FDA 510(k) Search - By Innolitics (SaMD and AI Experts)

The FilmArray Respiratory Panel 2 plus (RP2plus) is a multiplexed nucleic acid test intended for use with FilmArray 2.0 or FilmArray Torch systems for the simultaneous qualitative detection and identification of nucleic acids from Middle East Respiratory Syndrome Coronavirus (MERS-CoV) and multiple common viral and bacterial respiratory pathogens in nasopharyngeal swabs (NPS) obtained from individuals meeting MERS-CoV clinical and/or epidemiological criteria.

Testing with the FilmArray RP2plus should not be performed unless the patient meets clinical and/or epidemiologic criteria for testing suspected MERS-CoV specimens. This includes: clinical signs and symptoms associated with MERS-CoV infection, contact with a probable or confirmed MERS-CoV case, history of travel to geographic locations where MERS-CoV cases were detected, or other epidemiological links for which MERS-CoV testing may be indicated.

The FilmArray RP2plus identifies:

Middle East Respiratory Syndrome Coronavirus (MERS-CoV) ●
And the following viral and bacterial respiratory pathogen types and subtypes:
Adenovirus
Coronavirus 229E ●
Coronavirus HKU1 ●
Coronavirus NL63
Coronavirus OC43 ●
Human Metapneumovirus
Human Rhinovirus/Enterovirus ●
Influenza A. including subtypes H1. H1-2009, and H3 ●
Influenza B
Parainfluenza Virus 1
Parainfluenza Virus 2
Parainfluenza Virus 3 ●
Parainfluenza Virus 4
Respiratory Syncytial Virus ●
Bordetella parapertussis (IS 1001) ●
Bordetella pertussis (ptxP)
. Chlamydia pneumoniae
. Mycoplasma pneumoniae

The detection and identification of specific viral and bacterial nucleic acids from MERS-CoV and other respiratory pathogens in individuals meeting MERS-CoV clinical and/or epidemiological criteria aids in the differential diagnosis of MERS-CoV infection, if used in conjunction with other clinical and epidemiological information in accordance with the guidelines provided by the appropriate public health authorities.

FilmArray RP2plus MERS-CoV positive results are for the presumptive identification of MERS-CoV. The definitive identification of MERS-CoV requires additional testing and confirmation procedures in consultation with the appropriate public health authorities (e.g., local or state public health departments, etc.) for whom reporting is necessary. The diagnosis of MERS-CoV infection must be made based on history, signs, symptoms, exposure likelihood, and other laboratory evidence in addition to the identification of MERS-CoV.

FilmArray RP2plus MERS-CoV negative results, even in the context of a FilmArray RP2plus positive result for one or more of the common respiratory pathogens, do not preclude MERS-CoV infection and should not be used as the sole basis for patient management decisions. The levels of MERS-CoV that would be present in NPS specimens from individuals with early infection and from asymptomatic MERS-CoV carriers are not well understood. The FilmArray RP2plus MERS-CoV negative results may also be due to lower respiratory tract infection with MERS-CoV that may not be detected by an NPS specimen. In this context, collection of lower respiratory and serum specimens (if possible) for MERS-CoV testing using other laboratory tests is highly recommended in addition to testing for MERS-CoV RNA in NPS specimens (i.e., upper respiratory specimens) using the FilmArray RP2plus. A negative FilmArray RP2plus MERS-CoV result in an asymptomatic individual does not rule out the possibility of future illness and does not demonstrate that the individual is not infectious.

Viral culture should not be attempted in the cases of positive FilmArray RP2plus results for MERS-CoV unless a BSL 3 facility is available to receive and culture specimens.

Negative FilmArray RP2plus results in the setting of a respiratory illness may be due to infection with pathogens that are not detected by this test, or other pathogens that may not be detected by an NPS specimen. Positive FilmArray RP2plus results do not rule out coinfection with other organisms: the agent(s) detected by the FilmArray RP2plus may not be the definite cause of disease.

Due to the genetic similarity between Human Rhinovirus and Enterovirus, the FilmArrav RP2plus cannot reliably differentiate them. A positive FilmArray RP2plus Rhinovirus/Enterovirus result should be followed up using an alternate method (e.g., cell culture or sequence analysis) if differentiation is required.

Performance characteristics for Influenza A were established when Influenza A H1-2009, A H1, and A H3 were the predominant Influenza A viruses in circulation. Performance of detecting Influenza A may vary if other Influenza A strains are circulating or a novel Influenza A virus emerges. 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.

Device Description

The FilmArray Respiratory Panel 2 plus (RP2plus) is designed to simultaneously detect and identify MERS-CoV and 21 different common pathogens (see the Indications for Use section) of respiratory tract infection from a single NPS specimen in a time frame (~45 minutes) that may allow the test results to be used as an aid in determining appropriate patient treatment and management. FilmArray RP2plus is compatible with BioFire Diagnostics' (BioFire) PCR-based in vitro diagnostic FilmArray 2.0 and FilmArray Torch systems for infectious disease testing. A specific software module (i.e., FilmArray RP2plus pouch module) is used to perform FilmArray RP2plus testing on these systems.

A test is initiated by loading Hydration Solution into one port of the FilmArray pouch and a NPS sample (in transport media) mixed with the provided Sample Buffer into the other port of the FilmArray RP2plus pouch and placing it in a FilmArray instrument. The FilmArray pouch contains all the reagents required for specimen testing and analysis in a freeze-dried format; the addition of Hydration Solution and Sample/Buffer Mix rehydrates the reagents. After the pouch is prepared, the FilmArray Software guides the user though the steps of placing the pouch into the instrument, scanning the pouch barcode, entering the sample identification, and initiating the run.

The FilmArray instrument contains a coordinated system of inflatable bladders and seal points, which act on the pouch to control the movement of liquid between the pouch blisters. When a bladder is inflated over a reagent blister, it forces liquid from the blister into connecting channels. Alternatively, when a seal is placed over a connecting channel it acts as a valve to open or close a channel. In addition, electronically-controlled pneumatic pistons are positioned over multiple plungers in order to deliver the rehydrated reagents into the blisters at the appropriate times. Two Peltier devices control heating and cooling of the pouch to drive the PCR reactions and the melt curve analysis.

Nucleic acid extraction occurs within the FilmArray pouch using mechanical and chemical lysis followed by purification using standard magnetic bead technology. After extracting and purifying nucleic acids from the unprocessed sample, the FilmArray performs a nested multiplex PCR that is executed in two stages. During the first stage, the FilmArray performs a single, large volume, highly multiplexed reverse transcription PCR (RT-PCR) reaction, PCR1. The products from first stage PCR are then diluted and combined with a fresh, primerfree master mix and a fluorescent double stranded DNA binding dye (LC Green Plus, BioFire Diagnostics, LLC). The solution is then distributed to each well of the array. Array wells contain sets of primers designed specifically to amplify sequences internal to the PCR products generated during the first stage PCR reaction. The 2nd stage PCR, or nested PCR, PCR2. is performed in singleplex fashion in each well of the array. At the conclusion of the 2nd stage PCR, the array is interrogated by melt curve analysis for the detection of signature amplicons denoting the presence of specific targets. A digital camera placed in front of the 2nd stage PCR captures fluorescent images of the PCR reactions and software interprets the data.

The FilmArray Software automatically interprets the results of each DNA melt curve analysis and combines the data with the results of the internal pouch controls to provide a test result for each organism on the panel.

AI/ML Overview

Table of Acceptance Criteria and Reported Device Performance:

Criterion	Acceptance Criteria (Implicit from context)	Reported Device Performance (FilmArray RP2plus)
Analytical Performance
Reproducibility (Agreement with Expected Result)	High agreement across sites and systems (Implicitly >95% for most analytes, 100% for negative controls).	Overall: MERS-CoV (100%), Adenovirus (98.3-99.2%), CoV-229E (100%), CoV-HKU1 (100%), CoV-NL63 (100%), CoV-OC43 (97.5%), hMPV (98.3-100%), HRV/EV (100%), FluA H3 (99.2-100%), FluA H1/H1-2009 (100% Not Detected), FluB (100%), PIV1 (100%), PIV2 (96.7-98.3%), PIV3 (100%), PIV4 (98.3-100%), RSV (98.3-100%), B. parapertussis (93.3-99.2%), B. pertussis (98.3-100%), C. pneumoniae (97.5-100%), M. pneumoniae (100%). Most analytes showed >97% agreement for positive samples and 100% for negative samples.
Reproducibility (Tm Standard Deviation)	≤ ± 0.5°C	All analytes observed within ± 0.2°C to ± 0.3°C.
Limit of Detection (LoD) Confirmation	≥95% detection rate at 1×LoD and 90% for most analytes with sufficient sample size)	Prospective: Varied by analyte, generally high (e.g., Adenovirus 94.6%, HRV/EV 97.5%, FluA 100%, RSV 99.4%, CoV-HKU1 100%, CoV-NL63 100%). Lower for some with small N (e.g., B. pertussis 66.7%, B. parapertussis 85.7%). Retrospective: Most 100%, lowest HRV/EV 94.7%, B. pertussis 96.2%. Contrived: MERS-CoV 100%, FluA H1 97.9%.
Clinical Performance (Negative Percent Agreement - NPA)	High NPA (implicitly >95% for most analytes).	Prospective: Varied by analyte, generally very high (e.g., MERS-CoV 100%, Adenovirus 96.9%, CoV-229E 99.7%, CoV-HKU1 99.2%, HRV/EV 93.5% (lowest), RSV 98.3%). Retrospective: Most 100%, lowest HRV/EV 96.0%. Contrived: MERS-CoV 100%, FluA H1 100%.

2. Sample sizes used for the test set and the data provenance:

Reproducibility Study Test Set: 120 data points per sample, across 4 contrived NPS samples, totaling 480 valid runs. The data was from a combined total of 15 different FilmArray 2.0 instruments and 19 different FilmArray Torch modules at three testing sites. The samples were contrived NPS samples in simulated VTM.
LoD Confirmation Test Set: For each analyte, 40 replicates (20 on FilmArray 2.0, 20 on FilmArray Torch) at 1xLoD, and 40 replicates at 0.1xLoD. Samples were contrived in simulated NPS in VTM.
Analytical Reactivity Test Set: Each isolate/strain was tested in triplicate (one replicate on each of three different reagent lots) near 3xLoD. Tested at 10xLoD or higher if not reliably detected. Samples were contrived in Remel M4 Transport Medium.
Analytical Specificity/Cross-Reactivity Test Set: Each organism tested in triplicate on three different lots of FilmArray RP2plus pouches at high concentrations (typically ≥1.0E+06 CFU/ml for bacteria and fungi and ≥1.0E+05 TCID50/mL for viruses). Samples were in Remel M4 transport medium.
Interfering Substances Test Set: Each test substance added to a contrived sample containing a mix of five analytes (each near LoD).
Comparator Assay for B. parapertussis: Validation testing of the PCR followed by sequencing assays used samples (nature and number not specified beyond demonstrating equivalent analytical sensitivity to RP2plus).
MERS-CoV Comparative Analytical Sensitivity: A MERS-CoV proficiency test panel (QCMD, U.S. government contracted) containing MERS-CoV samples and common coronaviruses.
Prospective Clinical Study Test Set: 1612 residual NPS specimens in VTM after exclusions. Data provenance: Three geographically distinct U.S. study sites (Salt Lake City, UT; Chicago, IL; Columbus, OH) during portions of the 2015-2016 and 2016-2017 respiratory illness seasons. Samples were retrospective (archived/frozen) and prospective (fresh).
Retrospective Clinical Study - Common Respiratory Pathogens Test Set: A total of 214 archived NPS in VTM specimens after exclusions. These were preselected specimens previously tested positive at the source laboratory. Data provenance: BioFire Diagnostics (testing site), specimens were archived from various source laboratories (presumably US-based).
Retrospective Clinical Study - MERS-CoV Test Set: 3 archived retrospective NPS in VTM specimens from confirmed cases of MERS-CoV infection. Data provenance: Laboratory in South Korea during the 2015 MERS-CoV outbreak.
Contrived Clinical Specimens Test Set: 50 MERS-CoV positive contrived specimens, 48 Influenza A H1 positive contrived specimens, and 50 un-spiked negative specimens. Samples were prepared using unique residual NPS specimens that previously tested negative from a clinical site. Data provenance: One of the three clinical sites from the prospective evaluation.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts:

Analytical Studies (Reproducibility, LoD, Analytical Reactivity, Analytical Specificity, Interfering Substances, MERS-CoV Comparative Analytical Sensitivity): The document does not specify a number of "experts" for ground truth outside of the internal process for developing the melt detector algorithm. Ground truth for these was established using known concentrations of cultured isolates, molecular quantification (qPCR/RT-PCR), or known positive/negative status of contrived samples. The melt detector algorithm's performance was compared to "expert annotation," but the number and qualifications of these experts are not explicitly stated.
Prospective Clinical Study: Ground truth was established by an FDA-cleared multiplexed respiratory pathogens panel (for most analytes) and two analytically-validated PCR followed by bidirectional sequencing assays (for B. parapertussis). For MERS-CoV, the ground truth was the expected negative result in this population. The performance of these comparator methods, acting as the reference standard, generally implies expert oversight in their validation and historical use, but no specific human experts are mentioned for establishing the ground truth for this particular study.
Retrospective Clinical Study - Common Respiratory Pathogens: Ground truth was established by the same comparator methods as the prospective study (FDA-cleared multiplexed respiratory pathogens panel and B. parapertussis PCR/sequencing).
Retrospective Clinical Study - MERS-CoV: Ground truth was established by standard of care methods, specifically two rRT-PCR assays targeting upE and ORF1A (based on WHO primer/probe sequences) used during the 2015 MERS-CoV outbreak. These methods would have been operated by trained laboratory personnel, implying expertise, but no specific number or qualification of experts is provided for creating the ground truth for this study.
Contrived Clinical Specimens: Ground truth was based on the known spiking of negative specimens with quantified isolates of Influenza A H1 and MERS-CoV.

4. Adjudication method (e.g. 2+1, 3+1, none) for the test set:

Analytical Studies: Adjudication methods are not explicitly described for discrepancies in analytical tests. Deviations from expected results (e.g., non-detection at 3xLoD) led to retesting at higher concentrations. The Melt Detector algorithm validation involved comparison to "expert annotation" without a specified adjudication protocol.
Clinical Studies (Prospective and Retrospective - Common Respiratory Pathogens): Discrepant results (FilmArray RP2plus vs. comparator method) were subjected to further investigation. The discrepancy investigation was mainly conducted by performing independent molecular methods with primers different from the FilmArray RP2plus and/or comparator method retesting. This indicates a form of adjudication, where a third, independent method or re-run of the comparator served to resolve the discrepancy, but a specific "X+Y" voting method (like 2+1) is not detailed.
Retrospective Clinical Study - MERS-CoV: This study involved only three positive samples, and the FilmArray RP2plus showed 100% agreement. No discrepancies were observed, so no adjudication method was needed or described.
Contrived Clinical Specimens: Ground truth was defined by the known spiking protocol. Any deviations from expected results were analyzed for causes (e.g., presence of a specific strain of Influenza A/Weiss/43 leading to equivocal result).

5. 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?

This document describes the evaluation of a fully automated in vitro diagnostic (IVD) device (FilmArray Respiratory Panel 2 plus), which is a nucleic acid amplification test. It is not an AI-assisted diagnostic device where human readers interact with AI. Therefore, a multi-reader multi-case (MRMC) comparative effectiveness study evaluating human reader performance with and without AI assistance was not applicable and not performed. The device itself performs the analysis and provides a result without human interpretation of raw data.

6. If a standalone (i.e., algorithm only without human-in-the-loop performance) was done?

Yes, a standalone performance evaluation was done. The entire submission details the performance of the FilmArray RP2plus, which is described as a "multiplexed nucleic acid test intended for use with FilmArray 2.0 or FilmArray Torch systems for the simultaneous qualitative detection and identification of nucleic acids..." (Section D). The device "automatically interprets the results of each DNA melt curve analysis and combines the data with the results of the internal pouch controls to provide a test result for each organism on the panel" (Section I). This clearly indicates an algorithm-only (standalone) performance. The clinical studies compare the device's output directly to comparator methods, not to human interpretations that the device might aid.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc):

Analytical Studies (Reproducibility, LoD, Analytical Reactivity, Analytical Specificity, Interfering Substances): The ground truth was primarily based on known concentrations of cultured isolates, molecular quantification (e.g., qPCR/RT-PCR), or the inherent design of contrived samples. For the internal Melt Detector validation, it was compared to "expert annotation."
Prospective Clinical Study: The ground truth was established using a combination of FDA-cleared multiplexed respiratory pathogen panels (molecular comparator devices) and analytically-validated PCR followed by bidirectional sequencing assays for B. parapertussis. For MERS-CoV, the ground truth was the expected negative result in the general study population. Discrepancies were further investigated using independent molecular methods.
Retrospective Clinical Study - Common Respiratory Pathogens: The ground truth was established by the same comparator methods as the prospective study (FDA-cleared multiplexed respiratory pathogen panels and B. parapertussis PCR/sequencing).
Retrospective Clinical Study - MERS-CoV: The ground truth was established by standard of care reference molecular methods (two rRT-PCR assays based on WHO primer/probe sequences) used during the 2015 MERS-CoV outbreak, confirming positive MERS-CoV infection.
Contrived Clinical Specimens: The ground truth was based on the known positive status due to spiking with quantified isolates and the known negative status of un-spiked specimens.

8. The sample size for the training set:

Melt Detector Algorithm: The "Melt Detector" algorithm was "tuned against a large data set comprising typical and atypical melting curves... with expert annotation (positive or negative calls) during the development of the original FilmArray RP." A specific number for this training set is not explicitly provided in the given text, but it's described as "large" and stemming from the development of the original FilmArray RP.
Other aspects of the FilmArray RP2plus development: The document hints at iterative development and testing, but a distinct "training set" in the context of machine learning for all aspects of the device is not detailed. The performance evaluations presented are essentially "test set" evaluations against defined ground truths.

9. How the ground truth for the training set was established:

Melt Detector Algorithm Training: The ground truth for the "large data set comprising typical and atypical melting curves" used to tune the Melt Detector algorithm was established through "expert annotation (positive or negative calls)." The qualifications of these experts are not explicitly stated.

Summary

Regulation Number and Section

§ 866.4001 A multiplex respiratory panel to detect and identify emerging respiratory pathogen(s) and common respiratory pathogens in human clinical specimens.

(a)
Identification. A multiplex respiratory panel to detect and identify emerging respiratory pathogen(s) and common respiratory pathogens in human clinical specimens is identified as an in vitro diagnostic device intended for the qualitative detection and identification of both emerging and common respiratory pathogens from individuals meeting specific emerging respiratory pathogen clinical and/or epidemiological criteria. For example, clinical signs and symptoms associated with infection of the emerging respiratory pathogen, contact with a probable or confirmed emerging respiratory pathogen case, history of travel to geographic locations where cases of the emerging respiratory pathogen were detected, or other epidemiological links for which testing of the emerging respiratory pathogen may be indicated. A device to detect and identify emerging respiratory pathogen(s) and common respiratory pathogens in human clinical specimens, and in turn to distinguish emerging respiratory pathogen(s) from common respiratory pathogens, is intended to aid in the differential diagnosis of the emerging respiratory pathogen infection, in conjunction with other clinical, epidemiologic, and laboratory data, in accordance with the guidelines provided by the appropriate public health authorities.(b)
Classification. Class II (special controls). The special controls for this device are:(1) The intended use for the labeling required under § 809.10 of this chapter must include a description of what the device detects and measures, the specimen types, the results provided to the user, the clinical indications for which the test is to be used, the specific intended population(s), the testing location(s) where the device is to be used (if applicable), and other conditions of use as appropriate.
(2) The labeling required under § 809.10 of this chapter must include:
(i) A device description, including the parts that make up the device, ancillary reagents required but not provided, and an explanation of the methodology.
(ii) Performance characteristics from analytical studies, including cut-off (if applicable), analytical sensitivity (
i.e., limit of detection), inclusivity, reproducibility, interference, cross-reactivity, instrument carryover/cross-contamination (if applicable), and specimen stability.(iii) Detailed instructions for minimizing the risk of potential users' exposure to the emerging respiratory pathogen(s) that may be present in test specimens and those used as control materials.
(iv) Detailed instructions for minimizing the risk of generating false positive test results due to carry-over contamination from positive test specimens and/or positive control materials.
(v) A warning statement that the interpretation of test results requires experienced healthcare professionals who have training in principles and use of infectious disease diagnostics and reporting of results, in conjunction with the patient's medical history, clinical signs and symptoms, and the results of other diagnostic tests.
(vi) A warning statement that culture should not be attempted in cases of positive results for an emerging respiratory pathogen unless a facility with an appropriate level of laboratory biosafety (
e.g., BSL 3 and BSL 3+) is available to receive and culture specimens.(vii) A warning statement that device positive results for one or more common respiratory pathogens do not rule out bacterial infection, or co-infection with other common respiratory pathogens.
(viii) A warning statement that respiratory pathogen(s) detected may not be the definite cause of disease.
(ix) A warning statement that the use of additional laboratory testing (
e.g. bacterial culture, immunofluorescence, x-ray findings) and clinical presentation must be taken into consideration in order to obtain the final diagnosis of a respiratory infection.(x) A limiting statement that device negative results for the common respiratory pathogens do not preclude infection of a respiratory pathogen and should not be used as the sole basis for diagnosis, treatment, or other patient management decisions.
(xi) A limiting statement that analyte targets (
e.g., pathogen nucleic acid sequences or other molecular signatures) may persist in vivo, independent of organism viability. Detection of analyte target(s) does not imply that the corresponding pathogen(s) is infectious, nor is the causative agent(s) for clinical symptoms.(xii) A limiting statement that detection of pathogen nucleic acid sequences or other molecular signatures is dependent upon proper specimen collection, handling, transportation, storage and preparation. Failure to observe proper procedures in any one of these steps can lead to incorrect results. There is a risk of false negative values resulting from improperly collected, transported, or handled specimens.
(xiii) A limiting statement that there is a risk of false positive values resulting from cross-contamination by target organisms, their nucleic acids or amplified product, or from non-specific signals in the assay.
(xiv) A limiting statement that there is a risk of false negative results due to the presence of nucleic acid sequence variants in the pathogen targets of the device.
(xv) A limiting statement that device performance was not established in immunocompromised patients.
(xvi) A limiting statement that positive and negative predictive values are highly dependent on prevalence. The device performance was established during one or more specific respiratory seasons. The performance for some respiratory pathogens may vary depending on the prevalence and patient population tested. False positive test results are likely when prevalence of disease due to a particular respiratory pathogen is low or non-existent in a community.
(xvii) In situations where the performance of the device was estimated based largely on testing pre-selected banked retrospective clinical specimens and/or contrived clinical specimen, a limiting statement that the estimated device performance of that specific pathogen or pathogen subtype may not reflect the performance or prevalence in the intended use population.
(xviii) For devices with an intended use that includes detection of emerging respiratory pathogen(s), a limiting statement that testing with the device should not be performed unless the patient meets clinical and/or epidemiologic criteria for testing suspected specimens of the emerging respiratory pathogen.
(xix) For devices with an intended use that includes detection of emerging respiratory pathogen(s), a limiting statement that positive results obtained with the device for the emerging respiratory pathogen are for the presumptive identification of that pathogen and that the definitive identification of the emerging respiratory pathogen requires additional testing and confirmation procedures in consultation with the appropriate public health authorities (
e.g., local or state public health departments) for whom reporting is necessary.(xx) For devices with an intended use that includes detection of emerging respiratory pathogen(s), a limiting statement that negative results for the emerging respiratory pathogen, even in the context of device positive results for one or more of the common respiratory pathogens, do not preclude infection with the emerging respiratory pathogen and should not be used as the sole basis for patient management decisions.
(xxi) For devices with an intended use that includes detection of emerging respiratory pathogen(s), a limiting statement that negative results for the emerging respiratory pathogen may be due to infection of the emerging respiratory pathogen at a specific respiratory tract location that may not be detected by a particular clinical specimen type. A negative result for the emerging respiratory pathogen in an asymptomatic individual does not rule out the possibility of future illness and does not demonstrate that the individual is not infectious.
(xxii) For devices with an intended use that includes detection of emerging respiratory pathogen(s), a limiting statement that a nationally notifiable Rare Disease of Public Health Significance caused by an emerging respiratory pathogen must be reported, as appropriate, to public health authorities in accordance with local, state, and federal law.
(3) Design verification and validation must include:
(i) Performance results of an appropriate clinical study (
e.g., a prospective clinical study) for each specimen type, and, if appropriate, results from additional characterized samples. The clinical study must be performed on a study population consistent with the intended use population and must compare the device performance to results obtained using FDA-accepted comparator methods or to expected negative results if the infection is not generally expected in the intended use population. Clinical specimens evaluated in the study must contain relevant organism concentrations applicable to the specimen type(s) and the targeted analyte(s). 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.(ii) For devices with an intended use that includes detection of emerging respiratory pathogen(s) for which an FDA recommended panel is available, design verification and validation must include the performance results of an analytical study testing an FDA recommended reference panel of characterized samples that contain the emerging respiratory pathogen. 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.
(iii) An appropriate risk mitigation strategy, including a detailed description of all procedures and methods, for the post-market identification of genetic mutations and/or novel respiratory pathogen isolates or strains (
e.g., regular review of published literature and annual in silico analysis of target sequences to detect possible mismatches. The required documentation for this device must also include all of the results, including any findings, from the application of this post-market mitigation strategy.(iv) For devices with an intended use that includes detection of multiple common respiratory pathogens, in addition to detecting emerging respiratory pathogen(s) in human clinical specimens, a detailed description of the identity, phylogenetic relationship, or other recognized characterization of the common respiratory pathogens that the device is designed to detect is addressed. Also, address in detail how the device results might be used in a diagnostic algorithm and other measures that might be needed for a laboratory diagnosis of respiratory tract infection. Perform 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.
(v) A detailed device description, including the parts that make up the device, 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), 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 and appropriate.(vi) A detailed description of the device software, including software applications and hardware-based devices that incorporate software.
(vii) For devices with an intended use that includes detection of Influenza A and Influenza B viruses and/or detection and differentiate between the Influenza A virus subtypes in human clinical specimens, in addition to detecting emerging respiratory pathogen(s), 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. Perform 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.
(4) For devices with an intended use that includes detection of Influenza A and Influenza B viruses and/or detection and differentiate between the Influenza A virus subtypes in human clinical specimens, in addition to detecting emerging respiratory pathogen(s), the labeling required under § 809.10 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. When other Influenza A viruses are emerging, performance characteristics may vary.
(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 required under § 809.10(b)(9) of this chapter must include a clear interpretation instruction for all valid and invalid output combinations, and recommendations for any required follow up 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 (
e.g., 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.(5) The manufacturer must perform annual analytical reactivity testing of the device with contemporary influenza strains. This annual analytical reactivity testing must meet the following criteria:
(i) The appropriate strains to be tested will be identified by FDA in consultation with the Centers for Disease Control and Prevention (CDC) and sourced from CDC or an FDA designated source. If the annual strains are not available from CDC, FDA will identify an alternative source for obtaining the requisite strains.
(ii) The testing must be conducted according to a standardized protocol considered and determined by FDA to be acceptable and appropriate.
(iii) By July 31 of each calendar year, the results of the last 3 years of annual analytical reactivity testing must be included as part of the device's labeling. If a device has not been on the market long enough for 3 years of annual analytical reactivity testing to have been conducted since the device received marketing authorization from FDA, then the results of every annual analytical reactivity testing since the device received marketing authorization from FDA must be included. The results must be presented as part of the device's labeling in a tabular format, which includes the detailed information for each virus tested as described in the certificate of authentication, either by:
(A) Placing the results directly in the device's labeling required under § 809.10(b) of this chapter that physically accompanies the device in a separate section of the labeling where the analytical reactivity testing data can be found; or
(B) In the device's label or in other labeling that physically 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 home page, as well as the primary part of the manufacturer's website that discusses the device, must provide a prominently placed hyperlink to the web page containing this information and must allow unrestricted viewing access.
(6) If one of the actions listed at section 564(b)(1)(A)-(D) of the FD&C Act occurs with respect to an influenza viral strain, or if the Secretary of Health and Human Services (HHS) 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 viral samples in accordance with a standardized protocol considered and determined by FDA to be acceptable and appropriate. The procedure and location of testing may depend on the nature of the emerging virus.
(ii) Within 60 days from the date that FDA notifies manufacturers that characterized 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 physically 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 physically 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 home page, as well as the primary part of the manufacturer's website that discusses the device, must provide a prominently placed hyperlink to the web page containing this information and must allow unrestricted viewing access.