The BIOFIRE FILMARRAY Pneumonia Panel (BIOFIRE Pneumonia Panel) is a multiplexed nucleic acid test intended for use with BIOFIRE FILMARRAY 2.0 (BIOFIRE 2.0) or BIOFIRE FILMARRAY TORCH (BIOFIRE TORCH) systems for the simultaneous detection of multiple respiratory viral and bacterial nucleic acids, as well as select antimicrobial resistance genes, in sputum-like speciorated sputum, or endotracheal aspirates) or bronchoalveolar lavage (BAL)-like specimens (BAL) obtained from individuals suspected of lower respiratory tract infection.

The following bacteria are reported semi-quantitatively with bins representing approximately 10^4, 10^5, or ≥10°7 genomic copies of bacterial nucleic acid per milliliter (copies/mL) of specimen, to aid in estimating relative abundance of nucleic acid from these common bacteria within a specimen:

Bacteria reported with bins of 10^4, 10^5, 10^6, or ≥10^7 copies/mL

· Acinetobacter calcoaceticus-baumannii complex
· Klebsiella oxytoca
· Serratia marcescens
· Enterobacter cloacae complex
Klebsiella pneumoniae group
· Staphylococcus aureus
· Escherichia coli
· Moraxella catarrhalis
· Streptococcus agalactiae
Haemophilus influenzae
· Proteus spp.
· Streptococcus pneumoniae
Klebsiella aerogenes
Pseudomonas aeruginosa
· Streptococcus pyogenes

The following atypical bacteria, viruses, and antimicrobial resistance genes are reported qualitatively:

Atypical Bacteria

Chlamydia pneumoniae
· Legionella pneumophila
Mycoplasma pneumoniae

Viruses

· Adenovirus
Human rhinovirus/enterovirus
· Parainfluenza virus
· Coronavirus
· Influenza A virus
Respiratory syncytial virus

• Human metapneumovirus

Influenza B virus
Antimicrobial Resistance Genes
· CTX-M
IMP
КРС
NDM
OXA-48-like
VIM
· mecA/C and MREJ (MRSA)

The detection and identification of specific viral and bacterial nucleic acids, as well as the estimation of relative abundance of nucleic acid from common bacterial analytes, within specimens collected from individuals exhibiting signs and/or symptoms of a respiratory infection, aids in the diagnosis of lower respiratory infection with other clinical and epidemiological information. The results of this test should not be used as for diagnosis, treatment, or other patient management decisions.

Negative results in the setting of a respiratory illness may be due to infection with pathogens that are not detected by this test, pathogens below the limit of detection, or in the case of bacterial analytes, present at levels below the lowest reported 10^4 copies/mL bin. Detection of analytes does not rule out co-infection with other organisms; the agent(s) detected by the BIOFIRE Pneumonia Panel may not be the definite cause of disease. Additional laboratory testing (e.g. bacterial and viral culture, immunofluorescence, and radiography) may be necessary when evaluating a patient with possible lower respiratory tract infection.

Detection of bacterial nucleic acid may be indicative of colonizing or normal respiratory flora and may not indicate the causative agent of pneumonia. Semi-quantitative Bin (copies/mL) results generated by the BIOFIRE Pneumonia Panel are not equivalent to CFU/mL and do not consistently correlate with the quantity of bacterial analytes compared to CFU/mL. For specimens with multiple bacteria detected, the relative abundance of nucleic acids (copies/mL) may not correlate with the relative abundance of bacteria as determined by culture (CFU/mL). Clinical correlation is advised to determine significance of semi-quantitative Bin (copies/mL) for clinical management.

The antimicrobial resistance gene detected may or may not be associated with the agent(s) responsible for disease. Negative results for these antimicrobial resistance gene assays do not indicate susceptibility to corresponding classes of antimicrobials, as multiple mechanisms of antimicrobial resistance exist.

Antimicrobial resistance can occur via multiple mechanisms. A "Not Detected" result for a genetic marker of antimicrobial resistance does not indicate susceptibility to associated antimicrobial drugs or drug classes. A "Detected" result for a genetic marker of antimicrobial resistance cannot be definitively linked to the microorganism(s) detected. Culture is required to obtain isolates for antimicrobial susceptibility testing, and BIOFIRE Pneumonia Panel results should be used in conjunction with culture results for determination of bacterial susceptibility or resistance.

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

Culture is required to identify pathogens not detected by the BIOFIRE Pneumonia Panel, to further speciate analytes in genus, complex, or group results if desired, to identify bacterial pathogens present below the 10°4 copies/mL bin if desired, and for antimicrobial susceptibility testing.

BIOFIRE FILMARRAY Pneumonia Panel plus:

The BIOFIRE FILMARRAY Pneumonia Panel plus (BIOFIRE Pneumonia Panel plus) is a multiplexed nucleic acid test intended for use with BIOFIRE FILMARRAY 2.0 (BIOFIRE 2.0) or BIOFIRE FILMARRAY TORCH (BIOFIRE TORCH) systems for the simultaneous detection and identification of nucleic acids from Middle East respiratory syndrome coronavirus (MERS-CoV) and multiple respiratory viral and bacterial nucleic acids, as well as select antimicrobial resistance genes, in sputum-like specimens (induced or expectorated sputum, or endotracheal aspirates) or bronchoalveolar lavage (BAL)-like specimens (BAL or mini-BAL) obtained from individuals meeting MERS-CoV clinical and/or epidemiological criteria.

Testing with BIOFIRE Pneumonia Panel plus should not be performed unless the patient meets clinical and/or epidemiologic criteria for testing suspected MERS-CoV specimens. Thical signs and symptoms assocated 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.

Bacteria reported with bins of 10^4, 10^5, 10^6, or ≥10^7 copies/mL

Acinetobacter calcoaceticus-baumannii complex
Enterobacter cloacae complex
Escherichia coli
Haemophilus influenzae
Klebsiella aerogenes
· Klebsiella oxytoca
· Klebsiella pneumoniae group
Moraxella catarrhalis
Proteus spp.
Pseudomonas aeruginosa
· Serratia marcescens
Staphylococcus aureus
Streptococcus agalactiae
· Streptococcus pneumoniae
· Streptococcus pyogenes

The following atypical bacteria, viruses, and antimicrobial resistance genes are reported qualitatively: Atypical Bacteria

Chlamydia pneumoniae
· Legionella pneumophila
Mycoplasma pneumoniae

Viruses

· Middle East respiratory syndrome coronavirus (MERS-CoV)
Adenovirus
Coronavirus
Human metapneumovirus
Human rhinovirus/enterovirus
· Influenza A virus
Influenza B virus
Parainfluenza virus
· Respiratory syncytial virus

Antimicrobial Resistance Genes

CTX-M
IMP
· KPC
NDM
OXA-48-like
VIM
· mecA/C and MREJ (MRSA)

The detection and identification of specific viral and bacterial nucleic acids from MERS-CoV and other respiratory pathogens, as well as the estimation of relative abundance of nucleic acid from common bacterial analytes, within specimens collected from 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.

BIOFIRE Pneumonia Panel plus 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.

BIOFIRE Pneumonia Panel plus MERS-CoV negative results, even in the context of a BIOFIRE Pneumonia Panel plus 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 sputum-like or BAL-like specimens from individuals with early infection and from asymptomatic MERS-CoV carriers are not well understood. A negative BIOFIRE Pneumonia Panel plus 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 on specimens with positive BIOFIRE Pneumonia Panel plus results for MERS-CoV unless a BSL 3 facility is available to receive and culture specimens.

Negative results in the setting of a respiratory illness may be due to infection with pathogens that are not detected by this test, pathogens below the limit of detection, or in the case of bacterial analytes, present at levels below the lowest reported 10^4 copies/mL bin. Detection of analytes does not rule out co-infection with other organisms; the agent(s) detected by the BIOFIRE Pneumonia Panel plus may not be the definite cause of disease. Additional laboratory testing (e.g. bacterial and viral culture, immunofluorescence, and radiography) may be necessary when evaluating a patient with possible lower respiratory tract infection.

Detection of bacterial nucleic acid may be indicative of colonizing or normal respiratory flora and may not indicate the causative agent of pneumonia. Semi-quantitative Bin (copies/mL) results generated by the BIOFIRE Pneumonia Panel plus are not equivalent to CFU/mL and do not consistently correlate with the quantity of bacterial analytes compared to CFU/mL. For specimens with multiple bacteria detected, the relative abundance of nucleic acids (copies/mL) may not correlate with the relative abundance of bacteria as determined by culture (CFU/mL). Clinical correlation is advised to determine significance of semi-quantitative Bin (copies/mL) for clinical management.

Antimicrobial resistance can occur via multiple mechanisms. A "Not Detected" result for a genetic marker of antimicrobial resistance does not indicate susceptibility to associated antimicrobial drugs or drug classes. A "Detected" result for a genetic marker of antimicrobial resistance cannot be definitively linked to the microorganism(s) detected. Culture is required to obtain isolates for antimicrobial susceptibility testing, and BIOFIRE Pneumonia Panel plus results should be used in conjunction with culture results for determination of bacterial susceptibility or resistance.

Culture is required to identify pathogens not detected by the BIOFIRE Pneumonia Panel plus, to further speciate analytes in genus, complex, or group results if desired, to identify bacterial pathogens present below the 10°4 copies/mL bin if desired, and for antimicrobial susceptibility testing.

Device Description

The BIOFIRE® FILMARRAY® Pneumonia Panel and BIOFIRE® FILMARRAY® Pneumonia Panel plus use nested, multiplex reverse transcription polymerase chain reaction (PCR), followed by melting curve analysis for the detection of select organisms and antimicrobial resistance (AMR) genes in sputum-like (induced and expectorated sputum as well as endotracheal aspirate, ETA) and bronchoalveolar lavage (BAL)-like (BAL and mini-BAL) specimens. The panels allow for the identification of specific bacteria, atypical bacteria, viruses, and AMR genes as indicated in Table 1. The BIOFIRE Pneumonia Panel and BIOFIRE Pneumonia Panel plus pouches are identical, but the BIOFIRE Pneumonia Panel plus includes reporting of Middle East Respiratory Syndrome Coronavirus (MERS-CoV), which is not included in the BIOFIRE Pneumonia Panel. Reporting of MERS-CoV is controlled through software masking of the MERS-CoV result for the BIOFIRE Pneumonia Panel.

The BIOFIRE Pneumonia Panels are compatible with bioMérieux's PCR-based in vitro diagnostic BIOFIRE® FILMARRAY® 2.0 and BIOFIRE® FILMARRAY® TORCH Systems for infectious disease testing. Specific software module (i.e. BIOFIRE Pneumonia Panel Pouch Module Software) are used to perform BIOFIRE Pneumonia Panels testing on these systems.

AI/ML Overview

This document refers to a 510(k) premarket notification for a medical device (BIOFIRE FILMARRAY Pneumonia Panel and BIOFIRE FILMARRAY Pneumonia Panel plus). This type of submission focuses on demonstrating substantial equivalence to a legally marketed predicate device rather than presenting a full de novo study with strict acceptance criteria and performance validation against a test set. The document clearly states that the submission is for software updates to mitigate false positive Coronavirus and CTX-M results and that "Reanalysis of the performance data with the modified pouch module software did not result in an overall change of the study conclusions or performance claims for non-clinical/analytical studies."

Therefore, the information typically requested in your prompt regarding acceptance criteria, study details, sample sizes, expert ground truth establishment, MRMC studies, and standalone performance might not be explicitly detailed in this type of FDA submission as it would be for a de novo marketing authorization. However, I can extract what is available and clarify what is not.

Based on the provided text, here's a breakdown of the requested information:

1. A table of acceptance criteria and the reported device performance

The document does not explicitly state formal "acceptance criteria" in a quantitative table format as might be seen for a new device submission. Instead, the focus is on the impact of the software update on existing performance. The relevant performance change mentioned is:

Performance Metric	Previous Performance (without software update)	Reported Performance (with software update)
Clinical specificity/NPA of Coronavirus assay in BAL specimens	98.4%	98.7%
Clinical specificity/NPA of Coronavirus assay in Sputum specimens	99.3%	99.5%

The document implies that these updated specificities are acceptable because they represent an improvement in mitigating false positives and "did not result in an overall change of the study conclusions or performance claims for non-clinical/analytical studies."

2. Sample sizes used for the test set and the data provenance (e.g. country of origin of the data, retrospective or prospective)

The document mentions a "Clinical Prospective Study" for which the Coronavirus specificity numbers are reported. It does not provide the exact sample size for this specific study, nor does it explicitly state the country of origin. It indicates that the reanalysis of existing performance data was done.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g. radiologist with 10 years of experience)

This information is not provided in the document. As this is a molecular diagnostic test, ground truth would typically be established by highly sensitive and specific laboratory methods (e.g., PCR, sequencing, culture) rather than expert human interpretation in the way radiologists interpret images.

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

This information is not provided.

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

An MRMC study is not applicable here as this is a molecular diagnostic device, not an AI-assisted diagnostic imaging device that involves human reader interpretation.

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

This refers to the performance of the assay itself. The document implicitly discusses the "standalone" performance of the BIOFIRE FILMARRAY Pneumonia Panel and Panel Plus, which is a molecular diagnostic test. The reported specificities are a measure of this standalone performance. The software update is an internal modification to the assay's interpretation logic.

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

The document implies that the ground truth for the clinical performance evaluations was established through highly sensitive and specific methods for pathogen detection, as is standard clinical laboratory practice for molecular diagnostics. It does not explicitly state the specific ground truth methods but mentions that "Culture is required to obtain isolates for antimicrobial susceptibility testing, and BIOFIRE Pneumonia Panel results should be used in conjunction with culture results for determination of bacterial susceptibility or resistance." This suggests that culture and other definitive laboratory tests would be part of the ground truth establishment, particularly for bacterial analytes and antimicrobial resistance genes.

8. The sample size for the training set

This document describes a software update to an already cleared device. It does not provide details about a "training set" in the context of machine learning model development. The software update appears to be a rule-based or algorithmic adjustment to optimize melting curve analysis and mitigate cross-reactivity with human genomic DNA, rather than a re-training of a complex AI model. The modification was driven by "routine post-market monitoring and complaint investigations combined with concurrent findings from an internal product development study."

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

As there's no mention of a traditional "training set" in the context of an AI model, this information is not provided. The "ground truth" that informed the software change was likely observations of false positives in clinical samples, identified through investigations and potentially confirmed by orthogonal testing or characterization of the offending interactions (cross-reactivity with hgDNA).

Summary

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November 6, 2024

BioFire Diagnostics, LLC (bioMerieux) Karli Plenert Director, Regulatory Affairs 515 Colorow Drive Salt Lake City, Utah 84108

Re: K243222

Trade/Device Name: BIOFIRE FILMARRAY Pneumonia Panel (BIOFIRE Pneumonia Panel); BIOFIRE FILMARRAY Pneumonia Panel plus (BIOFIRE Pneumonia Panel plus) Regulation Number: 21 CFR 866.4001 Regulation Name: A Multiplex Respiratory Panel To Detect And Identify Emerging Respiratory Pathogen(S) And Common Respiratory Pathogens In Human Clinical Specimens Regulatory Class: Class II Product Code: ODS. ODP Dated: October 3, 2024 Received: October 7, 2024

Dear Karli Plenert:

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 (the 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 available 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.

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Additional information about changes that may require a new premarket notification are provided in the FDA guidance documents entitled "Deciding When to Submit a 510(k) for a Change to an Existing Device" (https://www.fda.gov/media/99812/download) and "Deciding When to Submit a 510(k) for a Software Change to an Existing Device" (https://www.fda.gov/media/99785/download).

Your device is also subject to, among other requirements, the Quality System (OS) regulation (21 CFR Part 820), which includes, but is not limited to, 21 CFR 820.30, Design controls; 21 CFR 820.90, Nonconforming product; and 21 CFR 820.100, Corrective and preventive action. Please note that regardless of whether a change requires premarket review, the QS regulation requires device manufacturers to review and approve changes to device design and production (21 CFR 820.30 and 21 CFR 820.70) and document changes and approvals in the device master record (21 CFR 820.181).

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 Part 803) for devices or postmarketing safety reporting (21 CFR Part 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safetyreporting-combination-products); good manufacturing practice requirements as set forth in the quality systems (OS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR Part 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR Parts 1000-1050.

All medical devices, including Class I and unclassified devices and combination product device constituent parts are required to be in compliance with the final Unique Device Identification System rule ("UDI Rule"). The UDI Rule requires, among other things, that a device bear a unique device identifier (UDI) on its label and package (21 CFR 801.20(a)) unless an exception or alternative applies (21 CFR 801.20(b)) and that the dates on the device label be formatted in accordance with 21 CFR 801.18. The UDI Rule (21 CFR 830.300(a) and 830.320(b)) also requires that certain information be submitted to the Global Unique Device Identification Database (GUDID) (21 CFR Part 830 Subpart E). For additional information on these requirements, please see the UDI System webpage at https://www.fda.gov/medical-device-advicecomprehensive-regulatory-assistance/unique-device-identification-system-udi-system.

Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR 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-regulatory

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assistance/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,

Digitally signed by Bryan M. Bryan M. Grabias -S Grabias -> 14:35:01 -05'00' Bryan Grabias, Ph. D. Acting 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) K243222

Device Name

BIOFIRE FILMARAY Pneumonia Panel (BIOFIRE Pneumonia Panel); BIOFIRE FILMARRAY Pneumonia Panel plus (BIOFIRE Pneumonia Panel plus)

Indications for Use (Describe)

BIOFIRE FILMARRAY Pneumonia Panel:

Bacteria reported with bins of 10^4, 10^5, 10^6, or ≥10^7 copies/mL

· Acinetobacter calcoaceticus-baumannii complex
· Klebsiella oxytoca
· Serratia marcescens
· Enterobacter cloacae complex
Klebsiella pneumoniae group
· Staphylococcus aureus
· Escherichia coli
· Moraxella catarrhalis
· Streptococcus agalactiae
Haemophilus influenzae
· Proteus spp.
· Streptococcus pneumoniae
Klebsiella aerogenes
Pseudomonas aeruginosa
· Streptococcus pyogenes

The following atypical bacteria, viruses, and antimicrobial resistance genes are reported qualitatively:

Atypical Bacteria

Chlamydia pneumoniae
· Legionella pneumophila
Mycoplasma pneumoniae

Viruses

· Adenovirus
Human rhinovirus/enterovirus
· Parainfluenza virus
· Coronavirus
· Influenza A virus
Respiratory syncytial virus

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• Human metapneumovirus

Influenza B virus
Antimicrobial Resistance Genes
· CTX-M
IMP
КРС
NDM
OXA-48-like
VIM
· mecA/C and MREJ (MRSA)

BIOFIRE FILMARRAY Pneumonia Panel plus:

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TORCH) systems for the simultaneous detection and identification of nucleic acids from Middle East respiratory syndrome coronavirus (MERS-CoV) and multiple respiratory viral and bacterial nucleic acids, as well as select antimicrobial resistance genes, in sputum-like specimens (induced or expectorated sputum, or endotracheal aspirates) or bronchoalveolar lavage (BAL)-like specimens (BAL or mini-BAL) obtained from individuals meeting MERS-CoV clinical and/or epidemiological criteria.

Bacteria reported with bins of 10^4, 10^5, 10^6, or ≥10^7 copies/mL

Acinetobacter calcoaceticus-baumannii complex
Enterobacter cloacae complex
Escherichia coli
Haemophilus influenzae
Klebsiella aerogenes
· Klebsiella oxytoca
· Klebsiella pneumoniae group
Moraxella catarrhalis
Proteus spp.
Pseudomonas aeruginosa
· Serratia marcescens
Staphylococcus aureus
Streptococcus agalactiae
· Streptococcus pneumoniae
· Streptococcus pyogenes

The following atypical bacteria, viruses, and antimicrobial resistance genes are reported qualitatively: Atypical Bacteria

Chlamydia pneumoniae
· Legionella pneumophila
Mycoplasma pneumoniae

Viruses

· Middle East respiratory syndrome coronavirus (MERS-CoV)
Adenovirus
Coronavirus
Human metapneumovirus
Human rhinovirus/enterovirus
· Influenza A virus
Influenza B virus
Parainfluenza virus
· Respiratory syncytial virus

Antimicrobial Resistance Genes

CTX-M
IMP

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· KPC
NDM
OXA-48-like
VIM
· mecA/C and MREJ (MRSA)

Viral culture should not be attempted on specimens with positive BIOFIRE Pneumonia Panel plus results for MERS-CoV unless a BSL 3 facility is available to receive and culture specimens.

Negative results in the setting of a respiratory illness may be due to infection with pathogens that are not detected by this test, pathogens below the limit of detection, or in the case of bacterial analytes, present at levels below the lowest reported 10^4 copies/mL bin. Detection of analytes does not rule out co-infection with other organisms; the agent(s) detected by the BIOFIRE Pneumonia Panel plus may not be the definite cause of disease. Additional laboratory testing (e.g. bacterial and viral culture, immunofluorescence, and radiography) may be necessary when evaluating a patient with possible lower respiratory tract infection.

Detection of bacterial nucleic acid may be indicative of colonizing or normal respiratory flora and may not indicate the causative agent of pneumonia. Semi-quantitative Bin (copies/mL) results generated by the BIOFIRE Pneumonia Panel plus are not equivalent to CFU/mL and do not consistently correlate with the quantity of bacterial analytes compared to CFU/mL. For specimens with multiple bacteria detected, the relative abundance of nucleic acids (copies/mL) may not correlate with the relative abundance of bacteria as determined by culture (CFU/mL). Clinical correlation is advised to determine significance of semi-quantitative Bin (copies/mL) for clinical management.

Antimicrobial resistance can occur via multiple mechanisms. A "Not Detected" result for a genetic marker of antimicrobial resistance does not indicate susceptibility to associated antimicrobial drugs or drug classes. A "Detected" result for a genetic marker of antimicrobial resistance cannot be definitively linked to the microorganism(s) detected. Culture is required to obtain isolates for antimicrobial susceptibility testing, and BIOFIRE Pneumonia Panel plus results should be used in conjunction with culture results for determination of bacterial susceptibility or resistance.

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Type of Use (Select one or both, as applicable)

X Prescription Use (Part 21 CFR 801 Subpart D)

Over-The-Counter Use (21 CFR 801 Subpart C)

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Image /page/8/Picture/0 description: The image shows the logo for bioMérieux, a French multinational biotechnology company. The logo consists of a blue circle at the top, with the company name "BIOMÉRIEUX" in white letters inside. The bottom half of the circle is split into two colors, yellow and green, with a white horizontal line separating the top and bottom halves of the circle.

BIOFIRE® FILMARRAY® Pneumonia Panel BIOFIRE® FILMARRAY® Pneumonia Panel plus

Special 510(k) Summary BioFire Diagnostics, LLC

Introduction:

The content of this Special 510(k) submission is limited to obtaining FDA clearance for the BIOFIRE® FILMARRAY® Pneumonia Panel (BIOFIRE Pneumonia Panel) (K212727) and the BIOFIRE® FILMARRAY® Pneumonia Panel plus (BIOFIRE Pneumonia Panel plus) (K222601) with software updates to mitigate the risk of false positive Coronavirus and CTX-M results.

According to the requirements of 21 CFR 807.92, the following information provides sufficient detail to understand the basis for a determination of substantial equivalence.

Submitted by:

BioFire Diagnostics, LLC (bioMérieux) 515 Colorow Drive Salt Lake City, UT 84108

Contact: Karli Plenert, MBA Telephone: +1 385-414-4985 Email: Karli.Plenert@biomerieux.com

Date Submitted: November 5, 2024

Device Name and Classification:

Trade Name: BIOFIRE FILMARRAY Pneumonia Panel (BIOFIRE Pneumonia Panel)

Regulation Number: 21 CFR 866.3985 ●
Classification Name: Device to detect and identify microorganisms and associated resistance ● marker nucleic acids directly in respiratory specimens

Trade Name: BIOFIRE FILMARRAY Pneumonia Panel plus (BIOFIRE Pneumonia Panel plus)

Requlation Number: 21 CFR 866.4001 ●
. Classification Name: MERS-CoV and common respiratory pathogens semi-quantitative and quantitative multiplex nucleic acid detection system

Predicate Devices:

K212727 BIOFIRE FILMARRAY Pneumonia Panel (BIOFIRE Pneumonia Panel) ●
K222601 BIOFIRE FILMARRAY Pneumonia Panel plus (BIOFIRE Pneumonia Panel plus) ●

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Background:

Routine post-market monitoring and complaint investigations combined with concurrent findings from an internal product development study identified a previously unrecognized risk and/or rate of false positive Coronavirus (CoV) results on the BIOFIRE Pneumonia Panel and BIOFIRE Pneumonia Panel plus.

A corrective and preventative action (CAPA) investigation was initiated and a field safety notice indicating a risk of false positive Coronavirus results was issued for the BIOFIRE Pneumonia Panel and BIOFIRE Pneumonia Panel plus (FDA Recall Event # 93592 (Z-0993-2024).

The internal study also identified several runs with a unique amplicon melt profile for the CTX-M assay. This profile corresponded to a higher than anticipated rate of positive CTX-M assay results (suspected false positive) for the panel under development. A higher rate of positive CTX-M assay results associated with this melt profile has not been observed in the field with the BIOFIRE Pneumonia Panel and BIOFIRE Pneumonia Panel plus, but the risk for these panels was investigated as a precaution.

Investigations concluded that there is a risk for false positive CoV results as a consequence of non-specific interactions (cross-reactivity) between panel primers and high levels of human genomic DNA (hgDNA) present in some lower respiratory samples tested by the BIOFIRE Pneumonia Panel and BIOFIRE Pneumonia Panel plus. It was concluded that the CTX-M assay can also cross-react with high levels of hgDNA, but the non-specific amplicon melt is routinely excluded (called negative) by the existing analysis.

The BIOFIRE Pneumonia Panel and BIOFIRE Pneumonia Panel plus pouch modules (software) have been updated to mitigate the risk of false positive CoV results from cross-reactivity with hgDNA, and to further protect against a risk of false CTX-M results from hgDNA cross-reactivity. The software change does not impact the performance and analysis of the other analytes detected by the panels.

Software Update:

	Previous Version	Updated Version
BIOFIRE Pneumonia Panel Pouch Module Software	v2.0 – v2.1.3	v2.0 – v2.1.4
BIOFIRE Pneumonia Panel plus Pouch Module	v2.0 – v2.1.0	v2.0 – v2.1.1

The software update includes modifications to the software analysis parameters of the BIOFIRE Pneumonia Panel Pouch Module and BIOFIRE Pneumonia Panel plus Pouch Module.

Reanalysis of the performance data with the modified pouch module software did not result in an overall change of the study conclusions or performance claims for non-clinical/analytical studies. While mitigated by the software modification, a description of the cross-reactivity with human genomic DNA has been added to the Analytical Specificity (exclusivity) study. For the clinical performance evaluations, there was a slight increase in the clinical specificity/NPA of the Coronavirus assay from 98.4% to 98.7% in BAL specimens and from 99.3% in 99.5% in sputum specimens from the prospective evaluation. Additionally, the change in interpretation of four Coronavirus results in the Clinical Prospective Study from Detected, resulted in an update to the Expected Values data.

The additional cross-reactivity and the clinical performance changes are documented in the updated BIOFIRE Pneumonia Panel and BIOFIRE Pneumonia Panel plus IFUs.

Instructions for Use Update:

The instructions for use for both BIOFIRE Pneumonia Panels have been updated to reflect the increase in the clinical specificity/NPA of the coronavirus assay changes due to the software modification, along with additional updates to performance tables (unrelated to the software change).

The software change does not affect the intended use, design, manufacture, or labeling of the BIOFIRE Pneumonia Panel and BIOFIRE Pneumonia Panel plus reagent pouches or reagent kits.

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Intended Use: BIOFIRE FILMARRAY Pneumonia Panel

The BIOFIRE® FILMARRAY® Pneumonia Panel (BIOFIRE Pneumonia Panel) is a multiplexed nucleic acid test intended for use with BIOFIRE® FILMARRAY® 2.0 (BIOFIRE 2.0) or BIOFIRE®FILMARRAY® TORCH (BIOFIRE TORCH) systems for the simultaneous detection and identification of multiple respiratory viral and bacterial nucleic acids, as well as select antimicrobial resistance genes, in sputum-like specimens (induced or expectorated sputum, or endotracheal aspirates) or bronchoalveolar lavage (BAL)-like specimens (BAL or mini-BAL) obtained from individuals suspected of lower respiratory tract infection.

The following bacteria are reported semi-quantitatively with bins representing approximately 10^4, 10^6, or ≥10^7 genomic copies of bacterial nucleic acid per milliliter (copies/mL) of specimen, to aid in estimating relative abundance of nucleic acid from these common bacteria within a specimen:

Bacteria reported with bins of 10^4, 10^5, 10^6, or ≥10^7 copies/mL
Acinetobacter calcoaceticus-baumannii complex	Klebsiella oxytoca	Serratia marcescens
Enterobacter cloacae complex	Klebsiella pneumoniae group	Staphylococcus aureus
Escherichia coli	Moraxella catarrhalis	Streptococcus agalactiae
Haemophilus influenzae	Proteus spp.	Streptococcus pneumoniae
Klebsiella aerogenes	Pseudomonas aeruginosa	Streptococcus pyogenes

The following atypical bacteria, viruses, and antimicrobial resistance genes are reported qualitatively:

Atypical Bacteria
Chlamydia pneumoniae	Legionella pneumophila	Mycoplasma pneumoniae
Viruses
Adenovirus	Human rhinovirus/enterovirus	Parainfluenza virus
Coronavirus	Influenza A virus	Respiratory syncytial virus
Human metapneumovirus	Influenza B virus
Antimicrobial Resistance Genes
CTX-M	NDM	mecA/C and MREJ (MRSA)
IMP	OXA-48-like
KPC	VIM

The detection and identification of specific viral and bacterial nucleic acids, as well as the estimation of relative abundance of nucleic acid from common bacterial analytes, within specimens collected from individuals exhibiting signs and/or symptoms of a respiratory infection, aids in the diagnosis of lower respiratory infection if used in conjunction with other clinical and epidemiological information. The results of this test should not be used as the sole basis for diagnosis, treatment, or other patient management decisions.

Negative results in the setting of a respiratory illness may be due to infection with pathogens that are not detected by this test, pathogens below the limit of detection, or in the case of bacterial analytes, present at levels below the lowest reported 104 copies/mL bin. Detection of analytes does not rule out co-infection with other organisms; the agent(s) detected by the BIOFIRE Pneumonia Panel may not be the definite cause of disease. Additional laboratory testing (e.g. bacterial and viral culture, immunofluorescence, and radiography) may be necessary when evaluating a patient with possible lower respiratory tract infection.

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antimicrobials, as multiple mechanisms of antimicrobial resistance exist.

Antimicrobial resistance can occur via multiple mechanisms. A "Not Detected" result for a genetic marker of antimicrobial resistance does not indicate susceptibility to associated antimicrobial drugs or drug classes. A "Detected" result for a genetic marker of antimicrobial resistance cannot be definitively linked to the microorganism(s) detected. Culture is required to obtain isolates for antimicrobial susceptibility testing, and BIOFIRE Pneumonia Panel in conjunction with culture results for determination of bacterial susceptibility or resistance.

Due to the genetic similarity between human rhinovirus, the test cannot reliably differentiate them. A positive Rhinovirus result should be followed up using an alternate method (e.g., cell culture or sequence analysis) if differentiation is required.

Culture is required to identify pathogens not detected by the BIOFIRE Pneumonia Panel, to further speciate analytes in genus, complex, or group results if desired, to identify bacterial pathogens present below the 10% copies/mL bin if desired, and for antimicrobial susceptibility testing.

Intended Use: BIOFIRE FILMARRAY Pneumonia Panel plus

The BIOFIRE® FILMARRAY® Pneumonia Panel plus (BIOFIRE Pneumonia Panel plus) is a multiplexed nucleic acid test intended for use with BIOFIRE® FILMARRAY® 2.0 (BIOFIRE 2.0) or BIOFIRE® FILMARRAY® TORCH (BIOFIRE TORCH) systems for the simultaneous detection and identification of nucleic acids from Middle East respiratory syndrome coronavirus (MERS-CoV) and multiple respiratory viral and bacterial nucleic acids, as well as select antimicrobial resistance genes, in sputum-like specimens (induced or expectorated sputum, or endotracheal aspirates) or bronchoalveolar lavage (BAL)-like specimens (BAL or mini-BAL) obtained from individuals meeting MERS-CoV clinical and/or epidemiological criteria.

Testing with BIOFIRE Pneumonia Panel plus should not be 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 following bacteria are reported semi-quantitatively with bins representing approximately 10^4, 10^5, or ≥10^7 genomic copies of bacterial nucleic acid per milliliter (copies/mL) of specimen, to aid in estimating relative abundance of nucleic acid from these common bacteria within a specimen:

Bacteria reported with bins of 10^4, 10^5, 10^6, or ≥10^7 copies/mL
Acinetobacter calcoaceticus-baumannii complex	Klebsiella oxytoca	Serratia marcescens
Enterobacter cloacae complex	Klebsiella pneumoniae group	Staphylococcus aureus
Escherichia coli	Moraxella catarrhalis	Streptococcus agalactiae
Haemophilus influenzae	Proteus spp.	Streptococcus pneumoniae
Klebsiella aerogenes	Pseudomonas aeruginosa	Streptococcus pyogenes

The following atypical bacteria, viruses, and antimicrobial resistance genes are reported qualitatively:

Atypical Bacteria
Chlamydia pneumoniae	Legionella pneumophila	Mycoplasma pneumoniae
Viruses
Middle East respiratory syndrome coronavirus (MERS-CoV)
Adenovirus	Human rhinovirus/enterovirus	Parainfluenza virus
Coronavirus	Influenza A virus	Respiratory syncytial virus
Human metapneumovirus	Influenza B virus
Antimicrobial Resistance Genes
CTX-M	NDM	mecA/C and MREJ (MRSA)
IMP	OXA-48-like

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КРС

The detection and identification of specific viral and bacterial nucleic acids from MERS-CoV and other respiratory pathogens, as well as the estimation of relative abundance of nucleic acid from common bacterial analytes, within specimens collected from individuals meeting MERS-CoV clinical and/or epidemiological criterial l diagnosis of MERS-CoV infection, if used in conjunction with other clinical and epidemiological information in accordance with the quidelines provided by the appropriate public health authorities.

BIOFIRE Pneumonia Panel plus MERS-CoV negative results, even in the context of a BIOFIRE Pneumonia Panel plus 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 sputumlike or BAL-like specimens from individuals with early infection and from asymptomatic MERS-CoV carriers are not well understood. A negative BIOFIRE Pneumonia Panel plus 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 on specimens with positive BIOFIRE Pneumonia Panel plus results for MERS-CoV unless a BSL 3 facility is available to receive and culture specimens.

Negative results in the setting of a respiratory illness may be due to infection with pathogens that are not detected by this test, pathogens below the limit of detection, or in the case of bacterial analytes, present at levels below the lowest reported 104 copies/mL bin. Detection of analytes does not rule out co-infection with other organisms; the agent(s) detected by the BIOFIRE Pneumonia Panel plus may not be the definite cause of disease. Additional laboratory testing (e.g. bacterial and viral culture, immunofluorescence, and radiography) may be necessary when evaluating a patient with possible lower respiratory tract infection.

Detection of bacterial nucleic acid may be indicative of colonizing or normal respiratory flora and may not indicate the causative agent of pneumonia. Semi-quantitative Bin (copies/mL) results generated by the BIOFIRE Pneumonia Panel plus are not equivalent to CFU/mL and do not consistently correlate with the quantity of bacterial analytes compared to CFU/mL. For specimens with multiple bacteria detected, the relative abundance of nucleic acids (copies/mL) may not correlate with the relative abundance of bacteria as determined by culture (CFU/mL). Clinical correlation is advised to determine significance of semi-quantitative Bin (copies/mL) for clinical management.

Antimicrobial resistance can occur via multiple mechanisms. A "Not Detected" result for a genetic marker of antimicrobial resistance does not indicate susceptibility to associated antimicrobial drugs or drug classes. A "Detected" result for a genetic marker of antimicrobial resistance cannot be definitively linked to the microorganism(s) detected. Culture is required to obtain isolates for antimicrobial susceptibility testing, and BIOFIRE Pneumonia Panel plus results should be used in conjunction with culture results for determination of bacterial susceptibility or resistance.

Culture is required to identify pathogens not detected by the BIOFIRE Pneumonia Panel plus, to further speciate analytes in genus, complex, or group results if desired, to identify bacterial pathogens present below the 1044 copies/mL bin if desired, and for antimicrobial susceptibility testing.

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Device Description:

Device Comparison:

Table 1 outlines the similarities and differences between the modified panels and the predicate panels.

Element	Modified Device:BIOFIRE Pneumonia Panel / BIOFIRE Pneumonia Panelplus(with software update)	Predicate:BIOFIRE Pneumonia Panel (K212727) /BIOFIRE Pneumonia Panel plus(K222601)
	See Intended Use: BIOFIRE FILMARRAY Pneumonia PanelThe BIOFIRE® FILMARRAY® Pneumonia Panel (BIOFIREPneumonia Panel) is a multiplexed nucleic acid test intended foruse with BIOFIRE® FILMARRAY® 2.0 (BIOFIRE 2.0) orBIOFIRE® FILMARRAY® TORCH (BIOFIRE TORCH) systemsfor the simultaneous detection and identification of multiplerespiratory viral and bacterial nucleic acids, as well as selectantimicrobial resistance genes, in sputum-like specimens(induced or expectorated sputum, or endotracheal aspirates) orbronchoalveolar lavage (BAL)-like specimens (BAL or mini-BAL)obtained from individuals suspected of lower respiratory tractinfection.	Same
Intended Use	See Intended Use: BIOFIRE FILMARRAY Pneumonia PanelplusThe BIOFIRE® FILMARRAY® Pneumonia Panel plus (BIOFIREPneumonia Panel plus) is a multiplexed nucleic acid testintended for use with BIOFIRE® FILMARRAY® 2.0 (BIOFIRE2.0) or BIOFIRE® FILMARRAY® TORCH (BIOFIRE TORCH)systems for the simultaneous detection and identification ofnucleic acids from Middle East respiratory syndrome coronavirus(MERS-CoV) and multiple respiratory viral and bacterial nucleicacids, as well as select antimicrobial resistance genes, insputum-like specimens (induced or expectorated sputum, orendotracheal aspirates) or bronchoalveolar lavage (BAL)-likespecimens (BAL or mini-BAL) obtained from individuals meetingMERS-CoV clinical and/or epidemiological criteria.Testing with BIOFIRE Pneumonia Panel plus should not beperformed unless the patient meets clinical and/or epidemiologiccriteria for testing suspected MERS-CoV specimens. Thisincludes: clinical signs and symptoms associated with MERS-CoV infection, contact with a probable or confirmed MERS-CoVcase, history of travel to geographic locations where MERS-CoVcases were detected, or other epidemiological links for whichMERS-CoV testing may be indicated.	Same
Element	Modified Device:BIOFIRE Pneumonia Panel / BIOFIRE Pneumonia Panelplus(with software update)	Predicate:BIOFIRE Pneumonia Panel (K212727) /BIOFIRE Pneumonia Panel plus(K222601)
OrganismsDetected	Bacteria: Acinetobacter calcoaceticus-baumannii complex,Enterobacter cloacae complex, Escherichia coli , Haemophilusinfluenzae, Klebsiella aerogenes, Klebsiella oxytoca, Klebsiellapneumoniae group, Moraxella catarrhalis, Proteus spp.,Pseudomonas aeruginosa, Serratia marcescens,Staphylococcus aureus, Streptococcus agalactiae,Streptococcus pneumoniae, Streptococcus pyogenesAtypical Bacteria: Chlamydia pneumoniae, Legionellapneumophila, Mycoplasma pneumoniaeAntimicrobial Resistance Genes: CTX-M, IMP, KPC, mecA/C +MREJ, NDM, OXA48-like, VIMViruses: Adenovirus, Coronavirus, Human Metapneumovirus,Human Rhinovirus/Enterovirus, Influenza A,Only available on the BIOFIRE Pneumonia Panel plus:Middle East Respiratory Syndrome Coronavirus (MERS-CoV)	Same
Analyte	DNA/RNA	Same
Specimen Types	BAL-like specimens and Sputum-like specimens	Same
TechnologicalPrinciples	Nested multiplex PCR followed by high resolution meltinganalysis to confirm the identity of amplified product.	Same
Instrumentation	BIOFIRE 2.0 System or BIOFIRE TORCH System	Same
Time to result	About 1 hour	Same
Test Interpretation	Automated test interpretation and report generation. Usercannot access raw data.	Same
Sample PreparationMethod	Sample Processing is automated in the BIOFIRE System.	Same
Reagent Storage	Reagents are stored at room temperature.	Same
Shelf-Life	12 months from Date of Manufacture,with the exception that pouches aged greater than 6 monthspost manufacture have an elevated risk of erroneous reportingof Adenovirus Not Detected results when testing low titersamples containing adenovirus species C isolates.	Same
Controls	Two controls are included in each reagent pouch to control forsample processing and both stages of PCR and melt analysis.	Same
User Complexity	High	Same

Table 1. Comparison of the BIOFIRE Pneumonia Panels with current BIOFIRE Pneumonia Panels.

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Conclusion:

The software update and update to the labeling (instructions for use) do not affect the fundamental scientific technology, performance claims, or risk of the BIOFIRE Pneumonia Panel and BIOFIRE Pneumonia Panel plus. Therefore, the modified BIOFIRE Pneumonia Panel and BIOFIRE Pneumonia Panel plus are substantially equivalent to their predicate devices.

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.