MeMed BV
Device Facts
| Record ID | K210254 |
|---|---|
| Device Name | MeMed BV |
| Applicant | MeMed Diagnostics, Ltd. |
| Product Code | QPS · Microbiology |
| Decision Date | Sep 1, 2021 |
| Decision | SESE |
| Submission Type | Traditional |
| Regulation | 21 CFR 866.3215 |
| Device Class | Class 2 |
| Attributes | Pediatric |
Indications for Use
The MeMed BV™ test is an automated semi-quantitative immunoassay that measures three non-microbial (host) proteins (TRAIL, IP-10, and CRP) in adult and pediatric serum samples and is intended for use in conjunction with clinical assessments and other laboratory findings as an aid to differentiate bacterial from viral infection. MeMed BV™ is indicated for use in patients presenting to the emergency department or urgent care center and with samples collected at hospital admission from patients with suspected acute bacterial or viral infection, who have had symptoms for less than seven days. The MeMed BV™ test generates a numeric score that falls within discrete interpretation bins based on the increasing likelihood of bacterial infection.
Device Story
MeMed BV is an in-vitro diagnostic immunoassay measuring host proteins TRAIL, IP-10, and CRP in serum. The system comprises an automated analyzer (MeMed Key) and a disposable cartridge containing reagents. The device processes serum samples via chemiluminescence-based measurement; computational integration (MeMed Key) transforms analyte concentrations into a numeric score. Used in ED/urgent care settings by clinical laboratory technicians; results are provided to healthcare providers to aid in differentiating bacterial from viral infection. The output score, categorized into discrete interpretation bins, assists clinical decision-making regarding infection etiology, potentially optimizing patient management.
Clinical Evidence
Prospective, multicenter, observational, blinded study (Apollo) of 1,016 subjects (476 prospective, 540 archived). Primary endpoint: diagnostic performance for differentiating bacterial vs. viral infection using expert adjudication. Results showed significant trend of increasing bacterial likelihood with higher MeMed BV scores (Cochran-Armitage p < 0.0001). Likelihood ratios for bins 1, 2, 4, and 5 excluded 1. Subgroup analyses confirmed performance across age, sex, ethnicity, and comorbidities.
Technological Characteristics
Automated chemiluminescent immunoassay (CLIA) measuring TRAIL, IP-10, and CRP. System includes MeMed Key analyzer and disposable cartridges. Connectivity: standalone analyzer. Calibration: every two weeks. Sample volume: 100 µL. Run time: ~15 minutes.
Indications for Use
Indicated for adult and pediatric patients (over 90 days old) presenting to the emergency department or urgent care center with suspected acute bacterial or viral infection and symptoms duration < 7 days. Used as an aid to differentiate bacterial from viral infection.
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
- VIDAS B.R.A.H.M.S. PCT (K162827)
Related Devices
- K222332 — MeMed BV · MeMed Diagnostics, Ltd. · Mar 23, 2023
- K230944 — MeMed BV · MeMed Diagnostics, Ltd. · Jun 30, 2023
- K213936 — LIAISON MeMed BV, LIAISON MeMed BV Control Set · DiaSorin, Inc. · Jul 14, 2022
Submission Summary (Full Text)
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September 1, 2021
MeMed Diagnostics Ltd. Efrat Hartog-David Director of Regulatory Affairs and Quality Assurance Nahum Heth 5 Tirat Carmel, 3508504 Israel
Re: K210254
Trade/Device Name: MeMed BV 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: Class II Product Code: QPS Dated: January 29, 2021 Received: January 29, 2021
Dear Efrat Hartog-David:
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. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database located at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. The general controls provisions of the Act include requirements for annual registration. listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.
If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.
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
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requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR 803) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-products); good manufacturing practice requirements as set forth in the quality systems (OS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
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 https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.
For comprehensive regulatory information about mediation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).
Sincerely,
Kristian Roth, Ph.D. Branch Chief Division of Microbiology Devices OHT7: Office of In Vitro Diagnostics and Radiological Health Office of Product Evaluation and Quality Center for Devices and Radiological Health
Enclosure
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# Indications for Use
510(k) Number (if known) K210254
Device Name MeMed BV™M
#### Indications for Use (Describe)
The MeMed BV test is an automated semi-quantitative immunoassay that measures three non-microbial (host) proteins (TRAIL, IP-10, and CRP) in adult and pediatric serum samples and is intended for use in conjunction with clinical assessments and other laboratory findings as an aid to differentiate bacterial from viral infection. MeMed BV is indicated for use in patients presenting to the emergency department or urgent care center and with samples collected at hospital admission from patients with suspected acute bacterial or viral infection, who have had symptoms for less than seven days. The MeMed BV test generates a numeric score that falls within discrete interpretation bins based on the increasing likelihood of bacterial infection.
| 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
#### MeMed Diagnostics Ltd.'s MeMed BV™
#### Submitter
MeMed Diagnostics Ltd. Nahum Heth 5 Tirat Carmel, 3508504, Israel
Phone: +972-4-8500302 Contact Person: Efrat Hartog-David, Ph.D.
Date Prepared: January 29, 2021
Name of Device: MeMed BV™
Common or Usual Name: MeMed BV™
Classification Name: Immunoassay for host biomarkers of infection
Regulatory Class: Class II
Product Code: QPS
#### Predicate Devices
BioMerieux, Inc, VIDAS B.R.A.H.M.S. PCT (PCT) (K162827)
## Device Description
The MeMed BV™ ("BV test" or the "test") is an In-Vitro-Diagnostic device that measures in parallel the blood concentrations of TRAIL, IP-10 and CRP. The test consists of an automated analyzer with built-in hardware and software that conduct chemiluminescencebased analyte measurements of patient serum samples and their computational integration (MeMed Key™), and a disposable cartridge that contains the reagents and controls needed to detect the analytes of interest (MeMed BV™ cartridge). The test generates an answer to each sample, with a test run time of approximately 15 minutes.
## Intended Use / Indications for Use
The MeMed BV™ test is an automated semi-quantitative immunoassay that measures three nonmicrobial (host) proteins (TRAIL, IP-10, and CRP) in adult and pediatric serum samples and is intended for use in conjunction with clinical assessments and other laboratory findings as an aid to differentiate bacterial from viral infection. MeMed BV™ is indicated for use in patients presenting to the emergency department or urgent care center and with samples collected at hospital admission from patients with suspected acute bacterial or viral infection, who have had symptoms for less than seven days. The MeMed BV™ test generates a numeric score that falls within discrete interpretation bins based on the increasing likelihood of bacterial infection.
## Comparison with Predicate Device
The MeMed BV is substantially equivalent to the predicate device the VIDAS B.R.A.H.M.S. PCT (PCT) (K162827). The MeMed BV has similar intended and indications for use, as
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well as similar basic technological principles to the predicate device. The minor differences in technological characteristics are supported by the performance testing and do not raise any new questions of safety and efficacy. A substantial equivalence table summarizing the similarities and differences between the MeMed BV and its predicate device is provided below.
## Performance Data
- 1. Analytical performance:
- a. Limit of Quantitation
The Total Error and precision for the lowest concentration of each measurand that could be reliably measured (i.e., Limit of Quantification or LoQ) by the MeMed BV test was evaluated in accordance with CLSI EP17-A2, Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures. The study used two cartridge lots with one MeMed Key analyzer and the samples described in Table 1. Each sample was tested three times on three non-consecutive days.
| Analyte | Total Error Accuracy Goal |
|---------|---------------------------|
| TRAIL | TE < 30% |
| IP-10 | TE < 40% |
| CRP | TE < 30% |
Table 1. Predefined acceptance criteria for LOQ
The TE (total error) was calculated for each of the four concentration levels for three analytes as 2 x SD observed.
The results obtained for LLOQ testing on two cartridge lots are summarized in Table 2.
| Cartridge Lot | | M21244 | | | M21532 | | |
|---------------|-----------|------------------|------------------|---------------|------------------|------------------|---------------|
| Sample | Parameter | TRAIL<br>(pg/ml) | IP-10<br>(pg/ml) | CRP<br>(mg/L) | TRAIL<br>(pg/ml) | IP-10<br>(pg/ml) | CRP<br>(mg/L) |
| 1 | MEAN | 13.4 | 90.3 | 0.9 | 13.9 | 80.4 | 0.9 |
| 1 | STD | 0.8 | 7.0 | 0.1 | 1.1 | 11.0 | 0.1 |
| 1 | CV | 6% | 8% | 7% | 8% | 14% | 8% |
| 1 | TE | 11% | 15% | 13% | 16% | 27% | 16% |
| 2 | MEAN | 15.0 | 98.7 | 1.0 | 15.8 | 85.8 | 1.0 |
| 2 | STD | 1.2 | 14.0 | 0.1 | 1.0 | 11.6 | 0.1 |
| 2 | CV | 8% | 14% | 7% | 6% | 13% | 11% |
| 2 | TE | 16% | 28% | 14% | 12% | 27% | 22% |
| 3 | MEAN | 17.3 | 106.2 | 1.1 | 16.9 | 93.6 | 1.1 |
| 3 | STD | 2.5 | 5.4 | 0.0 | 1.6 | 2.8 | 0.1 |
| 3 | CV | 14% | 5% | 3% | 10% | 3% | 13% |
| 3 | TE | 29% | 10% | 7% | 19% | 6% | 26% |
| 4 | MEAN | 18.1 | 111.1 | 1.2 | 18.1 | 103.3 | 1.2 |
| 4 | STD | 1.1 | 4.4 | 0.1 | 1.6 | 15.7 | 0.1 |
Table 2. Total error for LLOQ measurements for two cartridge lots
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| Cartridge Lot | M21244 | | | M21532 | | | |
|---------------|-----------|---------------|---------------|------------|---------------|---------------|------------|
| Sample | Parameter | TRAIL (pg/ml) | IP-10 (pg/ml) | CRP (mg/L) | TRAIL (pg/ml) | IP-10 (pg/ml) | CRP (mg/L) |
| | CV | 6% | 4% | 9% | 9% | 15% | 9% |
| | TE | 12% | 8% | 18% | 18% | 30% | 18% |
The results show that for all the tested samples, MeMed BV test passes the acceptance criteria of TE. The formal LLOQ is established to values corresponding to TRAIL -15pg/mL, CRP-1 mg/mL, IP-10 - 100 pg/mL as is set in MeMed Key analyzer.
## b. Reproducibility/Precision:
The repeatability, intermediate precision and reproducibility studies for each measurand (TRAIL/IP-10/CRP) of the MeMed BV™ test were conducted using the MeMed Key™ Analyzer. The MeMed BV test score used a panel of 4 scores representing infectious bacteria, infectious virus, equivocal and noninfectious scores during the studies. Studies were performed in accordance with CLSI EP05-A3 Evaluation of Precision of Quantitative Measurement Procedures.
The serum panel members representing the MeMed BV test scores used for these studies included the following:
| Panel member | Sample type | Score |
|--------------|---------------------------|---------------------|
| A | Infectious serum specimen | High (Score = 96) |
| B | Infectious serum specimen | Medium (Score = 53) |
| C | Infectious serum specimen | Low (Score = 1) |
| D | Healthy serum specimen | Healthy (Score = 4) |
## Table 3. Patient Specimen Panel Members
The study was performed in three laboratories. The measurements were performed over 5 nonconsecutive days. At each site, a single operator conducted the tests on two different MeMed Key analyzers using one cartridge lot, with three runs performed each day per panel member. Calibration was performed on the first day for each MeMed Key analyzer using one calibrator lot. External Controls were run daily using one lot of external controls.
For each measurand, TRAIL, IP-10, and CRP, the acceptance criteria for measurements was CV ≤ 15 %. This acceptance criteria were not applicable to IP-10 and CRP concentration of healthy specimens since the concentrations were expected to be below the LoQ of IP-10 and CRP assays. The acceptance criterion for the MeMed BV test score was set at SD < 12.5 score units.
The results of the repeatability, intermediate precision and reproducibility studies are summarized below.
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| | | | | Repeatability | | Intermediate<br>Precision | | Reproducibility | |
|-----------------|-----------------------|-------|----|---------------|-----|---------------------------|-----|-----------------|------|
| Panel<br>member | Measurand<br>or score | Mean | N | SD | CV% | SD | CV% | SD | CV% |
| A | TRAIL | 34.0 | 90 | 2.9 | 8.5 | 2.9 | 8.5 | 4.1 | 12.0 |
| B | TRAIL | 68.0 | 90 | 6.0 | 8.9 | 6.3 | 9.3 | 7.6 | 11.1 |
| C | TRAIL | 266.5 | 90 | 17.6 | 6.6 | 18.1 | 6.8 | 25.9 | 9.7 |
| D | TRAIL | 77.2 | 90 | 7.0 | 9.1 | 7.7 | 9.9 | 9.8 | 12.7 |
| A | IP-10 | 930.7 | 90 | 40.1 | 4.3 | 43.2 | 4.7 | 48.6 | 5.2 |
| B | IP-10 | 372.3 | 90 | 20.0 | 5.4 | 20.5 | 5.5 | 21.3 | 5.7 |
| C | IP-10 | 558.4 | 90 | 22.3 | 4.0 | 24.4 | 4.4 | 25.8 | 4.6 |
| D | IP-10 | 101.4 | 90 | 6.2 | 6.1 | 6.2 | 6.1 | 6.3 | 6.2 |
| A | CRP | 126.0 | 90 | 10.5 | 8.3 | 10.5 | 8.3 | 14.6 | 11.6 |
| B | CRP | 63.2 | 90 | 5.2 | 8.3 | 5.7 | 9.0 | 6.5 | 10.2 |
| C | CRP | 60.9 | 90 | 4.9 | 8.1 | 5.3 | 8.6 | 6.3 | 10.4 |
| D | CRP | 1.0 | 90 | 0.1 | 4.9 | 0.1 | 5.0 | 0.1 | 5.0 |
| A | Score | 96.0 | 90 | 1.3 | | 1.3 | | 1.8 | |
| B | Score | 53.4 | 90 | 7.5 | | 7.7 | | 9.4 | |
| C | Score | 0.9 | 90 | 0.3 | | 0.3 | | 0.4 | |
| D | Score | 3.6 | 90 | 1.0 | | 1.2 | | 1.4 | |
Table 4. Repeatability, Intermediate precision and reproducibility results for four panel members
The reproducibility results complied with the pre-established acceptance criteria for score and individual analytes.
## c. Lot-to-Lot Reproducibility
A lot-to-lot reproducibility study was conducted to estimate lot-to-lot variance, for each MeMed BV test measurand (TRAIL/IP-10/CRP) and the MeMed BV test score for the four panel members as described in Table 4 above.
The lot-to-lot study was performed on 3 days with one operator at one site using three runs per day for each of the four panel members using two lots of cartridges on one MeMed Key Analyzer. Two calibration lots were used, one for each cartridge lot. External controls were run daily using one lot of External Control reagents.
For each of TRAIL, IP-10, and CRP, the acceptance criterion for measurement was set at CV ≤ 15 %. This acceptance criteria are not applicable to IP-10 and CRP concentration of healthy individual since it is expected to be below the LoQ of IP-10 and CRP assays. The acceptance criterion for the score was set at SD < 12.5 score units.
| Panel<br>member | Measurand<br>or score | Mean | N | Between Lots | |
|-----------------|-----------------------|-------|----|--------------|-----|
| | | | | SD | CV% |
| A | TRAIL | 33.1 | 18 | 0.5 | 1.6 |
| B | TRAIL | 66.4 | 18 | 0.0 | 0.0 |
| C | TRAIL | 258.8 | 18 | 0.0 | 0.0 |
| D | TRAIL | 74.5 | 18 | 0.0 | 0.0 |
| A | IP-10 | 950.1 | 18 | 69.7 | 7.3 |
Table 5. Between lots analysis of components of variance
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| Panel<br>member | Measurand<br>or score | Mean | N | Between Lots | |
|-----------------|-----------------------|-------|----|--------------|-----|
| | | | | SD | CV% |
| B | IP-10 | 385.8 | 18 | 16.9 | 4.4 |
| C | IP-10 | 575.2 | 18 | 44.4 | 7.7 |
| D | IP-10 | 100.0 | 18 | 0.0 | 0.0 |
| A | CRP | 117.6 | 18 | 0.8 | 0.7 |
| B | CRP | 60.8 | 18 | 0.0 | 0.0 |
| C | CRP | 58.5 | 18 | 0.7 | 1.2 |
| D | CRP | 1.0 | 18 | 0.0 | 0.6 |
| A | Score | 95.8 | 18 | 0.0 | 0.0 |
| B | Score | 54.2 | 18 | 0.0 | 0.0 |
| C | Score | 1.0 | 18 | 0.0 | 0.0 |
| D | Score | 3.8 | 18 | 0.0 | 0.0 |
The lot-to-lot reproducibility results comply with the pre-established acceptance criteria for score and individual analytes.
- d. Linearity
Linearity of the MeMed BV test for each of the three measurands (TRAIL/IP-10/CRP) was evaluated in accordance with CLSI EP06-A Evaluation of the Linearity of Quantitative Measurement Procedures: A Statistical Approach. The study was performed in one laboratory with one MeMed Key Analyzer, two lots of cartridges, one lot of calibration reagents and one lot of External Control reagents. Calibration was performed before initiating the study for each cartridge lot. External Controls were run daily.
Four replicates of eleven dilutions of each MeMed BV test measurand were measured in the linearity study. The order of measurement of the dilution series was random. The eleven dilutions used in the study are represented in Table 6.
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| Dilution<br># | Volume<br>of low<br>positive<br>material<br>[mL] | Volume<br>of high<br>positive<br>material<br>[mL] | TRAIL<br>(pg/mL) | IP-10<br>(pg/mL) | CRP<br>(ug/mL) |
|---------------|--------------------------------------------------|---------------------------------------------------|------------------|------------------|----------------|
| 1 | 2 | 0 | 15 | 96 | 1 |
| 2 | 1.8 | 0.2 | 49 | 301 | 27 |
| 3 | 1.6 | 0.4 | 80 | 500 | 52 |
| 4 | 1.4 | 0.6 | 111 | 699 | 78 |
| 5 | 1.2 | 0.8 | 142 | 898 | 103 |
| 6 | 1 | 1 | 173 | 1097 | 129 |
| 7 | 0.8 | 1.2 | 204 | 1295 | 154 |
| 8 | 0.6 | 1.4 | 235 | 1494 | 180 |
| 9 | 0.4 | 1.6 | 266 | 1693 | 205 |
| 10 | 0.2 | 1.8 | 297 | 1892 | 231 |
| 11 | 0 | 2 | 290 | 1930 | 289 |
Table 6. Preparation of dilutions for linearity testing
The linearity criterion is that measurement bias due to non-linearity is less than 10% or 10mg/L for CRP, 10% or 10 pg/mL for TRAIL and 10% or 50 pg/mL for IP-10 of the value corresponding to the linear fit. The absolute value thresholds are intended to reflect differences at low concentrations for which defined relative errors result in extremely low absolute value.
Polynomial regression analysis was performed for first-, second- and third-order polynomials.
For CRP and IP-10 Lot 1 and IP-10 Lot 2 significance was identified for second order coefficients. However, the degree of non-linearity is within the acceptance criteria.
## e. Hook Effect
A recombinant sample where each analyte was present at the upper limit of quantitation (ULOQ, sample #1) was used as well as three additional samples where each analyte was present at higher concentrations (samples 2-4).
The samples were prepared by spiking protein rich buffer with each of the three measurands (recombinant proteins). This approach was used to generate Sample 1 and 4 as indicated in Table 7. Sample 2 was prepared by mixing Sample 1 and 4 samples in a ratio of 2/3 and 1/3, respectively. Sample 3 sample was prepared by mixing Level 1 and 4 samples in a ratio of 1/3 and 2/3, respectively. For each concentration level, 3 runs were measured on one MeMed Key Analyzer, on the same day.
| Samples | TRAIL (pg/ml) | IP-10 (pg/ml) | CRP (mg/L) |
|-----------------|---------------|---------------|------------|
| Sample 1 (ULOQ) | 300 | 6000 | 250 |
| Sample 2 | 533 | 7333 | 333 |
| Sample 3 | 767 | 8666 | 417 |
| Sample 4 | 1000 | 10000 | 500 |
| Table 7. Analyte concentrations levels to be tested for hook effect assessment | | |
|--------------------------------------------------------------------------------|--|--|
|--------------------------------------------------------------------------------|--|--|
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Hook effect was determined to be excluded if the responses obtained for concentrations up to level 4 were no less than the response obtained for upper limit of quantification (ULoQ). If one or more of the assessed concentration levels deviated from this criterion, hook effect concentration was established as the lowest concentration for which the obtained response was lower than the response corresponding to ULoQ.
For each concentration level average signal was calculated and compared against the average response obtained for sample 1 (ULOQ). The results are summarized in Table 8.
| Sample | Measurement by analyzer (RLUs) | | |
|--------------------|--------------------------------|----------|---------|
| | TRAIL | IP-10 | CRP |
| Sample 1<br>(ULOQ) | 2018979 | 6645676 | 3656138 |
| Sample 2 | 3209761 | 8029144 | 4693431 |
| Sample 3 | 4448549 | 9508794 | 5348636 |
| Sample 4 | 6111236 | 10904508 | 6125845 |
| Sample | Analyte | Expected<br>Value | MeMed Key<br>Analyzer | Difference | % Difference |
|--------|---------|-------------------|-----------------------|------------|--------------|
| 1 | CRP | 100 mg/L | 98.7 mg/L | -1.3 mg/L | -1.3% |
| 2 | CRP | 100 mg/L | 98.8 mg/L | -1.2 mg/L | -1.2% |
| 3 | PCT | 100 ng/mL | 98.7 ng/mL | -1.3 ng/mL | -1.3% |
| 4 | PCT | 100 ng/mL | 98.8 ng/mL | -1.2 ng/mL | -1.2% |
No hook effect was seen for concentrations up to TRAIL of 1,000 pg/mL, IP-10 of 10,000 pg/mL, and CRP of 500 mg/L.
#### f. Carry over
Because each specimen tested with the MeMed BV test is processed in a separate disposable cartridge and within the cartridge, each one of the three immunoassays is processed using a separate disposable filtered tip, with a unique tip dedicated to each measurand, the likelihood of carry over between specimens is negligible. A carry over study was, nonetheless, conducted to address the low risk of potential carry over. Sequential runs of ("L") and high score ("H") clinical samples were used in the study. No carry-over was assessed based on 1) the difference between average score of high score sample ran after low score sample and high score sample baseline average score of no more than 12.5 score units; and 2) the difference between average score of low score sample ran after high score sample and low score sample baseline average score of no more than 12.5 score units.
Two clinical samples were run in two sequences 1 and 2 of high to low scores and low to high scores, each sequence on a different MeMed Key analyzer: The high to low score (Table 9) and low to high score (Table 10) are represented below.
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| Table 9. High to low score series | | | Table 10. Low to high score series | | |
|-----------------------------------|--------------------------|------|------------------------------------|------|----|
| 1 | High | 95 | 1 | Low | 3 |
| 2 | High | 88 | 2 | Low | 3 |
| 3 | High | 95 | 3 | Low | 5 |
| 4 | High | 96 | 4 | Low | 5 |
| 5 | High | 95 | 5 | Low | 4 |
| 6 | Low | 4 | 6 | High | 96 |
| 7 | High | 90 | 7 | Low | 2 |
| 8 | Low | 2 | 8 | High | 94 |
| 9 | High | 93 | 9 | Low | 3 |
| 10 | Low | 3 | 10 | High | 94 |
| 11 | High | 97 | 11 | Low | 4 |
| 12 | Low | 7 | 12 | High | 98 |
| 13 | High | 97 | 13 | Low | 5 |
| 14 | Low | 3 | 14 | High | 97 |
| 15 | High | 97 | 15 | Low | 6 |
| | Baseline high score mean | 93.8 | Baseline low score mean | | 4 |
| | Test high score mean | 94.8 | Test low score mean | | 4 |
| Difference | | 1 | Difference | | 0 |
The maximal difference in score obtained for high score sample (1 score unit difference) demonstrates that no carry-over occurred with the MeMed BV test.
## g. Interference/Cross Reactivity
Interfering substances and cross-reactants were evaluated for the MeMed BV test score. Each interferent and cross-reactant was tested using two serum panel members that represented score a 'low' score of approximately 5 and 'high' score of approximately 95. The study was performed in one laboratory using one lot of cartridges, one lot of calibration reagents and one lot of External Control reagents. Each interferant and cross-reactant was tested by 8 repeat runs of spiked and non-spiked sample for each clinical sample using 2 MeMed Key Analyzers.
Master stock interferant/cross reactant solutions were spiked into serum specimens at concentrations of less than 10% v/v of the total sample volume. Detailed descriptions of each interferant/cross-reactant concentration is provided in Table 11 and Table 12. The Interference/cross reactivity was assessed by comparison of the spiked sample Test result to a non-spiked sample Test result (appropriate diluent/buffer was added to the non-spiked sample). Interference was determined as bias between spiked and non-spiked score results was ± 12.5 score units.
{11}------------------------------------------------
| Interferent | Stock concentration | Reference<br>matrix | Volume spiked | Final Concentration tested |
|---------------------------------------------|---------------------------|---------------------|---------------|-------------------------------------|
| Acetaminophen (Tylenol) | 312 mg/dL | Aqueous | 5% v/v | 0.156 mg/mL |
| Acetyl Salicylic Acid<br>(Aspirin) | 60 mg/dL | Ethanol | 5% v/v | 0.03 mg/mL |
| Alcohol | 100% | Aqueous | 5% v/v | 0.5% V/V |
| Amoxicillin | 108 mg/dL | Aqueous | 5% v/v | 54 µg/mL |
| Ampicillin | 150 mg/dL | Aqueous | 5% v/v | 75 µg/mL |
| Azithromycin | 22.2 mg/dL | Ethanol | 5% v/v | 11.1 µg/mL |
| Bilirubin (conjugated) | >400 mg/dL | Aqueous | 10% v/v | 0.4 mg/mL |
| Bilirubin (unconjugated) | >400 mg/dL | 0.1M NaOH | 10% v/v | 0.4 mg/mL, in 0.1M NaOH |
| Caffeine | 216 mg/dL | Aqueous | 5% v/v | 108 µg/mL |
| Cetirizine HCL | 8.7 mg/dL | Aqueous | 5% v/v | 4.35 µg/mL |
| Dextramethorphan | 0.0312 mg/dL | Aqueous | 5% v/v | 15.6 ng/mL |
| Doxycycline | 36 mg/dL | Aqueous | 5% v/v | 18 µg/mL |
| HAMA (human α-mouse<br>Ab) | 168 ng/mL<br>>640 (titer) | N/A | N/A | N/A |
| Hemoglobin | >10,000 mg/dL | Aqueous | 10% v/v | 10 mg/ mL, zero spike: 0.9%<br>NaCl |
| Heparin | 66,000 U/L | Aqueous | 5% v/v | 3300 U/L |
| Human serum Albumin<br>(HSA, total protein) | powder | Aqueous | 10% v/v | 60 mg/mL, in serum |
| Ibuprofen (Motrin) | 438 mg/dL | Ethanol | 5% v/v | 219 µg/mL |
| Levofloxacin | 72 mg/dL | HCl | 5% v/v | 36 µg/mL |
| Loratidine | 0.0174 mg/dL | Ethanol | 5% v/v | 87 ng/mL |
| Nicotine | 0.1983 mg/dL | Ethanol | 5% v/v | 969 ng/mL |
| Oxymetazoline HCl | 0.0012 µg/mL | Aqueous | 5% v/v | 0.0006 µg/mL |
| Phenylephrine | 0.06 mg/dL | Aqueous | 5% v/v | 30 ng/mL |
| Prednisolone | 0.198 mg/dL | Ethanol | 5% v/v | 1200 ng/mL |
| Rheumatoid Factor (RF) | 25 kU/L | Aqueous | 2% v/v | 500 IU/mL |
| Triglycerides/Triolein | >15,000 mg/dL | Sucrose and<br>NaCl | 10% v/v | 15 mg/mL, in Ethanol |
| | | | Table 11. Panel of interferents for screening1 |
|--|--|--|------------------------------------------------|
|--|--|--|------------------------------------------------|
1. Concentrations based on recommended testing concentrations in CLSI EP7-A2 Interference testing in clinical chemistry and CLSI EP37 supplemental tables for interference testing in clinical chemistry)
| Cross-reactant | Stock | Reconstitution<br>volume | Reference<br>matrix | Volume<br>spiked | Final<br>Concentration<br>tested |
|----------------------------------------------------------------|-------|--------------------------|---------------------|------------------|----------------------------------|
| Recombinant Human 4-1BB<br>Ligand/TNFSF9 Protein | 25 µg | 250 µL | PBS | 5% v/v | 50 ng/mL |
| Recombinant Human CD40<br>Ligand/TNFSF5 (HEK293-<br>expressed) | 25 µg | 250 µL | PBS | 5% v/v | 50 ng/mL |
| Recombinant Human<br>Lymphotoxin alpha1/beta2<br>Protein | 25 µg | 100 µL | PBS | 5% v/v | 50 ng/mL |
| Recombinant Human<br>Lymphotoxin alpha2/beta1<br>Protein | 10 µg | 100 µL | PBS | 5% v/v | 50 ng/mL |
| Recombinant Human TNF-<br>alpha Protein | 20 µg | 200 µL | PBS | 5% v/v | 50 ng/mL |
| Recombinant Human | 10 µg | 100 µL | PBS | 5% v/v | 50 ng/mL |
{12}------------------------------------------------
| Cross-reactant | Stock | Reconstitution<br>volume | Reference<br>matrix | Volume<br>spiked | Final<br>Concentration<br>tested |
|--------------------------------------------------------------|----------------|--------------------------|---------------------|------------------|----------------------------------|
| Lymphotoxin-alpha/TNF-beta<br>Protein | | | | | |
| Recombinant Human<br>Adiponectin/Acrp30 Protein | 0.266<br>mg/mL | NA | PBS | 5% v/v | 50 ng/mL |
| Recombinant Human<br>CXCL13/BLC/BCA-1 Protein | 25 µg | 250 µL | PBS | 5% v/v | 50 ng/mL |
| Recombinant Human<br>CXCL5/ENA-78 Protein | 25 µg | 250 µL | PBS | 5% v/v | 50 ng/mL |
| Recombinant Human<br>CXCL6/GCP-2 Protein | 25 µg | 250 µL | PBS | 5% v/v | 50 ng/mL |
| Recombinant Human<br>CXCL1/GRO alpha Protein | 10 µg | 100 µL | PBS | 5% v/v | 50 ng/mL |
| Recombinant Human<br>CXCL3/GRO gamma Protein | 10 µg | 100 µL | PBS | 5% v/v | 50 ng/mL |
| Recombinant Human IFN-<br>gamma Protein | 100 µg | 500 µL | DDW | 5% v/v | 50 ng/mL |
| Recombinant Human IL-<br>8/CXCL8 Protein | 50 µg | 500 µL | PBS | 5% v/v | 50 ng/mL |
| Recombinant Human<br>CXCL11/I-TAC Protein | 25 µg | 250 µL | PBS | 5% v/v | 50 ng/mL |
| Recombinant Human<br>CXCL7/NAP-2 Protein | 10 µg | 100 µL | PBS | 5% v/v | 50 ng/mL |
| Recombinant Human<br>CXCL9/MIG Protein | 10 µg | 100 µL | PBS | 5% v/v | 50 ng/mL |
| Recombinant Human/Rhesus<br>Macaque/Feline CXCL12/SDF-<br>1a | 10 µg | 100 µL | PBS | 5% v/v | 50 ng/mL |
| Recombinant Human/Feline<br>CXCL12/SDF-1 beta aa 22-93 | 10 µg | 100 µL | PBS | 5% v/v | 50 ng/mL |
| Recombinant Human<br>Pentraxin 2/SAP Protein | 50 µg | 200 µL | DDW | 5% v/v | 50 ng/mL |
| Recombinant Human<br>Pentraxin 3/TSG-14 Protein | 50 µg | 100 µL | PBS | 5% v/v | 50 ng/mL |
The data shows that the 95% confidence interval for the bias lies within +/-12.5 score units for all the interferants and cross-reactants in the indicated concentrations for both bacterial and viral clinical samples. Thus, it can be concluded that there is no interference or cross-reactivity caused by the above mentioned compounds at the indicated concentrations.
## h. Human Anti-Mouse Antibody (HAMA) Interference
Interference of human anti-mouse antibody (HAMA) was conducted by a dose-response experimental design consisting of 5 serum levels with different amounts of HAMA: Low Pool as described in Table 13 below. The Interference of HAMA was assessed by a comparison of TRAIL, CRP, and IP10 concentrations in the measured serum samples to their nominal concentration values.
Each sample was run on 2 MeMed Key Analyzers with a total of 8 repeats for each sample. The acceptance criterion was that TRAIL, CRP, and IP10 concentrations, when run on clinical serum sample mixed with HAMA positive sample, shall measure concentrations within +/- 10% compared to their nominal concentration. The interference of HAMA on analytes concentration was examined by two independent experiments using two different HAMA-positive samples.
{13}------------------------------------------------
| | TRAIL | | | CRP | | | IP10 | | | | | | |
|-------------|---------|----------------------|---------------------|----------------|---------------|----------------------|---------------------|----------------|---------------|----------------------|---------------------|----------------|---------------|
| Sample | | Mean<br>measur<br>ed | Mean<br>nomin<br>al | Recov<br>ery % | Pass<br>/Fail | Mean<br>measur<br>ed | Mean<br>nomin<br>al | Recove<br>ry % | Pass<br>/Fail | Mean<br>measur<br>ed | Mean<br>nomin<br>al | Recove<br>ry % | Pass<br>/Fail |
| Sample<br>1 | Level 1 | 132.3 | | | | 109.5 | | | | 1338.6 | | | |
| | Level 2 | 103.8 | 107.0 | 97% | Pass | 78.1 | 84.7 | 92% | Pass | 991.8 | 1010.2 | 98% | Pass |
| | Level 3 | 81.7 | 84.0 | 97% | Pass | 59.8 | 55.3 | 108% | Pass | 681.7 | 756.8 | 90% | Pass |
| | Level 4 | 57.3 | 58.8 | 98% | Pass | 32.1 | 30.4 | 106% | Pass | 409.7 | 428.3 | 96% | Pass |
| | Level 5 | 35.8 | | | | 1.0 | | | | 175.0 | | | |
| Sample<br>2 | Level 1 | 138.1 | | | | 109.7 | | | | 1293.6 | | | |
| | Level 2 | 115.5 | 115.7 | 100% | Pass | 83.7 | 85.0 | 98% | Pass | 967.0 | 977.3 | 99% | Pass |
| | Level 3 | 93.4 | 100.2 | 93% | Pass | 60.4 | 55.6 | 109% | Pass | 661.1 | 697.3 | 95% | Pass |
| | Level 4 | 79.9 | 77.8 | 103% | Pass | 31.9 | 30.9 | 103% | Pass | 355.5 | 381.1 | 93% | Pass |
| | Level 5 | 62.3 | | | | 1.5 | | | | 101.1 | | | |
Table 13. HAMA interference testing results
For both HAMA samples the recovery of TRAIL, IP-10 and CRP are within the +/- 10%. The results show that the three assays are tolerant to high HAMA concentrations.
#### i. In-Use Stability
An in-use stability study was conducted to demonstrate the allowable handling conditions from blood draw to serum sample input into the cartridge. Stability was assessed for each MeMed BV test measurand (TRAIL/IP-10/CRP) and the MeMed BV test resulting score for four patient serum panel members representing two samples with 'low' scores of approximately 5 and two samples with 'high' scores of approximately 95 as described in Table 14.
The study was performed in one laboratory on four days, one day per panel member. Three MeMed Key analyzers and one lot of cartridges were used. Calibration was performed at the beginning of the study using one lot of calibration reagents.
| Panel member | Sample type | Score | Number of patients |
|--------------|---------------------------|----------------------------------|--------------------|
| A1, A2 | Infectious serum specimen | High (score<br>approximately 95) | 2 |
| B1, B2 | Infectious serum specimen | Low (score<br>approximately 5) | 2 |
## Table 14. Patient specimens (panel members)
For each panel member, the incubations listed Table 15 were performed with the package insert indicated SST tube before centrifugation and testing with the MeMed BV Test. There were three replicate runs for each time point performed in parallel on three MeMed Key analyzers.
| SST<br>Tube # | Time at room temp before centrifugation (mins) |
|---------------|------------------------------------------------------------------------------|
| 1 | 30 (shortest time for coagulation according to the IFU of BD SST Vacutainer) |
| 2 | 60 |
| 3 | 90 |
## Table 15. Incubation Time at Room Temperature
{14}------------------------------------------------
| SST<br>Tube # | Time at room temp before centrifugation (mins) |
|---------------|------------------------------------------------|
| 4 | 120 |
| 5 | 150 |
The mean values, regression lines, confidence intervals and significance level of the difference of the slope from 0 were examined for each of the incubation times. The minimum acceptable incubation time was approximately 130 minutes and the incubation time before an observed failure was 120 minutes. Thus, the 120 minute time period at room temperature before centrifygation preparation for use in the MeMed BV test was established as 120 minutes.
#### j. Freeze-thaw stability
A study was conducted to validate stability between fresh and frozen specimens. This study examined the stability of the MeMed BV test result (score) using 40 paired fresh and frozen specimens as indicated in Table 16. The study was performed in one laboratory. Each sample was tested three times on the same MeMed Key analyzer using one lot of cartridges and one lot of calibrator reagents. Calibration was performed on the first day and repeated after two weeks.
| Score bin | Interpretation | # of specimen tested |
|--------------------|-----------------------------------------------|----------------------|
| $90 \le s \le 100$ | High likelihood of<br>bacterial infection | 12 |
| $65 < s < 90$ | Moderate likelihood of<br>bacterial infection | 6 |
| $35 \le s \le 65$ | Equivocal | 4 |
| $10 < s <35$ | Moderate likelihood of<br>viral infection | 6 |
| $0 \le s \le 10$ | High likelihood of viral<br>infection | 12 |
Table 16. Sample Score Ranges and Specimen Numbers per S
The acceptance criteria for equivalency between fresh and frozen specimens for the score was that all scores within the 95% confidence interval are within the same or adjacent score categories and do not result in a move between non-adjacent scores.
Passing Bablok regression was used to compare the means of results from the fresh and the frozen specimens. A 95% confidence interval for the regression was calculated using bootstraping.
The confidence intervals do not intersect the lines representing the adjacent test scores and demonstrates the frozen and fresh samples demonstrated score results corresponding to the same or adjacent scores within the 95% confidence interval, thus demonstrating equivalency between fresh and frozen samples for the MeMed BV test.
## k. Calibrator Traceability
The company conducted metrological traceability testing of the MeMed BV™ multi-standard calibrator material to ensure that analytical results used for patient care are accurate as well as consistent over time and when using different devices and systems.
{15}------------------------------------------------
All three analytes are traceable to a standard. The material was produced following ISO Guide 34:2009. The test was performed to assign the TRAIL, CRP and IP10 portion of the Master Lot-Calibrator a concentration that is based on their respective reference standard, in order to assign a value to the MeMed BV Calibrators. The test was performed with a calibration curve.
Lastly, testing was conducted to verify that the released calibrators are able to accurately quantify known samples on the MeMed Key analyzer using MeMed BV cartridges. The Lot was released only if all the parameters comply with the acceptance criteria.
#### Calibrator, External Controls, and Cartridges Stability Testing 1.
MeMed BV calibrators (i.e., CAL1, CAL2, and CAL3), external controls (ECs), and cartridges were subjected to real time stability, iransportation stability, shelf life validation, stability monitoring, and calibration interval testing (for ECs and calibrators only) in order to show that they maintain their respective performance characteristics over a defined time interval under indicated storage conditions. MeMed BV cartridges were also subjected to calibration interval testing.
The results of this testing demonstrated that the calibrators, ECs have a shelf life of 3.5 months and the cartridges have a shelf life of 12 months.
## m. Reference Interval
Reference Interval study, conducted based on CLSI EP28-A3c Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory, demonstrated that:
The lower limit of the score (corresponding to the 2.5th percentile) is 0 [90% Cl: 0-1].
The upper limit of the score (corresponding to the 97.5th percentile) is 46 [90% Cl: 36-75].
## Clinical Studies
## a. Apollo Clinical Study
The diagnostic performance of the MeMed BV™ test was established by a prospective, multicenter, observational, blinded study. The primary objective of the Apollo clinical study was to establish the diagnostic performance of the MeMed BV™ test for differentiating bacterial from viral infection in patients with suspected acute bacterial or viral infection using expert adjudication comparator method (forced diagnosis for indeterminate cases) with the experts blinded to Creactive protein (CRP) and procalcitonin (PCT) values. A secondary objective was to establish the diagnostic performance of MeMed BV™ for differentiating bacterial from viral infection using expert adjudication comparator method (indeterminate cases removed from analysis) with the experts given CRP and PCT values. This study included 1.016 infectious subjects (476 prospectively recruited adult and pediatric patients and 540 archived cases) from 11 medical centers (9 in the US and 2 in Israel). The study population comprised hospital admitted, Emergency Department
{16}------------------------------------------------
(ED) and urgent care center patients over the age of 90 days, with suspected acute bacterial or viral infection, and healthy subjects.
The bins used in the study correspond to Table 16.
Image /page/16/Figure/2 description: The image shows the text "Primary Objective Cohort (Forced Bacterial Viral Cohort Based on Adjudication Blinded to CRP and PCT)". The text is underlined. The text describes the primary objective cohort.
Image /page/16/Figure/3 description: This image is a decision tree showing the distribution of a study population (n=1016) into different bins based on a score. The population is first divided into "Forced Bacterial Viral Cohort" (n=1016) and "Indeterminate" (n=0). The "Forced Bacterial Viral Cohort" is further divided into five bins based on score ranges: Bin 1 (0 ≤ score ≤ 10, n=478), Bin 2 (10 < score < 35, n=173), Bin 3 (35 ≤ score ≤ 65, n=102), Bin 4 (65 < score < 90, n=94), and Bin 5 (90 ≤ score ≤ 100, n=169). Each bin is then divided into "Bacterial" and "Viral" categories with corresponding counts.
Figure 1: Primary Objective Cohort Disposition
* Viral includes viral and non-infectious comparator method outcomes
The performance of MeMed BV™ test in differentiating between bacterial and viral infection was assessed in the primary objective cohort using two pre-specified statistical tests:
- . The Cochran-Armitage (CA) Test demonstrated a significant trend in increasing probability of bacterial infection with higher MeMed BV™ score (p < 0.0001).
- . The 95% Confidence Interval (CI) of the Likelihood Ratio (LR) for some of the bins (Bins 1,2,4,5) excluded 1 (Table 17).
These statistical tests validate that the higher the score, the higher the likelihood of a bacterial infection and therefore the study successfully achieves its the primary objective.
| Score Bin | N | N<br>(Reference<br>Bacterial) | N<br>(Reference<br>Viral and<br>Non-<br>Infectious) | %<br>Patients | %<br>Reference<br>Bacterial<br>Patients | %<br>Reference<br>Viral and<br>Non-<br>Infectious<br>Patients | Likelihood<br>Ratio<br>(Confidence<br>Interval) |
|-----------------|------|-------------------------------|-----------------------------------------------------|---------------|-----------------------------------------|---------------------------------------------------------------|-------------------------------------------------|
| 90 ≤ score ≤100 | 169 | 102 | 67 | 16.6 | 60.4 | 39.6 | 8.1 (6.3-10.5) |
| 65 < score <90 | 94 | 26 | 68 | 9.3 | 27.7 | 72.3 | 2.1 (1.3-3.1) |
| 35 ≤ score ≤ 65 | 102 | 16 | 86 | 10.0 | 15.7 | 84.3 | 1.0 (0.6-1.7) |
| 10 < score <35 | 173 | 9 | 164 | 17.0 | 5.2 | 94.8 | 0.3 (0.2-0.6) |
| 0 ≤ score ≤10 | 478 | 7 | 471 | 47.1 | 1.5 | 98.5 | 0.1 (0.0-0.2) |
| Total | 1016 | 160 | 856 | 100 | | | |
Table 17: MeMed BV™ Performance in Primary Objective Cohort
{17}------------------------------------------------
Image /page/17/Figure/0 description: This image shows a flow chart of a study population. The study population starts with n=1016, which then splits into two groups: Suspected Bacterial Viral Cohort (n=872) and Indeterminate (n=144). The Suspected Bacterial Viral Cohort is then divided into five bins based on score ranges: Bin 1 (0 ≤ score ≤ 10, n=458), Bin 2 (10 < score < 35, n=155), Bin 3 (35 ≤ score ≤ 65, n=72), Bin 4 (65 < score < 90, n=65), and Bin 5 (90 ≤ score ≤ 100, n=122). Each bin is further divided into Bacterial and Viral categories with corresponding counts.
Secondary Objective Cohort (Suspected Bacterial Viral Cohort Based on Adjudication NOT
Figure 2: Secondary Objective Cohort Disposition
* Viral includes viral and non-infectious comparator method outcomes
The performance of MeMed BV™ test in differentiating between bacterial and viral infection was assessed in the secondary objective cohort using two statistical tests:
- The Cochran-Armitage (CA) Test demonstrated a significant trend in increasing probability of bacterial infection with higher MeMed BV™ score (p < 0.0001).
- . The 95% Confidence Interval (CI) of the Likelihood Ratio (LR) for some of the bins (Bins 1,2,4,5) excluded 1 (Table 18).
These statistical tests validate that the higher the higher the likelihood of a bacterial infection and therefore the study successfully achieves its secondary objective.
| Score Bin | N | N<br>(Reference Bacterial) | N<br>(Reference Viral and<br>Non-Infectious) | % Patients | % Reference<br>Bacterial<br>Patients | % Reference<br>Viral and<br>Non-Infectious<br>Patients | Likelihood<br>Ratio<br>(Confidence<br>Interval) |
|-----------------|-----|----------------------------|----------------------------------------------|------------|--------------------------------------|--------------------------------------------------------|-------------------------------------------------|
| 90 ≤ score ≤100 | 122 | 99 | 23 | 14.0 | 81.2 | 18.9 | 25.0 (16.6-37.8) |
| 65 < score <90 | 65 | 19 | 46 | 7.5 | 29.2 | 70.8 | 2.4 (1.5-4.0) |
| 35 ≤ score ≤ 65 | 72 | 6 | 66 | 8.3 | 8.3 | 91.7 | 0.5 (0.2-1.2) |
| 10 < score <35 | 155 | 1 | 154 | 17.8 | 0.7 | 99.4 | 0.0 (0.0-0.3) |
| 0 ≤ score ≤10 | 458 | 3 | 455 | 52.5 | 0.7 | 99.3 | 0.0 (0.0-0.1) |
| Total | 872 | 128 | 744 | 100 | | | |
Table 18: MeMed BV™ Performance in Secondary Objective Cohort
{18}------------------------------------------------
Table 19 summarizes the results of a bin analysis for the prospectively recruited patients (primary objective), and Table 20 summarizes the results of a bin analysis for the archived cases (primary objective).
| Table 19: Diagnostic performance of MeMed BV™ for prospectively recruited patients | |
|------------------------------------------------------------------------------------|--|
| (primary objective) | |
| Score Bin | n | nBacterial | nViral | %Patients | %Bacterial<br>Patients | %Viral<br>Patients | Likelihood<br>Ratio |
|-----------------|-----|------------|--------|-----------|------------------------|--------------------|---------------------|
| 90 ≤ score ≤100 | 42 | 27 | 15 | 8.8 | 64.3 | 35.7 | 12.25 (6.9-21.7) |
| 65 < score <90 | 39 | 13 | 26 | 8.2 | 33.3 | 66.7 | 3.40 (1.8-6.3) |
| 35 ≤ score ≤ 65 | 46 | 10 | 36 | 9.7 | 21.7 | 78.3 | 1.89 (1.0-3.6) |
| 10 < score <35 | 77 | 7 | 70 | 16.2 | 9.1 | 90.9 | 0.68 (0.3-1.4) |
| 0 ≤ score ≤10 | 272 | 4 | 268 | 57.1 | 1.5 | 98.5 | 0.10 (0.0-0.3) |
| Total | 476 | 61 | 415 | 100 | | | |
| Table 20: Diagnostic performance of MeMed BV™ for archived cases (primary objective) | |
|--------------------------------------------------------------------------------------|--|
|--------------------------------------------------------------------------------------|--|
| Score Bin | n | nBacterial | nViral | %Patients | %Bacterial<br>Patients | %Viral<br>Patients | Likelihood<br>Ratio |
|-----------------|-----|------------|--------|-----------|------------------------|--------------------|---------------------|
| 90 ≤ score ≤100 | 127 | 75 | 52 | 23.5 | 59.1 | 40.9 | 6.42 (4.9-8.5) |
| 65 < score <90 | 55 | 13 | 42 | 10.2 | 23.6 | 76.4 | 1.38 (0.8-2.5) |
| 35 ≤ score ≤ 65 | 56 | 6 | 50 | 10.4 | 10.7 | 89.3 | 0.53 (0.2-1.2) |
| 10 < score <35 | 96 | 2 | 94 | 17.8 | 2.1 | 97.9 | 0.09 (0.0-0.4) |
| 0 ≤ score ≤10 | 206 | 3 | 203 | 38.2 | 1.5 | 98.5 | 0.07 (0.0-0.2) |
| Total | 540 | 99 | 441 | 100 | | | |
## Subgroup Analyses
For both the primary and secondary objective cohort, the MeMed BV™ score increased significantly with the likelihood of bacterial infection irrespective of sex, age, ethnicity, race, preenrollment antibiotics, time from symptom onset, and comorbidities (hypertension, ischemic heart disease, hyperlipidemia, diabetes, and COPD adults). As expected, there was a difference in bacterial prevalence in children versus adults (e.g., in the primary objective cohort 10.6% versus 19.5%, respectively). Nevertheless, both statistical tests of performance were passed for all ages.
Based on the clinical performance as documented in the clinical study, the MeMed BV™ test has a safety and effectiveness profile that is similar to the predicate device.
{19}------------------------------------------------
## Conclusions
The MeMed BV™ is as safe and effective as the VIDAS B.R.A.H.M.S. PCT (PCT) (K162827). The MeMed BV™ and the predicate test have the same general intended use and similar indications for use, technological characteristics and principles of operation.
In addition, the minor technological differences between the MeMed BV™ test and its predicate devices raise no new issues of safety or effectiveness. Performance data demonstrate that the MeMed BV™ is as safe and effective as the VIDAS B.R.A.H.M.S. PCT (PCT). Thus, the MeMed BV™ is substantially equivalent.
{20}------------------------------------------------
| | MeMed BV test | VIDAS® B·R·A·H·M·S PCT™ Test<br>(K162827) |
|------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Intended Use /<br>Indications for<br>Use | The MeMed BV™ test is an automated<br>semi-quantitative immunoassay that<br>measures three non-microbial (host)<br>proteins (TRAIL, IP-10, and CRP) in adult<br>and pediatric serum samples and is<br>intended for use in conjunction with<br>clinical assessments and other laboratory<br>findings as an aid to differentiate bacterial<br>from viral infection. MeMed BV™ is<br>indicated for use in patients presenting to<br>the emergency department or urgent care<br>center and with samples collected at<br>hospital admission from patients with<br>suspected acute bacterial or viral<br>infection, who have had symptoms for<br>less than seven days. The MeMed BV™<br>test generates a numeric score that falls<br>within discrete interpretation bins based<br>on the increasing likelihood of bacterial<br>infection. | VIDAS® B·R·A·H·M·S PCT™ (PCT) is an<br>automated test for use on the instruments<br>of the VIDAS® family for the determination<br>of human procalcitonin in human serum or<br>plasma (lithium heparinate) using the ELFA<br>(Enzyme-Linked Fluorescent Assay)<br>technique.<br><br>Used in conjunction with other laboratory<br>findings and clinical assessments, VIDAS<br>B·R·A·H·M·S PCT is intended for use as<br>follows:<br>• to aid in the risk assessment of critically<br>ill patients on their first day of ICU<br>admission for progression to severe<br>sepsis and septic shock,<br>• to aid in assessing the cumulative 28-<br>day risk of all-cause mortality for<br>patients diagnosed with severe sepsis<br>or septic shock in the ICU or when<br>obtained in the emergency department<br>or other medical wards prior to ICU<br>admission, using a change in PCT level<br>over time,<br>• to aid in decision making on antibiotic<br>therapy for patients with suspected or<br>confirmed lower respiratory tract<br>infections (LRTI) defined as community-<br>acquired pneumonia (CAP), acute<br>bronchitis, and acute exacerbation of<br>chronic obstructive pulmonary disease<br>(AECOPD) - in an inpatient setting or<br>an emergency department,<br>• to aid in decision making on antibiotic<br>discontinuation for patients with<br>suspected or confirmed sepsis. |
| User Population | Health Care Providers requesting samples<br>to be tested by clinical laboratory<br>technicians | Health Care Providers requesting samples<br>to be tested by clinical laboratory<br>technicians |
| Specimen | Human serum | Human serum or plasma (lithium heparinate) |
| Assay Principle | Sandwich immunoassay technology | Sandwich immunoassay technology…
