(88 days)
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.
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.
The Lumos Diagnostics FebriDx Bacterial / Non-bacterial Point-of-Care Assay is a qualitative visually read rapid immunoassay designed to detect human host response proteins (Myxovirus resistance protein A (MxA) and C-reactive protein (CRP)) from fingerstick blood. It is intended for use in patients aged 12-64 with acute respiratory infection symptoms for less than 7 days and within 3 days of fever onset, presenting to urgent care or emergency care settings. The assay aids in diagnosing bacterial acute respiratory infection and differentiating it from non-bacterial etiology, to be used in conjunction with other clinical and diagnostic findings.
Here's an analysis of the acceptance criteria and the study proving the device meets them:
1. Table of Acceptance Criteria and Reported Device Performance
The provided document does not explicitly state pre-defined acceptance criteria for the clinical performance. However, regulatory bodies typically look for high Positive Percent Agreement (PPA) and Negative Percent Agreement (NPA) to establish substantial equivalence. Based on the clinical study results, the following can be inferred as performance benchmarks.
| Characteristic | Reported Device Performance (Overall) |
|---|---|
| PPA (Bacterial Inf.) | 93.2% (68 / 73) |
| NPA (Non-Bacterial E.) | 88.4% (374 / 423) |
| PPV (Bacterial Inf.) | 58.1% (68 / 117) |
| NPV (Non-Bacterial E.) | 98.7% (374 / 379) |
| LR+ | 8.0 |
| LR- | 0.08 |
Note: For microbiologically confirmed bacterial infections, the PPA increased to 100% (33/33) and NPA improved to 91.0% (263/289).
2. Sample Size Used for the Test Set and Data Provenance
- Test Set (Clinical Study):
- Symptomatic Participants (ARI cohort): 520 participants.
- Asymptomatic Controls: 170 participants (160 for the NPA analysis).
- Total Enrolled: 708 participants (520 symptomatic, 170 asymptomatic, 18 withdrawals after consent).
- Data Provenance: The study was a "well-controlled, prospective, multi-center blinded clinical trial conducted in the United States (U.S.)" between October 2019 and April 2021.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications
- Number of Experts: Two independent expert reviewers.
- Qualifications: The document states they were "two independent expert reviewers" but does not explicitly detail their specific qualifications (e.g., "radiologist with 10 years of experience"). However, given the nature of the study (diagnosis of bacterial acute respiratory infection), it can be inferred they are likely medical professionals with expertise in infectious diseases, emergency medicine, or urgent care.
4. Adjudication Method for the Test Set
The adjudication method was based on a "composite Clinical Reference Algorithm" in conjunction with "adjudication by two independent expert reviewers, who were blinded to FebriDx results." This suggests a consensus-based approach where the experts reach a final decision after reviewing all available clinical and laboratory testing data.
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was Done
- No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not conducted. The clinical study evaluated the standalone performance of the FebriDx device against a clinical reference algorithm and expert adjudication. It did not involve comparing human readers with and without AI assistance.
6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) was done
- Yes, a standalone performance study was conducted. The "Clinical Performance" section directly assesses the FebriDx device's accuracy (PPA, NPA, etc.) against the adjudicated clinical truth. The device itself is a visually-read rapid immunoassay, implying a human reads the result, but the assessment of its diagnostic accuracy is the "standalone" performance of the assay itself compared to the ground truth. The study reports the performance characteristics of the device's output.
7. The Type of Ground Truth Used
The ground truth, referred to as "Final diagnosis (Clinical Truth)," was based on:
- A composite Clinical Reference Algorithm which incorporated:
- Pathogen detection testing (e.g., bacterial culture, multiplex PCR for various viruses/bacteria, SARS-CoV-2 PCR, EBV IgM).
- Measures of host immune response (e.g., Hematology: Complete Blood Cell Count (CBC), B.R.A.H.M.S Procalcitonin).
- Adjudication by two independent expert reviewers who were blinded to the FebriDx results and made a final qualitative diagnosis after review of all clinical and laboratory testing data.
- Outcomes data: Participants admitted to the hospital for pneumonia with objective evidence of bacterial infection were reclassified, indicating that outcomes were a component of confirming or revising the "clinical truth."
8. The Sample Size for the Training Set
The document does not provide information regarding the sample size used for the training set. The descriptions focus on the analytical performance (precision, LoD, hook effect, stability) and the clinical study which serves as the validation/test set for regulatory submission.
9. How the Ground Truth for the Training Set was Established
Since information on a distinct "training set" is not provided, the method for establishing its ground truth is also not specified in this document. It is common for such devices to use internal development or historical data for training, and the clinical study described is the primary validation performed for regulatory submission.
§ 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.