lmmunoassay for the in vitro qualitative detection of antibodies to hepatitis C virus (HCV) in human adult and pediatric (ages 18 months through 21 years) serum and plasma (potassium EDTA, lithium heparin, sodium heparin, and sodium citrate). Assay results, in conjunction with other laboratory results and clinical information, may be used to aid in the presumptive diagnosis of HCV infection in persons with signs and symptoms of hepatitis and in persons at risk for hepatitis C infection. The test does not determine the state of infection or associated disease. The electrochemiluminescence immunoassay "ECLIA" is intended for use on cobas e immunoassay analyzers.
Device Story
In vitro diagnostic immunoassay; detects total antibodies to HCV in human serum/plasma. Uses two-step sandwich ECLIA technology; 18-minute duration. Input: 50 µL sample + biotinylated HCV antigens + ruthenium-labeled HCV antigens. Process: formation of sandwich complex; binding to streptavidin-coated microparticles; magnetic capture on electrode; chemiluminescent emission induced by voltage; measured by photomultiplier. Used in clinical laboratories on cobas e immunoassay analyzers. Software automatically compares signal to calibration cut-off to determine qualitative result. Updated version includes streptavidin interference reducing agent to improve biotin tolerance (up to 1200 ng/mL). Results aid clinicians in presumptive diagnosis of HCV infection; supports clinical decision-making when combined with other laboratory/clinical data.
Clinical Evidence
Bench testing only. Precision studies (single and multi-analyzer) confirmed reproducibility with CV < 4.5%. Interference testing validated biotin tolerance up to 1200 ng/mL. Method comparison study (n=219) between current and updated assay showed overall PPA of 96.33% (95% CI: 90.94-98.56%) and NPA of 99.63% (95% CI: 95.27-100.00%). Regression analysis and bias estimation confirmed comparability.
Technological Characteristics
Two-step sandwich electrochemiluminescence immunoassay (ECLIA). Reagents: biotinylated HCV antigens, ruthenium-labeled HCV antigens, streptavidin-coated microparticles. Includes streptavidin interference reducing agent. Analyzers: cobas e series. Detection: photomultiplier-based chemiluminescence. Biotin tolerance: ≤ 1200 ng/mL. Software: automated signal processing and cut-off comparison.
Indications for Use
Indicated for in vitro qualitative detection of anti-HCV antibodies in human serum and plasma (potassium EDTA, lithium heparin, sodium heparin, sodium citrate) for adults and pediatric patients (18 months to 21 years). Used to aid presumptive diagnosis of HCV infection in symptomatic individuals or those at risk. Does not determine infection state or disease status.
Regulatory Classification
Identification
A hepatitis C virus (HCV) antibody test is identified as an in vitro diagnostic device intended for use with human serum, plasma, or other matrices as a prescription device that aids in the diagnosis of HCV infection in persons with signs and symptoms of hepatitis and in persons at risk for hepatitis C infection. The test is not intended for screening blood, plasma, cell, or tissue donors.
Special Controls
*Classification.* Class II (special controls). The special controls for this device are:(1) The labeling required under § 809.10(b) of this chapter must include:
(i) A prominent statement that the test is not intended for the screening of blood, plasma, and cell or tissue donors.
(ii) Limitations, which must be updated to reflect current clinical practice and disease presentation and management. The limitations must include, but are not limited to, statements that indicate:
(A) When appropriate, the performance characteristics of the test have not been established in populations of immunocompromised or immunosuppressed patients or, other special populations where test performance may be affected.
(B) The detection of HCV antibodies indicates a present or past infection with hepatitis C virus, but does not differentiate between acute, chronic, or resolved infection.
(C) The specimen types for which the device has been cleared, and that use of the test with specimen types other than those specifically cleared for this device may result in inaccurate test results.
(D) Test results are to be interpreted by qualified licensed healthcare professionals in conjunction with the individual's clinical presentation, history, and other laboratory results.
(E) A non-reactive test result may occur early during acute infection, prior to development of a host antibody response to infection, or when analyte levels are below the limit of detection of the test.
(iii) A detailed explanation of the principles of operation and procedures for performing the test.
(2) Design verification and validation must include the following:
(i) A detailed device description, including all parts that make up the device, ancillary reagents required but not provided, an explanation of the device methodology, and design of the antigen(s) and capture antibody(ies) sequences, rationale for the selected epitope(s), degree of amino acid sequence conservation of the target, and the design and nature of all primary, secondary, and subsequent standards used for calibration.
(ii) Documentation and characterization (
*e.g.,* supplier, determination of identity, and stability) of all critical reagents (including description of the antigen(s) and capture antibody(ies)), and protocols for maintaining product integrity throughout its labeled shelf life.(iii) Risk analysis and management strategies, such as Failure Modes Effects Analysis and/or Hazard Analysis and Critical Control Points summaries and their impact on test performance.
(iv) Final release criteria to be used for manufactured test lots with appropriate evidence that lots released at the extremes of the specifications will meet the claimed analytical and clinical performance characteristics as well as the stability claims.
(v) Stability studies for reagents must include documentation of an assessment of real-time stability for multiple reagent lots using the indicated specimen types and must use acceptance criteria that ensure that analytical and clinical performance characteristics are met when stability is assigned based on the extremes of the acceptance range.
(vi) All stability protocols, including acceptance criteria.
(vii) Final release test results for each lot used in clinical studies.
(viii) Multisite reproducibility study that includes the testing of three independent production lots.
(ix) Analytical performance studies and results for determining the limit of blank (LoB), limit of detection (LoD), cutoff, precision (reproducibility) including lot-to-lot and/or instrument-to-instrument precision, interference, cross reactivity, carryover, hook effect, seroconversion panel testing, matrix equivalency, specimen stability, reagent stability, and cross-genotype antibody detection sensitivity, when appropriate.
(x) Analytical sensitivity of the test is the same or better than that of other cleared or approved tests.
(xi) Detailed documentation of clinical performance testing from a multisite clinical study. Performance must be analyzed relative to an FDA cleared or approved HCV antibody test, or a comparator that FDA has determined is appropriate. This study must be conducted using appropriate patient samples, with an acceptable number of HCV positive and negative samples in applicable risk categories. Additional relevant patient groups must be validated as appropriate. The samples may be a combination of fresh and repository samples, sourced from geographically diverse areas. The study designs, including number of samples tested, must be sufficient to meet the following criteria:
(A) Clinical sensitivity of the test must have a lower bound of the 95 percent confidence interval of greater than or equal to 95 percent.
(B) Clinical specificity of the test must have a lower bound of the 95 percent confidence interval of greater than or equal to 96 percent.
(3) For any HCV antibody test intended for Point of Care (PoC) use, the following special controls, in addition to those listed in paragraphs (b)(1) and (2) of this section, apply:
(i) Clinical studies must be conducted at PoC sites.
(ii) Additional labeling must include a brief summary of the instructions for use that are appropriate for use in a PoC environment.
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FDA U.S. FOOD & DRUG ADMINISTRATION
# 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY
## I Background Information:
A 510(k) Number
K221693
B Applicant
Roche Diagnostics
C Proprietary and Established Names
Elecsys Anti-HCV II
D Regulatory Information
| Product Code(s) | Classification | Regulation Section | Panel |
| --- | --- | --- | --- |
| MZO | Class II | 21 CFR 866.3169
Hepatitis C virus antibody tests | MI - Microbiology |
## II Submission/Device Overview:
A Purpose for Submission:
Clearance for the updated Elecsys Anti-HCV II assay that improve tolerance to biotin interference.
B Measurand:
Antibodies to Hepatitis C virus
C Type of Test:
Electrochemiluminescence immunoassay (ECLIA)
## III Intended Use/Indications for Use:
A Intended Use(s):
Immunoassay for the in vitro qualitative detection of antibodies to hepatitis C virus (HCV) in human adult and pediatric (ages 18 months through 21 years) serum and plasma (potassium EDTA, lithium heparin, sodium heparin, and sodium citrate). Assay results, in conjunction with other laboratory results and clinical information, may be used to aid in the presumptive diagnosis of HCV infection in persons with signs and symptoms of hepatitis and in persons at risk for hepatitis C infection. The test does not determine the state of infection or associated disease.
Food and Drug Administration
10903 New Hampshire Avenue
Silver Spring, MD 20993-0002
www.fda.gov
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The electrochemiluminescence immunoassay "ECLIA" is intended for use on cobas e immunoassay analyzers.
## B Indication(s) for Use:
See Intended Use above.
## C Special Conditions for Use Statement(s):
Rx - For Prescription Use Only
## D Special Instrument Requirements:
The electrochemiluminescence immunoassay "ECLIA" is intended for use on cobas e immunoassay analyzers.
## IV Device/System Characteristics:
### A Device Description:
The Elecsys Anti-HCV II immunoassay requires the use of reagents specific for (A) Anti-HCV II immunoassay and (B) the recommended PreciControl Anti-HCV. The reagent and calibrators are packaged together in the Elecsys Anti-HCV II assay kit, while the PreciControl Anti-HCV is packaged separately.
#### (A) The Elecsys Anti-HCV II immunoassay kit consists of five components:
- Three reagent cassettes/bottles (components M, R1, and R2) - are combined in the so-called "rackpack," a bundle of the three reagent bottles, that is placed on the instrument as a single unit
| Name | Description |
| --- | --- |
| M# | Streptavidin-coated microparticles |
| R1# | Biotinylated antigens |
| R2# | Ruthenylated antigens |
- Two calibrators (components negative Cal1 and positive Cal2) – These ready-to-use calibrators are used to calibrate the Elecsys Anti-HCV II immunoassay on the cobas e immunoassay analyzers.
#### (B) The PreciControl Anti-HCV kit consists of two ready-to-use reagents:
- PreciControl Anti-HCV 1 contains human serum, negative for anti-HCV
- PreciControl Anti-HCV 2 contains inactivated positive human serum for anti-HCV in a low positive concentration.
| Name | Description |
| --- | --- |
| PC A-HCV1 | PreciControl Anti-HCV 1, negative for anti-HCV antibodies |
| PC A-HCV2 | PreciControl Anti-HCV 2, positive for anti-HCV antibodies |
### Interpretation of Results
The interpretation of results is presented below:
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| Initial Elecsys Anti-HCV II assay | | | |
| --- | --- | --- | --- |
| COI | Result | Interpretation of results | Retest procedure |
| < 0.90 | Non-reactive | No antibodies to HCV were detected | No retest required |
| 0.90 ≤ COI < 1.00 | Border | Borderline zone (undetermined) | Retest in duplicate with the Elecsys Anti-HCV II assay |
| ≥ 1.00 | Reactive | Antibodies to HCV detected | Presumptive HCV infection, follow CDC recommendations for supplemental testing |
e) Please note, per www.CDC.gov: If a patient is known to be at high risk of HCV infection, or is symptomatic, and the physician’s suspicion of HCV infection is high, HCV RNA testing is often employed and is of diagnostic value, even after an initial negative anti-HCV test result.
All initially reactive or borderline samples are being instructed to be redetermined in duplicate using the Elecsys Anti-HCV II assay. If no reactivity is found in both cases, the sample is negative for anti-HCV. If the result from either of the two measurements is reactive or borderline, then the sample is repeatedly reactive. Repeatedly reactive samples must be investigated by supplemental methods (e.g. immunoblot or detection of HCV RNA). If one or both measurements remain borderline, the analysis of a follow-up sample is recommended.
| Final Elecsys Anti-HCV II assay | | | |
| --- | --- | --- | --- |
| Initial result | Result after retest (COI) | Final results | Interpretation of results |
| Non-reactive | No retest required | NON-REACTIVEe) | Antibodies to HCV were not detected; does not exclude the possibility of exposure to HCV |
| Border | If 2 of the 3 results have a COI < 1.00 | NON-REACTIVE | Antibodies to HCV were not detected; does not exclude the possibility of exposure to HCV |
| | If 2 of the 3 results have a COI ≥ 1.00 | REACTIVE | Presumptive evidence of antibodies to HCV. Follow CDC recommendations for supplemental testing. |
| Reactive | No retest required | REACTIVE | Presumptive evidence of antibodies to HCV. Follow |
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| Final Elecsys Anti-HCV II assay | | | |
| --- | --- | --- | --- |
| Initial result | Result after retest (COI) | Final results | Interpretation of results |
| | | | CDC recommendations for supplemental testing. |
## B Principle of Operation:
This assay is based on the sandwich principle. The total duration of the assay is 18 minutes.
- 1st incubation: 50 µL of sample, 55 µL of a reagent containing biotinylated HCV specific antigens and 55 µL of a reagent containing HCV specific antigens labeled with a ruthenium complex⁴) react to form a sandwich complex.
- 2nd incubation: After addition of streptavidin-coated microparticles, the complex becomes bound to the solid phase via interaction of biotin and streptavidin.
- The reaction mixture is aspirated into the measuring cell where the microparticles are magnetically captured onto the surface of the electrode. Unbound substances are then removed with ProCell/ProCell M. Application of a voltage to the electrode then induces chemiluminescent emission which is measured by a photomultiplier.
- Results are determined automatically by the software by comparing the electrochemiluminescence signal obtained from the reaction product of the sample with the signal of the cutoff value previously obtained by calibration.
a) Tris(2,2'-bipyridyl)ruthenium(II)-complex (Ru(bpy))
## C Instrument Description Information:
1. Instrument Name: cobas e immunoassay analyzers
2. Specimen Identification: See P140021.
3. Specimen Sampling and Handling: See P140021.
4. Calibration: See P140021.
5. Quality Control: See P140021.
## V Substantial Equivalence Information:
### A Predicate Device Name(s):
Elecsys Anti-HCV II Immunoassay
### B Predicate 510(k) Number(s):
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P140021
C Comparison with Predicate(s):
| Device & Predicate Device(s): | K221693 | P140021 |
| --- | --- | --- |
| Device Trade Name | Elecsys Anti-HCV II | Elecsys Anti-HCV II |
| General Device Characteristic Similarities | | |
| Intended Use/Indications For Use | Immunoassay for the in vitro qualitative detection of antibodies to hepatitis C virus (HCV) in human adult and pediatric (ages 18 months through 21 years) serum and plasma (potassium EDTA, lithium heparin, sodium heparin, and sodium citrate). Assay results, in conjunction with other laboratory results and clinical information, may be used to aid in the presumptive diagnosis of HCV infection in persons with signs and symptoms of hepatitis and in persons at risk for hepatitis C infection. The test does not determine the state of infection or associated disease. The electrochemiluminescence immunoassay “ECLIA” is intended for use on cobas e immunoassay analyzers.¹ | Immunoassay for the in vitro qualitative detection of antibodies to hepatitis C virus (HCV) in human adult and pediatric (ages 18 months through 21 years) serum and plasma (potassium EDTA, lithium heparin, sodium heparin, and sodium citrate). Assay results, in conjunction with other laboratory results and clinical information, may be used to aid in the presumptive diagnosis of HCV infection in persons with signs and symptoms of hepatitis and in persons at risk for hepatitis C infection. The test does not determine the state of infection or associated disease. The electrochemiluminescence immunoassay “ECLIA” is intended for use on Elecsys and cobas e immunoassay analyzers. |
| Technology | Same | ECLIA |
| Test Format | Same | Sandwich |
| Test Type | Same | Qualitative |
| Application Time | Same | 18 min |
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| Assay Protocol | Same | 1st Incubation: R1+R2+sample
2nd incubation: Addition of streptavidin-coated microparticles (beads) |
| --- | --- | --- |
| Pipetting Volume (samples) | Same | cobas e 601
49 μL |
| Pipeting Volume (beads) | Same | cobas e 601
36μL |
| Pipetting volume (R1) | Same | cobas e 601
55 μL |
| Pipetting volume (R2) | Same | cobas e 601
56μL |
| Buffer Composition R1 | Same | HEPES |
| | Addition of 300 mM NaCl and 0.05% SDS | Not added |
| Antibodies used in R1 | Same | Same |
| Buffer Composition R2 | Same | HEPES |
| Antigens used in R2 | Same | 1) rec. HCV-NS3-sulfoBPRu(NHS)
2) HCV, core(9-48) (BPRu(UE)MH)
3) HCV,NS4(KN4.1-BPRu)amid |
| Reporting of values | Same | COI and result message (nonreactive, borderline, or reactive)
COI < 0.9 = non-reactive
0.90 ≤ COI < 1.00 = borderline
COI ≥ 1.0 = reactive |
| General Device Characteristic Differences | | |
| Antigens used in R1 | 1) rec. HCV-NS3-(PEG)24-Bi
2) no change
3) no change | 1) rec. HCV-NS3-hyBi(DSS)
2) HCV, core(9-48) (Bi(UE)25MH) |
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| | | 3) HCV,NS4(KN4.1-Bi)amid |
| --- | --- | --- |
| Interference elimination for streptavidin | Streptavidin rec. Mutein Polymer | None |
| Antibodies used in R2 | Anti-Biotin Antibody fragment specific for free, unconjugated Biotin (“scavenger antibody”) | Same |
| Biotin tolerance | 1200 ng/mL | 44 ng/mL |
| Calibrators | Preservative: MIT / Oxypyrion | Preservative: Bronidox |
1 - The Elecsys instruments were discontinued and are therefore no longer included in the Intended Use.
VI Standards/Guidance Documents Referenced:
Standard/Guidance Documents referenced are below:
- Evaluation of Precision of Quantitative Measurement Procedures; Approved Guideline - Third Edition CLSI EP05-A3 7-251
- Interference Testing in Clinical Chemistry CLSI EP07 3rd Edition 7-275
- Measurement Procedure Comparison and Bias Estimation Using Patient Samples CLSI EP09c-ED3
- Evaluation of Stability of In Vitro Diagnostic Reagents; Approved Guideline CLSI EP25-A 7-235
- User Protocol for Evaluation of Qualitative Test Performance; Approved Guideline - Second Edition. CLSI EP12-A2 7 - 152
VII Performance Characteristics (if/when applicable):
A Analytical Performance:
1. Precision/Reproducibility:
Roche conducted a single-analyzer and a multi-analyzer precision study.
Within laboratory single-analyzer precision study was determined using 1 reagent lot of Elecsys Anti-HCV II assay reagents, calibrators and controls in a protocol based on CLSI (Clinical and Laboratory Standards Institute) EP05-A3. The test sample panel consisted of 5 human serum samples of different CMV IgG concentrations (see Table X). The negative sample (HS 1) consists of a human serum pool. Panel members HS 2 - HS 5 were prepared by a human serum pool or unique negative serum samples spiked with unique anti-HCV positive serum from individual donors. Samples and assay controls were measured in duplicates in each of the 2 runs per day, for 12 days with one reagent lot on the cobas e 601 Analyzer. Calibration of the assay was performed according to the package insert.
The single-analyzer precision study followed a 12 days x 2 runs x 2 replicates study design. The acceptance criteria for this study is as follows:
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Table 1: Acceptance criteria for the single-analyzer precision study
| Sample concentration | Acceptable Variance |
| --- | --- |
| ≤ 0.5 COI | SD ≤ 0.12 COI |
| > 0.5 - < 1.0 COI | SD ≤ 0.10 COI |
| ≥ 1.0 COI | CV ≤ 10% |
The following results were obtained for the single-analyzer precision study:
Table 2: Overall Statistical Analysis of the Single-Analyzer Precision Study of Elecsys Anti-HCV II on cobas e 601 analyzer
| Sample | Mean [COI] | Repeatability (within-run) | | Intermediate Precision (within-lab) | |
| --- | --- | --- | --- | --- | --- |
| | | SD [COI] (95% UCL) | CV (%) (95% UCL) | SD [COI] (95% UCL) | CV (%) (95% UCL) |
| HS 1 | 0.038 | 0.0009 (0.001) | 2.50 (3.30) | 0.0009 (0.001) | 2.50 (3.00) |
| HS 2 | 0.776 | 0.026 (0.034) | 3.40 (4.40) | 0.034 (0.042) | 4.30 (5.40) |
| HS 3 | 1.06 | 0.013 (0.017) | 1.20 (1.60) | 0.020 (0.026) | 1.80 (2.40) |
| HS 4 | 1.99 | 0.035 (0.046) | 1.80 (2.30) | 0.048 (0.062) | 2.40 (3.10) |
| HS 5 | 5.65 | 0.085 (0.112) | 1.50 (2.00) | 0.113 (0.145) | 2.00 (2.60) |
| PC 1 | 0.048 | 0.0009 (0.001) | 1.90 (2.50) | 0.0009 (0.001) | 1.90 (2.30) |
| PC 2 | 3.34 | 0.043 (0.057) | 1.30 (1.70) | 0.069 (0.093) | 2.10 (2.80) |
| HS = human serum, PC = PreciControl Anti-HCV UCL = Upper Confidence Limit | | | | | |
Roche concluded that the results of the precision studies performed with Elecsys Anti-HCV II were acceptable as the observed $\% \mathrm{CV}$ was less than $4.5\%$ .
An additional within laboratory multi-analyzer precision study was conducted internally (Roche Diagnostics, Penzberg) on three different cobas e 601 analyzers with one reagent lot. This study was conducted with 6 human sera samples and two levels of the PreciControl Anti-HCV. The following table shows the sample panel:
Table 3: Details of sample panel
| Sample Source | Sample | Mean | N |
| --- | --- | --- | --- |
| Human serum pool | HS 01 | 0.040 | 90 |
| | HS 02 | 0.796 | 90 |
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The multi-analyzer study followed the 5 days x 2 runs x 3 replicates study design. The acceptance criteria for this study are as follows:
Table 4: Acceptance criteria for the multi-analyzer precision study
| Sample concentration | Acceptable Variance |
| --- | --- |
| ≤ 0.5 COI | SD ≤ 0.15 COI |
| > 0.5 - < 1.0 COI | SD ≤ 0.15 COI |
| ≥ 1.0 COI | CV ≤ 15% |
The results of the multi-analyzer study are presented below:
Table 5: Overall Statistical Analysis of the Multi-Analyzer Study of Elecsys Anti-HCV II on cobas e 601 analyzer
| Sample | Mean | N | Repeatability | | Between-Run | | Between-Day | | Between-Device | | Reproducibility | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | SD | CV [%] | SD | CV [%] | SD | CV [%] | SD | CV [%] | SD | CV [%] |
| HS 01 | 0.040 | 90 | 0.001 | 2.2 | 0.000 | 0.8 | 0.000 | 1.1 | 0.001 | 2.0 | 0.001 | 3.3 |
| HS 02 | 0.796 | 90 | 0.021 | 2.6 | 0.006 | 0.7 | 0.016 | 2.0 | 0.000 | 0.0 | 0.027 | 3.4 |
| HS 03 | 0.827 | 90 | 0.009 | 1.0 | 0.010 | 1.2 | 0.014 | 1.7 | 0.007 | 0.9 | 0.021 | 2.5 |
| HS 04 | 1.21 | 90 | 0.022 | 1.8 | 0.006 | 0.5 | 0.024 | 2.0 | 0.000 | 0.0 | 0.033 | 2.7 |
| HS 05 | 2.05 | 90 | 0.024 | 1.2 | 0.022 | 1.1 | 0.033 | 1.6 | 0.025 | 1.2 | 0.052 | 2.6 |
| HS 06 | 5.85 | 90 | 0.068 | 1.2 | 0.073 | 1.2 | 0.107 | 1.8 | 0.091 | 1.6 | 0.172 | 2.9 |
| PC 1 | 0.05 | 90 | 0.001 | 1.5 | 0.000 | 1.0 | 0.001 | 1.5 | 0.001 | 1.8 | 0.001 | 2.9 |
| PC 2 | 3.24 | 90 | 0.028 | 0.9 | 0.031 | 1.0 | 0.055 | 1.7 | 0.015 | 0.5 | 0.071 | 2.2 |
HS = human serum
PC = PreciControl Anti-HCV
According to Roche the results (see above) of the multi-analyzer precision study performed with Elecsys Anti-HCV II fulfilled the designated specifications.
2. Linearity:
Not applicable.
3. Analytical Specificity/Interference:
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To evaluate the effect of elevated levels of hemoglobin, bilirubin, lipemia (intralipid), biotin, and total protein on the Elecsys Anti-HCV II assay with four anti-HCV samples (negative, high negative, low positive and positive samples) were spiked with the potential interferents. Samples containing hemoglobin, bilirubin, intralipid, total protein, and rheumatoid factor were tested in duplicate on the cobas e601 analyzer with an acceptance criteria of sample recovery of $\pm 0.2$ COI for samples $< 1.0$ COI and $80 - 120\%$ of unspiked result COI of samples $\geq 1.0$ COI.
The purpose of this study was to evaluate potential endogenous interference with biotin measured on the cobas e 601 analyzer for anti-HCV concentrations at clinically relevant concentrations. For biotin, serum samples that contain biotin at a concentration of 1200 ng/mL demonstrate less than or equal to $10\%$ bias in COI values.
The acceptance criteria of $\pm 0.20$ COI for negative samples and $\pm 10\%$ for positive samples was used to assess the result so the biotin interference study. The results of the biotin interference are were tested up to the $3600~\mathrm{ng / mL}$ and no impact was observed at the requested claim of $1200~\mathrm{ng / mL}$.
4. Assay Reportable Range: See P140021.
5. Traceability, Stability, Expected Values (Controls, Calibrators, or Methods):
a. Traceability: See P140021.
b. Reagent Stability: Roche conducted the following reagent stability studies with the biotin updated Elecsys Anti-HCV II assay and obtained the following claims:
Table 6: Stability Claim
| Study | Claim |
| --- | --- |
| On board reagent stability | 31 days |
| Open kit reagent stability | 57 days (8 weeks) |
| Real-time stability | 12 months at 2-8°C |
| Calibration lot stability | 28 days |
| Onboard reagent stability | 7 days |
6. Detection Limit: Not applicable.
7. Assay Cut-Off: See P140021.
8. Accuracy (Instrument): See P140021.
9. Carry-Over: See P140021.
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# B Comparison Studies:
## 1. Method Comparison with Predicate Device:
The Method Comparison Study was conducted to evaluate the equivalence of the current and biotin-updated Elecsys Anti-HCV II assay. One reagent lot (506983) of the current Elecsys Anti-HCV II assay and 3 reagent lots (527094, 527095 and 527096) of the biotin-updated Elecsys Anti-HCV II assay.
A total of 219 samples were tested in this study. Native clinical and contrived samples were tested in this study to adequately represent the measuring range of Elecsys Anti-HCV II assay. Contrived samples were prepared by diluting individual positive samples with individual negative clinical samples to achieve concentrations close to cut-off.
Based on the results of the reference assay results 91 samples were < 0.9 COI, 19 samples were between ≥ 0.9 to < 1.0 COI, 109 were ≥ 1.0 COI.
The equivalence of the current assay and biotin-updated assay design was evaluated by the following:
a. Determination of Percent Agreement
b. Estimation of Systematic Difference
c. Regression analysis
## Acceptance Criteria
The percent agreements should have the lower limits of the 95% two-sided Confidence Interval ≥ 90.0%.
The results of the method comparison study are presented below:
## A. Determination of Percent Agreement
The positive and negative percent agreement (PPA and NPA, respectively) between the biotin-updated and the current assay were determined with each lot of the biotin updated Elecsys Anti-HCV II assay. The re-test sample results were counted against the performance. Presented below are the calculated positive and negative percent agreements:
Table 7: Agreement Table - Lot 506983 (reference) vs Lot 527094 (MP01)
| Updated Elecsys Anti-HCV II | Current Elecsys Anti-HCV II | | | |
| --- | --- | --- | --- | --- |
| | | Negative | Re-test | Positive |
| | Negative < 0.9 COI | 91 | 13 | 0 |
| | Re-test ≥ 0.9 - < 1.0 COI | 0 | 6 | 3 |
| | Positive ≥ 1.0 COI | 0 | 0 | 106 |
| | Overall | 91 | 19 | 109 |
$$
\mathrm{PPA} = 97.25\% (106/109) [92.22\% \text{ to } 99.06\%]
$$
$$
\mathrm{NPA} = 100\% (91/91) [95.95\% \text{ to } 100.00\%]
$$
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Table 8: Agreement Table - Lot 506983 (reference) vs Lot 527095
| Updated Elecsys Anti-HCV II | Current Elecsys Anti-HCV II | | | |
| --- | --- | --- | --- | --- |
| | | Negative | Re-test | Positive |
| | Negative < 0.9 COI | 90 | 17 | 1 |
| | Re-test ≥ 0.9 - < 1.0 COI | 1 | 2 | 5 |
| | Positive ≥ 1.0 COI | 0 | 0 | 103 |
| | Overall | 91 | 19 | 109 |
PPA = 94.50% (103/109) [88.51% to 97.45%]
NPA = 98.90% (90/91) [94.04% to 99.81%]
Table 9: Agreement Table - Lot 506983 (reference) vs Lot 527096
| Updated Elecsys Anti-HCV II | Current Elecsys Anti-HCV II | | | |
| --- | --- | --- | --- | --- |
| | | Negative | Re-test | Positive |
| | Negative < 0.9 COI | 91 | 10 | 0 |
| | Re-test ≥ 0.9 - < 1.0 COI | 0 | 9 | 3 |
| | Positive ≥ 1.0 COI | 0 | 0 | 106 |
| | Overall | 91 | 19 | 109 |
PPA = 97.25% (106/109) [92.22% to 99.06%]
NPA = 100.00% (91/91) [95.95% to 100.00%]
The summary of percent agreements is presented below:
Table 10: Overall percent agreements
| Reagent Lots | Agreement Rate
Positive Agreement
(%)
(95% CI) | Agreement Rate
Negative Agreement
(%)
(95% CI) |
| --- | --- | --- |
| 1 | 97.25%
106/109
(92.22% to 99.26%) | 100.00%
91/91
(95.95% to 100.00%) |
| 2 | 94.50%
103/109
(88.51% to 97.45%) | 98.90%
90/91
(94.04% to 99.81%) |
| 3 | 97.25%
106/109
(92.22 to 99.06%) | 100.00%
91/91
(95.95% to 100.00%) |
| Overall (all lots combined) | 96.33%
(90.94% to 98.56%)* | 99.63%
(95.27% to 100.00%)* |
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{12}
*95% CI are based on the Wilson score method, which uses an independent results assumption. This CI may be overstated.
# B. Estimation of Systematic Difference
Roche determined the bias at the medical decision point of 1.0 COI which is presented below:
| Lots tested | Bias at medical point | 95% CI [COI] |
| --- | --- | --- |
| 527094 | -0.04 | -0.06, -0.02 |
| 527095 | -0.09 | -0.10, -0.07 |
| 527096 | -0.04 | -0.05, -0.03 |
| All lots combined | -0.05 | -0.07, -0.03 |
Based on the bias estimation, Roche concluded that there was no systematic difference between the biotin-updated and the current Elecsys Anti-HCV II assay.
# C. Regression analysis
Roche assessed the regression analysis of the biotin updated and the current Elecsys Anti-HCV II assay for each of the three lots of the biotin updated Elecsys Anti-HCV II assay. The regression plots are presented below.
Figure: Regression analysis of the biotin updated vs the current Elecsys Anti-HCV II assay
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{13}
The regression analyses for each lot of the biotin updated Elecsys Anti-HCV II assay and the combination of lots were acceptable.
Based on the percent agreement, bias estimation and the regression analyses, Roche concluded the biotin updated Elecsys Anti-HCV II assay was comparable to the current Elecsys Anti-HCV II assay.
2. Matrix Comparison: See P140021.
C Clinical Studies:
1. Clinical Sensitivity: See P140021.
2. Clinical Specificity: See P140021.
3. Other Clinical Supportive Data (When 1. and 2. Are Not Applicable): Not Applicable.
D Clinical Cut-Off: Not applicable.
E Expected Values/Reference Range: See P140021.
F Other Supportive Instrument Performance Characteristics Data: Not applicable.
VIII Proposed Labeling: The labeling supports the finding of substantial equivalence for this device.
IX Conclusion: The submitted information in this premarket notification is complete and supports a substantial equivalence decision.
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Two short videos show you everything — or skip straight to the written tutorial if you'd rather read. You can reopen this any time from the Tutorial button in the top bar.
Part 1 — Search, results, and everyday workflows 16 min
Part 2 — Embeddings: the galaxy map 3 min
1. Search: exact and fuzzy
Type a phrase like "coronary artery calcification" into the search box. You get two kinds of results. Exact results match the literal phrase — prefix searches work ("coronary artery calcificati") but suffix searches do not. Fuzzy results match on the meaning and intent of your phrase rather than the exact words, and are sorted by relevance score. Hover over the Exact or Fuzzy badge on any row to see exactly why it matched.
Use the checkboxes above the results to narrow: SaMD keeps only software-only devices, AI / ML keeps only devices with AI.
Exact vs. fuzzy search: what's the difference?
Exact matches on the literal phrase (prefix search works, suffix does not). Fuzzy matches on the meaning and intent of the phrase rather than the exact words. Hover over the badge on any row to see why it matched.
You search "coronary artery calcification" and want only software devices with AI. What two filters do you apply?
Narrow by SaMD (software-only devices), then narrow by AI/ML (devices with AI).
2. The results table
Scroll right in the results table. The intended use is extracted for you — no need to open the PDF. The device story gives a high-level snapshot of what the device does and how it's used. The AI Performance sub-table shows each output name, acceptance criteria, observed values, and development/test dataset descriptions — the same format Innolitics uses for regulatory strategy outputs, and the fastest high-level fingerprint of an AI device. It is AI-generated but has been very reliable in practice.
Where do you find a device's intended use without opening the PDF?
Scroll right in the search results table. The intended use column is extracted for you; no need to dig into the 510(k) summary PDF.
What does the AI Performance sub-table show, and why is it useful?
Output name, acceptance criteria, observed values, development dataset description, and test dataset description. It's the same format we use for regulatory strategy output and Fast 510(k) input, and the fastest high-level fingerprint of an AI device. AI-generated but reliable in practice.
3. Judging fuzzy relevance
Fuzzy results trail off in relevance as you scroll. Use three signals to decide how far down to go: the fuzzy badge explanations, the intended use column, and whether your target output (e.g., Cobb angle) still appears in the AI Performance sub-table. Once it stops appearing, you're past the relevant zone. A top hit with a low score (~0.4) and a stretched explanation is a hint the closest predicates are far away — the project may be headed for De Novo. Note the fuzzy search is a pattern match: it doesn't handle negation ("not") well, and hardware devices can appear — filter by SaMD/AI ML to cut them.
How do you judge how far down fuzzy search results to go?
Use the relevancy signals: the fuzzy badge explanations, the intended use column, and whether the target output (e.g., Cobb angle) still appears in the AI Performance sub-table. Once it stops appearing, results are trailing off in relevancy.
4. Device detail page: chat and citations
Click a device name to open its detail page: device facts on the left, a chat window on the right. Ask something like "Describe the training data". The answer carries little citation bubbles — click one to jump to the highlighted passage in the source PDF, so you can verify every AI answer against the document. There's also a Download PDF button for sharing.
How do you verify an AI chat answer on the device detail page?
Click the citation bubbles to jump to the relevant highlight in the source document.
Reading rule for every project: how many summaries do you read in full?
At least the three most relevant 510(k) or De Novo summaries, in full. After that, use targeted chat questions to confirm your memory quickly. The tool supports this professional habit — it doesn't replace it.
5. Side-by-side comparison
Select multiple rows in the results table (aim for under ~10), then open the PDF Viewer tab. Ask one question — it goes to all selected devices in parallel, each with citations. This is the fastest way to compare and contrast devices: training data, PCCP scope, how they handled adding new scanners, and so on.
What does the side-by-side PDF viewer mode do?
Select multiple devices, open the PDF viewer tab, and ask one question (e.g., "Describe the training data"). It queries all selected devices simultaneously with citations, so you can compare and contrast quickly.
6. Collections
With rows selected, go to the Collections tab and create a labeled collection (e.g., "Cobb Angle Project"). Reload that selection any time — before a client call, pull up the collection and ask questions across all of its devices at once.
How do you save a set of selected devices for later use?
Select the rows, go to the Collections tab, and create a labeled collection (e.g., "Cobb Angle Project"). You can reload the selection anytime and carry it into the PDF viewer and other tabs that support selections.
7. Product codes and the regulations tree
Click a product code in the results to jump to it in the regulations tree — identification text, sibling product codes, and devices you can open in a PDF viewer on the right. Click a regulation number to see its identification, special controls, and related product codes. You can also search by product code or regulation number at the top of the tree. Always read the special controls if any exist for your device — it broadens your search and sharpens pre-kickoff research.
What can you do from the regulations tree view?
Browse product codes and regulation numbers, read the identification text and special controls, browse sibling product codes, open device PDFs on the right, and search by product code or regulation number at the top of the tree.
8. Chart view
Click Show Chart and segment by regulation number (or product code) to see which regulations dominate your result set. Clicking a regulation takes you into the regulations tree. Great for spotting that most matches are, say, hardware laparoscopic devices — a cue to go back and filter.
How do you see which regulations dominate a search result set?
Click "Show Chart" and segment by Regulation Number. Clicking a regulation takes you to the regulations tree.
9. The predicate graph
Open the Predicates tab for a family-tree view of predicate relationships. Click a node to trace its parents and children; selections from search carry over pre-selected. Commonly predicated devices are worth reading — a lot of people predicated them for a reason. The visual lineage is also handy on client calls, e.g. to show how a predicate family evolved and justify why your predicate still holds.
In the predicate graph, why are commonly predicated devices worth reading?
A lot of people predicated them for a reason. Clicking a node traces parents and children, and selections from search carry over pre-selected.
10. Embeddings: the galaxy map
The Embeddings tab plots every matching document in a 2-D "galaxy map" where semantically similar devices cluster together. Hover or click clusters to explore, and let AI label the clusters for you. Embeddings beat product codes for grouping: two devices can carry different product codes (LLZ vs. QIH) yet do the same thing — the embedding captures the meaning of the intended use and device story. This is also exactly how retrieval-augmented generation (RAG) works under the hood, and it makes a great visual on client calls.
Try it yourself
Head to the search page and work through a few of these AI/ML fuzzy searches to build intuition: perivascular fat on CT · aortic valve calcification opportunistic screening on noncontrast CT · breast cancer prediction on digital pathology slides · autism detection · gestational age prediction · a hearing aid that can also detect a pulse · foundation model based analysis of ECG · large language models · penetration test. Watch how the relevance scores, intended use, and AI Performance tables tell you when results stop being meaningful.
