The BD Veritor™ System for Rapid Detection of Flu A+B is a rapid chromatographic immunoassay for the direct and qualitative detection of influenza A and B viral nucleoprotein antigens from nasal and nasopharyngeal swabs of symptomatic patients. The BD Veritor System for Rapid Detection of Flu A+B (also referred to as the BD Veritor System and BD Veritor System Flu A+B) is a differentiated test, such that influenza A viral antigens can be distinguished from influenza B viral antigens from a single processed sample using a single device. The test is to be used as an aid in the diagnosis of influenza A and B viral infections. A negative test is presumptive and it is recommended that these results be confirmed by viral culture or an FDA-cleared influenza A and B molecular assay. Outside the U.S., a negative test is presumptive and it is recommended that these results be confirmed by viral culture or a molecular assay cleared for diagnostic use in the country of use. FDA has not cleared this device for use outside of the U.S. Negative test results do not preclude influenza viral infection and should not be used as the sole basis for treatment or other patient management decisions. The test is not intended to detect influenza C antigens.

Device Description

The BD Flu A+B test is a chromatographic assay to qualitatively detect influenza A and B viral antigens in respiratory specimens. The patient specimen is mixed in a prefilled unitized tube containing RV Reagent D and added to the test device. RV Reagent D contains mucolytic agents that function to break down mucus in a patient specimen thereby exposing viral antigens and enhancing detection in the assay device. Processed specimens are expressed through a filter tip into a single sample well on the BD Flu A+B test device.

The specimen is mixed and added to the test device where influenza A or influenza B viral antigens bind to anti-influenza antibodies conjugated to detector particles on the BD Flu A+B test strip. The antigen-conjugate complex migrates across the test strip to the reaction area and is captured by an antibody line on the membrane. The assay utilizes a proprietary enhanced colloidal-gold particle at the test lines as the means for identifying the presence of influenza A or B viral antigens. The BD Flu A+B test devices are designed with five spatially-distinct zones including positive and negative control line positions, separate test line positions for the target analytes, and a background zone. The test lines for the target analytes are labeled on the test device as 'A' for Flu A position, and 'B' for Flu B position. The onboard positive control ensures the sample has flowed correctly and is indicated on the test device as 'C'. Two of the five distinct zones on the test device are not labeled. These two zones are an onboard negative control line and an assay background zone. The onboard negative control zone addresses non-specific signal generation and is not labeled on the test device. The remaining zone is used to measure the assay background and is also not labeled.

The BD Flu A+B assay incorporates an active negative control feature in each test to identify and compensate for sample-related, nonspecific signal generation. The BD Veritor™ System Reader uses a proprietary algorithm which subtracts nonspecific signal at the negative control line from the signal present at both the Flu A and Flu B test lines. If the resultant test line signal is above a pre-selected assay cutoff, the specimen is scored as positive. If the resultant test line signal is below the cutoff, the specimen is scored as negative. Use of the active negative control feature allows the BD Veritor™ System reader to correctly interpret test results that cannot be scored visually because the human eye is unable to accurately perform the subtraction of the nonspecific signal.

The BD Veritor™ System Reader measures the amount of light reflected from various zones along the assay strip. The measurement of the assay background zone is an important factor during test interpretation as the reflectance is compared to that of the control and test zones. A background area that is white to light pink indicates the device has performed correctly. The instrument analyzes the reflectance data to provide the proper interpretation.

AI/ML Overview

The provided document describes a Special 510(k) submission for a modification to the BD Veritor™ System for Rapid Detection of Flu A+B. The modification involves updating the product insert with new strain reactivity data, which did not change the intended use or fundamental scientific technology of the device.

Here's a breakdown of the requested information based on the provided text:

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

Acceptance Criteria	Reported Device Performance
Ability to detect additional Flu strains.	Veritor was successful in detecting all strains tested. (From "RESULTS OF THE ANALYSIS" section)
A positive instrumented read with samples of subject flu viruses.	The study listed specific LODs (Limit of Detection) for each of the 14 tested influenza A and B strains, indicating that the device provided a positive instrumented read at these concentrations. For example, A/Fujian-Gulou/1896/2009 H1N1 was detected at $4.5 \times 10^5$ CEID50/mL.
No cross-reactivity between Flu A and Flu B lines.	For Flu A strains, "none cross react with the Flu B line." For Flu B strains, "none cross react with the Flu A line." (From "Conclusions" section)
Reduce the probability of occurrence for the hazard of "False Negative".	The study results reduced the probability of occurrence from P-3 ("Occasional") to P-1 ("Improbable"), thereby reducing the risk to the "negligible" category (GR). (From "RESULTS OF THE ANALYSIS" section)

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

Test Set Sample Size:
- Viruses: 9 Flu A strains and 5 Flu B strains (total of 14 strains).
- Replicates: 10-fold dilutions from the stock were tested in triplicate. This means 14 strains * an unspecified number of 10-fold dilutions * 3 replicates. The exact number of dilutions isn't specified, but it's more than just 14 individual tests.
Data Provenance:
- Country of Origin of Data: The study was conducted at the R/D laboratories in San Diego, CA, USA.
- Retrospective or Prospective: Not explicitly stated, but the study was conducted to confirm reactivity to new strains forecasted for the 2015/2016 Influenza Season and other available strains (CDC and WHO). This suggests a prospective testing approach for these specific strains. The primary clinical performance for the original device was established "during January through March of 2011" (mentioned in the "Indications for Use" section), but this specific submission focuses on new strain reactivity, which implies a prospective evaluation of freshly acquired or newly relevant strains.

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)

The ground truth for the test set was established by viral culture and titration, not clinical expert consensus. The viral material was obtained from the WHO Collaborating Centre for Surveillance, Epidemiology and Control of Influenza and the US Centres for Disease Control, and some were amplified and titred following procedures outlined in the WHO Manual on Animal Influenza Diagnosis and Surveillance (2002). The study was conducted "under the direction of Richard Anderson Ph.D. at the R/D laboratories." The expertise involved is in virology and laboratory methods for viral quantification (TCID50, EID50, HA), not clinical diagnosis by medical experts.

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

Not applicable. The ground truth was established by laboratory methods (viral culture and titration) and objective instrument readings, not by human interpretation or adjudication processes involving multiple experts making subjective judgments. The device itself uses a "proprietary algorithm which subtracts nonspecific signal at the negative control line from the signal present at both the Flu A and Flu B test lines" to score results.

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

No MRMC comparative effectiveness study was done. This device is a rapid chromatographic immunoassay read by an instrument (BD Veritor™ System Reader), not by human readers interpreting images or complex data that would typically involve an MRMC study. The focus is on the device's ability to detect different viral strains, not on human interpretive performance.

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

Yes, a standalone study was performed. The BD Veritor™ System Reader automatically interprets the test strip signals using its proprietary algorithm without human-in-the-loop decision-making for the result itself. The study focused on the device's ability to objectively detect the viral antigens at specific concentrations.

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

The ground truth used was based on laboratory-confirmed viral presence and quantification via methods like TCID50 (Tissue Culture Infectious Dose 50%), CEID50 (Chicken Embryo Infectious Dose 50%), EID50 (Egg Infectious Dose 50%), and HA (Hemagglutination assay) titers. This is a form of highly objective, laboratory-based "pathology" in the context of infectious disease diagnostics.

8. The sample size for the training set

The document does not explicitly state a sample size for a training set. This submission is for a modification to an already cleared device, focusing on analytical reactivity to new strains. The device's core algorithm and performance characteristics (established in previous 510(k) clearances, K112277, K132259, K132692) would have been based on extensive development and potentially training data, but those details are not provided in this document for this modification. The current study is an analytical verification rather than a de novo development or clinical training study.

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

As no training set is explicitly discussed in this document, the method for establishing its ground truth is also not detailed. For the analytical study described, the "ground truth" (i.e., the known presence and concentration of specific viral strains) was established through laboratory methods of viral culture, amplification, and titration, as detailed in point 3 above.

Summary

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Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002

June 10, 2015

Becton Dickinson and Company Gregory Payne, RAC Director of Regulatory Affairs 10865 Road to the Cure, Suite 200 San Diego CA 92121

Re: K151291

Trade/Device Name: BD Veritor TM System for Rapid Detection of Flu A+B Regulation Number: 21 CFR 866.3330 Regulation Name: Influenza virus serological reagents Regulatory Class: I Product Code: GNX Dated: May 14, 2015 Received: May 15, 2015

Dear Mr. Payne:

We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food. Drug. and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. 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.

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 Parts 801 and 809); medical device reporting (reporting of medical device-related adverse events) (21 CFR 803); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

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If you desire specific advice for your device on our labeling regulations (21 CFR Parts 801 and 809), please contact the Division of Industry and Consumer Education at its toll-free number (800) 638 2041 or (301) 796-7100 or at its Internet address

http://www.fda.gov/MedicalDevices/Resourcesfor You/Industry/default.htm. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to

http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm for the CDRH's Office of Surveillance and Biometrics/Division of Postmarket Surveillance.

You may obtain other general information on your responsibilities under the Act from the Division of Industry and Consumer Education at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address

http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm.

Sincerely yours,

Tamara V. Feldblyum -S for

Sally Hojvat, M.Sc., Ph.D. Director Division of Microbiology Devices Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health

Enclosure

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Indications for Use

510(k) Number (if known) K151291

Device Name

BD VeritorTM System for Rapid Detection of Flu A+B

Indications for Use (Describe)

Performance characteristics for influenza A and B were established during January through March of 2011 when influenza viruses A/2009 H1N1, A/H3N2, B/Victoria lineage, and B/Yamagata lineage were the predominant influenza viruses in circulation according to the Mortality Weekly Report from the CDC entitled "Update: Influenza Activity-United States, 2010-2011 Season, and Composition of the 2011-2012 Influenza Vaccine." Performance characteristics may vary against other emerging influenza viruses.

If infection with a novel influenza 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 the state or local health department for testing. Virus culture should not be attempted in these cases unless a BSL 3+ facility is available to receive and culture specimens.

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

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

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510(K) SUMMARY

SUBMITTED BY:	BECTON, DICKINSON AND COMPANY10865 Road to the Cure, Suite 200San Diego, CA 92121Tel: (858) 795 7890Fax: (858) 795 7885
CONTACT NAME:	Gregory P. Payne, RAC, Director Regulatory Affairs
DATE PREPARED:	June 2, 2015
DEVICE TRADE NAME:	BD Veritor™ System for Rapid Detection of Flu A+B(Physician Office)
DEVICE COMMON NAME:	Influenza virus serological reagents
DEVICE CLASSIFICATION:	21 CFR 866.3330
PREDICATE DEVICES :	BD Veritor™ System for Rapid Detection of Flu A+B(K112277, K132259, K132692)

INTENDED USE :

The BD Veritor System for Rapid Detection of Flu A+B is a rapid chromatographic immunoassay for the direct and qualitative detection of influenza A and B viral nucleoprotein antigens from nasal and nasopharyngeal swabs of symptomatic patients. The BD Veritor System for Rapid Detection of Flu A+B (also referred to as the BD Veritor System and BD Veritor System Flu A+B) is a differentiated test, such that influenza A viral antigens can be distinquished from influenza B viral antigens from a single processed sample using a single device. The test is to be used as an aid in the diagnosis of influenza A and B viral infections. A negative test is presumptive and it is recommended that these results be confirmed by viral culture or an FDA-cleared influenza A and B molecular assay. Outside the U.S., a negative test is presumptive and it is recommended that these results be confirmed by viral culture or a molecular assay cleared for diagnostic use in the country of use. FDA has not cleared this device for use outside of the U.S. Negative test results do not preclude influenza viral infection and should not be used as the sole basis for treatment or other patient management decisions. The test is not intended to detect influenza C antigens. Performance characteristics for influenza A and B were established during January through March of 2011 when influenza viruses A/2009 H1N1, A/H3N2, B/Victoria lineage, and B/Yamaqata lineage were the predominant influenza viruses in circulation according to the Morbidity and Mortality Weekly Report from the CDC entitled "Update: Influenza Activity-United States, 2010-2011 Season, and Composition of the 2011-2012 Influenza Vaccine." Performance characteristics may vary against other emerging influenza viruses. If infection with a novel influenza 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

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virulent influenza viruses and sent to the state or local health department for testing, Virus culture should not be attempted in these cases unless a BSL 3+ facility is available to receive and culture specimens.

DEVICE DESCRIPTION :

Positive Ctrl Flu B test line Flu A test line Negative Ctrl Background

Image /page/4/Figure/10 description: The image shows a white, rectangular container with rounded corners. Inside the container are four horizontal, black bars that are evenly spaced. The bars appear to be solid and opaque. The container is oriented vertically.

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DEVICE COMPARISON:

The modified device differs from the currently marketed BD Veritor™ System Flu A+B (Physician Office) assay in the following way:

The labeling has been changed to reflect the addition of strain reactivity data for the following strains:

A/Fujian-Gulou/1896/2009	H1N1	B/Massachusetts/2/2012 (Yamagata Lineage)
A/Washington/24/2012	H1N1	B/Montana/5/2012
A/Switzerland//9715293/2013	H3N2	B/Phuket/3073/2013
A/Texas/50/2012	H3N2	B/Texas/06/2011 (Yamagata Lineage)
A/Anhui/01/05	H5N1	B/Wisconsin/01/2010 (Yamagata Lineage)
A/Vietnam/1203/04	H5N1
A/Pheasant/NewJersey/1355/1998	H5N2
A/Mallard/Netherlands/12/2000	H7N7
A/Chicken/HongKong/G9/1997/	H9N2

SUBSTANTIAL EQUIVALENCE:

The modified device BD Veritor™ System Flu A+ B (Physician Office) assay is substantially equivalent to the current legally marketed device, BD Veritor™ System Flu A+B (Physician Office) assay. Additions made to the labeling to add additional strain testing did not change the intended use of the device or the fundamental scientific technology.

A Risk Analysis was conducted and is detailed in the Design Control Summary Section. No new issues of safety and effectiveness were identified during this process.

Additions are as follows:

Change		Potential Impact of Change
Addition of data for Strain reactivity of:		Additional information provided tousers regarding strain reactivity.
A/Fujian-Gulou/1896/2009	H1N1
A/Washington/24/2012	H1N1
A/Switzerland//9715293/2013	H3N2
A/Texas/50/2012	H3N2
A/Anhui/01/05	H5N1
A/Vietnam/1203/04	H5N1
A/Pheasant/NewJersey/1335/1998	H5N2
A/Mallard/Netherlands/12/2000	H7N7
A/Chicken/HongKong/G9/1997	H9N2
B/Massachusetts/2/2012 (Yamagata Lineage)
B/Montana/5/2012
B/Phuket/3073/2013
B/Texas/06/2011 (Yamagata Lineage)
B/Wisconsin/01/2010 (Yamagata Lineage)

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1. SUBMISSION STRATEGY

This premarket notification is submitted in accordance with the requirements of 21 CFR 807.81 as a Special 510(k): Device Modification for a device that has been cleared under the 510(k) process but has been modified using the design control requirements of the Quality Systems Regulations (QSR). Modifications made to the BD Veritor™ System Flu A+ B product insert did not change the intended use of the device or the fundamental scientific technology thereby meeting the requirements for submission of a Special 510(k).

This device submission is a modification of the currently marketed BD Veritor™ System Flu A+ B assay product insert to update the strain reactivity section of the product insert to include information on 14 new influenza strains.

2. DEVICE INFORMATION (CURRENT AND MODIFIED)

Device Trade Name	BD Veritor™ System for Rapid Detection of FluA+B (Physician Office)
Common/Classification Name	Influenza virus serological reagents
Device Classification	21 CFR 866.3330 Class I
Product Code	GNX
Device Panel	Microbiology
Premarket Notification	K112277, K132259, K132692
MODIFIED DEVICE
Device Trade Name	BD Veritor™ System for Rapid Detection of FluA+B (Physician Office)
Common/Classification Name	Influenza virus serological reagents
Device Classification	21 CFR 866.3330 Class I
Product Code	GNX

LEGALLY MARKETED DEVICE (CURRENT)

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3. DEVICE DESCRIPTION

The BD Flu A+B (Physician Office) test is a chromatographic assay to qualitatively detect influenza A and B viral antigens in samples processed from respiratory specimens. The processed specimen is added to the test device where influenza A or influenza B viral antigens bind to anti-influenza antibodies conjugated to detector particles on the A+B test strip. The antigen-conjugate complex migrates across the test strip to the reaction area and is captured by an antibody line on the membrane. Results are interpreted by the BD Veritor™ System Reader, a portable electronic device which uses a reflectance-based measurement method to evaluate the line signal intensities on the assay test strip, and applies specific algorithms to determine the presence or absence of any target analyte(s). A liquid crystal display (LCD) on the instrument communicates the results to the operator.

4. PRINCIPLE OF PROCEDURE

The BD Flu A+B (Physician Office) test is a chromatographic assay to qualitatively detect influenza A and B viral antigens in respiratory specimens. The patient specimen is mixed in a prefilled unitized tube containing RV Reagent D and added to the test device. RV Reagent D contains mucolytic agents that function to break down mucus in a patient specimen thereby exposing viral antigens and enhancing detection in the assay device. Processed specimens are expressed through a filter tip into a single sample well on the BD Flu A+B test device.

The BD Flu A+B test devices are designed with five spatially-distinct zones including positive and negative control line positions, separate test line positions for the target analytes, and a background zone. The test lines for the target analytes are labeled on the test device as 'A' for Flu A position, and 'B' for Flu B position. The onboard positive control ensures the sample has flowed correctly and is indicated on the test device as 'C'. Two of the five distinct zones on the test device are not labeled. These two zones are an onboard negative control line and an assay background zone. The onboard negative control zone addresses non-specific signal generation and is not labeled on the test device. The remaining zone is used to measure the assay background and is also not labeled.

Positive Ctrl C Flu B test line L4 Flu A test line L3 Negative Ctrl L2 Background

Image /page/7/Figure/9 description: The image shows a white rectangular object with rounded corners at the top. Inside the rectangle, there are five horizontal black lines evenly spaced apart. The lines appear to be solid and of uniform thickness. The object is oriented vertically and appears to be a simplified representation of a ladder or a similar structure.

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5. DEVICE COMPARISON

The BD Veritor™ System Flu A+ B (Phvsician Office) assav is substantially equivalent to the current legally marketed device, BD Veritor™ System Flu A+ B assay. Modifications made to the BD Veritor™ System Flu A+ B (Physician Office) product insert did not change the intended use of the device or the fundamental scientific technology.

The BD Veritor™ System Flu A+ B (Physician Office) product insert differs from the current legally marketed BD Veritor™ System Flu A+ B (Physician Office) assay product insert in the following way:

The product inserts includes an update to include information on Strain Reactivity to 14 additional strains of flu virus.

6. DESIGN CONTROL SUMMARY

Our Risk Assessment process is based on a BD Product Risk Management procedure which meets the requirement for risk management as set forth in ISO 14971:2007 and EN ISO 14971:2012. Using this procedure, the following are estimated:

the Hazard. .
. the Adverse Effect (Harm to Patient),
the Potential Causes of the Hazard, i
I The probability of Severity and
I The probability of Occurrence are estimated.

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Based on a resulting calculated Risk Index, Risk Control Measures are identified, required verification and validation activities are determined, and verification of the effectiveness of risk control measures is determined.

The tables below are taken from the procedure and provide guidelines to determine the probability of severity and occurrence. Additionally, a risk chart is provided below which depicts the areas of risk.

Indicator	Category	Definition
S-1	Negligible	No adverse health consequences; may result in annoyance to user orto patient. Could include cosmetic defect and/or need to replacedefective product prior to initial use.
S-2	Limited	Injury, without a significant discomfort or any degree ofdisability. Symptoms are transient easily tolerated with no interferencewith subject's daily activities. Illness or injuries are transient, self-limited and require no medical intervention or require medicalintervention that is limited in scope (i.e., non-significant risk).Device Examples: product failure requiring: reinsertion of a peripheralIV catheter, repeat skin injection (without impact to dose), peripheralvenous blood sampling, or one which results in clean (unused onpatient, not contaminated) needle stick and/or blade injury, or whichresults in a mild, non-painful electrical shock, first degree (superficial)burns, or mild retinal laser light exposures.
		IVD Examples:Patient : erroneous patient results (e.g. false positive results, falsenegative results, incorrect patient ID with results), delayed treatment forIVD medical devices which are not the sole determinant and areclassified in lower risk classes. Although the erroneous patient resultsmight not be corrected by other means, the impact to the patient isnegligible to none.Third party (e.g. user, service engineer, etc.): non painful electricalshock, first degree (superficial) burns, mild retinal laser light exposure.
S-3	Moderate	Injury which may include significant discomfort, minor non-permanentinjury and/or temporary disability. Symptoms are temporary and /orreversible. These injuries usually require medical intervention to treatthe injury. This category includes, but is not limited to:Injuries which require the need for minor, local surgery or theneed to repeat a semi-invasive low-risk procedure due toproduct failure. The misdiagnosis or wrong treatment of a non-serious illnessdue to erroneous results
		Device Examples: product failures resulting in fractured needlerequiring local exploratory surgery to remove part, requiring reinsertionof a central venous catheter, peripherally inserted central catheter, orinvasive diagnostic procedure such as a spinal tap, or which results in acontaminated sharps injury without seroconversion or transmission ofblood borne disease, or which results in painful electrical shock, seconddegree (partial thickness) burns or moderate retinal laser lightexposure.IVD Examples:
		negative results, incorrect patient ID with results), delayed treatment forIVD medical devices which are not the sole determinant but which areclassified in higher risk classes.Third party (e.g. user, service engineer, etc.): painful electrical shock,second degree burns, moderate retinal laser light exposure,contaminated sharps injury without seroconversion or transmission ofblood borne disease.
S-4	Severe	Injury which results in severe symptoms, significant injury, potentiallong-term risk to health, or permanent impairment as a direct result ofproduct failure, or due to a delay in treatment as a result of productfailure. The injury/symptoms may be irreversible despite medicalintervention, but are not immediately life threatening. This categoryincludes, but is not limited to:☐ Injuries which require major or invasive (i.e., moderate to high-risk) surgery or other intervention for treatment, exposure of patient to ahigh level of cumulative risk due to multiple medical interventions, orinjuries which require patient hospitalization or which extend length ofpatient hospitalization for treatment.☐ The transmission or causation of a potentially chronicallydebilitating or life threatening disease as a result of the productmalfunction☐ The misdiagnosis or wrong treatment of a serious illness due toerroneous resultsDevice Examples: product failures that require such procedures asexploratory laparotomy or other invasive diagnostic procedure withsignificant risk, removal and reinsertion of a fully inserted pulmonaryarterial catheter, or retrieval of catheter fragment from the heart. Alsoincluded are product failures which result in loss of sight, amputation orloss of use of a limb, pneumonia, bacteremia, seroconversion for bloodborne disease such as HIV/AIDS or Hepatitis C, electrical exposureabove the "let go" threshold but which does not result in cardiac orrespiratory compromise, widespread partial thickness or limited full-thickness (third degree) burns or severe moderate retinal laser lightexposure.IVD Examples:Patient : erroneous patient results (e.g. false positive results, falsenegative results, incorrect patient ID with results), delayed treatment forIVD medical devices which are the sole determinant and/or are in thehighest risk classThird party (e.g. user, service engineer, etc.): electrical exposureabove the "let go" threshold but which does not result in cardiac orrespiratory compromise, third degree burns, severe retinal laser lightexposure, contaminated sharps injury with seroconversion for bloodborne disease such as HIV/AIDS or Hepatitis C.
S-5	Catastrophic	Fatal or immediately life threatening. Fatal means death has alreadyoccurred. Life threatening means that death could occur in the nearterm despite treatment or that the patient was or would be at immediaterisk of death if medical intervention had not occurred
		Device Examples: anaphylactic reaction, severe hemorrhage, cardiactamponade, cardiac arrest, septic shock, electrocution with cardiac orrespiratory compromise, extensive third-degree burns.
	IVD Examples:Patient: erroneous patient results (e.g. false positive results, falsenegative results, incorrect patient ID with results) for IVD medicaldevices with a large public health risk (e.g. contamination of the bloodsupply).Third party (e.g. user, service engineer, etc.): electrocution with cardiacor respiratory compromise, extensive third-degree burns.

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ProbabilityIndicator	Category	Probability of Harm (Definition)
P1	Improbable	Extremely unlikely in the life of the system at anygiven site
P2	Remote	Likely to occur once in the life of the system at anygiven site
P3	Occasional	Likely to occur once every year for each system atany given site
P4	ReasonablyProbable	Likely to occur a few times per year for each systemat any given site
P5	Frequent	Likely to occur many times per year for each systemat any given site

Three-Region Risk Chart

		Severity
		S1	S2	S3	S4	S5
Occurrence	P5	GR	RE	RE	RE	RE
	P4	GR	YE	RE	RE	RE
	P3	GR	GR	YE	RE	RE
	P2	GR	GR	GR	YE	RE
	P1	GR	GR	GR	YE	YE

Risk regions include:

Insignificant (GR) - individual risks in the green region are deemed negligible in comparison with other risks and in relation to the benefit of using the product. Even if the risk falls into this region, the risk must be reduced as far as possible. For risks falling into this region, the medical benefit is considered to outweigh the individual residual risk since the combination of the occurrence and severity is considered low. These risks do not require individual risk benefit analysis. Because risk of harm in this region are deemed negligible, risk control measures implemented in this region, will not require documented verification of risk control measure effectiveness.

Investigate (YE) - individual risks in the yellow region are not negligible in comparison with other risks, therefore further risk reduction must be investigated. This category requires evaluation for risk reduction and once all possible risk control measures have

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been implemented, the residual risk is not reduced to insignificant (GR) is not possible, the individual item in this region require a documented risk/benefit analysis to document acceptance of the residual risk (See Attachment 3 for a Risk Benefit Analysis model.

Unacceptable/Intolerable (RE) - individual risks in the red region are unacceptable. This region requires the implementation of risk control measures to reduce the risk. In general, BDDS products should not have items with residual risks falling into this reqion. However, in an exceptional and rare circumstance, these items may be documented in the risk/benefit analysis with approval by Medical Affairs at a director level or higher.

The risk assessment identified the need to confirm the Veritor system's reactivity to new strains forecast for 2015/2016 Influenza Season, as well as other strains not previously tested available through CDC and WHO.

RESULTS OF THE ANALYSIS:

The results of the analysis indicated an initial possible combination of severity and occurrence that fell into S-3/P-3 category. To implement the indicated investigation, Protocol SDSP15001 was developed and approved based on previously accepted FDA submissions regarding strain reactivity. The design of the study is below and is replicated from a previous Special 510(k) submission. Acceptability criteria was the ability of the BD Veritor test to detect these additional Flu strains. Veritor was successful in detecting all strains tested. The data to be included in the insert are the actual values obtained during this testing. The results of the strain testing reduced the probability of occurrence from P-3 to P-1 and reduced the risk to the "negligible" category.

Hazard	False Negative	Testing
AdverseEffect (Harm)	Effect on patient is that theycould be inappropriately treatedleading to flu progression	Obtain and test additional flu strains
Probability ofSeverity	S-3	Risk ControlMeasure	Labeling
PotentialCauses of theHazard	Assay does not detect thepredicted strains for 2015/2016Flu Season or other availablenew and circulating strains		Update PI with new reactivity afterFDA special 510(k) clearance
Probability ofOccurrence	P-3	Risk ControlMeasureEffectivenessReference	SDSP15001
Existing RiskControlMeasure	Current strain reactivity hasbeen determined and isprovided in the Product Insert	Probability ofSeverity	S-3
Risk Index	YE	Probability ofOccurrence	P-1
Responsibilityfor RiskControlMeasure	R&D	Risk Index	GR

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Finally, after review and clearance of this submission by FDA, a change control will be initiated to document this activity in the design history file and to route the new PI for approval.

Modifications to the product insert will be implemented in accordance to BD Change Control Procedure RDQP0401.

SUMMARY OF STUDIES 7.

Study acceptance criteria were that the Veritor Flu A+B assay system needed to give a positive instrumented read with samples of subject flu viruses in order to make this claim in a revised Package Insert. Subject Flu strains were chosen based on strains forecasted for the 2015/2016 Flu season, additional influenza strains available from CDC and WHO and also in response to customer requests. The testing protocol was the same as has been used in previous submissions to FDA regarding strain reactivity and is detailed in BD protocol Document SDSP15001. This study was conducted under the direction of Richard Anderson Ph.D. at the R/D laboratories in San Diego, CA. Viral material in allantoic fluid from chicken eggs was used in this study.

Viruses tested

Twelve virus strains were provided by the WHO Collaborating Centre for Surveillance, Epidemiology and Control of Influenza and the US Centres for Disease Control.The two strains provided by National Institute for Biological Standards and Control (UK) used in this testing, A/Switzerland//9715293/2013 and B/Phuket/3073/2013, were received as lyophilized preparations and were subsequently reconstituted, amplified in culture and titred following procedures outlined in the WHO Manual on Animal Influenza Diagnosis and Surveillance (2002) before supplying this material for reactivity testing in the Veritor system.

Materials and procedures for this step are as follows:

MDCK cells: TPCK-trypsin (2 mg/ml): Complete MEM medium for MDCK cells: Penicillin (10.000 U/ml) + Streptomycin (10,000 μg/ml) Fetal Bovine Serum DMSO

ATCC, Cat# CCL-34 Sigma, Cat #T1426-50MG ATCC, Cat # 30-2003 Invitrogen, Cat # 15140-122 Sigma Cat. # 30-2020 Sigma Cat #D2438

1. Prepare TPCK-trypsin stocks:
- a. Dissolve 20 mg TPCK-trypsin in 10 mL dHzO. Filter through 0.2 uL membrane. Store in aliquots at -20°C
1. Prepare Complete MEM medium (CMM):
- a. 500 mL MEM + 5.5 mL Penicillin (10.000 U/mL)/ Streptomycin (10,000 ua/mL)
1. Prepare cell growth medium (CGM) from CMM above: 500mL CMM + 50mL FBS
1. Prepare compete virus growth medium (VGM) : 0.5 mL of TPCK-trypsin to CMM.

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1. Freeze Medium: Add 5% DMSO to cell growth medium, freeze overnight at minus 80°C in liquid Nitrogen.
  MDCK cells are routinely maintained in T-75 flasks in Cell Growth Media (CGM) supplemented with 10 % (v/v) FBS and Penicillin/Streptomycin. One day before virus infection, MDCK cells were seeded into T-25 and T-75 flasks at 50-60% confluency resulting in 90-100% confluency at the time of infection. Reconstituted virus was incubated with CGM and VGM at 37°C, in a 5% CO2 incubator for 1 hour. The flasks containing MDCK cells were washed with VGM and 1 ml of the incubated virus was added to a T-25 flask and the remaining to a T-75 flask, and then incubated at 37°C, 5% CO2 incubator for 2 hours. These flasks were washed twice with VGM, and then 3 mL of VGM was added to the T-25 flask, 10 mL of VGM was added to the T-75 flask. The infected cells were incubated at 37°C, in a 5% CO2 incubator for 2-5 days. The flasks were examined under a microscope for signs of infection. When more than 80% cells were infected, the supernatants were aliquoted into 1 mL tubes and kept in liquid nitrogen. These preparations were assigned a lot number based on date.

Viral titer was measured using a 96 well plate with MDCK host cells inoculated with 10 fold serial dilutions of virus. After 3-4 days at 37°C in a CO2 incubator, the titration plate was examined for Viral Cytopathic effects and TCID50 is calculated by the Reed-Muench formula.

No.	Sample Description	Lot No.	Titer of stock
1	A/Fujian-Gulou/1896/2009 H1N1	59433572	$1.8 x 10^9$ CEID50/mL
2	A/Washington/24/2012 H1N1	7/12/2013	$3.16 x 10^8$ EID50/mL
3	A/Switzerland//9715293/2013 H3N2	02262015	$1.3 x 10^6$ TCID50/mL
4	A/Texas/50/2012 H3N2	61757568	$3.5 x 10^6$ TCID50/mL
5	A/Anhui/01/05 H5N1	62539790	512 HA
6	A/Vietnam/1203/04 H5N1	59613801	512 HA
7	A/Pheasant/NewJersey/1355/1998 H5N2	61647886	256 HA
8	A/Mallard/Netherlands/12/2000 H7N7	61572488	512 HA
9	A/Chicken/HongKong/G9/1997 H9N2	60429654	1024 HA
10	B/Massachusetts/2/2012(Yamagata Lineage)	61649126	$1.0 x 10^{10}$ CEID50/mL
11	B/Montana/5/2012	7/12/2013	$2.51 x 10^8$ EID50/mL
12	B/Phuket/3073/2013	04102015	2.43x $10^7$ TCID50/mL
13	B/Texas/06/2011 (Yamagata Lineage)	61070013	$6.2 x 10^8$ CEID50/mL
14	B/Wisconsin/01/2010 (Yamagata Lineage)	61176817	$2.8 x 10^6$ CEID50/mL

10 fold dilutions from the stock received were tested in triplicate using the BD Veritor System Flu A+B test to establish the approximate level for the LOD. Based

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on previous submissions and agreement with FDA, the data obtained with liquid samples is also used to report reactivity of the (Physician Office) kit.

BD Veritor System Flu A+B test materials

Veritor System Flu A+B devices: two lots expiration date 2017/07/24 expiration date 2015/10/13 Reagent C, lot# 11071104, #13092703 Unitized tube, lot# IM046-0000 Test Standard diluent lot #90-185 Veritor System Readers SN #1212145789CN2

Conclusions

Nine Flu A strains and Five Flu B strains were enrolled in this study. The data indicate that all Flu A strains enrolled in this study can be detected by the Flu A line of the Veritor System Flu A+B device and none cross react with the Flu B line. All five Flu B strains enrolled in this study can be detected by the Flu B line of the Veritor System Flu A+B device and none cross react with the Flu A line. The lowest concentration (LOD) of influenza A and influenza B viruses that can be detected by Veritor System Flu A+B device are listed here:

No.	Strain	Final DilutionFactor	LOD¹
1	A/Fujian-Gulou/1896/2009 H1N1	4000	$4.5 \times 10^5$CEID50/mL
2	A/Washington/24/2012 H1N1	10000	$3.16 \times 10^4$EID50/mL
3	A/Switzerland//9715293/2013 H3N2	4000	$3.25 \times 10^2$TCID50/mL
4	A/Texas/50/2012 H3N2	2000	$1.75 \times 10^3$TCID50/mL
5	A/Anhui/01/05 H5N1	2000	0.512 HA
6	A/Vietnam/1203/04 H5N1	2000	0.512 HA
7	A/Pheasant/NewJersey/1355/1998 H5N2	1000	0.256 HA
8	A/Mallard/Netherlands/12/2000 H7N7	2000	0.256 HA
9	A/Chicken/HongKong/G9/1997 H9N2	1000	1.024 HA
10	B/Massachusetts/2/2012(Yamagata Lineage)	8000	$1.25 \times 10^6$CEID50/mL
11	B/Montana/5/2012	800	$3.14 \times 10^5$EID50/mL
12	B/Phuket/3073/2013	4000	$6.08 \times 10^3$TCID50/mL
13	B/Texas/06/2011(Yamagata Lineage)	1000	$6.2 \times 10^5$CEID50/mL

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14	B/Wisconsin/01/2010(Yamagata Lineage)	4000	$7.0 \times 10^2$ CEID50/mL
----	-------------------------------------------	------	-----------------------------

1 Estimated LOD is the lowest concentration of influenza A and B virus strains that can be detected by the BD Veritor System Flu A + B Assay in 3/3 replicates.

DECLARATION OF CONFORMITY 8.

The manufacturing facility is in conformance with design control procedure requirements as specified in 21 CFR 820.30. This statement can be found in Appendix 1.

9. CONCLUSION FROM THE TESTING

The studies conducted on the BD Veritor™ System for Rapid Detction of Flu A+B assay demonstrated that labeling changes can be made to the product insert to reflect the analytical sensitivity and reactivity data generated. This will be used to update the strain reactivity section of the product insert to include information on the aforementioned strains.

10. LABELING

Copies of the revised product inserts for the BD Veritor System for Rapid Detection of Flu A+B assay are provided in Attachment 3. The labeling for this device has been modified from the current labeling to update the strain reactivity section of the product insert. The changes can be found in Appendix 3.

The intended use of this modified device as described in the labeling has not changed as a result of this modification.

All performance characteristics as well as other sections of the Package Insert from the current BD Veritor System Flu A+B assay have remained the same in the revised Package Insert.

Regulation Number and Section

§ 866.3328 Influenza virus antigen detection test system.

(a)
Identification. An influenza virus antigen detection test system is a device intended for the qualitative detection of influenza viral antigens directly from clinical specimens in patients with signs and symptoms of respiratory infection. The test aids in the diagnosis of influenza infection and provides epidemiological information on influenza. Due to the propensity of the virus to mutate, new strains emerge over time which may potentially affect the performance of these devices. Because influenza is highly contagious and may lead to an acute respiratory tract infection causing severe illness and even death, the accuracy of these devices has serious public health implications.(b)
Classification. Class II (special controls). The special controls for this device are:(1) The device's sensitivity and specificity performance characteristics or positive percent agreement and negative percent agreement, for each specimen type claimed in the intended use of the device, must meet one of the following two minimum clinical performance criteria:
(i) For devices evaluated as compared to an FDA-cleared nucleic acid based-test or other currently appropriate and FDA accepted comparator method other than correctly performed viral culture method:
(A) The positive percent agreement estimate for the device when testing for influenza A and influenza B must be at the point estimate of at least 80 percent with a lower bound of the 95 percent confidence interval that is greater than or equal to 70 percent.
(B) The negative percent agreement estimate for the device when testing for influenza A and influenza B must be at the point estimate of at least 95 percent with a lower bound of the 95 percent confidence interval that is greater than or equal to 90 percent.
(ii) For devices evaluated as compared to correctly performed viral culture method as the comparator method:
(A) The sensitivity estimate for the device when testing for influenza A must be at the point estimate of at least 90 percent with a lower bound of the 95 percent confidence interval that is greater than or equal to 80 percent. The sensitivity estimate for the device when testing for influenza B must be at the point estimate of at least 80 percent with a lower bound of the 95 percent confidence interval that is greater than or equal to 70 percent.
(B) The specificity estimate for the device when testing for influenza A and influenza B must be at the point estimate of at least 95 percent with a lower bound of the 95 percent confidence interval that is greater than or equal to 90 percent.
(2) When performing testing to demonstrate the device meets the requirements in paragraph (b)(1) of this section, a currently appropriate and FDA accepted comparator method must be used to establish assay performance in clinical studies.
(3) Annual analytical reactivity testing of the device must be performed 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 § 809.10(b) of this chapter compliant labeling 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 Web site where the analytical reactivity testing data can be found. The manufacturer's home page, as well as the primary part of the manufacturer's Web site that discusses the device, must provide a prominently placed hyperlink to the Web page containing this information and must allow unrestricted viewing access.
(4) If one of the actions listed at section 564(b)(1)(A)-(D) of the Federal Food, Drug, and Cosmetic Act occurs with respect to an influenza viral strain, or if the Secretary of Health and Human Services (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 § 809.10(b) of this chapter compliant labeling 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 Web site where the analytical reactivity testing data can be found. The manufacturer's home page, as well as the primary part of the manufacturer's Web site that discusses the device, must provide a prominently placed hyperlink to the Web page containing this information and must allow unrestricted viewing access.