(177 days)
The Visby Medical Respiratory Health Test is a single-use (disposable), fully integrated, automated Reverse Transcription Polymerase Chain Reaction (RT-PCR) in vitro diagnostic test intended for the simultaneous qualitative detection and differentiation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza A, and influenza B RNA in nasopharyngeal swab and anterior nasal swab specimens from individuals with signs and symptoms of respiratory tract infection. Clinical signs and symptoms of respiratory tract infection due to SARS-CoV-2, influenza A, and influenza B can be similar.
The Visby Medical Respiratory Health Test is intended for use as an aid in the differential diagnosis of SARS-CoV-2, influenza A, and influenza B infection if used in conjunction with other clinical and epidemiological information, and laboratory findings. SARS-CoV-2, influenza A, and influenza B viral RNA are generally detectable in nasopharyngeal swab and anterior nasal swab specimens during the acute phase of infection. This test is not intended to detect influenza C virus infections.
Positive results are indicative of the identified virus, but do not rule out bacterial infection or co-infection with other organisms not detected by the test. The agent(s) detected by the Visby Medical Respiratory Health Test may not be the definitive cause of disease. Negative results do not preclude SARS-CoV-2, influenza A, or influenza B infection. The results of this test should not be used as the sole basis for diagnosis, treatment, or other patient management decisions.
The Visby Medical Respiratory Health Test is a single-use (disposable), fully integrated, compact device containing a reverse transcription polymerase chain reaction (RT-PCR) based assay for qualitative detection of influenza B, and/or SARS-CoV-2 viral RNA in upper respiratory tract specimens. The device automatically performs all steps required to complete lysis, reverse transcription (RT), PCR amplification, and detection.
Specimen collected using nasopharyngeal (NP) or anterior nasal (AN) swabs (without transport media) are placed in the Visby Medical Respiratory Health Buffer and then transferred into the sample port of the device using the provided fixed volume pipette. The sample enters a lysis module and rehydrates the RT enzyme and RT primers. The mixture then moves through a sample preparation module where viruses and human cells are simultaneously lysed, and RNA is reverse transcribed. The resulting fluid (containing cDNA) is then mixed with lyophilized PCR reagents containing the DNA polymerase enzyme and PCR primers. The PCR mixture (containing cDNA template and reagents) is then thermal cycled to amplify the targets, including human beta-2 microglobulin (B2M) RNA, which serves as a process control. After PCR, the biotinylated product is hybridized to covalently bound capture probes at specific locations along a flow channel. The flow channel is configured to facilitate an enzymatic reaction that uses streptavidin bound horseradish peroxidase (HRP) and a colorimetric substrate that forms a purple precipitate. The operator observes a color change at the specific locations indicating the presence of an amplified target. Test results can be expected in approximately 30 minutes: illumination of a "DONE" status light on the front of the device and a purple color in the "RESULTS VALID" spot, indicate a successful test. A purple spot adjacent to "Flu A", "Flu B", and/or "COVID-19" signifies the presence of, influenza A, influenza B, and/or SARS-CoV-2 viral RNA.
Here's an analysis of the acceptance criteria and study detailed in the provided text:
Acceptance Criteria and Reported Device Performance
The document doesn't explicitly state "acceptance criteria" in a separate table. However, based on the Summary of Performance Data, the inferred acceptance criteria are the achieved Positive Percentage Agreement (PPA) and Negative Percentage Agreement (NPA) values in the clinical evaluation. The study aims to demonstrate substantial equivalence to the predicate device, implying that the performance needs to be comparable or better.
Here's a table summarizing the reported device performance, which implicitly represents the met acceptance criteria:
| Target | Specimen Type | Reported PPA (95% CI) | Reported NPA (95% CI) |
|---|---|---|---|
| Influenza A | NP | 97.1% (85.1-99.5%) | 99.5% (98.7-99.8%) |
| Influenza A | AN | 96.8% (89.1-99.1%) | 99.2% (98.1-99.7%) |
| Influenza A | NP+AN | 96.9% (91.3-98.9%) | 99.4% (98.8-99.7%) |
| Influenza B | NP | 100% (79.6-100%) | 99.8% (99.1-99.9%) |
| Influenza B | AN | 100% (79.6-100%) | 99.9% (99.1-100%) |
| Influenza B | NP+AN | 100% (88.7-100%) | 99.8% (99.4-99.9%) |
| SARS-CoV-2 | NP | 96.3% (91.6-98.4%) | 99.0% (97.9-99.5%) |
| SARS-CoV-2 | AN | 98.3% (94.0-99.5%) | 99.1% (97.9-99.6%) |
| SARS-CoV-2 | NP+AN | 97.2% (94.4-98.7%) | 99.0% (98.3-99.5%) |
Study Details:
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Sample size used for the test set and the data provenance:
- Sample Size: A total of 1,501 subjects were included in the performance analysis after exclusions. 1,575 Visby tests were initially performed.
- Data Provenance: Prospectively collected fresh specimens from subjects presenting with signs and symptoms of a viral respiratory infection at five CLIA Waived study sites in the US (urgent care and family care clinics). Specimens were collected and tested between May 2022 and Feb 2024.
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Number of experts used to establish the ground truth for the test set and the qualifications of those experts:
- The document does not specify the number or qualifications of experts used to establish ground truth for the test set. Instead, it states that the comparator assays define the ground truth.
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Adjudication method (e.g., 2+1, 3+1, none) for the test set:
- The document describes comparing the Visby Medical Respiratory Health Test results against an "FDA-cleared influenza molecular test and an FDA-EUA authorized SARS-CoV-2 RT-PCR test as a comparator." It also mentions "alternate molecular assay" for discordant results (footnotes a, b, e, f, g, h, i, j in Table 2). This indicates that the ground truth was established by these comparator assays, potentially with some form of reference-standard-based comparison and possibly resolution of discrepancies with alternate assays, rather than a multi-expert adjudication method on the test set itself.
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If a multi reader multi case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance:
- No, an MRMC comparative effectiveness study was not done. This device is an in vitro diagnostic (IVD) test for molecular detection of viruses, not an AI-assisted diagnostic imaging or human-read interpretation system. The "operators" in the reproducibility study were "non-laboratorians representing healthcare professionals," but their performance was evaluated against expected results for spiked samples, not in comparison to their own performance with and without an AI assistant on clinical cases.
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If a standalone (i.e., algorithm only without human-in-the-loop performance) was done:
- Yes, a standalone performance evaluation was primarily done for the device. The clinical study evaluated the device's ability to detect viral RNA in specimens. While "typical CLIA Waived operators" performed the test, their role was to execute the device's protocol, and the device's detection accuracy was then compared against the comparator assays. The "device automatically performs all steps required to complete lysis, reverse transcription (RT), PCR amplification, and detection," implying it functions as a standalone diagnostic unit once the sample is loaded.
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The type of ground truth used (expert consensus, pathology, outcomes data, etc.):
- The ground truth for the clinical evaluation was established by comparator molecular assays: an "FDA-cleared influenza molecular test" and an "FDA-EUA authorized SARS-CoV-2 RT-PCR test." Discordant results were sometimes further investigated with an "alternate molecular assay."
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The sample size for the training set:
- The document does not specify a separate training set or its sample size. For IVD devices like this RT-PCR test, the "training" typically refers to the assay development and optimization process in the lab, rather than a distinct training set in the way AI/ML models are trained. The clinical performance study evaluates the final, optimized device.
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How the ground truth for the training set was established:
- As no distinct "training set" in the context of an AI/ML model is described, this information is not applicable. The development and optimization of such a diagnostic test would involve analytical studies (e.g., LoD, inclusivity, cross-reactivity) where the "ground truth" for those specific experiments (e.g., known concentrations of viral targets) is established by careful spiking and molecular characterization in a laboratory setting.
§ 866.3981 Device to detect and identify nucleic acid targets in respiratory specimens from microbial agents that cause the SARS-CoV-2 respiratory infection and other microbial agents when in a multi-target test.
(a)
Identification. A device to detect and identify nucleic acid targets in respiratory specimens from microbial agents that cause the SARS-CoV-2 respiratory infection and other microbial agents when in a multi-target test is an in vitro diagnostic device intended for the detection and identification of SARS-CoV-2 and other microbial agents when in a multi-target test in human clinical respiratory specimens from patients suspected of respiratory infection who are at risk for exposure or who may have been exposed to these agents. The device is intended to aid in the diagnosis of respiratory infection in conjunction with other clinical, epidemiologic, and laboratory data or other risk factors.(b)
Classification. Class II (special controls). The special controls for this device are:(1) The intended use in the labeling required under § 809.10 of this chapter must include a description of the following: Analytes and targets the device detects and identifies, the specimen types tested, the results provided to the user, the clinical indications for which the test is to be used, the specific intended population(s), the intended use locations including testing location(s) where the device is to be used (if applicable), and other conditions of use as appropriate.
(2) 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 specimen types claimed by this device; alternatively, the sample collection device must be cleared in a premarket submission as a part of this device.
(3) The labeling required under § 809.10(b) of this chapter must include:
(i) A detailed device description, including reagents, instruments, ancillary materials, all control elements, and a detailed explanation of the methodology, including all pre-analytical methods for processing of specimens;
(ii) Detailed descriptions of the performance characteristics of the device for each specimen type claimed in the intended use based on analytical studies including the following, as applicable: Limit of Detection, inclusivity, cross-reactivity, interfering substances, competitive inhibition, carryover/cross contamination, specimen stability, precision, reproducibility, and clinical studies;
(iii) Detailed descriptions of the test procedure(s), the interpretation of test results for clinical specimens, and acceptance criteria for any quality control testing;
(iv) A warning statement that viral culture should not be attempted in cases of positive results for SARS-CoV-2 and/or any similar microbial agents unless a facility with an appropriate level of laboratory biosafety (
e.g., BSL 3 and BSL 3+, etc.) is available to receive and culture specimens; and(v) A prominent statement that device performance has not been established for specimens collected from individuals not identified in the intended use population (
e.g., when applicable, that device performance has not been established in individuals without signs or symptoms of respiratory infection).(vi) Limiting statements that indicate that:
(A) A negative test result does not preclude the possibility of infection;
(B) The test results should be interpreted in conjunction with other clinical and laboratory data available to the clinician;
(C) There is a risk of incorrect results due to the presence of nucleic acid sequence variants in the targeted pathogens;
(D) That positive and negative predictive values are highly dependent on prevalence;
(E) Accurate results are 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
(F) When applicable (
e.g., recommended by the Centers for Disease Control and Prevention, by current well-accepted clinical guidelines, or by published peer-reviewed literature), that the clinical performance may be affected by testing a specific clinical subpopulation or for a specific claimed specimen type.(4) Design verification and validation must include:
(i) Detailed documentation, including performance results, from a clinical study that includes prospective (sequential) samples for each claimed specimen type and, as appropriate, additional characterized clinical samples. The clinical study must be performed on a study population consistent with the intended use population and compare the device performance to results obtained using a comparator that FDA has determined is appropriate. Detailed documentation must include the clinical study protocol (including a predefined statistical analysis plan), study report, testing results, and results of all statistical analyses.
(ii) Risk analysis and documentation demonstrating how risk control measures are implemented to address device system hazards, such as Failure Modes Effects Analysis and/or Hazard Analysis. This documentation must include a detailed description of a protocol (including all procedures and methods) for the continuous monitoring, identification, and handling of genetic mutations and/or novel respiratory pathogen isolates or strains (
e.g., regular review of published literature and periodic in silico analysis of target sequences to detect possible mismatches). All results of this protocol, including any findings, must be documented and must include any additional data analysis that is requested by FDA in response to any performance concerns identified under this section or identified by FDA during routine evaluation. Additionally, if requested by FDA, these evaluations must be submitted to FDA for FDA review within 48 hours of the request. Results that are reasonably interpreted to support the conclusion that novel respiratory pathogen strains or isolates impact the stated expected performance of the device must be sent to FDA immediately.(iii) A detailed description of the identity, phylogenetic relationship, and other recognized characterization of the respiratory pathogen(s) that the device is designed to detect. In addition, detailed documentation describing how to interpret the device results and other measures that might be needed for a laboratory diagnosis of respiratory infection.
(iv) A detailed device description, including device components, ancillary reagents required but not provided, and a detailed explanation of the methodology, including molecular target(s) for each analyte, design of target detection reagents, rationale for target selection, limiting factors of the device (
e.g., saturation level of hybridization and maximum amplification and detection cycle number, etc.), internal and external controls, and computational path from collected raw data to reported result (e.g., how collected raw signals are converted into a reported signal and result), as applicable.(v) A detailed description of device software, including software applications and hardware-based devices that incorporate software. The detailed description must include documentation of verification, validation, and hazard analysis and risk assessment activities, including an assessment of the impact of threats and vulnerabilities on device functionality and end users/patients as part of cybersecurity review.
(vi) For devices intended for the detection and identification of microbial agents for which an FDA recommended reference panel is available, design verification and validation must include the performance results of an analytical study testing the FDA recommended reference panel of characterized samples. Detailed documentation must be kept of that study and its results, including the study protocol, study report for the proposed intended use, testing results, and results of all statistical analyses.
(vii) For devices with an intended use that includes detection of Influenza A and Influenza B viruses and/or detection and differentiation between the Influenza A virus subtypes in human clinical specimens, the design verification and validation must include a detailed description of the identity, phylogenetic relationship, or other recognized characterization of the Influenza A and B viruses that the device is designed to detect, a description of how the device results might be used in a diagnostic algorithm and other measures that might be needed for a laboratory identification of Influenza A or B virus and of specific Influenza A virus subtypes, and a description of the clinical and epidemiological parameters that are relevant to a patient case diagnosis of Influenza A or B and of specific Influenza A virus subtypes. An evaluation of the device compared to a currently appropriate and FDA accepted comparator method. Detailed documentation must be kept of that study and its results, including the study protocol, study report for the proposed intended use, testing results, and results of all statistical analyses.
(5) When applicable, performance results of the analytical study testing the FDA recommended reference panel described in paragraph (b)(4)(vi) of this section must be included in the device's labeling under § 809.10(b) of this chapter.
(6) For devices with an intended use that includes detection of Influenza A and Influenza B viruses and/or detection and differentiation between the Influenza A virus subtypes in human clinical specimens in addition to detection of SARS-CoV-2 and similar microbial agents, the required labeling under § 809.10(b) of this chapter must include the following:
(i) Where applicable, a limiting statement that performance characteristics for Influenza A were established when Influenza A/H3 and A/H1-2009 (or other pertinent Influenza A subtypes) were the predominant Influenza A viruses in circulation.
(ii) Where applicable, a warning statement that reads if infection with a novel Influenza A virus is suspected based on current clinical and epidemiological screening criteria recommended by public health authorities, specimens should be collected with appropriate infection control precautions for novel virulent influenza viruses and sent to State or local health departments for testing. Viral culture should not be attempted in these cases unless a BSL 3+ facility is available to receive and culture specimens.
(iii) Where the device results interpretation involves combining the outputs of several targets to get the final results, such as a device that both detects Influenza A and differentiates all known Influenza A subtypes that are currently circulating, the device's labeling must include a clear interpretation instruction for all valid and invalid output combinations, and recommendations for any required followup actions or retesting in the case of an unusual or unexpected device result.
(iv) A limiting statement that if a specimen yields a positive result for Influenza A, but produces negative test results for all specific influenza A subtypes intended to be differentiated (
i.e., H1-2009 and H3), this result requires notification of appropriate local, State, or Federal public health authorities to determine necessary measures for verification and to further determine whether the specimen represents a novel strain of Influenza A.(7) If one of the actions listed at section 564(b)(1)(A) through (D) of the Federal Food, Drug, and Cosmetic Act occurs with respect to an influenza viral strain, or if the Secretary of Health and Human Services determines, under section 319(a) of the Public Health Service Act, that a disease or disorder presents a public health emergency, or that a public health emergency otherwise exists, with respect to an influenza viral strain:
(i) Within 30 days from the date that FDA notifies manufacturers that characterized viral samples are available for test evaluation, the manufacturer must have testing performed on the device with those influenza viral samples in accordance with a standardized protocol considered and determined by FDA to be acceptable and appropriate.
(ii) Within 60 days from the date that FDA notifies manufacturers that characterized influenza viral samples are available for test evaluation and continuing until 3 years from that date, the results of the influenza emergency analytical reactivity testing, including the detailed information for the virus tested as described in the certificate of authentication, must be included as part of the device's labeling in a tabular format, either by:
(A) Placing the results directly in the device's labeling required under § 809.10(b) of this chapter that accompanies the device in a separate section of the labeling where analytical reactivity testing data can be found, but separate from the annual analytical reactivity testing results; or
(B) In a section of the device's label or in other labeling that accompanies the device, prominently providing a hyperlink to the manufacturer's public website where the analytical reactivity testing data can be found. The manufacturer's website, as well as the primary part of the manufacturer's website that discusses the device, must provide a prominently placed hyperlink to the website containing this information and must allow unrestricted viewing access.