VIDAS B.R.A.H.M.S. PCT (PCT)

K160911 · bioMerieux, Inc. · PMT · Jun 28, 2016 · Microbiology

Device Facts

• Record ID: K160911
• Device Name: VIDAS B.R.A.H.M.S. PCT (PCT)
• Applicant: bioMerieux, Inc.
• Product Code: PMT · Microbiology
• Decision Date: Jun 28, 2016
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 866.3215
• Device Class: Class 2

Intended Use

VIDAS® B·R·A·H·M·S PCT™ (PCT) is an automated test for use on the instruments of the VIDAS® family for the determination of human procalcitonin in human serum or plasma (lithium heparinate) using the ELFA (Enzyme-Linked Fluorescent Assay) technique. VIDAS® B·R·A·H·M·S PCT™ (PCT) is intended for use in conjunction with other laboratory findings and clinical assessments to aid in the risk assessment of critically ill patients on their first day of ICU admission for progression to severe sepsis and septic shock. VIDAS® B·R·A·H·M·S PCT™ (PCT) is also intended for use to determine the change of PCT level over time as an aid in assessing the cumulative 28-day risk of all-cause mortality in conjunction with other laboratory findings and clinical assessments for patients diagnosed with severe sepsis or septic shock in the ICU or when obtained in the emergency department or other medical wards prior to ICU admission.

Device Story

Automated quantitative ELFA immunoassay for procalcitonin (PCT) in human serum/plasma; performed on VIDAS family instruments. Uses sandwich immunoassay principle with anti-PCT antibodies on Solid Phase Receptacle (SPR). Instrument automates sample/conjugate cycling, washing, and fluorescent detection of 4-methyl-umbelliferone at 450 nm. Fluorescence intensity proportional to PCT concentration. Used in ICU/ED settings by laboratory personnel. Output is quantitative PCT concentration; used with clinical assessments to aid sepsis risk stratification and 28-day mortality prediction. Includes web-based calculator for ΔPCT (percent change over time) to assist clinical decision-making regarding mortality risk. Benefits include objective biomarker-based assessment of sepsis progression and mortality risk, aiding clinical management.

Clinical Evidence

Prospective clinical trial (MOSES study, NCT01523717) of 858 adult patients with severe sepsis/septic shock. Per-protocol population (N=598) evaluated for 28-day all-cause mortality. Primary endpoint: ΔPCT (percent change from Day 0/1 to Day 4). Hazard ratios for ΔPCT ≤80% vs >80% were 2.27 (VIDAS 3) and 2.05 (VIDAS). Sensitivity/specificity for mortality prediction reported across subgroups. Bench testing confirmed precision (CV 1.3-14.6%), linearity (0.05-200 ng/mL), and LoQ (0.043-0.05 ng/mL).

Technological Characteristics

ELFA immunoassay; sandwich principle. Materials: mouse monoclonal anti-human PCT immunoglobulins on SPR. Energy: fluorescent detection at 450 nm. Connectivity: standalone instrument (VIDAS family). Calibration: 2-point, MLE data-driven. Software: embedded instrument firmware; web-based calculator for ΔPCT (client-side only). Sterilization: N/A (reagents).

Indications for Use

Indicated for risk assessment of critically ill patients on first day of ICU admission for progression to severe sepsis and septic shock, and for assessing cumulative 28-day all-cause mortality risk in patients diagnosed with severe sepsis or septic shock. For prescription use only.

Regulatory Classification

Identification

A device to detect and measure non-microbial analyte(s) in human clinical specimens to aid in assessment of patients with suspected sepsis is identified as an in vitro device intended for the detection and qualitative and/or quantitative measurement of one or more non-microbial analytes in human clinical specimens to aid in the assessment of patients with suspected sepsis when used in conjunction with clinical signs and symptoms and other clinical and laboratory findings.

Special Controls

A device to detect and measure non-microbial analyte(s) in human clinical specimens to aid in assessment of patients with suspected sepsis must comply with the following special controls:

*Classification.* Class II (special controls). The special controls for this device are:(1) Premarket notification submissions must include the device's detailed Indications for Use statement describing what the device detects and measures, the results provided to the user, whether the measure is qualitative and/or quantitative, the clinical indications for which the test is to be used, and the specific population(s) for which the device use is intended. (2) Premarket notification submissions must include detailed documentation of the device description, including (as applicable), all device components, software, ancillary reagents required but not provided, explanation of the device principle and methodology, and for molecular devices include detailed documentation of the primer/probe sequence, design, and rationale for sequence selection. (3) Premarket notification submissions must include detailed documentation of applicable analytical studies, such as, analytical sensitivity (Limit of Detection, Limit of Blank, and Limit of Quantitation), precision, reproducibility, analytical measuring range, interference, cross-reactivity, and specimen stability. (4) Premarket notification submissions must include detailed documentation of a prospective clinical study or, if appropriate, results from an equivalent sample set. This detailed documentation must include the following information: (i) Results must demonstrate adequate device performance relative to a well-accepted comparator. (ii) Clinical sample results must demonstrate consistency of device output throughout the device measuring range likely to be encountered in the Intended Use population. (iii) Clinical study documentation must include the original study protocol (including predefined statistical analysis plan), study report documenting support for the Indications for Use(s), and results of all statistical analyses. (5) Premarket notification submissions must include evaluation of the level of the non-microbial analyte in asymptomatic patients with demographic characteristics ( *e.g.,* age, racial, ethnic, and gender distribution) similar to the Intended Use population.(6) As part of the risk management activities performed under 21 CFR 820.10(c) design and development, you must document an appropriate end user device training program that will be offered as part of your efforts to mitigate the risk of failure to correctly operate the instrument. (7) A detailed explanation of the interpretation of results and acceptance criteria must be included in the device's 21 CFR 809.10(b)(9) compliant labeling, and a detailed explanation of the interpretation of the limitations of the samples ( *e.g.,* collected on day of diagnosis) must be included in the device's 21 CFR 809.10(b)(10) compliant labeling.

Predicate Devices

• B·R·A·H·M·S PCT sensitive KRYPTOR® (DEN150009)
• VIDAS® B·R·A·H·M·S PCT™ (K071146)

Submission Summary (Full Text)

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June 28, 2016

Public Health Service

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

BIOMERIEUX, INC. THI DANG REGULATORY AFFAIRS SPECIALIST 595 ANGLUM RD. HAZELWOOD, MO 63042

Re: K160911

Trade/Device Name: VIDAS® BRAHMS PCT™ (PCT) Regulation Number: 21 CFR 866.3215

Regulation Name: Device to detect and measure non-microbial analyte(s) in human clinical specimens to aid in assessment of patients with suspected sepsis

Regulatory Class: II Product Code: PMT Dated: March 31, 2016 Received: April 1, 2016

Dear Ms. Dang:

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 (OS) 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 [phone] or [phone] or at its Internet address

http://www.fda.gov/MedicalDevices/ResourcesforYou/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 [phone] or [phone] or at its Internet address

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

Sincerely yours,

# Steven R. Gitterman -S

For Uwe Scherf, 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) K160911

#### Device Name VIDAS B.R.A.H.M.S PCT (PCT)

#### Indications for Use (Describe)

VIDAS® B·R·A·H·M·S PCT " (PCT) is an automated test for use on the instruments of the VIDAS® family for the determination of human procalcitonin in human serum or plasma (lithium heparinate) using the ELFA (Enzyme-Linked Fluorescent Assay) technique.

VIDAS® B·R·A·H·M·S PCT™ (PCT) is intended for use in conjunction with other laboratory findings and clinical assessments to aid in the risk assessment of critically ill patients on their first day of ICU admission for progression to severe sepsis and septic shock.

VIDAS® B·R·A·H·M·S PCT™ (PCT) is also intended for use to determine the change of PCT level over time as an aid in assessing the cumulative 28-day risk of all-cause mortality in conjunction with other laboratory findings and clinical assessments for patients diagnosed with severe sepsis or septic shock in the ICU or when obtained in the emergency department or other medical wards prior to ICU admission.

Procalcitonin (PCT) is a biomarker associated with the inflammatory response to bacterial infection that aids in the risk assessment of critically ill patients on their first day of Intension for progression to severe sepss and septic shock. The percent change in PCT level over time also aids in the prediction of cumulative 28-day mortality in patients with severe sepsis and septic shock.

PCT levels on the first day of ICU admission above 2.0 ng/mL are associated with a higher risk for progression to severe sepsis and/or septic shock than PCT levels below 0.5 ng/mL.

A PCT level that declines < 80% from the day that severe sepsis or septic shock was clinically diagnosed (Day 0) to four days after clinical diagnosis (Day 4) is associated with higher cumulative 28-day risk of all-cause mortality than a decline > 80%.

The combination of the first PCT level (≤2.0 ng/mL or > 2.0 ng/mL) at initial diagnosis of severe sepsis or septic shock with the patient's clinical course and the change in PCT level over time until Day 4 provides important adout the mortality risk.

The PCT level on Day 1 (the day after severe sepsis or septic shock is first clinically diagnosed) can be used to calculate the percent change in PCT level at Day 4 if the Day 0 measurement is unavailable.

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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## 510(K) SUMMARY

This 510(k) summary of safety and effectiveness information is being submitted in accordance with the requirement of Safe Medical Devices Act of 1990 and 21 CFR 807.92.

## VIDAS® B·R·A·H·M·S PCT™

### A. Submitter Information

| Submitter's Name: | bioMérieux, Inc. |
|----------------------|----------------------------------------|
| Address: | 595 Anglum Road<br>Hazelwood, MO 63042 |
| Contact Person: | Thi My Lan Dang |
| Phone Number: | 314-731-8799 |
| Fax Number: | 314-731-8689 |
| Date of Preparation: | March 31, 2016 |

#### B. Device Name

| Trade Name: | VIDAS® B·R·A·H·M·S PCT™ (PCT) |
|----------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Common Name: | Endotoxin Assay |
| Classification Name: | Device to detect and measure non-microbial analyte(s) in human<br>clinical specimens to aid in assessment of patients with suspected<br>sepsis (21 CFR 866.3215, Product Code PMT) – Class II in vitro<br>Diagnostic device |

#### C. Predicate Devices

Predicate device 1, trade name: B·R·A·H·M·S PCT Sensitive KRYPTOR® (DEN150009)

Predicate device 2, trade name: VIDAS® B·R·A·H·M·S PCT™ (K071146)

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Image /page/4/Picture/0 description: The image shows the logo for bioMérieux, a French multinational biotechnology company. The logo features a stylized globe with blue and white lines, with a green sprout emerging from the top. Below the globe is the company name, "BIOMÉRIEUX," in a bold, sans-serif font. The background transitions from green to yellow.

### D. Device Description

The assay principle combines a one-step immunoassay sandwich method with a final fluorescent detection (ELFA).

The Solid Phase Receptacle (SPR®), serves as the solid phase as well as the pipetting device. Reagents for the assay are ready-to-use and pre-dispensed in the sealed reagent strips.

All of the assay steps are performed automatically by the instrument. The sample is transferred into the wells containing anti-procalcitonin antibodies labeled with alkaline phosphatase (conjugate). The sample/conjugate mixture is cycled in and out of the SPR® several times. This operation enables the antigen to bind with the immunoglobulins fixed to the interior wall of the SPR® and the conjugate to form a sandwich. Unbound compounds are eliminated during washing steps.

Two detection steps are performed successively. During each step, the substrate (4-Methylumbelliferyl phosphate) is cycled in and out of the SPR®. The conjugate enzyme catalyzes the hydrolysis of this substrate into a fluorescent product (4-Methyl-umbelliferone) the fluorescence of which is measured at 450 nm. The intensity of the fluorescence is proportional to the concentration of antigen present in the sample.

At the end of the assay, results are automatically calculated by the instrument in relation to two calibration curves corresponding to the two detection steps. A fluorescence threshold value determines the calibration curve to be used for each sample. The results are then printed out.

#### E. Indications for Use

VIDAS® B+R+A+H+M+S PCT™ (PCT) is an automated test for use on the instruments of the VIDAS® family for the determination of human procalcitonin in human serum or plasma (lithium heparinate) using the ELFA (Enzyme-Linked Fluorescent Assay) technique.

VIDAS® B+R+A+H+M+S PCT™ (PCT) is intended for use in conjunction with other laboratory findings and clinical assessments to aid in the risk assessment of critically ill patients on their first day of ICU admission for progression to severe sepsis and septic shock.

VIDAS® B+R+A+H+M+S PCT™ (PCT) is also intended for use to determine the change of PCT level over time as an aid in assessing the cumulative 28-day risk of all-cause mortality in conjunction with other laboratory findings and clinical assessments for patients diagnosed with severe sepsis or septic shock in the ICU or when obtained in the emergency department or other medical wards prior to ICU admission.

Procalcitonin (PCT) is a biomarker associated with the inflammatory response to bacterial infection that aids in the risk assessment of critically ill patients on their first day of Intensive Care Unit (ICU) admission for progression to severe sepsis and septic shock. The percent change in PCT level over time also aids in the prediction of cumulative 28-day mortality in patients with severe sepsis and septic shock.

PCT levels on the first day of ICU admission above 2.0 ng/mL are associated with a higher risk for progression to severe sepsis and/or septic shock than PCT levels below 0.5 ng/mL.

A PCT level that declines ≤ 80% from the day that severe sepsis or septic shock was clinically diagnosed (Day 0) to four days after clinical diagnosis (Day 4) is associated with higher cumulative 28day risk of all-cause mortality than a decline > 80%.

The combination of the first PCT level (≤ 2.0 ng/mL or > 2.0 ng/mL) at initial diagnosis of severe sepsis or septic shock with the patient's clinical course and the change in PCT level over time until Day 4 provides important additional information about the mortality risk.

The PCT level on Day 1 (the day after severe sepsis or septic shock is first clinically diagnosed) can be used to calculate the percent change in PCT level at Day 4 if the Day 0 measurement is unavailable.

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Image /page/5/Picture/0 description: The image shows the logo for bioMérieux, a French multinational biotechnology company. The logo features the company name in a sans-serif font, with the "BIO" portion in a darker, bolder font than the "MÉRIEUX" portion. Above the name is a stylized graphic consisting of a blue sphere with curved lines and a green curved line extending upwards from the sphere. The logo also has a green and yellow gradient bar at the bottom.

### F. Technological Characteristics Summary

A general comparison of the similarities and differences of the assay with the predicates is presented in the following table.

| Item | Proposed Device:<br>VIDAS® B-R-A-H-M-S™ PCT | Predicate device 1:<br>B·R·A·H·M·S PCT Sensitive<br>KRYPTOR® (DEN150009) | Predicate device 2:<br>VIDAS® B-R-A-H-M-S PCT™<br>(K071146) |
|------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Indications<br>for use | VIDAS® B·R·A·H·M·S PCT™<br>(PCT) is an automated test for<br>use on the instruments of the<br>VIDAS® family for the<br>determination of human<br>procalcitonin in human serum or<br>plasma (lithium heparinate)<br>using the ELFA (Enzyme-Linked<br>Fluorescent Assay) technique.<br>VIDAS® B·R·A·H·M·S PCT™<br>(PCT) is intended for use in<br>conjunction with other laboratory<br>findings and clinical<br>assessments to aid in the risk<br>assessment of critically ill<br>patients on their first day of ICU<br>admission for progression to<br>severe sepsis and septic shock.<br>VIDAS® B·R·A·H·M·S PCT™<br>(PCT) is also intended for use to<br>determine the change of PCT<br>level over time as an aid in<br>assessing the cumulative 28-day<br>risk of all-cause mortality in<br>conjunction with other laboratory<br>findings and clinical<br>assessments for patients<br>diagnosed with severe sepsis or<br>septic shock in the ICU or when<br>obtained in the emergency<br>department or other medical<br>wards prior to ICU admission. | The B·R·A·H·M·S PCT sensitive<br>KRYPTOR® is an<br>immunofluorescent assay using<br>Time-Resolved Amplified<br>Cryptate Emission (TRACE®)<br>technology to determine the<br>concentration of PCT<br>(procalcitonin) in human serum<br>and EDTA or heparin plasma.<br>The B·R·A·H·M·S PCT sensitive<br>KRYPTOR® is intended to be<br>performed on the B·R·A·H·M·S<br>KRYPTOR® analyzer family.<br>The B·R·A·H·M·S PCT sensitive<br>KRYPTOR® is intended for use<br>in conjunction with other<br>laboratory findings and clinical<br>assessments to aid in the risk<br>assessment of critically ill<br>patients on their first day of<br>Intensive Care Unit (ICU)<br>admission for progression to<br>severe sepsis and septic shock.<br>The B·R·A·H·M·S PCT sensitive<br>KRYPTOR® is also intended for<br>use to determine the change in<br>PCT level over time as an aid in<br>assessing the cumulative 28-day<br>risk of all-cause mortality in<br>conjunction with other laboratory<br>findings and clinical<br>assessments for patients<br>diagnosed with severe sepsis or<br>septic shock in the ICU or when<br>obtained in the emergency<br>department or other medical<br>wards prior to ICU admission.<br>Procalcitonin (PCT) is a<br>biomarker associated with the<br>inflammatory response to<br>bacterial infection that aids in the<br>risk assessment of critically ill | VIDAS® B·R·A·H·M·S PCT™<br>(PCT) is an automated test for<br>use on the instruments of the<br>VIDAS® family for the<br>determination of human<br>procalcitonin in human serum or<br>plasma (lithium heparinate)<br>using the ELFA (Enzyme-Linked<br>Fluorescent Assay) technique.<br>VIDAS® B·R·A·H·M·S<br>PCT™ (PCT) is intended for use<br>in conjunction with other<br>laboratory findings and clinical<br>assessments to aid in the risk<br>assessment of critically ill<br>patients on their first day of ICU<br>admission for progression to<br>severe sepsis and septic shock.<br><br>Procalcitonin (PCT) is a<br>biomarker associated with the<br>inflammatory response to<br>bacterial infection that aids in the<br>risk assessment of critically ill<br>patients on their first day of<br>Intensive Care Unit (ICU)<br>admission for progression to<br>severe sepsis and septic shock.<br>The percent change in PCT level<br>over time also aids in the |
| Item | Proposed Device:<br>VIDAS® B-R-A-H-M-STM PCT | Predicate device 1:<br>B-R-A-H-M-S PCT Sensitive<br>KRYPTOR® (DEN150009) | Predicate device 2:<br>VIDAS® B-R-A-H-M-S PCTTM<br>(K071146) |
| | are associated with a higher risk<br>for progression to severe sepsis<br>and/or septic shock than PCT<br>levels below 0.5 ng/mL.<br>A PCT level that declines ≤ 80%<br>from the day that severe sepsis<br>or septic shock was clinically<br>diagnosed (Day 0) to four days<br>after clinical diagnosis (Day 4) is<br>associated with higher<br>cumulative 28-day risk of all-<br>cause mortality than a decline ><br>80%.<br>The combination of the first PCT<br>level (≤ 2.0 ng/mL or > 2.0<br>ng/mL) at initial diagnosis of<br>severe sepsis or septic shock<br>with the patient's clinical course<br>and the change in PCT level<br>over time until Day 4 provides<br>important additional information<br>about the mortality risk.<br>The PCT level on Day 1 (the day<br>after severe sepsis or septic<br>shock is first clinically<br>diagnosed) can be used to<br>calculate the percent change in<br>PCT level at Day 4 if the Day 0<br>measurement is unavailable. | prediction of cumulative 28-day<br>mortality in patients with severe<br>sepsis and septic shock.<br>PCT levels on the first day of<br>ICU admission above 2.0 µg/L<br>are associated with a higher risk<br>for progression to severe sepsis<br>and/or septic shock than PCT<br>levels below 0.5 µg/L.<br>A PCT level that declines ≤ 80%<br>from the day that severe sepsis<br>or septic shock was clinically<br>diagnosed (Day 0) to four days<br>after clinical diagnosis (Day 4) is<br>associated with higher<br>cumulative 28-day risk of all-<br>cause mortality than a decline ><br>80%.<br>The combination of the first PCT<br>level (≤ 2.0 µg/L or > 2.0 µg/L) at<br>initial diagnosis of severe sepsis<br>or septic shock with the patient's<br>clinical course and the change in<br>PCT level over time until Day 4<br>provides important additional<br>information about the mortality<br>risk.<br>The PCT level on Day 1 (the day<br>after severe sepsis or septic<br>shock is first clinically<br>diagnosed) can be used to<br>calculate the percent change in<br>PCT level at Day 4 if the Day 0<br>measurement is unavailable. | |
| Specimen | Human serum or plasma (lithium<br>heparinate). | Human serum, plasma (EDTA,<br>heparin) | Same as the proposed device |
| Analyte | Procalcitonin (PCT) | Same as the proposed device | Same as the proposed device |
| Automated | Automated assay | Same as the proposed device | Same as the proposed device |
| Assay<br>Technique | ELFA (Enzyme-Linked<br>Fluorescent Assay) technique. | Immunofluorescent assay | Same as the proposed device |
| Assay<br>principle | Immunoassay based on<br>sandwich principle | Immunofluorescent assay based<br>on sandwich principle | Same as the proposed device |
| Detection<br>method | Fluorescence (ELFA) of 4-<br>methyl-umbelliferyl measured at<br>450 nm | Measuring principle based on<br>TRACE® technology which<br>measures the signal emitted<br>from an immunocomplex with<br>time delay | Same as the proposed device |

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#### G. Nonclinical Test

A summary of the non-clinical (analytical) results is presented below.

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#### Dilution for sample volumes between 50 uL and 200 uL

A dilution study was performed on the VIDAS® according to a protocol based on the CLSI EPG-A guideline. Sample volumes between 50 µL and 200 µL can be tested after performing a manual dilution up to 1:4 (1 volume of test sample + 3 volume of diluent) before testing with the VIDAS® B·R·A·H·M·S PCT assay.

#### Limits of detection and quantitation

The Limit of Blank (LoB), the limit of Detection (LoD) and the Limit of Quantitation (LoQ) were determined on the VIDAS® and VIDAS®3 instruments according to the CLSI® EP17-A2 recommendations. The limits reported below apply for all the instruments of the VIDAS family:

| Limit of Blank (LoB) | 0.01 ng/mL |
|-----------------------------|------------|
| Limit of Detection (LoD) | 0.03 ng/mL |
| Limit of Quantitation (LoQ) | 0.05 ng/mL |

The Limit of Quantitation (LoQ) is the lowest concentration of PCT measured with a level of acceptable precision of 20% CV.

#### Precision

The study was performed according to the recommendations of CLSI® document EP5-A3. A panel of 9 human samples covering the measuring range were tested in 2 runs per day, over 20 days using 3 VIDAS® and 3 VIDAS® 3 instruments (N=240 values for each sample) at 3 sites (one instrument per site). Two reagent lots were used: 10 days of tests and 6 calibrations were performed for each lot. The repeatability, between-day precision, within-laboratory precision and reproducibility/total precision (between-laboratory precision) were estimated for each sample and are reported in the following tables:

### VIDAS®

| | | Mean<br>concentration<br>(ng/mL) | Repeatability | | Between-Day<br>precision | | Within-Laboratory<br>precision | | Reproducibility /<br>Total precision | |
|----------|-----|----------------------------------|----------------------------------|-----------|----------------------------------|-----------|----------------------------------|-----------|--------------------------------------|-----------|
| Sample | N | | Standard<br>Deviation<br>(ng/mL) | CV<br>(%) | Standard<br>Deviation<br>(ng/mL) | CV<br>(%) | Standard<br>Deviation<br>(ng/mL) | CV<br>(%) | Standard<br>Deviation<br>(ng/mL) | CV<br>(%) |
| Sample 1 | 240 | 0.12 | 0.011 | 9.0% | 0.013 | 10.9% | 0.018 | 14.6% | 0.018 | 14.6% |
| Sample 2 | 240 | 0.16 | 0.010 | 6.6% | 0.013 | 8.5% | 0.020 | 12.7% | 0.020 | 12.7% |
| Sample 3 | 240 | 0.20 | 0.011 | 5.4% | 0.013 | 6.1% | 0.017 | 8.2% | 0.017 | 8.2% |
| Sample 4 | 240 | 0.53 | 0.013 | 2.4% | 0.017 | 3.2% | 0.023 | 4.2% | 0.023 | 4.2% |
| Sample 5 | 240 | 2.14 | 0.027 | 1.3% | 0.048 | 2.3% | 0.081 | 3.8% | 0.081 | 3.8% |
| Sample 6 | 240 | 23.20 | 0.506 | 2.2% | 0.749 | 3.2% | 0.962 | 4.1% | 0.962 | 4.1% |
| Sample 7 | 240 | 93.01 | 3.136 | 3.4% | 5.343 | 5.7% | 6.962 | 7.5% | 6.962 | 7.5% |
| Sample 8 | 240 | 129.86 | 5.368 | 4.1% | 8.436 | 6.5% | 12.664 | 9.8% | 12.664 | 9.8% |
| Sample 9 | 240 | 164.85 | 7.364 | 4.5% | 10.613 | 6.4% | 18.445 | 11.2% | 18.445 | 11.2% |

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Image /page/8/Picture/0 description: The image shows the logo for bioMérieux. The logo features the company name in a sans-serif font, with the "bio" portion in a darker, bolder font than the "Mérieux" portion. Above the company name is a stylized graphic consisting of a blue globe-like shape with curved lines, bisected by a green, curved line that resembles a plant stem or leaf.

| | N | Mean<br>concentration<br>(ng/mL) | Repeatability | | Between-Day<br>precision | | Within-Laboratory<br>precision | | Reproducibility /<br>Total precision | |
|----------|-----|----------------------------------|----------------------------------|-----------|----------------------------------|-----------|----------------------------------|-----------|--------------------------------------|-----------|
| Sample | | | Standard<br>Deviation<br>(ng/mL) | CV<br>(%) | Standard<br>Deviation<br>(ng/mL) | CV<br>(%) | Standard<br>Deviation<br>(ng/mL) | CV<br>(%) | Standard<br>Deviation<br>(ng/mL) | CV<br>(%) |
| Sample 1 | 240 | 0.12 | 0.010 | 8.6% | 0.010 | 8.6% | 0.015 | 12.6% | 0.015 | 12.6% |
| Sample 2 | 239 | 0.15 | 0.013 | 8.3% | 0.014 | 9.2% | 0.017 | 11.2% | 0.017 | 11.2% |
| Sample 3 | 239 | 0.20 | 0.012 | 6.2% | 0.013 | 6.6% | 0.016 | 8.2% | 0.017 | 8.5% |
| Sample 4 | 239 | 0.52 | 0.020 | 3.8% | 0.022 | 4.2% | 0.026 | 5.0% | 0.031 | 6.1% |
| Sample 5 | 240 | 2.06 | 0.042 | 2.0% | 0.061 | 3.0% | 0.095 | 4.6% | 0.100 | 4.9% |
| Sample 6 | 240 | 21.85 | 0.583 | 2.7% | 0.694 | 3.2% | 0.844 | 3.9% | 0.955 | 4.4% |
| Sample 7 | 240 | 83.60 | 3.365 | 4.0% | 3.520 | 4.2% | 4.791 | 5.7% | 5.815 | 7.0% |
| Sample 8 | 240 | 110.83 | 5.494 | 5.0% | 5.750 | 5.2% | 7.884 | 7.1% | 8.669 | 7.8% |
| Sample 9 | 240 | 140.35 | 6.470 | 4.6% | 7.329 | 5.2% | 11.301 | 8.1% | 13.026 | 9.3% |

### Linearity

VIDAC® 2

The test linearity was studied on the VIDAS® and VIDAS® 3 instruments according to a procedure taken from the CLSI EP6-A guideline. The test is linear over the complete measurement range.

#### Clinical Testing H.

A study was conducted on a population of 858 adult patients recruited across 13 investigational sites in the US to assess the performance of VIDAS® BRANHIM SPCT™ (PCT) on VIDAS® and VIDAS for the prediction of cumulative 28-day all-cause mortality.

In the per protocol population (598 patients) was comprised of 44% female and 56% male patients with a mean age of 64 years, diagnosed either with severe sepsis (51%) or septic shock (49%), presenting mainly with community acquired infections (91%) and less frequently with nosocomial infections (9%). All patients were admitted into ICU at some point during their hospital stay, 44% were still located in ICU at Day 4 of the study ("ICU" group), where at Day 4 already transferred to a location outside of the ICU ("non-ICU" group).

Demographics with patients outcome and % mortality information are shown below:

| Variable | Class | N* | Dead | Alive | % Mortality |
|-----------|------------------|-----|------|-------|-------------|
| Gender | Female | 264 | 46 | 218 | 17.4% |
| Gender | Male | 334 | 55 | 279 | 16.5% |
| Age | ≤ 30 | 39 | 1 | 38 | 2.6% |
| (years) | 31-45 | 45 | 4 | 41 | 8.9% |
| | 46-55 | 74 | 8 | 66 | 10.8% |
| | 56-65 | 149 | 26 | 123 | 17.4% |
| | 66-75 | 125 | 21 | 104 | 16.8% |
| | > 75 | 166 | 41 | 125 | 24.7% |
| Ethnicity | African-American | 202 | 32 | 170 | 15.8% |
| | Asian | 7 | 0 | 7 | 0.0% |
| | Caucasian | 362 | 64 | 298 | 17.7% |
| | Hispanic | 23 | 5 | 18 | 21.7% |
| | Other | 4 | 0 | 4 | 0.0% |

*per protocol population

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Image /page/9/Picture/0 description: The image features the logo of bioMérieux, a company specializing in in-vitro diagnostics. The logo consists of the company name in a sans-serif font, with the "bio" portion in a darker shade and the "Mérieux" portion in a lighter shade. Above the name is a stylized graphic of a blue globe with green curved lines extending from the bottom, resembling a plant or growth symbol. Below the logo is a horizontal bar with a gradient fill, transitioning from yellow to green.

Cumulative 28-day all-cause mortality did not differ significantly for male vs. female patients ($χ$2 pvalue = 0.84).

| Variable | Class | VIDAS® 3 | | | | VIDAS® | | | |
|-------------------------|--------------|----------|------|-------|-------------|--------|------|-------|-------------|
| | | N | Dead | Alive | % Mortality | N | Dead | Alive | % Mortality |
| PCT on Day 0<br>(ng/mL) | < 0.5 | 101 | 17 | 84 | 16.8% | 97 | 16 | 81 | 16.5% |
| | 0.5-2.0 | 89 | 10 | 79 | 11.2% | 92 | 10 | 82 | 10.9% |
| | > 2.0 | 373 | 70 | 303 | 18.8% | 367 | 69 | 298 | 18.8% |
| | Unavailable* | 35 | 4 | 31 | 11.4% | 42 | 6 | 36 | 14.3% |

Initial PCT levels at Day 0 with patients outcome and % mortality were as follows:

* Unavailable patients results were either not available for testing (VIDAS 3 n = 24, VIDAS n = 29), or were below assay measuring range of 0.05 ng/mL (VIDAS 3 n = 11, VIDAS n = 13).

The study demonstrated that for patients diagnosed with severe sepsis or septic shock, the 28-Day mortality was statistically significantly increased for patients with ΔPCT ≤ 80% compared to patients with ΔPCT > 80%:

- Binary ΔPCT was significantly associated with 28-day cumulative mortality (Two-sided Fisher's ● Exact Test p-value 0.0003 and 0.002 for VIDAS®3 and VIDAS® respectively for ΔPCT based on Day 0 and p-value = 0.003 and 0.019 for VIDAS®3 and VIDAS® respectively for $\Delta$PCT based on Day 1) and this association remained significant in each patient location subgroup, ICU vs. non ICU at Day 4 (for VIDAS 3 and VIDAS® respectively Cochran-Mantel-Haenszel Test p-value =0.006 and 0.016 using $\Delta$PCT based on Day 0 and p-value = 0.023 and 0.073 using $\Delta$PCT based on Day 1). The mortality in the group with $\Delta$PCT $\leq$ 80 % was increased by a factor of 2.1 on on Day of the more and to the group with APCT > 80% using JPCT based on Day 0 (factor 1.8 on VIDAS 3 and 1.6 on VIDAS® using ΔPCT based on Day 1). The observed mortality risk was generally higher in the ICU subgroup than in the non-ICU group (5.4 to 11.4% vs. 18.4 to 31.6%). In each subgroup, the mortality was even higher for patients with a ΔΡCT ≤ 80% than for patients with a $\Delta$PCT > 80%.
- Supplementary classification of patients based on the patient location on Day 4 and initial PCT . level (< 2.0 vs. ≥ 2.0 ng/mL) at Day 0 (or Day 1) showed that in each patient location and initial PCT level subgroup, a PCT decrease ≤ 80% from Day 0 (or Day 1) to Day 4 constitutes a higher risk for mortality within 28 days compared to a higher PCT decline (> 80%). For the prediction of absolute mortality risks, ICU disposition at Day 4 and initial PCT level at Day 0 (or Day 1) should be considered in addition to binary $\Delta$PCT ($\leq$ 80% or > 80%).

Significantly reduced or increased mortality were observed by patient location and initial PCT level subgroups:

a) Patients still receiving ICU care on Day 4 or patients with initial PCT level > 2.0 ng/mL have a higher mortality risk from study Day 4 to the end of follow-up time (28 days) when the $\Delta$PCT is $\leq$ 80% compared to when the $\Delta$PCT is > 80%.

b) among patients who are still in the ICU on Day 4, patients with $\Delta$PCT > 80% and an initial PCT level of ≤ 2.0 ng/mL on Day 0 have a particularly lower cumulative 28-day mortality risk compared to patients with an initial PCT level at Day 0 of > 2.0 ng/mL (2.2% vs. 20.3% on VIDAS®3; 1.8% vs. 21.4% on VIDAS®). In addition, regardless of the initial PCT level, patients in the ICU on Day 4

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Image /page/10/Picture/0 description: The image shows the logo for bioMérieux. The logo features the company name in a sans-serif font, with the "BIO" portion in a darker gray and the "MÉ RIEUX" portion in a lighter gray. Above the name is a blue globe-like shape with curved lines, and a green sprout-like shape extending from the top of the globe. The bottom of the image has a green to yellow gradient.

which have ΔΡCT ≤ 80% (Day 0 to Day 4) have an even higher mortality risk (26.4% to 34.1% on VIDAS3; 27.0% to 33.5% on VIDAS®).

c) even when they are no longer in the ICU on Day 4, patients with an initial PCT level > 2.0 ng/mL and with a ΔPCT ≤ 80% (Day 0 to Day 4) remain at high mortality risk (14.1% on VIDAS®3; 13.4% on VIDAS®). Overall, a lower mortality risk was observed for patients discharged from the ICU before or on Day 4 with an initial PCT level ≤ 2.0 ng/mL than for patients with an initial PCT level of > 2.0 ng/mL (3.7% to 9.5% vs. 5.8% to 14.1% on VIDAS3; 4.2% to 9.2% vs. 6.5% to 13.4% on VIDAS®).

The table below shows the 28-day cumulative mortality risk and prognostic accuracy by binary ΔPCT group (≤ 80% or > 80%), by the selection of either Day 0 or Day 1 for the ΔPCT calculation, by patient location at Day 4, and by initial PCT level.

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Image /page/11/Picture/0 description: The image shows the logo for bioMérieux. The logo consists of the company name in a sans-serif font, with a stylized graphic above it. The graphic includes a blue sphere with white lines and a green and yellow curved line that bisects the sphere and extends above and below it.

| | Mortality Risk by binary ΔPCT group and Prognostic Accuracy* by Patient Location on Day 4 and by initial PCT level | | | | | | | |
|-------------|--------------------------------------------------------------------------------------------------------------------|------------------------------|----------------------|------------------------|------------------------|--------------------------|-------------------------|-----------------------|
| | ΔPCT<br>Interval | Day 4<br>Patient<br>Location | Initial<br>PCT level | 28 Day Mortality Risk | | Prognostic Accuracy | | |
| | | | | ΔPCT > 80%<br>(95% CI) | ΔPCT ≤ 80%<br>(95% CI) | Sensitivity<br>(95% CI) | Specificity<br>(95% CI) | |
| VIDAS®<br>3 | Day 0 to<br>Day 4 | ICU | All PCT levels | 18.4%<br>(10.0-26.8%) | 31.3%<br>(24.5-38.1%) | 78.4%<br>(68.7-88.1%) | 35.7%<br>(28.7-42.7%) | |
| | | | ≤ 2.0 ng/mL | 2.2%<br>(0.0-15.1%) | 26.4%<br>(15.8-37.1%) | 98.8%<br>(91.7-100.0%) | 14.9%<br>(5.1-24.7%) | |
| | | | > 2.0 ng/mL | 20.3%<br>(11.1-29.5%) | 34.1%<br>(25.3-42.9%) | 71.6%<br>(59.4-83.8%) | 44.6%<br>(36.0-53.3%) | |
| | | non ICU | All PCT levels | 5.4%<br>(1.8-9.1%) | 11.4%<br>(6.8-16.1%) | 71.7%<br>(55.0-88.3%) | 47.0%<br>(40.9-53.0%) | |
| | | | ≤ 2.0 ng/mL | 3.7%<br>(0.0-11.0%) | 9.5%<br>(3.9-15.1%) | 91.0%<br>(74.2-100.0%) | 21.2%<br>(13.2-29.1%) | |
| | | | > 2.0 ng/mL | 5.8%<br>(1.6-10.0%) | 14.1%<br>(6.1-22.1%) | 59.6%<br>(36.4-82.8%) | 64.3%<br>(56.7-72.0%) | |
| | | ICU | All PCT levels | 18.4%<br>(10.1-26.7%) | 31.6%<br>(24.7-38.5%) | 77.2%<br>(67.2-87.2%) | 37.7%<br>(30.6-44.7%) | |
| | Day 1 to<br>Day 4 | | ≤ 2.0 ng/mL | 12.6%<br>(0.0-34.0%) | 22.2%<br>(11.6-32.7%) | 90.6%<br>(74.1-100.0%) | 16.8%<br>(6.4-27.2%) | |
| | | | > 2.0 ng/mL | 19.2%<br>(10.3-28.1%) | 36.8%<br>(27.8-45.7%) | 73.6%<br>(61.9-85.3%) | 46.7%<br>(38.0-55.3%) | |
| | | non ICU | All PCT levels | 7.0%<br>(2.8-11.2%) | 10.1%<br>(5.7-14.5%) | 63.8%<br>(45.8-81.8%) | 45.8%<br>(39.6-52.0%) | |
| | | | ≤ 2.0 ng/mL | 0.0%<br>(0.0-13.2*%) | 8.1%<br>(2.9-13.3%) | 100.0%<br>(66.4-100.0*%) | 20.7%<br>(12.9-28.4%) | |
| | | | > 2.0 ng/mL | 8.5%<br>(3.5-13.5%) | 13.0%<br>(5.2-20.9%) | 48.1%<br>(25.7-70.5%) | 63.5%<br>(55.6-71.5%) | |
| VIDAS® | | ICU | All PCT levels | 19.2%<br>(10.7-27.6%) | 31.0%<br>(24.2-37.8%) | 77.0%<br>(67.1-87.0%) | 36.1%<br>(29.1-43.1%) | |
| | | | Day 0 to<br>Day 4 | ≤ 2.0 ng/mL | 1.8%<br>(0.0-12.8%) | 27.0%<br>(16.3-37.8%) | 98.9%<br>(92.4-100.0%) | 16.4%<br>(6.4-26.5%) |
| | | | | > 2.0 ng/mL | 21.4%<br>(12.1-30.7%) | 33.5%<br>(24.6-42.3%) | 69.5%<br>(56.9-82.0%) | 44.8%<br>(36.1-53.5%) |
| | | non ICU | All PCT levels | 6.1%<br>(2.2-10.0%) | 10.9%<br>(6.3-15.4%) | 68.2%<br>(51.0-85.4%) | 46.6%<br>(40.6-52.7%) | |
| | | | | ≤ 2.0 ng/mL | 4.2%<br>(0.0-12.2%) | 9.2%<br>(3.8-14.7%) | 91.0%<br>(74.1-100.0%) | 19.0%<br>(11.4-26.6%) |
| | | | | > 2.0 ng/mL | 6.5%<br>(2.1-10.8%) | 13.4%<br>(5.3-21.5%) | 53.9%<br>(30.3-77.6%) | 65.5%<br>(57.9-73.2%) |
| | | ICU | All PCT levels | 20.2%<br>(11.7-28.6%) | 30.8%<br>(23.9-37.7%) | 74.6%<br>(64.3-85.0%) | 37.5%<br>(30.4-44.5%) | |
| | Day 1 to<br>Day 4 | | ≤ 2.0 ng/mL | 2.2%<br>(0.0-14.2%) | 22.2%<br>(11.8-32.7%) | 98.2%<br>(88.5-100.0%) | 17.7%<br>(7.3-28.1%) | |
| | | | > 2.0 ng/mL | 22.5%<br>(13.3-31.8%) | 35.6%<br>(26.6-44.5%) | 68.9%<br>(56.7-81.1%) | 46.2%<br>(37.5-54.8%) | |
| | | non ICU | All PCT levels | 7.3%<br>(2.9-11.6%) | 9.8%<br>(5.5-14.2%) | 63.6%<br>(45.5-81.7%) | 44.3%<br>(38.2-50.4%) | |
| | | | ≤ 2.0 ng/mL | 0.2%<br>(0.0-14.2%) | 6.9%<br>(2.1-11.8%) | 99.5%<br>(85.8-100.0%) | 19.0%<br>(11.5-26.4%) | |
| | | | > 2.0 ng/mL | 8.7%<br>(3.5-13.8%) | 13.9%<br>(6.0-21.8%) | 50.8%<br>(28.9-72.6%) | 62.3%<br>(54.3-70.2%) | |

*Prognostic accuracy refers to how the binary ΔPCT can accurately predict mortality risk.

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Image /page/12/Picture/0 description: The image shows the logo for bioMérieux. The logo consists of the company name in a sans-serif font, with the "BIO" portion in a darker gray and the "MÉ RIEUX" portion in a lighter gray. Above the name is a blue globe-like design with a green curved line extending from the top of the globe down between the two parts of the company name. The background is white, with a green and yellow gradient bar at the bottom.

Time-to-event analysis is illustrated by the Kaplan-Meier survival probability curves below.

Image /page/12/Figure/3 description: The image contains four Kaplan-Meier survival curves, comparing the survival rates of patients based on their procalcitonin (PCT) levels and the change in PCT levels (ΔPCT). The top two graphs show data for VIDAS®3, while the bottom two show data for VIDAS®. The graphs on the left show patients with PCT levels less than or equal to 2.0 ng/mL at Day 0, with N=76 for VIDAS®3 and N=77 for VIDAS®. The graphs on the right show patients with PCT levels greater than 2.0 ng/mL at Day 0, with N=189 for VIDAS®3 and N=187 for VIDAS®. Each graph plots the proportion of patients surviving over time (in days) for both test-negative (ΔPCT > 80%) and test-positive (ΔPCT ≤ 80%) groups.

### Survival probability until Day 28 for Patients still receiving ICU Care on Day 4

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Image /page/13/Picture/0 description: The image contains the logo for bioMérieux. The logo consists of the company name in a sans-serif font, with the "BIO" portion in a darker shade of gray and the "Mérieux" portion in a lighter shade. Above the name is a circular graphic that is half blue and half white with a green curved line extending upwards from the center. Below the name is a gradient bar that transitions from yellow to green.

Image /page/13/Figure/2 description: The image contains four Kaplan-Meier survival curves, comparing the survival rates of patients based on their procalcitonin (PCT) levels at Day 0 and the change in PCT levels (ΔPCT). The top two graphs show the survival curves for patients with PCT levels less than or equal to 2.0 ng/mL at Day 0 (left) and greater than 2.0 ng/mL at Day 0 (right) using VIDAS®3. The bottom two graphs show the survival curves for patients with PCT levels less than or equal to 2.0 ng/mL at Day 0 (left) and greater than 2.0 ng/mL at Day 0 (right) using VIDAS®. Each graph displays two curves: one for patients with a test neg…