. Reagents
The reagent working solutions include:
Rackpack (kit placed on analyzer)
- M: Streptavidin-coated microparticles,
- . R1: Anti-PCT-Ab~biotin
- . R2: Anti-PCT-Ab~Ru(bpy)32+
The following change is proposed to block the interference of biotin with the Elecsys BRAHMS PCT assay. Briefly, Roche is taking a one-step approach by adding an antibody to bind free biotin in the sample. For the neutralization of free biotin in serum and plasma, Roche developed an antibody which binds to free biotin. The antibodies are specific for free biotin and do not bind to, or interact with, the biotin-linker conjugates.
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2. INDICATIONS FOR USE
Immunoassay for the in vitro quantitative determination of PCT (procalcitonin) in human serum and plasma (K2 -EDTA, K3-EDTA and Li-Heparin).
The electrochemiluminescence immunoassay "ECLIA" is intended for use on cobas e immunoassay analyzers.
Used in conjunction with other laboratory findings and clinical assessments, Elecsys BRAHMS PCT is intended for use as follows:
- 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,
- to determine the change in PCT level over time as an aid in assessing the cumulative 28day risk of all-cause mortality for patients diagnosed with severe sepsis or septic shock in the ICU or when obtained in the emergency department or other medical wards prior to ICU admission,
- to aid in decision making on antibiotic therapy, for inpatients or patients in the emergency department with suspected or confirmed lower respiratory tract infections (LRTI) - defined as community-acquired pneumonia (CAP), acute bronchitis, and acute exacerbation of chronic obstructive pulmonary disease (AECOPD),
- . to aid in decision making on antibiotic discontinuation for patients with suspected or confirmed sepsis.
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3. Technological Characteristics
| Table 1: | Assay Comparison | |
|---|---|---|
| ---------- | -- | ------------------ |
| Feature | Predicate Device: Elecsys BRAHMS PCT(K173927) | Candidate Device: Elecsys BRAHMSPCT with biotin update |
|---|---|---|
| Intended Use/Indications for Use | Immunoassay for the in vitro quantitativedetermination of PCT (procalcitonin) in humanserum and plasma (K2 –EDTA, K3-EDTA andLi-Heparin).The electrochemiluminescence immunoassay"ECLIA" is intended for use on Elecsys andcobas e immunoassay analyzers.Used in conjunction with other laboratoryfindings and clinical assessments, ElecsysBRAHMS PCT is intended for use as follows:● to aid in the risk assessment ofcritically ill patients on their first day ofICU admission for progression tosevere sepsis and septic shock,● to determine the change in PCT levelover time as an aid in assessing thecumulative 28-day risk of all-causemortality for patients diagnosed withsevere sepsis or septic shock in the ICUor when obtained in the emergencydepartment or other medical wardsprior to ICU admission,● to aid in decision making on antibiotictherapy, for inpatients or patients in theemergency department with suspectedor confirmed lower respiratory tractinfections (LRTI) - defined ascommunity-acquired pneumonia(CAP), acute bronchitis, and acuteexacerbation of chronic obstructivepulmonary disease (AECOPD),● to aid in decision making on antibioticdiscontinuation for patients withsuspected or confirmed sepsis. | Same with the exception ofintended analyzers, ElecsysBRAHMS PCT with biotin updateis only intended for use on cobas einnunoassay analyzers. |
| Assay Protocol | The Elecsys BRAHMS PCT assay is a two-stepsandwich immunoassay with streptavidinmicroparticles and anelectrochemiluminescence detection system.The test system reagents contain a biotinylatedmonoclonal PCT-specific antibody and aruthenium labeled monoclonal PCT-specificantibody. | Same |
| Detection Protocol | Electrochemiluminescent immunoassay | Same |
| Applications | 18-minute application | Same |
| Instrument Platform | cobas e 411 analyzer | cobas e 601 analyzer |
| Sample Volume | 30 μL | Same |
| Sample Type | Human serum and plasma (Li-Heparin, K2/K3EDTA) | Same |
| Reagents | M: Streptavidin-coated microparticles:Steptavidin-coated microparticles; preservativeR1: Anti-PCT-Ab | M: Streptavidin-coated microparticles:Steptavidin-coated microparticles;preservativeR1: Anti-PCT-Ab |
| Calibrator | PCT Cal1 and PCT Cal2 | Same |
| Calibration Interval | Calibration must be performed once per reagentlot using PCT Cal1, PCT Cal2 and freshreagent (i.e. not more than 24 hours since thereagent kit was registered on the analyzer).Renewed calibration is recommended asfollows:• after 8 weeks when using the samereagent lot• after 7 days (when using the samereagent kit on the analyzer)• as required: e.g. quality control findingsoutside the specified limits | Same |
| Controls | PC PCT1 and PC PCT2 | Same |
| Traceability/ Standardization | This method has been standardized against theBRAHMS PCT LIA assay. | Same |
| Reagent Stability | Store at 2-8 °C. Do not freeze. Store theElecsys reagent kit upright in order to ensurecomplete availability of the microparticlesduring automatic mixing prior to use.Stability:● unopened at 2-8 ℃: up to the statedexpiration date● after opening at 2-8 ℃: 12 weeks● on the analyzers: 4 weeks | Same |
| Measuring Range | 0.02 - 100 ng/mL | Same |
| LoB | 0.015 ng/mL | Same |
| LoD | 0.02 ng/mL | Same |
| LoQ | 0.06 ng/mL | Same |
| Hook Effect | No hook effect up to 1000 ng/mL | Same |
| Biotin Limitations | Biotin interference can produce either falselyhigh or low results. Though the risk ofmisclassifying a test result due to biotininterference is lower than the risks fromaverage assay imprecision, biologicalvariability, or other known interference,patient biotin intake and the resulting % biasshould be taken into account when interpretingPCT assay values. (See Interference studybelow).Do not test samples from patients who haveindicated or whose clinical status or historywould indicate they are currently taking highdoses of biotin (> 10 mg per day). If biotininterference is suspected, follow yourestablished internal procedures to investigatethe interference per CLIA and GLPrecommendations.Serial draws are indicated for procalcitoninmeasurements. Biotin will metabolize andclear, serum levels will reduce over time. | Specimens with biotin concentrationsup to 1200 ng/mL did not demonstratebias in measured PCT values.Specimens with biotin concentrations >1200 ng/mL and ≤ 2600 ng/mLdemonstrated ≤ 10 % negative bias inmeasured PCT levels. Pharmacokineticstudies have shown that serumconcentrations of biotin can reach up to355 ng/mL within the first hour afterbiotin ingestion for subjects consumingsupplements of 20 mg biotin per dayand up to 1160 ng/mL for subjects aftera single dose of 300 mg biotin. |
| Method Comparison | 474 samples were run on the cobas e 601 and the predicate device (Elecsys BRAHMSPCT K173927)Passing BablokSlope: 0.990 (95% CI: 0.984; 0.994)Intercept: -0.003 ng/mL (95% CI: -0.004; -0.001)Pearson's r Coefficient: 1.000 |
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4. PERFORMANCE EVALUATION
The following data was requested by the FDA in Q171237/S0001 to support the updated
Indications for Use statement and is listed below:
- . Precision according to CLSI EP5-A3
- Serum/Plasma Comparison
- Interferences – Endogenous
- Interferences Exogenous (Drugs) ●
- Analytical Specificity/Cross-reactivity ●
- . Calibration Lot and On-board Stability
- Analytical Sensitivity: LoO according to CLSI EP17-A2 ●
- Clinical Performance Evaluation Method Comparison to Predicate .
The remaining data required to support the updated Indications for Use was supplied in the previous submissions K160729 and K173927:
- . Analytical Sensitivity: LoB and LoD
- . Linearity according to CLSI EP6-A
- High Dose Hook Effect
- Human Anti-Mouse Antibodies (HAMA)
- . Sample Stability
4.1. Precision
The repeatability and intermediate precision of the Elecsys BRAHMS PCT assay was conducted using the cobas e 601 analyzer. Studies were performed in accordance with CLSI guideline EP5-
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A3, "Evaluation of Precision Performance of Quantitative Measurement Methods". One reagent lot was evaluated. The precision study was conducted using the study design of 21 days x 2 runs per day x 2 replicates per sample. One (1) instrument was used for the study and calibration was performed according to the Instructions for Use. Aliquots of seven (7) human serum samples and two (2) QC samples (PC PCT 1 and PC PCT 2) distributed over the measuring range were assayed in duplicate and randomized order on the cobas e 601 analyzer using one lot of reagent. Data is acceptable and is summarized below. An analysis was also performed to calculate % Total Error across the measuring range. The total error was calculated using the one sided Westgard-Model as:
TE = 1.65* CV + %bias
The %CV used corresponds to the intermediate precision.
| Sample | Mean(ng/mL) | Repeatability (CV%) | Intermediate Precision(CV%) | % Total Error | ||
|---|---|---|---|---|---|---|
| Within Run | Within Lab | |||||
| SD (ng/mL) | CV% | SD (ng/mL) | CV% | |||
| Control1 | 0.478 | 0.012 | 2.5 | 0.020 | 4.3 | 10.6 |
| Control2 | 10.0 | 0.119 | 1.2 | 0.306 | 3.1 | 7.44 |
| Sample1 | 0.045 | 0.006 | 13.2 | 0.007 | 16.1 | 39.9 |
| Sample2 | 0.112 | 0.007 | 6.3 | 0.010 | 8.6 | 21.3 |
| Sample3 | 0.249 | 0.008 | 3.0 | 0.011 | 4.3 | 10.4 |
| Sample4 | 0.495 | 0.013 | 2.7 | 0.021 | 4.2 | 10.3 |
| Sample5 | 1.71 | 0.031 | 1.8 | 0.058 | 3.4 | 8.09 |
| Sample6 | 31.4 | 0.326 | 1.0 | 0.985 | 3.1 | 7.38 |
| Sample7 | 93.0 | 1.52 | 1.6 | 3.40 | 3.7 | 8.71 |
Table 2: Summary of Precision Results – Elecsys BRAHMS PCT Repeatability and Intermediate Precision
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Sample Matrix Comparison 4.2.
The effect on quantitation of analyte in the presence of anticoagulants with the Elecsys BRAHMS PCT immunoassay was determined by comparing values obtained from samples (native human serum samples, single donors as well as pools) drawn into serum and Li-Heparin, K2-EDTA, K3-EDTA plasma tubes. A minimum of 40 serum/plasma pairs per sample material were tested in singleton with one reagent lot on one cobas e 601 analyzer. Data were evaluated using a regression analysis according to Passing/Bablok.
Endogenous Interferences 4.3.
The effect on quantitation of PCT in the presence of five endogenous interfering substances (Hemoglobin, Biotin, Intralipid, Bilirubin, and Rheumatoid Factor) was tested using one cobas e 601 analyzer. Spiked serum pools were used for testing. The substances were found not to affect test performance at clinically relevant concentrations. Recovery was within ± 15 % of the initial value for PCT concentrations > 0.1 ng/mL and within 0.015 ng/mL for concentrations below 0.1 ng/mL
| Potential Interferent | Claim |
|---|---|
| Intralipid | 1500 mg/dL |
| Biotin | 1200 ng/mL |
| Bilirubin | 25 mg/dL |
| Hemoglobin | 900 mg/dL |
| Rheumatic Factor | 1500 IU/mL |
Table 3: Potentially Interfering Endogenous Substances and Test Concentrations
4.4. Exogenous Interferences - Drugs
The effect on quantitation of analyte in the presence of drugs was determined by comparing values obtained from samples spiked with 34 pharmaceutical compounds into two human serum
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samples and tested on the cobas e 601 analyzer. The substances were found not to affect test
performance at the tested concentration. Recovery was within ± 10 % of the reference value.
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Table 4: Potentially Interfering Drugs and Test Concentrations
| Potential Interferent | Drug Level Tested (mg/L) |
|---|---|
| Acetylcysteine | 150 |
| Ampicillin | 75 |
| Ascorbic acid | 52.5 |
| Cyclosporine | 1.8 |
| Cefoxitin | 750 |
| Heparin | 3300 U/L |
| Levodopa | 7.5 |
| Methyldopa | 22.5 |
| Metronidazole | 123 |
| Phenylbutazone | 321 |
| Doxycycline | 18 |
| Acetylsalicylic acid | 30 |
| Rifampicin | 48 |
| Acetaminophen | 156 |
| Ibuprofen | 219 |
| Theophylline | 60 |
| Imipenem | 1180 |
| Cefotaxime | 900 |
| Vancomycin | 3500 |
| Dopamine | 130 |
| Noradrenaline | 2 |
| Dobutamine | 11.2 |
| Furosemide | 20 |
| Cromolyn | 24 |
| Alcohol | 4000 |
| Azithromycin | 11.5 |
| Cetirizine HCl | 3.6 |
| Dextromethorphan | 1.4 |
| Levofloxacin | 17.5 |
| Loratadine | 0.3 |
| Nicotine | 1 |
| Oxymetazoline HCl | 0.09 |
| Phenylephrine | 0.18 |
| Tiotropium | 0.0216 |
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Analytical Specificity/Cross-reactivity 4.5.
The specificity of the Elecsys® BRAHMS PCT was determined using native human serum samples spiked with potential cross-reactant compounds.
The samples were tested on a cobas e 601 Immunoassay Analyzer. Recovery within ± 15 % of initial value at PCT concentrations of ~0.5 ng/mL and ~2 ng/mL were verified for the following cross-reactant concentrations:
- 30 ng/mL human katacalcin
- 10 ng/mL human calcitonin
- 10000 ng/mL human alpha-CGRP
- 10000 ng/mL human beta-CGRP
- . 30000 ng/mL Calcitonin Salmon
- . 30000 ng/mL Calcitonin Eel
4.6. Reagent On-Board Stability
A fresh Elecsys BRAHMS PCT test kit was placed on the cobas e 601 analyzer and calibrated. Reference values for the samples tested were determined (day 0). After 8, 15, 22 and 29 days (1, 2, 3 and 4 weeks) the same samples were measured with the same reagent kit kept under onboard condition. Re-calibration was performed at every measuring time point.
Samples tested include eight (8) human serum (HS) sample pools. Each sample was tested in two-fold determination. Samples were targeted with values near medical decision levels of 0.1 ng/mL, 0.25 ng/mL, 0.5 ng/mL and 2.0 ng/mL as one sample range, along with sample ranges at low, medium and high PCT concentration ranges relative to the measuring range. Mean recovery values for each sample range were calculated. Elecsys BRAHMS PCT reagent kits can be kept on board of the instruments for up to 4 weeks (28 days). A new calibration of the kit kept
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on board is recommended every 7 days.
4.7. Calibration Stability
The Elecsys BRAHMS PCT assay was calibrated with a fresh reagent kit on Day 0 using one cobas e 601 analyzer. After 3, 6, and 9 weeks a new reagent kit of the same lot was used with recovery of samples being determined using the calibration curve established on Day 0 for that reagent kit lot. Forteen (14) human serum samples were tested in duplicate. Recovery compared to the reference value was calculated as absolute deviation in ng/mL or relative deviation in %. Samples were targeted with values near medical decision levels of 0.1 ng/mL, 0.25 ng/mL, 0.5 ng/mL and 2.0 ng/mL along with samples spread across the measuring range. Mean recovery values for each sample range were calculated. The resulting data support the package-insert claim of 8 weeks lot calibration stability when using the same reagent kit lot.
4.8. LoQ according to CLSI EP17-A2
The Limit of Quantitation (LoO) of the Elecsys BRAHMS PCT assay was determined according to CLSI EP17-A2. The LoQ represents the lowest amount of analyte that can be quantitatively determined with stated accuracy, precision, and experimental conditions. The LoQ was calculated based on intermediate precision according to CLSI EP17-A2. The LoQ was determined as the lowest concentration of analyte that can be quantified with an intermediate precision of no more than 20%.
A five-day LoQ experiment was carried out with one reagent lot on one cobas e 601 analyzer. Samples tested included seven native human serum (HS) samples and were measured in five-fold determination for each run. A total of 150 measuring points were collected.
The mean values and the intermediate precision (coefficient of variation and standard deviation) for each LoQ sample were calculated. To determine the LoQ, samples were sorted according to the concentration of their measured mean value. The LoO is defined as the mean value of the
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sample that is first to fulfill the specification for intermediate precision, and for which there is no lower-concentration sample that exceeds the specification. The LoQ data are represented in the table below.
| SampleType | Day | Mean(ng/mL) | SD(ng/mL) | CV (%) | ||||
|---|---|---|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | 5 | ||||
| HS 1 | 0.032 | 0.029 | 0.026 | 0.021 | 0.021 | 0.025 | 0.004 | 18.0 |
| 0.030 | 0.021 | 0.031 | 0.028 | 0.028 | ||||
| 0.022 | 0.023 | 0.022 | 0.021 | 0.020 | ||||
| 0.033 | 0.020 | 0.032 | 0.023 | 0.024 | ||||
| 0.029 | 0.024 | 0.025 | 0.022 | 0.018 | ||||
| HS 2 | 0.042 | 0.041 | 0.043 | 0.041 | 0.045 | 0.043 | 0.003 | 7.7 |
| 0.046 | 0.044 | 0.037 | 0.041 | 0.041 | ||||
| 0.050 | 0.039 | 0.043 | 0.043 | 0.044 | ||||
| 0.038 | 0.047 | 0.037 | 0.040 | 0.045 | ||||
| 0.048 | 0.045 | 0.044 | 0.043 | 0.045 | ||||
| HS 3 | 0.056 | 0.057 | 0.052 | 0.052 | 0.057 | 0.049 | 0.004 | 9.0 |
| 0.050 | 0.046 | 0.048 | 0.040 | 0.046 | ||||
| 0.051 | 0.048 | 0.048 | 0.044 | 0.052 | ||||
| 0.047 | 0.043 | 0.045 | 0.045 | 0.049 | ||||
| 0.053 | 0.054 | 0.050 | 0.046 | 0.050 | ||||
| HS 4 | 0.066 | 0.063 | 0.067 | 0.059 | 0.062 | 0.066 | 0.004 | 5.8 |
| 0.068 | 0.058 | 0.070 | 0.064 | 0.064 | ||||
| 0.067 | 0.068 | 0.064 | 0.073 | 0.062 | ||||
| 0.069 | 0.065 | 0.071 | 0.073 | 0.067 | ||||
| 0.068 | 0.064 | 0.065 | 0.062 | 0.061 | ||||
| HS 5 | 0.069 | 0.062 | 0.068 | 0.067 | 0.068 | 0.066 | 0.004 | 6.8 |
| 0.068 | 0.067 | 0.058 | 0.058 | 0.056 | ||||
| 0.072 | 0.063 | 0.073 | 0.066 | 0.068 | ||||
| 0.072 | 0.065 | 0.063 | 0.064 | 0.062 | ||||
| 0.072 | 0.065 | 0.069 | 0.064 | 0.067 | ||||
| HS 6 | 0.088 | 0.090 | 0.088 | 0.083 | 0.089 | 0.089 | 0.004 | 4.4 |
| 0.091 | 0.092 | 0.089 | 0.093 | 0.089 | ||||
| 0.092 | 0.091 | 0.090 | 0.084 | 0.084 | ||||
| 0.095 | 0.085 | 0.094 | 0.091 | 0.097 | ||||
| 0.090 | 0.095 | 0.086 | 0.083 | 0.085 | ||||
| LoQ: 0.025 ng/mL |
Table 5. LoQ Data – cobas e 601 analyzer
HS: human serum
The LoQ was determined to be 0.025 ng/mL. The LoQ claim for the Elecsys BRAHMS PCT assay is 0.06 ng/mL.
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Based on LoQ testing the following total error values were calculated.
| Expected value (ng/ml) | %CV | Elecsys BRAHMS PCT | %Bias | %TE |
|---|---|---|---|---|
| 2.00 | 0.19 | 0.12 | 0.43 | |
| 0.50 | 0.77 | 0.54 | 1.81 | |
| 0.30 | 1.30 | 0.94 | 3.08 | |
| 0.25 | 1.56 | 1.15 | 3.72 | |
| 0.15 | 2.64 | 2.00 | 6.34 | |
| 0.10 | 3.99 | 3.10 | 9.69 | |
| 0.05 | 8.12 | 6.56 | 19.97 |
Table 6: Total Error
Clinical Performance Evaluation - Method Comparison to Predicate 4.9.
A method comparison of the Elecsys BRAHMS PCT assay and the predicate was performed using 496 native serum human clinical samples. A concordance analysis was performed with the predicate device. Only samples in which the result from the candidate and the predicate device were within the measuring range were included in the concordance analysis. The clinical concordance analysis of the Elecsys BRAHMS PCT clinical performance study shows more than 96% total agreement between the Elecsys BRAHMS PCT and the predicate device at the medical decision points 0.1, 0.25, 0.5 and 2.0 ng/mL. The regression slopes are within +/- 10% of identity in Passing-Bablok and Weighted Deming Analysis. This demonstrates equivalence to the predicate device to include all currently cleared claims of the predicate device in the labeling of the candidate device.
Further clinical performance study data can be found referenced in K173927 and K160729.
| Table 7: PCT Agreement between Elecsys BRAHMS PCT and Predicate at 0.1 ng/mL | ||
|---|---|---|
| -- | -- | ------------------------------------------------------------------------------ |
| Elecsys BRAHMS PCT oncobas e 601 | Predicate | Total | |
|---|---|---|---|
| > 0.1 ng/mL | ≤ 0.1 ng/mL | ||
| > 0.1 ng/mL | 354 | 1 | 355 |
| ≤ 0.1 ng/mL | 7 | 134 | 141 |
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| ﺍﯾﮏ ﮐﯿﺎ ﮨﮯ ﮐﮧ ﺍﯾﮏ ﺭﮨﺎﺋﺸﯽ ﮐﮯ ﺳﺎﺗﮫ ﺍﻭﺭ ﺍﺱ ﮐﮯ ﺍﯾﮏ ﺍﯾﮏ ﺍﯾﮏ ﺍﯾﮏ ﺍﯾﮏ ﺍﯾﮏ ﺍﯾﮏ ﺍﯾﮏ ﺍﯾﮏ ﺍﯾﮏ ﺍﯾﮏ ﺍﯾﮏ ﺍﯾﮏ ﺍﯾﮏ ﺍﯾﮏ ﺍﯾﮏ ﺍﯾﮏ ﺍﯾﮏ ﺍﯾﮏ ﺍﯾﮏ ﺍﯾﮏ ﺍﯾﮏ ﺍﯾﮏ ﺍﯾﮏ ﺍﯾﮏ ﺍﯾﮏ ﺍﯾﮏ ﺍﯾﮏ ﺍﯾﮏ ﺍﯾﮏ ﺍﯾﮏ ﺍﯾﮏ ﺍﯾ | C |
|---|
Table 8: PCT Agreement between Elecsys BRAHMS PCT and Predicate at 0.25 ng/mL
| Elecsys BRAHMS PCT oncobas e 601 | Predicate | Total | |
|---|---|---|---|
| > 0.25 ng/mL | ≤ 0.25 ng/mL | ||
| > 0.25 ng/mL | 278 | 1 | 279 |
| ≤ 0.25 ng/mL | 6 | 211 | 217 |
| Total | 284 | 212 | 496 |
PCT Agreement between Elecsys BRAHMS PCT and Predicate at 0.5 ng/mL Table 9:
| Elecsys BRAHMS PCT oncobas e 601 | Predicate | Total | |
|---|---|---|---|
| > 0.5 ng/mL | ≤ 0.5 ng/mL | ||
| > 0.5 ng/mL | 220 | 0 | 220 |
| ≤ 0.5 ng/mL | 4 | 272 | 276 |
| Total | 224 | 272 | 496 |
Table 10: PCT Agreement between Elecsys BRAHMS PCT and Predicate at 2.0 ng/mL
| Elecsys BRAHMS PCT oncobas e 601 | Predicate | Total | |
|---|---|---|---|
| > 2.0 ng/mL | ≤ 2.0 ng/mL | ||
| > 2.0 ng/mL | 141 | 2 | 143 |
| ≤ 2.0 ng/mL | 3 | 350 | 353 |
| Total | 144 | 352 | 496 |
Table 11: Comparison Elecsys BRAHMS PCT vs Predicate
N = 496 (135 ≤ 0.1 ng/mL, 212 ≤ 0.25 ng/mL; 272 ≤ 0.5 ng/mL; 352 ≤ 2.0 ng/mL)
| Cutoff (> vs. ≤) | Positive Agreement(95% CI) | Negative Agreement(95% CI) | Total Agreement | Cohen's Kappa |
|---|---|---|---|---|
| 0.10 ng/mL | 98.1%(96.1 - 99.1) | 99.3%(95.9 - 99.9) | 98.4% | 0.960 |
| 0.25 ng/mL | 97.9%(95.5 - 99.0) | 99.5%(97.4 - 99.9) | 98.6% | 0.971 |
| 0.50 ng/mL | 98.2%(95.5 - 99.3) | 100.0%(98.6 -100.0) | 99.2% | 0.984 |
| 2.00 ng/mL | 97.9%(94.1 - 99.3) | 99.4%(98.0 - 99.8) | 99.0% | 0.975 |
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Table 12: Weighted Deming and Passing Bablok Regression Analysis
| Parameter | Passing Bablok Regression | Weighted Deming (λ=1) RegressionAnalysis |
|---|---|---|
| n | 474 | 474 |
| Slope | 0.990 | 0.969 |
| 95% CI | [0.984; 0.994] | [0.963; 0.975] |
| Intercept | -0.003 | 0.004 |
| 95% CI | [-0.004; -0.001] | [0.002; 0.005] |
| Pearson Correlation Coefficient (R) | 1.000 | 1.000 |
| Sample Range | [0.02; 85.69] | [0.02; 85.69] |
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Figure 1: Weighted Deming Regression plots of Elecsys BRAHMS PCT versus Predicate
Image /page/21/Figure/3 description: This image is a scatter plot that compares two different methods of measuring a certain quantity. The x-axis represents the Elecsys Brahms PCT, and the y-axis represents the Biotin Update Elecsys Brahms PCT. The plot includes a regression line, represented by the equation 0 + 0.97 * X, and an identity line. The Pearson's r correlation coefficient is 1, and the weighted Deming regression fit has n=474.
Weighted Deming Regression Fit, Instruments Pooled
Elecsys Brahms PCT
{22}------------------------------------------------
Figure 2: Passing Bablok Regression plots of Elecsys BRAHMS PCT versus Predicate
Image /page/22/Figure/3 description: This image is a scatter plot that shows the correlation between two different methods of measuring Biotin. The x-axis represents the Elecsys Brahms PCT, and the y-axis represents the Biotin Update Elecsys Brahms PCT. The plot includes a Passing Bablok Regression Fit line, represented by the equation 0 + 0.99 * X, and an identity line. The Pearson's r correlation coefficient is 1, indicating a strong positive correlation between the two methods, and the sample size is 474.
Passing Bablok Regression Fit, Instruments Pooled
Elecsys Brahms PCT
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5. ADDITIONAL INFORMATION
The calibration materials PCT Cal1 and PCT Cal2 as well as the control material PreciControl PCT1 and PreciControl PCT2 are in the Elecsys BRAHMS PCT kit and are not changed as a result of the new claims. The Elecsys BRAHMS PCT CalCheck 5 is also not changed as a result of the change. See K160729 for additional information.
6. CONCLUSIONS
The information provided in this 510(k) Premarket Notification will support a determination of substantial equivalence for the Elecsys BRAHMS PCT test system. The data supports a safe, effective device which performs as well as or better than the predicate device.
§ 866.3215 Device to detect and measure non-microbial analyte(s) in human clinical specimens to aid in assessment of patients with suspected sepsis.
(a)
Identification. A device to detect and measure non-microbial analyte(s) in human clinical specimens to aid in assessment of patients with suspected sepsis is identified as an in vitro device intended for the detection and qualitative and/or quantitative measurement of one or more non-microbial analytes in human clinical specimens to aid in the assessment of patients with suspected sepsis when used in conjunction with clinical signs and symptoms and other clinical and laboratory findings.(b)
Classification. Class II (special controls). The special controls for this device are:(1) Premarket notification submissions must include the device's detailed Indications for Use statement describing what the device detects and measures, the results provided to the user, whether the measure is qualitative and/or quantitative, the clinical indications for which the test is to be used, and the specific population(s) for which the device use is intended.
(2) Premarket notification submissions must include detailed documentation of the device description, including (as applicable), all device components, software, ancillary reagents required but not provided, explanation of the device principle and methodology, and for molecular devices include detailed documentation of the primer/probe sequence, design, and rationale for sequence selection.
(3) Premarket notification submissions must include detailed documentation of applicable analytical studies, such as, analytical sensitivity (Limit of Detection, Limit of Blank, and Limit of Quantitation), precision, reproducibility, analytical measuring range, interference, cross-reactivity, and specimen stability.
(4) Premarket notification submissions must include detailed documentation of a prospective clinical study or, if appropriate, results from an equivalent sample set. This detailed documentation must include the following information:
(i) Results must demonstrate adequate device performance relative to a well-accepted comparator.
(ii) Clinical sample results must demonstrate consistency of device output throughout the device measuring range likely to be encountered in the Intended Use population.
(iii) Clinical study documentation must include the original study protocol (including predefined statistical analysis plan), study report documenting support for the Indications for Use(s), and results of all statistical analyses.
(5) Premarket notification submissions must include evaluation of the level of the non-microbial analyte in asymptomatic patients with demographic characteristics (
e.g., age, racial, ethnic, and gender distribution) similar to the Intended Use population.(6) As part of the risk management activities performed under 21 CFR 820.30 design controls, you must document an appropriate end user device training program that will be offered as part of your efforts to mitigate the risk of failure to correctly operate the instrument.
(7) A detailed explanation of the interpretation of results and acceptance criteria must be included in the device's 21 CFR 809.10(b)(9) compliant labeling, and a detailed explanation of the interpretation of the limitations of the samples (
e.g., collected on day of diagnosis) must be included in the device's 21 CFR 809.10(b)(10) compliant labeling.