(88 days)
Not Found
No
The device description and performance studies focus on a qualitative, visually read lateral flow immunoassay, with no mention of AI or ML technologies for interpretation or analysis.
No
The device is a diagnostic immunoassay used to detect host response proteins to aid in the diagnosis of bacterial acute respiratory infection, not to provide therapy.
Yes
The device is explicitly described as an "aid in the diagnosis of bacterial acute respiratory infection and differentiation from non-bacterial etiology" and is used to detect human host response proteins from fingerstick blood, indicating its purpose in diagnosing medical conditions.
No
The device description clearly states it is a "rapid lateral flow immunoassay" and an "all-in-one integrated platform that includes a lateral flow test strip, a built-in retractable safety lancet, blood collection and transfer tube and buffer delivery system." This indicates a physical, hardware-based medical device, not a software-only one.
Yes, this device is an IVD (In Vitro Diagnostic).
Here's why:
- "in vitro detection": The device description explicitly states it is for the "in vitro detection" of host response proteins. "In vitro" means "in glass" or "outside the body," which is a key characteristic of IVDs.
- "directly from fingerstick blood": The sample being tested is blood, a biological specimen taken from the human body.
- "aid in the diagnosis": The intended use states that the test results are intended to be used as an "aid in the diagnosis" of bacterial acute respiratory infection. IVDs are used to provide information that helps in the diagnosis of diseases or conditions.
- "qualitative visually read rapid immunoassay": This describes the technology used, which is a common format for IVD tests that detect specific substances in biological samples.
The information provided clearly aligns with the definition and purpose of an In Vitro Diagnostic device.
N/A
Intended Use / Indications for Use
The FebriDx® Bacterial/Non-Bacterial Point-of-Care Assay is a qualitative visually read rapid immunoassay for the detection of human host response proteins, Myxovirus resistance protein A (MxA) and C-reactive protein (CRP) directly from fingerstick blood. FebriDx is indicated for use in patients aged 12-64 who present to urgent care or emergency care settings for evaluation of acute respiratory infection who have had symptoms for less than 7 days and within 3 days of fever onset.
FebriDx test results are intended to be used in conjunction with other clinical and diagnostic findings as an aid in the diagnosis of bacterial acute respiratory infection and differentiation from non-bacterial etiology. The assessment of whether a bacterial infection is present should always be based on consideration of all available information, and not based solely on the FebriDx test results. FebriDx test results are not intended to identify a specific pathogen or the severity of infection.
FebriDx External Controls are used in the FebriDx Test as assayed quality control samples to assess the performance and reliability of the FebriDx Test.
Special conditions for use statement(s):
- For in vitro diagnostic use
- For prescription use only
Product codes (comma separated list FDA assigned to the subject device)
QXA
Device Description
FebriDx is a rapid lateral flow immunoassay for the visual, qualitative, in vitro detection of elevated levels of host response proteins, Myxovirus resistance protein A (MxA) and Creactive protein (CRP), directly from fingerstick blood to aid in the evaluation of acute respiratory infections. The single-use, disposable FebriDx test is an all-in-one integrated platform that includes a lateral flow test strip, a built-in retractable safety lancet, blood collection and transfer tube and buffer delivery system. The FebriDx test produces a visualread qualitative result. Operators interpret the test and can visually see whether the infection may be due to a bacterial infection or other non-bacterial etiology.
FebriDx External Controls to monitor performance and reliability of the FebriDx test are sold separately. FebriDx External Controls are a two-vial set with one negative buffer and one positive control containing recombinant CRP and MxA.
Mentions image processing
Not Found
Mentions AI, DNN, or ML
Not Found
Input Imaging Modality
Not Found
Anatomical Site
Not Found
Indicated Patient Age Range
12-64
Intended User / Care Setting
urgent care or emergency care settings, Professional Use
Description of the training set, sample size, data source, and annotation protocol
Not Found
Description of the test set, sample size, data source, and annotation protocol
Not Found
Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)
A well-controlled, prospective, multi-center blinded clinical trial was conducted in the United States (U.S.) to evaluate the clinical performance of FebriDx. The study was conducted at 20 point-of-care (POC) testing sites that were representative of the intended user and setting. Patients who presented to urgent care or emergency care settings-for evaluation of acute respiratory infection (ARI) who had symptoms for less than 7 days and within 3 days of fever onset were screened for eligibility between October 2019-April 2021. Subjects were followed at study day 7 to identify participants who were admitted to the hospital for any reason. FebriDx was compared to a composite Clinical Reference Algorithm that incorporated pathogen detection testing (e.g., bacterial culture, multiplex PCR) as well as measures of host immune response. Physician adjudicators made a final qualitative diagnosis after review of all clinical and laboratory testing data.
Study Demographics: The study included 520 symptomatic participants with suspected acute respiratory infection who met inclusion and did not meet exclusion criteria. The cohort included male and female participants from each age group (pediatric, adult, elderly) with diverse ethnic backgrounds that were comparable to the 2020 U.S Census Bureau released demographic analysis. All participants enrolled in the symptomatic cohort had multiple symptoms, with cough and sore throat being the most prevalent. All participants presented with a fever > 100.5°F within 72 hours of enrollment, of which 31.9% were febrile at the time of enrollment.
Analysis: Of the total enrolled asymptomatic controls, FebriDx detected a bacterial infection in 3 cases where the adjudicated clinical reference algorithm classified the case as nonbacterial (NPA 98.1% (157/160), 95% CI (94.6%-99.4%)).
Of the total enrolled participants with acute respiratory infection, 14.0% (73/520) were classified as having bacterial infection and 81.3% (423/520) were classified as having non-bacterial etiology by the comparator.
Key results for overall bacterial infection performance:
PPA: 93.2% (68 / 73), 95% CI (84.9% - 97.0%)
NPA: 88.4% (374 / 423), 95% CI (85.0% - 91.1%)
PPV: 58.1% (68 / 117), 95% CI (49.1% - 66.7%)
NPV: 98.7% (374 / 379), 95% CI (96.9% - 99.4%)
LR+: 8.0, 95% CI (6.1 - 10.5)
LR-: 0.08, 95% CI (0.03 - 0.2)
FebriDx performance was analyzed as a subgroup of microbiologically confirmed infections. The performance for bacterial infection improved; PPA increased from 93.2% to 100%; NPA increased from 88.4% to 91.0%.
Key results for microbiologically confirmed bacterial infection performance:
PPA: 100% (33/33), 95% CI (89%, 100%)
NPA: 91.0% (263/289), 95% CI (87%, 94%)
PPV: 55.9% (33/59), 95% CI (47%, 65%)
NPV: 100% (263/263), 95% CI (98.6%, 100%)
LR+: 11.1, 95% CI (7.7, 16.0)
LR-: 0.0, 95% CI (7.7, 16.0)
FebriDx performance was analyzed for different age groups (1-21 years, 22-64 years, 65+ years). A Fisher's exact test was performed to evaluate the potential differences in age groups. The analysis showed there are no significant differences between the age groups for PPA. The DISRUPT study was not adequately powered to evaluate differences in performance among different age or demographic groups.
Key Metrics (Sensitivity, Specificity, PPV, NPV, etc.)
PPA: 93.2% (68 / 73)
NPA: 88.4% (374 / 423)
PPV: 58.1% (68 / 117)
NPV: 98.7% (374 / 379)
LR+: 8.0
LR-: 0.08
For microbiologically confirmed infections:
PPA: 100% (33/33)
NPA: 91.0% (263/289)
PPV: 55.9% (33/59)
NPV: 100% (263/263)
LR+: 11.1
LR-: 0.0
Predicate Device(s): If the device was cleared using the 510(k) pathway, identify the Predicate Device(s) K/DEN number used to claim substantial equivalence and list them here in a comma separated list exactly as they appear in the text. List the primary predicate first in the list.
Reference Device(s): Identify the Reference Device(s) K/DEN number and list them here in a comma separated list exactly as they appear in the text.
Not Found
Predetermined Change Control Plan (PCCP) - All Relevant Information for the subject device only (e.g. presence / absence, what scope was granted / cleared under the PCCP, any restrictions, etc).
Not Found
§ 866.3230 Device to detect and measure non-microbial analytes to aid in the detection and identification of localized human infections.
(a)
Identification. A device to detect and measure non-microbial analytes to aid in the detection and identification of localized human infections is identified as an in vitro diagnostic device intended for the detection and qualitative measurement, quantitative measurement, or both of one or more non-microbial analytes in human clinical specimens to aid in the assessment, identification, or both of a localized microbial infection 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) Any sample collection device used must be FDA-cleared, -approved, or -classified as 510(k) exempt (standalone or as part of a test system) for the collection of human specimens; alternatively, the sample collection device must be cleared in a premarket submission as a part of this device.
(2) The labeling required under § 809.10(b) of this chapter must include:
(i) An intended use with a detailed description of what the device detects and measures, the type of results provided to the user, the sample type, whether the measure is qualitative and/or quantitative, the clinical indications for the test use, and the specific population(s) for which the device is intended.
(ii) A detailed description of the performance characteristics of the device for all intended specimen types from the analytical and clinical studies (as applicable) required under paragraphs (b)(3)(ii) and (iii) of this section.
(iii) A detailed explanation of the interpretation of results, including acceptance criteria for evaluating the validity of individual runs (
e.g., assessment of internal and/or external quality controls, as applicable).(iv) The following limiting statements:
(A) A statement that a negative test result does not preclude the possibility of infection;
(B) A statement that the test results should be interpreted in conjunction with other clinical and laboratory data available to the clinician;
(C) A statement that consistent device performance is dependent on adequate specimen collection, transport, storage, and processing. Failure to observe proper procedures in any one of these steps can lead to incorrect results; and
(D) A statement that details any limitations associated with the samples, as appropriate (
e.g., collected on the day of admission to the intensive care unit).(3) Design verification and validation must include the following:
(i) A detailed device description, including as appropriate, all device parts; control elements incorporated into the test procedure; instrument requirements; reagents required but not provided; and the principle of device operation and test methodology, including all preanalytical methods for the processing of specimens and the methodology from obtaining a sample to the result; design of primer/probe sequences; rationale for target analyte selection; and computational path from collected raw data to reported result (
e.g., how collected raw signals are converted into a reported result).(ii) Detailed documentation of analytical studies including analytical sensitivity (Limit of Detection, Limit of Quantitation, and Limit of Blank), inclusivity, cross-reactivity, microbial interference, interfering substances, competitive inhibition, carryover/cross-contamination, specimen stability, within-lab precision, reproducibility, and linearity, as applicable.
(iii) Detailed documentation and results either from a clinical study, that includes prospective (sequentially collected) samples for each intended specimen type that are representative of the intended use populations and, when determined to be acceptable by FDA, additional characterized clinical samples; or, when determined to be acceptable by FDA, an equivalent sample set. The clinical study must compare the device performance to results obtained from an FDA-accepted reference method and/or FDA-accepted comparator method, as appropriate. Documentation from the clinical studies must include the clinical study protocol (
e.g., the predefined statistical analysis plan), clinical study report, testing results, and results of all statistical analyses.(iv) An evaluation of the level of the non-microbial analyte in asymptomatic patients with demographic characteristics (
e.g., age, racial, ethnic, and sex distribution) similar to the intended use population of the device.(v) Documentation of an appropriate end user device training program that will be offered as part of efforts to mitigate the risks of false results, failure to operate the device correctly, and failure to interpret test results correctly.
(vi) An appropriate risk mitigation strategy to ensure that the device does not prevent any other device(s) with which it is indicated for use, including incorporated device(s), from achieving their intended use (
e.g., safety and effectiveness of the functions of the indicated device(s) remain unaffected).(vii) A detailed description of the impact of any software, including software applications and hardware-based devices that incorporate software, on the device's functions.
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June 30, 2023
Lumos Diagnostics, Inc. Sue Hibbeln VP, Quality and Regulatory Affairs 2724 Loker Avenue Carlsbad, California 92010
Re: K230917
Trade/Device Name: FebriDx Bacterial / Non-bacterial Point of Care Assay Regulation Number: 21 CFR 866.3230 Regulation Name: Device To Detect And Measure Non-Microbial Analytes To Aid In The Detection And Identification Of Localized Human Infections Regulatory Class: Class II Product Code: QXA Dated: March 31, 2023 Received: April 3, 2023
Dear Sue Hibbeln:
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.
1
Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801 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 (QS) 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 medical devices and radiation-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.
Noel J. Gerald -S
Noel J. Gerald, Ph.D. Branch Chief Bacterial Respiratory and Medical Countermeasures Branch Division of Microbiology Devices OHT7: Office of In Vitro Diagnostics Office of Product Evaluation and Quality Center for Devices and Radiological Health
Enclosure
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Indications for Use
510(k) Number (if known) K230917
Device Name
FebriDx Bacterial / Non-bacterial Point-of-Care Assay FebriDx External Controls
Indications for Use (Describe)
The FebriDx Bacterial / Non-bacterial Point-of-Care Assay is a qualitative visually read rapid immunoassay for the detection of human host response protein A (MxA) and C-reactive protein A (MxA) and C-reactive protein (CRP) directly from fingerstick blood. FebriDx is indicated for use in patients aged 12-64 who present to urgent care or emergency care settings for evaluation of acute respiratory infection who have had symptoms for less than 7 days of fever onset.
FebriDx test results are intended to be used in conjunction with other clinical and diagnostic findings as and in the diagnosis of bacterial acute respiratory infection and differentiation from non-bacterial etiology. The assessment of whether a bacterial infection is present should always be based on consideration of all available information, and not based solely on the FebridDx test results are not intended to identify a specific pathogen or the severity of infection.
FebriDx External Controls are used in the FebriDx Test as assayed quality control samples to assess the performance and reliability of the FebriDx Test.
Special conditions for use statement(s):
- · For in vitro diagnostic use
- · For prescription use only
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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3
008 510(k) Summary
510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY
A. 510(k) Number: K230917
B. Applicant:
Lumos Diagnostics, Inc. 2724 Loker Avenue W Carlsbad, CA 92010
Contact: Sue Hibbeln, MS, RAC Telephone: 941.867.6150 Email: Sue.Hibbeln@LumosDiagnostics.com
Date Submitted: April 3, 2023
- C. Proprietary and Established Names: FebriDx® Bacterial / Non-bacterial Point-of-Care Assay, FebriDx® External Controls
- D. Purpose for Submission: To obtain a substantial equivalence determination for the FebriDx® device.
- E. Measurand: Dual biomarkers: Myxovirus resistance protein A (MxA) and C-reactive protein (CRP)
- F. Type of Test: Lateral flow qualitative immunoassay
- G. Regulatory Information:
-
- Regulation section: 21 CFR 866.3230
-
- Classification: Class II
-
- Product code(s): QXA
-
- Panel: MI Microbiology
-
H. Intended Use / Indications for Use:
The FebriDx® Bacterial/Non-Bacterial Point-of-Care Assay is a qualitative visually read rapid immunoassay for the detection of human host response proteins, Myxovirus resistance protein A (MxA) and C-reactive protein (CRP) directly from fingerstick blood. FebriDx is indicated for use in patients aged 12-64 who present to urgent care or emergency
4
care settings for evaluation of acute respiratory infection who have had symptoms for less than 7 days and within 3 days of fever onset.
FebriDx test results are intended to be used in conjunction with other clinical and diagnostic findings as an aid in the diagnosis of bacterial acute respiratory infection and differentiation from non-bacterial etiology. The assessment of whether a bacterial infection is present should always be based on consideration of all available information, and not based solely on the FebriDx test results. FebriDx test results are not intended to identify a specific pathogen or the severity of infection.
FebriDx External Controls:
FebriDx External Controls are used in the FebriDx Test as assayed quality control samples to assess the performance and reliability of the FebriDx Test.
Special conditions for use statement(s):
- For in vitro diagnostic use
- For prescription use only
I. Device Description:
FebriDx Test:
FebriDx is a rapid lateral flow immunoassay for the visual, qualitative, in vitro detection of elevated levels of host response proteins, Myxovirus resistance protein A (MxA) and Creactive protein (CRP), directly from fingerstick blood to aid in the evaluation of acute respiratory infections. The single-use, disposable FebriDx test is an all-in-one integrated platform that includes a lateral flow test strip, a built-in retractable safety lancet, blood collection and transfer tube and buffer delivery system. The FebriDx test produces a visualread qualitative result. Operators interpret the test and can visually see whether the infection may be due to a bacterial infection or other non-bacterial etiology.
5
FebriDx External Controls:
FebriDx External Controls to monitor performance and reliability of the FebriDx test are sold separately. FebriDx External Controls are a two-vial set with one negative buffer and one positive control containing recombinant CRP and MxA.
J. Test Principle:
Myxovirus resistance protein A (MxA) and C-reactive protein (CRP) are non-microbial proteins produced by the innate host response (e.g., interferons, interleukins, and the Complement System) in response to infection. The FebriDx test includes a built-in sample collection and transfer tube and detects the presence of MxA and CRP in fingerstick blood specimens using lateral flow technology. A sample of the fingerstick blood is added to the lateral flow test device; followed by a running buffer that provides sufficient volume to activate the test. The running buffer contains leukocyte membrane lysing agents that release intracellular MxA to allow subsequent detection. The first pad in the device filters out the cellular material as well as intact red-blood cells. The filtered sample then contacts a pad that contains the reagents to adjust pH and prevent non-specific binding. Prior to reaching the test strip, free MxA and CRP migrate through a dried formulation of latex beads that have been further conjugated to antibodies specific for binding a particular analyte (MxA or CRP). As the Analyte-Antibody-Bead complex continues to migrate across a porous nitrocellulose membrane, it can interact with one of three capture antibodies that are immobilized on the surface at distinct line positions, including the control line to verify that the device flowed properly. A black line present in the result window indicates a positive result (bacterial) and a red line in the result window or the absence of a line in the result window indicates a non-bacterial etiology, i.e., negative for bacterial infection. FebriDx® simultaneously detects MxA at the medical decision point of approximately 40 ng/mL and CRP of approximately 20 mg/L serum equivalent.
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K. Substantial Equivalence Information:
1. Predicate Device Name: Synovasure Alpha Defensin Lateral Flow Test Kit
-
- Predicate Number: DEN180032
3. Comparison with Predicate:
| DEN180032 | K230917 | |
|---|---|---|
| Synovasure Alpha Defensin | ||
| Lateral Flow Test Kit | FebriDx® Bacterial/Non-Bacterial | |
| Point-of-Care Assay | ||
| Manufacturer | CD Diagnostics | Lumos Diagnostics, Inc |
| Intended Use | ||
| Indications for Use | The Synovasure Alpha Defensin Lateral Flow Test Kit is a qualitative visually read immunochromatographic assay for the detection of human host response proteins, Alpha Defensins 1-3, in the synovial fluid of adults with a total joint replacement who are being evaluated for revision surgery. |
The Synovasure Alpha Defensin Lateral Flow Test Kit results are intended to be used in conjunction with other clinical and diagnostic findings as an aid in the diagnosis of periprosthetic joint infection (PJI). The Synovasure Alpha Defensin Lateral Flow Test Kit is not intended to identify the etiology or severity of a PJI. | The FebriDx® Bacterial/Non-bacterial Point-of-Care Assay is a qualitative visually read rapid immunoassay for the detection of human host response proteins, Myxovirus resistance protein A (MxA) and C-reactive protein (CRP) directly from fingerstick blood. FebriDx is indicated for use in patients aged 12-64 who present to urgent care or emergency care settings for evaluation of acute respiratory infection who have had symptoms for less than 7 and within 3 days of fever onset.
FebriDx test results are intended to be used in conjunction with other clinical and diagnostic findings as an aid in the |
| | DEN180032 | K230917 |
| | Synovasure Alpha Defensin
Lateral Flow Test Kit | FebriDx® Bacterial/Non-Bacterial
Point-of-Care Assay |
| | | diagnosis of bacterial acute respiratory
infection and differentiation from non-
bacterial etiology. The assessment of
whether a bacterial infection is present
should always be based on
consideration of all available
information, and not based solely on the
FebriDx test results. FebriDx test
results are not intended to identify a
specific pathogen or the severity of
infection. |
| Intended Use
External
Controls | The Synovasure Alpha Defensin
Control Kit is used in the Synovasure
Alpha Defensin Lateral Flow Test Kit
as assayed quality control samples to
monitor performance and reliability of
the Synovasure Alpha Defensin Lateral
Flow Test Kit. | FebriDx External Controls are used in
the FebriDx Test as assayed quality
control samples to assess the
performance and reliability of the
FebriDx Test. |
| Intended User | Professional Use | Professional Use |
| Equipment | Visually read | Visually read |
| Measurement | Qualitative | Qualitative |
| Device Format | Single use disposable | Single use disposable |
| Analyte | One or more non-microbial analytes | One or more non-microbial analytes |
| Measurand | Human Alpha Defensins 1-3 | MxA/CRP |
| Test Type | Lateral Flow immunochromatographic
assay | Lateral Flow immunochromatographic
assay |
| Components | Cassette with lateral flow test strip,
separate tube, separate sample cup, and | All-in-one cassette with lateral flow
test strip, safety lancet, blood collection |
| | DEN180032 | K230917 |
| | Synovasure Alpha Defensin
Lateral Flow Test Kit | FebriDx® Bacterial/Non-Bacterial
Point-of-Care Assay |
| | separate buffer bottle. | and transfer tube, and buffer delivery system. |
| Sample Type | Synovial fluid | Fingerstick blood |
| Sterility | Test not provided sterile/aspiration
device not included | Test not provided sterile/sterile lancet
included |
| Sample
Volume | 15 μl | 5 μl |
| External
Controls | External positive and negative controls
available | External positive and negative controls
available |
| Result time | 10 minutes (do not read after 20 minutes) | Minimum of 10 minutes (do not read after 1 hour) |
Table 1. Comparison of FebriDx and Predicate Device
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8
L. Standards/Guidance Documents Referenced:
-
- ISO 10993-1 Fifth edition 2018-08 Biological evaluation of medical devices Part 1: Evaluation and testing within a risk management process
-
- ISO 15223-1 Fourth Edition 2021-07 Medical Devices Symbols To Be Used With Medical Device Labels, Labelling, And Information To Be Supplied - Part 1: General Requirements
-
- CLSI EP07, Third Edition, Interference Testing in Clinical Chemistry
-
- CLSI EP12-A2, User Protocol for Evaluation of Qualitative Test Performance
-
- CLSI EP17-A2, Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures
-
- CLSI EP18-A2, Risk Management Techniques to Identify and Control Laboratory Error Sources
-
- CLSI EP25-A, Evaluation of Stability of In Vitro Diagnostic Reagents
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M. Performance Characteristics:
1. Analytical Performance:
- a. Precision/Reproducibility
The Precision & Reproducibility study was run at three (3) sites over five (5) days with two (2) medical professionals at each site who were representative of intended users, three (3) test kit lots and eighteen (18) blinded samples per run consisting of 3 blinded replicates of each sample. The evaluated panel members included C5 and C95 concentrations of both MxA and CRP as described below.
| Sample | Sample Description |
|---|---|
| P1 | C5 CRP / C95 MxA |
| P2 | C95 CRP / C5 MxA |
| P3 | C95 CRP/ C95 MxA |
| P4 | C95 CRP / high (120 ng/mL) MxA |
| P5 | High (150 ug/mL) CRP/ C95 MxA |
| P6 | Negative (0 CRP/ 0 MxA) |
The results demonstrate that the test is reproducible across the expected range of variability that would be encountered during normal expected use in the intended use setting. Results are summarized in the following table:
| Sample | % Agreement with Expected Results | ||||
|---|---|---|---|---|---|
| Site 1 | Site 2 | Site 3 | Overall | 95% CI | |
| P1 | 80% | ||||
| (24/30) | 70% | ||||
| (21/30) | 76.7% | ||||
| (23/30) | 75.6% | ||||
| (68/90) | 65.8-83.3% | ||||
| P2 | 100% | ||||
| (30/30) | 90% | ||||
| (27/30) | 73.3% | ||||
| (22/30) | 87.8% | ||||
| (79/90) | 79.4-93.0% | ||||
| P3 | 100% | 90% | 100% | 96.7% | 90.7-98.9% |
Table 2. Reproducibility Study Results Final Interpretation – By Site
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| (30/30) | (27/30) | (30/30) | (87/90) | ||
|---|---|---|---|---|---|
| P4 | 100% | ||||
| (30/30) | 100% | ||||
| (30/30) | 100% | ||||
| (30/30) | 100% | ||||
| (90/90) | 95.9-100% | ||||
| P5 | 100% | ||||
| (30/30) | 90% | ||||
| (27/30) | 93.3% | ||||
| (28/30) | 94.4% | ||||
| (85/90) | |||||
| P6 | 100% | ||||
| (30/30) | 90% | ||||
| (27/30) | 100% | ||||
| (30/30) | 96.7% | ||||
| (87/90) |
Table. 3 Reproducibility Study Results Final Interpretation – By Lot
| Sample | % Agreement with Expected Results | ||
|---|---|---|---|
| Lot 1 | Lot 2 | Lot 3 | |
| P1 | 75% | ||
| (27/36) | 80.5% | ||
| (29/36) | 66.7% | ||
| (12/18) | |||
| P2 | 83.3% (30/36) | 91.7% | |
| (33/36) | 88.9% | ||
| (16/18) | |||
| P3 | 100% | ||
| (36/36) | 100% | ||
| (36/36) | 83.3% | ||
| (15/18) | |||
| P4 | 100% | ||
| (36/36) | 100% | ||
| (36/36) | 100% | ||
| (18/18) | |||
| P5 | 91.7% (33/36) | 94.4% | |
| (34/36) | 100% | ||
| (18/18) | |||
| P6 | 100% | ||
| (36/36) | 100% | ||
| (36/36) | 83.3% | ||
| (15/18) |
11
- b. Analytical Specificity
- i. Cross-reactivity Not applicable.
- ii. Interfering Substances
The analytical specificity of the FebriDx test was determined by evaluating a series of samples that included MxA and CRP at the C95 concentration and negative levels in whole blood, spiked with interfering substances.
The following substances were evaluated on the FebriDx test and found to not interfere at the listed test concentrations:
| Test Substance | Concentration |
|---|---|
| Acetaminophen | 15.6 mg/dL |
| Acetylsalicylic acid | 3 mg/dL |
| Alcohol | 789 mg/dL |
| Azithromycin | 1.11 mg/dL |
| Biotin | 3500 ng/mL |
| Caffeine | 10 mg/dL |
| Celecoxib | 0.879 mg/dL |
| Cetirizine HCl | 0.435 mg/dL |
| Conjugated Bilirubin | 40 mg/dL |
| Dextromethorphan | 1.56 ug/dL |
| Doxycycline | 1.8 mg/dL |
| Furosemide | 1.59 mg/dL |
| HAMA | 524.6 ng/mL |
| Hemoglobin | 1000 mg/dL |
| Ibuprofen | 21.9 mg/dL |
| Imipenem | 18 mg/dL |
| Levofloxacin | 3.6 mg/dL |
| Loratadine | 0.5 mg/dL |
| Nicotine | 0.097 mg/dL |
| Oxymetazoline HCl | 0.09 mg/dL |
| Phenylephrine | 0.003 mg/dL |
| Prednisolone | 0.120 mg/dL |
| Protein (total) | 9 g/dL |
| Rheumatoid Factor (RF) | 50 IU/mL* |
| Salmeterol | 6.03 ug/dL |
| Tiotropium | 4.80 ng/dL |
Table 4. Concentrations of substances found to not interfere on FebriDx
12
| Triglycerides | 1500 mg/dL |
|---|---|
| Unconjugated Bilirubin | 40 mg/dL |
| Vancomycin | 12 mg/dL |
The results of the FebriDx Interfering Substances Verification Study showed that the test substances did not interfere with the FebriDx test at the listed concentrations and acceptance criteria were met. Of note (*), Rheumatoid Factor levels of up to 1000 IU/mL were evaluated and false negative/false positive results were identified. The interference effect disappeared at concentrations less than or equal to 50 IU/mL.
- c. Detection Limit
The Limits of Detection (LoD) for the CRP and MxA assays on the FebriDx test were determined on two (2) lots of tests. A series of whole blood samples spiked with MxA and CRP analytes at concentrations spanning the assay range were blinded to test operators, tested, and read to determine the Limit of Detection (LoD) concentration (C95) and the C5:
| MxA (ng/mL) | CRP (ug/mL) | |||
|---|---|---|---|---|
| Lot | C5 | C95 (LoD) | C5 | C95 (LoD) |
| 1 | 19 | 38 | 9 | 17 |
| 2 | 19 | 38 | 9 | 16 |
Table 5. Limit of Detection (LoD) Concentrations
Based on the study results, the LoD (C95) was conservatively established as 40 ng/mL for the MxA assay and as 20 ug/mL for the CRP assay.
- d. High Dose Hook Effect
The Hook Effect study assessed whether a hook effect exists on either the CRP and/or the MxA assays on the FebriDx test. MxA and CRP analytes were spiked into blood at the high concentrations shown in the table below and tested in replicates of ten (10) for each sample.
13
| Sample ID | MxA (ng/mL) | CRP (µg/mL) |
|---|---|---|
| 1 | 700 | 1000 |
| 2 | 600 | 800 |
| 3 | 500 | 600 |
| 4 | 400 | 500 |
| 5 | 200 | 250 |
| 6 | 100 | 125 |
| 7 | 50 | 62.5 |
| 8 | 0 | 0 |
Table 6. Hook Effect
These results indicate that there is no hook effect in the FebriDx test for the CRP assay up to a concentration of 1000 ug/mL and for the MxA assay up to a concentration of 700 ng/mL.
-
e. Assay cut-off
Not applicable. -
Matrix Equivalency f.
Due to difficulties obtaining sufficient volumes of capillary blood, analytical studies for the FebriDx test were conducted with venous whole blood. To demonstrate equivalent analytical performance between venous whole blood and capillary fingerstick blood, a matrix equivalency study was conducted and similar LoDs for MxA and CRP were established for both matrices.
Venous and fingerstick blood samples procured from patients with a recent clinical fever were run on the FebriDx test and a reference ELISA method. Results of the comparisons for both MxA and CRP proteins showed agreement between the two sample matrices. This data is not intended to support a venous blood sample type.
14
g. Controls
- i. Internal Controls
The FebriDx test has built-in procedural controls represented by a blue control line. For daily quality control. Lumos Diagnostics recommends documenting the procedural controls for the first sample tested each day.
ii. External Controls
External controls should be used to demonstrate that the reagents and assay perform properly. External controls (one positive and one negative) are optional and are not supplied with the FebriDx test kit (i.e. box of 25 devices). External controls should be used, consistent with good laboratory practices, to verify test performance. The manufacturer recommends external controls be run with every new lot, every new shipment, and with every first-time operator, but every testing site should follow their own protocols for running external controls.
- h. Stability
Real time Stability Study
Real time stability was performed on three (3) production lots of the FebriDx test to support the recommended storage conditions of 4-25°C and demonstrated stability of 24 months.
Transport Stability Study
A transport stability study was performed on one (1) production lot of the FebriDx test. Results demonstrated that the FebriDx test is stable when exposed to expected conditions of transport.
In-Use Stability Study
In-use stability of one (1) lot of FebriDx tests was evaluated at various timepoints by a minimum of three (3) operators at each timepoint after being removed from the sealed packaging and being exposed to the environment (open pouch stability).
15
The study demonstrated in-use stability of up to 45 minutes after removal from sealed packaging.
External Quality Controls Shelf-Life Testing
Real time stability was performed on three (3) production lots of the FebriDx External Quality Controls to support the recommended storage conditions of 15-25°C and demonstrated stability of 10 months.
16
2. Clinical Performance:
A well-controlled, prospective, multi-center blinded clinical trial was conducted in the United States (U.S.) to evaluate the clinical performance of FebriDx. The study was conducted at 20 point-of-care (POC) testing sites that were representative of the intended user and setting. Patients who presented to urgent care or emergency care settings-for evaluation of acute respiratory infection (ARI) who had symptoms for less than 7 days and within 3 days of fever onset were screened for eligibility between October 2019-April 2021. Subjects were followed at study day 7 to identify participants who were admitted to the hospital for any reason. FebriDx was compared to a composite Clinical Reference Algorithm that incorporated pathogen detection testing (e.g., bacterial culture, multiplex PCR) as well as measures of host immune response. Physician adjudicators made a final qualitative diagnosis after review of all clinical and laboratory testing data.
Comparator Method
Final diagnosis (Clinical Truth) was based on results of the Clinical Reference Algorithm (Comparator) in conjunction with adjudication by two independent expert reviewers, who were blinded to FebriDx results. Diagnostic accuracy was calculated by comparing the FebriDx result to the adjudicated Clinical Reference Algorithm. Primary analysis of diagnostic accuracy was based on positive percent agreement (PPA), negative percent agreement (NPA) and 95% confidence intervals (CI).
The following specimens were collected from each participant, on the day of FebriDx testing.
17
| Comparator Testing | Visit 1 |
|---|---|
| FilmArray® Respiratory Panel PCR | X |
| Epstein Barre Virus (EBV), Herpes Simplex Virus (HSV), | |
| Cytomegalovirus qPCR | X |
| Bocavirus, Fusobacterium necrophorum, Neisseria gonorrhoeae PCR | X |
| SARS-CoV-2 PCR | X |
| Bacterial Culture | X |
| Hematology: Complete Blood Cell Count (CBC) | X |
| Antibody Testing: EBV IgM | X |
| B.R.A.H.M.S Procalcitonin | X |
Table 7. Clinical Comparator
18
Study Demographics
Participants with symptoms for acute respiratory infection and a recent fever, were eligible for enrollment in the ARI cohort and participants without signs/symptoms of acute respiratory infection were eligible for enrollment in the asymptomatic control cohort. Demographics are summarized in the following table.
| Characteristics | Asymptomatic
Controls | ARI | Withdrawal after
Consent | Overall |
|-----------------------|--------------------------|--------------------|-----------------------------|--------------------|
| Sex | | | | |
| Female | 55.3% (94/170) | 55.8% (290/520) | 58.8% (10/17) | 55.7% (394/707) |
| Male | 44.7% (76/170) | 44.2% (230/520) | 41.2% (7/17) | 44.3% (313/707) |
| Age | | | | |
| N | 170 | 520 | 18 | 708 |
| Mean ± SD | $43.5 \u00b1 24.4$ | $35.2 \u00b1 17.7$ | $31.1 \u00b1 17.7$ | $37.1 \u00b1 19.8$ |
| Median | 38.0 | 32.0 | 28.5 | 33.0 |
| (IQR) | (19.0, 69.0) | (23.0, 48.0) | (24.0, 48.0) | (22.0, 50.0) |
| Min, Max | 3, 87 | 1, 95 | 2, 66 | 1, 95 |
| Age Group | | | | |
| 1-21 years | 31.2% (53/170) | 20.8% (108/520) | 22.2% (4/18) | 23.3% (165/708) |
| 22-64 years | 31.8% (54/170) | 71.7% (373/520) | 72.2% (13/18) | 62.1% (440/708) |
| 65+ years | 37.1% (63/170) | 7.5% (39/520) | 5.6% (1/18) | 14.5% (103/708) |
| Race | | | | |
| American Indian | 0 | 0.4% (2/520) | 0 | 0.3% (2/708) |
| Asian | 1.2% (2/170) | 2.7% (14/520) | 0 | 2.3% (16/708) |
| Black | 17.1% (29/170) | 21.2% (110/520) | 33.3% (6/18) | 20.5% (145/708) |
| Other | 2.4% (4/170) | 7.1% (37/520) | 11.1% (2/18) | 6.1% (43/708) |
| Pacific Islander | 0 | 0.2% (1/520) | 0 | 0.1% (1/708) |
| Unknown | 0 | 0 | 5.6% (1/18) | 0.1% (1/708) |
| White | 79.4% (135/170) | 68.5% (356/520) | 50.0% (9/18) | 70.6% (500/708) |
| Ethnicity | | | | |
| | | | | |
| Hispanic | 12.4% (21/170) | 18.7% (97/520) | 5.6% (1/18) | 16.8% (119/708) |
| Not Hispanic | 87.6% (149/170) | 80.6% (419/520) | 88.9% (16/18) | 82.5% (584/708) |
| Declined to
answer | 0 | 0.8% (4/520) | 5.6% (1/18) | 0.7% (5/708) |
Table 8. Demographics
19
The study included 520 symptomatic participants with suspected acute respiratory infection who met inclusion and did not meet exclusion criteria. The cohort included male and female participants from each age group (pediatric, adult, elderly) with diverse ethnic backgrounds that were comparable to the 2020 U.S Census Bureau released demographic analysis.
All participants enrolled in the symptomatic cohort had multiple symptoms, with cough and sore throat being the most prevalent. All participants presented with a fever > 100.5°F within 72 hours of enrollment, of which 31.9% were febrile at the time of enrollment.
External Controls
Positive and negative controls were performed every day of enrollment, with every new lot or shipment and with every first-time test operator. Prior to performing testing on study participants, 100% of positive and negative controls were read as positive and negative, respectively.
Analysis
Asymptomatic Controls
Of the total enrolled asymptomatic controls, FebriDx detected a bacterial infection in 3 cases where the adjudicated clinical reference algorithm classified the case as nonbacterial (NPA 98.1% (157/160), 95% CI (94.6%-99.4%)).
Acute Respiratory Infection (ARI) Cohort
Of the total enrolled participants with acute respiratory infection, 14.0% (73/520) were classified as having bacterial infection and 81.3% (423/520) were classified as having non-bacterial etiology by the comparator. FebriDx performance characteristics for bacterial infection are shown in the following table.
20
| Characteristic | Estimate | 95% CI |
|---|---|---|
| PPA | 93.2% (68 / 73) | 84.9% - 97.0% |
| NPA | 88.4% (374 / 423) | 85.0% - 91.1% |
| PPV | 58.1% (68 / 117) | 49.1% - 66.7% |
| NPV | 98.7% (374 / 379) | 96.9% - 99.4% |
| LR+ | 8.0 | 6.1 - 10.5 |
| LR- | 0.08 | 0.03 - 0.2 |
Table 9. FebriDx Performance Characteristics for Bacterial Infection (Overall)
FebriDx performance was analyzed as a subgroup of microbiologically confirmed infections. The performance for bacterial infection improved; PPA increased from 93.2% to 100%; NPA increased from 88.4% to 91.0%.
| Characteristic | Microbiologically
Confirmed | Overall
Performance |
|----------------|--------------------------------|------------------------|
| PPA | 100% (33/33) | 93.2% (68 / 73) |
| (95% CI) | (89%, 100%) | (84.9%, 97.0%) |
| NPA | 91.0% (263/289) | 88.4% (374/ 423) |
| (95% CI) | (87%, 94%) | (85.0%, 91.1%) |
| PPV | 55.9% (33/59) | 58.1% (68 / 117) |
| (95% CI) | (47%, 65%) | (49.1%, 66.7%) |
| NPV | 100% (263/263) | 98.7% (374/ 379) |
| (95% CI) | (98.6%, 100%) | (96.9%, 99.4%) |
| LR+ | 11.1 | 8.0 |
| (95% CI) | (7.7, 16.0) | (6.1, 10.5) |
| LR- | 0.0 | 0.08 |
| (95% CI) | (7.7, 16.0) | (0.03, 0.2) |
Table 10. FebriDx Performance Characteristics for Bacterial Infection
(Microbiologically Confirmed)
FebriDx performance was analyzed for different age groups (1-21 years, 22-64 years, 65+ years). A Fisher's exact test was performed to evaluate the potential differences in age groups. The analysis showed there are no significant differences between the age groups for PPA. The DISRUPT study was not adequately powered to evaluate differences in performance among different age or demographic groups.
21
| Characteristic | Estimate | 95% CI |
|---|---|---|
| 1-21 years | ||
| PPA | 100.0% (13 / 13) | 77.2%, 100.0% |
| NPA | 95.7% (88 / 92) | 89.3%, 98.3% |
| LR+ | 23.0 | 8.8, 60.0 |
| LR- | 0.0 | NA |
| 22-64 years | ||
| PPA | 92.3% (48 / 52) | 81.8%, 97.0% |
| NPA | 86.7% (260 / 300) | 82.4%, 90.1% |
| LR+ | 6.9 | 5.1, 9.3 |
| LR- | 0.1 | 0.03, 0.2 |
| 65+ years | ||
| PPA | 87.5% (7 / 8) | 52.9%, 97.8% |
| NPA | 83.9% (26 / 31) | 67.4%, 92.9% |
| LR+ | 5.4 | 2.3, 12.6 |
| LR- | 0.1 | 0.02, 0.9 |
Table 11. FebriDx Performance Characteristics (By Age)
Participants were contacted on study day 7 to identify participants who were admitted to the hospital for any reason. By study day seven, 0.96% (5/520) of participants were admitted to the hospital (i.e., discharged home and returned to the hospital, requiring an overnight stay). Participants classified as 'non-bacterial' by the comparator at the initial study visit, and subsequently required hospitalization for pneumonia with objective evidence of a bacterial infection had the final classification changed to 'bacterial'. None of the admitted patients met criteria for reclassification and there were no deaths, adverse events or unanticipated device effects that occurred during the study.
N. Proposed Labeling:
The labeling supports the determination of substantial equivalence for this device.
O. Conclusions:
The evidence provided in this Traditional 510(k) submission is sufficient to support a determination that the subject device is substantially equivalent to the legally marketed predicate device based on intended use, technology (basic design), performance, as well as the scientific rationale.