(603 days)
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No
The device description focuses on the reagents, calibrators, and controls used in an in vitro diagnostic test. The ELF score is calculated based on the quantitative measurements of specific biomarkers, which is a standard biochemical analysis, not an AI/ML algorithm. The performance studies analyze the predictive value of this calculated score, not the output of an AI/ML model.
No
The device is an in vitro diagnostic (IVD) tool used to determine an ELF score, which is a prognostic marker for assessing the likelihood of progression to cirrhosis and liver-related clinical events in patients with NASH and advanced fibrosis. It does not actively treat or alter the course of a disease.
Yes
The "Intended Use / Indications for Use" section explicitly states that the device is "for in vitro diagnostic use" and "indicated as a prognostic marker in conjunction with other laboratory findings and clinical assessments." These phrases clearly define the device's role in diagnosing or predicting a medical condition.
No
The device description explicitly lists physical reagents, calibrators, and controls, which are hardware components used in an in vitro diagnostic test. The device is an assay performed on an instrument (ADVIA Centaur XP system), not a standalone software application.
Yes, this device is an IVD (In Vitro Diagnostic).
Here's why:
- Intended Use/Indications for Use: The very first sentence explicitly states, "ADVIA Centaur® Enhanced Liver Fibrosis (ELF™) is for in vitro diagnostic use..." This is the most direct indicator.
- Device Description: The description details the components of the test, including reagents, calibrators, and controls. These are all typical components of an in vitro diagnostic test used to analyze biological samples.
- Input: The test uses human serum, which is a biological sample analyzed outside of the body.
- Intended User/Care Setting: The intended user is a "Licensed healthcare professional / Clinical laboratory," which is consistent with the use of an IVD in a clinical setting.
The device performs measurements on a biological sample (serum) to provide information about a patient's health status (likelihood of progression to cirrhosis and liver-related clinical events). This aligns perfectly with the definition of an in vitro diagnostic device.
N/A
Intended Use / Indications for Use
ADVIA Centaur® Enhanced Liver Fibrosis (ELF™) is for in vitro diagnostic use in the determination of an ELF score based on the combined quantitative measurements of hyaluronic acid, amino-terminal propeptide of type III procollagen, and tissue inhibitor of matrix metalloproteinase 1 in human serum using the ADVIA Centaur XP system.
ADVIA Centaur ELF is indicated as a prognostic marker in conjunction with other laboratory findings and clinical assessments in patients with advanced fibrosis (F3 or F4) due to non-alcoholic steatohepatitis (NASH), to assess the likelihood of progression to cirrhosis and liver-related clinical events.
Product codes (comma separated list FDA assigned to the subject device)
QQB
Device Description
The ADVIA Centaur ELF test contains the following:
Reagents: Lite Reagent and Solid Phase reagents for HA, PIIINP and TIMP-1, and Ancillary Well reagents for HA and PIIINP are contained within ReadyPack® reagent packs. Each ReadyPack reagent cartridge has a barcode label used to automatically transfer information to the instrument when loaded into the instrument.
Calibrators: ADVIA Centaur ELF Calibrator kit contains 2 levels of calibrators (Low and High). Calibration is performed using Low and High Calibrators of known value (as per the Calibrator Assigned Value card provided in the ELF Calibrator kit).
Controls: The ADVIA Centaur ELF QC kit contains 3 controls (Level 1, Level 2, Level 3).
Mentions image processing
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Mentions AI, DNN, or ML
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Input Imaging Modality
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Anatomical Site
Liver
Indicated Patient Age Range
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Intended User / Care Setting
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Description of the training set, sample size, data source, and annotation protocol
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Description of the test set, sample size, data source, and annotation protocol
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Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)
Clinical Studies:
Information was provided from "trials comprised of patients with bridging fibrosis and cirrhosis due to NASH. The information was gathered from trials intended to assess various investigational therapeutic substances but only data from the placebo arms of each trial was considered. Data was analyzed separately for patients by severity of fibrosis at the onset of the data collection period.
Cirrhotic population:
Three studies (trials 1 through 3) were provided in patients with cirrhosis at study entry. Each study assessed the ELF score ability to predict development of liverrelated clinical outcomes over the extent of each patient's follow up time.
Outcomes evaluated in cirrhotic trials:
- All-cause mortality* ●
- Liver transplantation
- Qualification for liver transplantation (Model for End-Stage Liver Disease ● (MELD) ≥ 15)
- Esophageal variceal bleeding requiring treatment
- . Clinically apparent ascites requiring treatment
- Hepatic encephalopathy of Grade 2 or above (according to Westhaven criteria) . and requiring treatment
- Newly diagnosed varices in a subject without prior varices (Trial 1 and 3 only) ●
- Progression from small to medium or large varices (Trial 3 only) ●
Key Results for Cirrhotic Population (pooled performance across 3 placebo arms):
| Group based on ELF Score | Total subjects (n) | Liver Related Event Yes | Liver Related Event No | Risk of Event (95% Confidence Intervals) |
|---|---|---|---|---|
| 11.3 | 81 | 17 | 64 | 21.0% (12.1-29.9%) |
| All | 305 | 26 | 279 | 8.5% (5.6-12.2%) |
Bridging fibrosis population:
Two studies (trials were provided in patients with bridging fibrosis at study entry. Each study assessed the ELF score ability to predict development of cirrhosis over the extent of each patient's follow up time.
Key Results for Bridging Fibrosis Population (pooled performance):
| Group based on ELF Score | Total subjects (n) | Liver Related Event Yes | Liver Related Event No | Risk of Event (95% Confidence Intervals) |
|---|---|---|---|---|
| 11.3 | 18 | 8 | 10 | 44.4% (21.5-67.4%) |
| All | 212 | 41 | 171 | 19.3% (14.2 -25.3%) |
Key Metrics (Sensitivity, Specificity, PPV, NPV, etc.)
Risk of Event, as shown in the Summary of Performance Studies.
Predicate Device(s): If the device was cleared using the 510(k) pathway, identify the Predicate Device(s) K/DEN number used to claim substantial equivalence and list them here in a comma separated list exactly as they appear in the text. List the primary predicate first in the list.
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Reference Device(s): Identify the Reference Device(s) K/DEN number and list them here in a comma separated list exactly as they appear in the text.
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Predetermined Change Control Plan (PCCP) - All Relevant Information for the subject device only (e.g. presence / absence, what scope was granted / cleared under the PCCP, any restrictions, etc).
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§ 862.1622 Prognostic test for assessment of liver related disease progression.
(a)
Identification. A prognostic test for assessment of liver related disease progression is intended to measure one or more analytes obtained from human samples as an aid in assessing progression of liver related disease. This device is not intended for diagnosis of any disease, for monitoring the effect of any therapeutic product, for assessing progression to hepatocellular carcinoma, or for assessing disease progression in individuals with viral hepatitis. It is also not intended for the detection of viruses, viral antigens, or antibodies to viruses.(b)
Classification. Class II (special controls). The special controls for this device are:(1) Design verification and validation must include clinical validation data providing:
(i) Information demonstrating clinical performance in a population of patients with liver disease for the different risk categories (
e.g., at lower risk, at higher risk) for progression of their disease using well characterized clinical specimens representing the intended use population collected from multiple intended clinical sites, or an alternative study design determined to be appropriate by FDA.(ii) Information demonstrating that the outcomes measured and the length of followup are clinically relevant for the progression of the specified liver disease.
(iii) Information demonstrating that the clinical criteria for determining whether the target disease is present and that the exclusion and inclusion criteria for subjects who have the target disease are appropriate.
(iv) Information demonstrating test performance of the complete test system, including any sample collection and processing steps.
(v) Information, provided or referenced, generated in samples from non-diseased individuals, that demonstrate the upper and lower reference intervals for the output provided by the device.
(2) The labeling required under 21 CFR 809.10(b) must include:
(i) A warning statement that test results are not intended to diagnose disease or for monitoring the effect of any therapeutic product.
(ii) A warning statement that test results are intended to be used in conjunction with other clinical and diagnostic findings, consistent with professional standards of practice, including information obtained by alternative methods, and clinical evaluation, as appropriate.
(iii) A warning statement that describes any limitations on the clinical interpretation(s) of the test results.
(iv) Detailed information on device performance, including any limitations to the data generated in the clinical study(ies) and information on device performance in relevant subgroups (
e.g., severity of liver disease at the beginning of the observation period) observed in the clinical study(ies).(v) Information on the analytical performance of the device, including demonstration of reproducibility across multiple sites and multiple reagent lots, or an alternative reproducibility study design determined to be appropriate by FDA.
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EVALUATION OF AUTOMATIC CLASS III DESIGNATION FOR ADVIA Centaur Enhanced Liver Fibrosis (ELFTM)
DECISION MEMORANDUM
A. DEN Number:
B. Purpose for Submission:
De Novo request for evaluation of automatic class III designation for the ADVIA Centaur Enhanced Liver Fibrosis (ELFTM)
C. Measurand:
The test reports an ELF score derived from the measurement of hyaluronic acid (HA), amino-terminal propeptide of type III procollagen (PIIINP), and tissue inhibitor of metalloproteinase 1 (TIMP-1)
D. Type of Test:
Quantitative immunoassay
E. Applicant:
Siemens Healthcare Diagnostics Inc.
F. Proprietary and Established Names:
ADVIA Centaur Enhanced Liver Fibrosis (ELFTM)
G. Regulatory Information:
| Regulation | Classification | Name | Product
Code | Panel |
|--------------------|----------------|---------------------------------------------------------------------------|-----------------|-------------------|
| 21 CFR
862.1622 | II | Prognostic test for
assessment of liver related
disease progression | QQB | Chemistry
(75) |
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H. Indications for Use:
1. Indications for Use:
ADVIA Centaur® Enhanced Liver Fibrosis (ELF™) is for in vitro diagnostic use in the determination of an ELF score based on the combined quantitative measurements of hyaluronic acid, amino-terminal propeptide of type III procollagen, and tissue inhibitor of matrix metalloproteinase 1 in human serum using the ADVIA Centaur XP system.
ADVIA Centaur ELF is indicated as a prognostic marker in conjunction with other laboratory findings and clinical assessments in patients with advanced fibrosis (F3 or F4) due to non-alcoholic steatohepatitis (NASH), to assess the likelihood of progression to cirrhosis and liver-related clinical events.
-
- Special conditions for use statement(s)
- For in vitro diagnostic use. ●
- For Prescription Use Only.
- CAUTION ● Federal (USA) law restricts this device to sale by or on the order of a licensed healthcare professional.
- The ADVIA Centaur ELF test is not for use in the diagnosis of NASH, or for staging ● of fibrosis.
- ADVIA Centaur ELF is not for use in the serial monitoring of disease progression or for the monitoring of effects of therapeutic products.
- Test results are intended to be used in conjunction with other clinical and diagnostic findings, consistent with professional standards of practice, including information obtained by alternative methods, and clinical evaluation as appropriate.
- Measurements for HA, PIIINP, and TIMP-1 must be obtained within 8 hours of one ● another for the ELF score to be valid.
- ADVIA Centaur ELF is limited to the detection of HA, PIIINP and TIMP-1 in human ● serum.
- Only use results obtained on ADVIA Centaur XP systems to calculate ELF scores.
- Do not use hemolyzed samples. ●
- Do not use in patients taking biotin supplements. ●
- Do not use samples that contain fluorescein. Samples with fluorescein may cause falsely depressed results. Evidence suggests that patients undergoing retinal fluorescein angiography can retain amounts of fluorescein in the body for up to 72 hours post-treatment. In cases of patients with renal insufficiency, including many diabetics, retention could be longer.
- Patient samples may contain heterophilic antibodies that could react in immunoassays . and cause falselv elevated or depressed results. This assay is designed to minimize interference from heterophilic antibodies. Additional information may be required for diagnosis.
2
- . An ELF score 10% change in a component assay or > 0.3 change in ELF score) was observed for the following drugs at the listed concentration:
| Therapeutic Substance | Highest Concentration Tested |
|---|---|
| Acetaminophen | 200 µg/mL |
| Acetylsalicylic acid | 652 µg/mL |
| Azathioprine | 2.58 µg/mL |
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| Therapeutic Substance | Highest Concentration Tested |
|---|---|
| Cetirizine | 4.35 µg/mL |
| Diphenhydramine | 774 ng/mL |
| Disulfiram | 1.14 µg/mL |
| Glyburide | 850 ng/mL |
| Hydroxzyine | 267 ng/mL |
| Ibuprofen | 219 µg/mL |
| Interferon α2a | 10 ng/mL |
| Interferon α2b | 10 ng/mL |
| Ledipasvir | 969 ng/mL |
| Liraglutide | 168 ng/mL |
| Loratadine | 87 ng/mL |
| Mesalamine | 20.4 µg/mL |
| Metformin | 12 µg/mL |
| Methotrexate | 1.36 mg/mL |
| Obeticholic Acid | 540 ng/mL |
| Pioglitazone | 4.76 µg/mL |
| Ribavirin | 25 µg/mL |
| Rifampicin | 48 µg/mL |
| Sofosbuvir | 1.85 µg/mL |
| Tenofovir | 978 ng/mL |
| Tolazamide | 45 µg/mL |
| Ursodiol (UDCA) | 169 µg/mL |
Significant interference was identified for both biotin and fluorescein. Serial dilution testing was performed to identify the concentration of each drug at which interference was observed.
While concentrations of biotin above approximately 65 ng/mL cause more than 10% interference with ADVIA Centaur PIIINP measurements, clinically significant interference (change of ≥ 0.3) in the ELF score was not observed up to biotin concentrations of 150 ng/mL.
The sponsor includes the following information in their labeling:
Specimens that contain biotin at a concentration of 150 ng/mL demonstrate a less than or equal to a 0.3 unit change in results for the ADVIA Centaur ELF Test. Biotin concentrations greater than these may lead to falsely depressed results for patient samples. Do not use in patients taking biotin supplements.
The recommended adult daily dietary intake for biotin is 30 ug/day. Over the counter dietary supplements promoted for use in hair, skin and nail health may contain 5 -100 mg of biotin, with recommendations to take multiple pills per day. Pharmacokinetic studies in healthy adults have shown that, in subjects ingesting 5 mg, 10 mg, and 20 mg of biotin, serum concentrations of biotin can reach up to 73 ng/mL, 141 ng/mL, and 355 ng/mL, respectively. Subjects who take up to 300 mg of
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biotin per day may have serum biotin levels as high as 1.160 ng/mL. These studies were performed in a small number of apparently healthy subjects. Clearance of biotin could be different in other patient vopulations, such as in patients with impaired renal function, which could lead to higher concentrations of biotin in serum or plasma.
Clinically significant interference for the ELF score (change of > 0.3) was observed at 850 ng/dL Fluorescein.
The sponsor includes the following limitation in their labeling:
Do not use samples that contain fluorescein. Samples with fluorescein may cause falsely depressed results in this assay. Evidence suggests that patients undergoing retinal fluorescein angiography can retain amounts of fluorescein in the body for up to 72 hours post-treatment. In cases of patients with renal insufficiency, including many diabetics, retention could be longer.
Endogenous Interference:
Serum patient pools were prepared that contained either low, mid or high levels of HA. PIIINP and TIMP-1 to cover the expected range of ELF scores. Pools were divided and designated as "control sample" (no endogenous substance present but spiked with the applicable diluent for the respective substance) or "test sample" (endogenous substance present). Testing was performed in replicates of 3 per sample on an ADVIA Centaur XP instrument.
No significant interference (greater than 10% or a change in ELF score of greater than 0.3) were met for bilirubin (conjugated), bilirubin (unconjugated), cholesterol, fructose, glucose, hemoglobin, protein (albumin), protein (total), and Intralipid (representative of triglycerides). The sponsor claims that no interference was observed at the following concentration:
| Substance | Test Concentration |
|---|---|
| Bilirubin (Conjugated) | 60 mg/dL |
| Bilirubin (Unconjugated) | 60 mg/dL |
| Cholesterol | 400 mg/dL |
| Glucose | 1000 mg/dL |
| Fructose | 18 mg/dL |
| Hemoglobin | 1000 mg/dL |
| Intralipid | 3500 mg/dL |
| Protein (Albumin) | 6 g/dL |
| Protein (Total) | 15 mg/dL |
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Heterophile Interference:
Human anti-mouse antibody (HAMA) and rheumatoid factor (RF) positive serum samples were used to identify possible interference from HAMA or RF. For each assay, a minimum of ® HAMA and ® RF samples were tested.
No significant interference was seen in the HAMA and RF interference studies.
The sponsor indicated that although the study is generally representative of the types of HAMA and RF expected in a clinical setting, these interferents are biologically variable. Therefore, the labeling includes the following limitation:
Patient samples may contain heterophilic antibodies that could react in immunoassays and cause falselv elevated or depressed results. This assay is designed to minimize interference from heterophilic antibodies. Additional information may be required for diagnosis.
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e. Assav Cut-off:
The sponsor previously conduçted a separate clinical study to determine the clinically
relevant cut off ELF scores of relevant cut off ELF scores of -
f. Specimen Stabilitv
Information was provided to support the specimen stability claims described in the labeling: -
Samples may be stored at room temperature for up to 24 hours prior to centrifugation.
-
Samples are stable for 8 hours onboard the system, for 48 hours at room temperature, and for 7 days at 2-8°C.
-
· Tightly capped specimens may be stored on the clot for up to 48 hours at 2-8°C.
-
· Freeze samples 11.3 | 81 | 17 | 64 | 21.0% (12.1-29.9%) |
| All | 305 | 26 | 279 | 8.5% (5.6-12.2%) |
The confidence intervals included in the table above were calculated using the pooled data without ability to adjust for differences in study population or length. Confidence intervals may overstate the statistical confidence of these measurements.
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Image /page/13/Figure/0 description: The image is a graph that shows the event-free probability over time for three different groups. The x-axis represents the follow-up time in months, ranging from 0 to 48. The y-axis represents the event-free probability, ranging from 0% to 100%. The three groups are defined as 1: = 9.80 to = 11.30, with corresponding numbers at risk listed below the graph.
Bridging fibrosis population:
Two studies (trials were provided in patients with bridging fibrosis at study entry. Each study assessed the ELF score ability to predict development of cirrhosis over the extent of each patient's follow up time.
NASH F3 (Trial 4)
The median follow up time for patients included in the analysis was (0) (4 months (interquartile range (b) (4) months).
NASH F3 (Trial 5)
The median follow up time for patients included in the analysis was (b) (4) months
(interquartile range (b) (4) = months).
The device is labeled with the following pooled performance:
| Group based
on ELF Score | Total
subjects
(n) | | Liver Related Event | | Risk of Event (95%
Confidence Intervals) |
|-----------------------------|--------------------------|-----|---------------------|---------------------|---------------------------------------------|
| | | Yes | No | | |
| 11.3 | 18 | 8 | 10 | 44.4% (21.5-67.4%) | |
| All | 212 | 41 | 171 | 19.3% (14.2 -25.3%) | |
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The confidence intervals included in the table above were calculated using the pooled data without ability to adjust for differences in study population or length. Confidence intervals may overstate the statistical confidence of these measurements.
Image /page/14/Figure/1 description: The image is a Kaplan-Meier survival plot showing the event-free probability over time for three groups. The x-axis represents follow-up time in months, ranging from 0 to 48. The y-axis represents the event-free probability, ranging from 0% to 100%. The three groups are defined by different values, with group 1 being less than 9.80, group 2 being greater than or equal to 9.80 and less than 11.30, and group 3 being greater than or equal to 11.30.
The sponsor provided information to support the long-term stability of the samples in these clinical studies.
The sponsor includes the following summary in their labeling: Interpret the ELF score using the following guidelines:
| ELF Score | Risk of Disease Progression (Development of
Cirrhosis or Liver-Related Events) |
|-------------|-----------------------------------------------------------------------------------|
|