(261 days)
Immunoassays for the in vitro quantitative determination of the soluble fms like tyrosine kinase-1/placental growth factor (sFlt-1/PlGF) ratio in human serum.
The sFlt-1/PlGF ratio is indicated as an aid in the risk assessment of pregnant women, with a singleton pregnancy (23+0 to 34+6/7 weeks' gestation) hospitalized for hypertensive disorders of pregnancy (preeclampsia, chronic hypertension with or without superimposed preeclampsia, or gestational hypertension), to develop preeclampsia with severe features within two weeks from testing. The sFit-1/PlGF ratio should be used in conjunction with clinical assessment and routine laboratory testing.
The electrochemiluminescence immunoassay "ECLIA" is intended for use on cobas e immunoassay analyzers.
The Elecsys sFlt-1 and Elecsys PlGF assays employ a sandwich principle using electrochemiluminescence immunoassay "ECLIA" technology. The total duration of each assay is 18 minutes. Samples are incubated with biotinylated and ruthenium-labeled monoclonal antibodies specific to sFlt-1 or PlGF, forming a sandwich complex. Streptavidin-coated microparticles are added, binding the complex to the solid phase. The microparticles are magnetically captured, unbound substances are removed, and a voltage is applied to induce chemiluminescent emission, which is measured by a photomultiplier. Results are determined via a calibration curve generated by 2-point calibration and a master curve provided via the reagent barcode. The reagents for each assay are combined in a "rackpack".
Here's a breakdown of the acceptance criteria and study information for the Elecsys sFlt-1 and Elecsys PlGF assays, based on the provided document.
Acceptance Criteria and Device Performance
| Acceptance Criteria Category | Specific Criteria | Reported Device Performance |
|---|---|---|
| Clinical Performance | Risk Assessment for Preeclampsia with Severe Features within two weeks from testing (Cutoff: >38): high Negative Predictive Value (NPV) and acceptable Positive Predictive Value (PPV) for pregnant women with singleton pregnancy (23+0 to 34+6/7 weeks' gestation) hospitalized for hypertensive disorders of pregnancy. | Overall Intended Use Population (N=556):- Sensitivity: 91.40% (95% CI: 86.41, 95.00)- Specificity: 77.30% (95% CI: 72.68, 81.47)- NPV (ratio ≤ 38): 94.70% (95% CI: 91.54, 96.94)- PPV (ratio > 38): 66.93% (95% CI: 60.77, 72.68) |
| Non-Clinical Performance | Precision: Low coefficients of variation (CV) for repeatability (within-run) and intermediate precision (within-laboratory). | Elecsys PlGF (N=84 per sample type):- Repeatability CV: 1.0% - 5.7%- Intermediate precision CV: 1.4% - 9.9%Elecsys sFlt-1 (N=84 per sample type):- Repeatability CV: 0.9% - 2.4%- Intermediate precision CV: 1.7% - 3.7%Ratio (N=84 per sample type):- Repeatability CV: 1.1% - 4.9%- Intermediate precision CV: 1.4% - 7.0% |
| Linearity/Assay Reportable Range: Measurements are linear across the claimed measuring range. | - Elecsys sFlt-1: 80-85000 pg/mL (claimed range)- Elecsys PlGF: 10-5400 pg/mL (claimed range)(Study concludes measurements are linear across these ranges) | |
| Limit of Blank (LoB): ≤ 2 pg/mL for PlGF and < 6 pg/mL for sFlt-1. (Highest observed measurement values for samples free of analyte). | - PlGF: 0.482 - 0.946 pg/mL across 3 lots (meets ≤ 2 pg/mL)- sFlt-1: 2.92 - 4.00 pg/mL across 3 lots (meets < 6 pg/mL) | |
| Limit of Detection (LoD): < 3 pg/mL for PlGF and < 10 pg/mL for sFlt-1. (Lowest amount of analyte detectable with 95% probability). | - PlGF: 1.65 - 2.19 pg/mL across 3 lots (meets < 3 pg/mL)- sFlt-1: 4.44 - 6.03 pg/mL across 3 lots (meets < 10 pg/mL) | |
| Limit of Quantitation (LoQ): < 10 pg/mL for PlGF and < 15 pg/mL for sFlt-1. (Lowest concentration quantifiable with stated accuracy and intermediate precision CV of no more than 20%). | - PlGF: 7.48 - 8.97 pg/mL across 3 lots (meets < 10 pg/mL)- sFlt-1: 10.2 - 12.6 pg/mL across 3 lots (meets < 15 pg/mL) | |
| High-Dose Hook Effect: No significant hook effect at high concentrations of analytes. | - No high-dose hook effect at sFlt-1 concentrations up to 200,000 pg/mL.- No high-dose hook effect at PlGF concentrations up to 100,000 pg/mL. | |
| HAMA Interference: Minimal to no interference by Human Anti-Mouse Antibodies (HAMA). | - No HAMA interference for Elecsys PlGF up to 81 ug/L HAMA concentration.- For sFlt-1 concentrations ≤ 2,190 pg/mL, HAMA showed interference resulting in ≥10% positive bias in sFlt-1/PlGF ratios. | |
| Other Interferences (Bilirubin, Hemoglobin, Intralipid, Rheumatoid Factors, Biotin, Pharmaceuticals): Minimal to no significant interference. | - Bilirubin: >26.4 mg/dL can cause up to 10% decrease in ratio.- Hemoglobin, Intralipid, Rheumatoid Factors, Biotin (up to 1200 ng/mL): No significant interference reported (implies within acceptable limits though quantitative data not listed).- Common Drugs (15 tested): No interference.- Additional Substances (13 tested): No interference.- Heparin: Interference with Elecsys PlGF for concentrations > 500 U/L. | |
| Analytical Specificity/Cross-Reactivity: Highly specific for sFlt-1 and PlGF, with minimal cross-reactivity with related substances. | - sFlt-1 cross-reactivity: <0.01% with VEGFR2/VEGFR3, <2.1% with VEGF-B.- PlGF cross-reactivity: <0.1% with VEGF-B, <0.2% with VEGF 165, <0.9% with VEGF/PlGF-1. Recombinant PlGF-2 protein shows up to 42% cross-reactivity. |
Study Details
-
Sample Size used for the Test Set and Data Provenance:
- Clinical Performance Study (PRAECIS): N=556 pregnant women.
- Data Provenance: The document does not explicitly state the country of origin for the PRAECIS study's clinical data, but it refers to the study as a "validation of the Roche sFlt-1/PlGF ratio cut-off." The reference range study (mentioned as a separate activity) collected samples from "$US" (United States) to establish normal reference ranges. Given the context, it's highly probable the PRAECIS clinical validation study also involved US patient data, though not explicitly stated for that specific study section.
- Retrospective or Prospective: The document describes the study as "Praecis 'Preeclampsia Risk Assessment: Evaluation of Cut-offs to Improve Stratification'" and states it included women "admitted to the hospital with (or develop while hospitalized) a hypertensive disorder." This strongly suggests a prospective design within the hospital setting, though "retrospective" is not explicitly excluded for patient inclusion/data collection aspects. However, the nature of "risk assessment...to develop preeclampsia with severe features within two weeks from testing" implies a prospective observation period.
-
Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications:
- The document does not specify the number of experts or their qualifications used to establish the ground truth for the clinical test set. The ground truth (preeclampsia with severe features within two weeks) would typically be established by clinicians based on diagnostic criteria, but further details are not provided.
-
Adjudication Method for the Test Set:
- The document does not specify an adjudication method (e.g., 2+1, 3+1, none) for establishing the clinical ground truth.
-
Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study:
- No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not mentioned or conducted in this submission. This device is an in-vitro diagnostic (IVD) immunoassay, not an imaging AI device that relies on human reader interpretation. Therefore, the concept of "human readers improve with AI vs without AI assistance" is not directly applicable here.
-
Standalone (Algorithm Only Without Human-in-the-Loop Performance) Study:
- Yes, the clinical performance evaluation (PRAECIS study) presents the standalone performance of the sFlt-1/PlGF ratio at a specified cutoff (38). It assesses the test's ability to predict clinical outcome (preeclampsia with severe features) directly. The "human-in-the-loop" aspect is that the results are "used in conjunction with clinical assessment and routine laboratory testing" by a physician, but the performance statistics presented (Sensitivity, Specificity, NPV, PPV) are for the assay's output itself.
-
Type of Ground Truth Used:
- Clinical Outcome Data: The ground truth used was the "development of preeclampsia with severe features within two weeks from testing," as defined by established medical guidelines (likely ACOG, given its mention for the predicate device). This is a clinical outcome.
-
Sample Size for the Training Set:
- The document does not explicitly describe a separate "training set" for an algorithm in the traditional sense, as these are immunoassays. The clinical validation study (PRAECIS) evaluates the performance of the established cutoff (38) for the sFlt-1/PlGF ratio. The cutoff itself might have been derived from earlier studies or internal research, which would implicitly act as a form of "training" or "development" data, but it's not detailed here with sample sizes. The reference range study for healthy pregnant women used 380 evaluable subjects to establish expected values.
-
How the Ground Truth for the Training Set Was Established:
- As there isn't an explicitly described "training set" for an algorithm to learn from, this question largely pertains to the development of the assay and its interpretive cutoffs. The cutoff of 38 for the sFlt-1/PlGF ratio is stated to be "validated" in the PRAECIS study. The process for initial establishment or derivation of this cutoff (38) is not detailed in this document. It's common for such cutoffs to be determined through prior multicenter clinical trials and statistical analysis to achieve optimal predictive performance targets.
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Roche Diagnostics Jane Phillips Senior Regulatory Manager 9115 Hague Road Indianapolis, Indiana 46250
Re: K241453
Trade/Device Name: Elecsys sFlt-1 and Elecsys PlGF Regulation Number: 21 CFR 862.1602 Regulation Name: Prognostic Test for Development or Progression of Preeclampsia Regulatory Class: Class II Product Code: QWH Dated: January 2, 2025 Received: January 6, 2025
Dear Jane Phillips:
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 (the 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 available 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.
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Additional information about changes that may require a new premarket notification are provided in the FDA guidance documents entitled "Deciding When to Submit a 510(k) for a Change to an Existing Device" (https://www.fda.gov/media/99812/download) and "Deciding When to Submit a 510(k) for a Software Change to an Existing Device" (https://www.fda.gov/media/99785/download).
Your device is also subject to, among other requirements, the Quality System (QS) regulation (21 CFR Part 820), which includes, but is not limited to, 21 CFR 820.30. Design controls; 21 CFR 820.90. Nonconforming product; and 21 CFR 820.100, Corrective and preventive action. Please note that regardless of whether a change requires premarket review, the QS regulation requires device manufacturers to review and approve changes to device design and production (21 CFR 820.30 and 21 CFR 820.70) and document changes and approvals in the device master record (21 CFR 820.181).
Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR Part 803) for devices or postmarketing safety reporting (21 CFR Part 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safetyreporting-combination-products); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR Part 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR Parts 1000-1050.
All medical devices, including Class I and unclassified devices and combination product device constituent parts are required to be in compliance with the final Unique Device Identification System rule ("UDI Rule"). The UDI Rule requires, among other things, that a device bear a unique device identifier (UDI) on its label and package (21 CFR 801.20(a)) unless an exception or alternative applies (21 CFR 801.20(b)) and that the dates on the device label be formatted in accordance with 21 CFR 801.18. The UDI Rule (21 CFR 830.300(a) and 830.320(b)) also requires that certain information be submitted to the Global Unique Device Identification Database (GUDID) (21 CFR Part 830 Subpart E). For additional information on these requirements, please see the UDI System webpage at https://www.fda.gov/medical-device-advicecomprehensive-regulatory-assistance/unique-device-identification-system-udi-system.
Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR 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-regulatory
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assistance/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, Joseph A. Kotarek -S Joseph Kotarek Branch Chief Division of Chemistry and Toxicology Devices OHT7: Office of In Vitro Diagnostics 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) K241453
Device Name Elecsys sFlt-1 and Elecsys PlGR
| Indications for Use (Describe) | |
|---|---|
| -------------------------------- | -- |
Immunoassays for the in vitro quantitative determination of the tyrosine kinase-1/placental growth factor (sFlt-1/PlGF) ratio in human serum.
The sFlt-1/PlGF ratio is indicated as an aid in the risk assessment of pregnant women, with a singleton pregnancy (23+0 to 34+6/7 weeks' gestation) hospitalized for hypertensive disorders of pregnancy (preeclampsia, chronic hypertension with or without superimposed preeclampsia, or gestational hypertension), to develop preeclampsia with severe features within two weeks from testing. The sFit-1/PIGF ratio should be used in conjunction with clinical assessment and routine laboratory testing.
The electrochemiluminescence immunoassay "ECLIA" is intended for use on cobas e immunoassay analyzers.
| 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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K241453 Elecsys sFlt-1 and Elecsys PIGF 510(k) Summary
This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of 21 CFR 807.92.
| Submitter Name | Roche Diagnostics |
|---|---|
| Address | 9115 Hague RoadP.O. Box 50416Indianapolis, IN 46250-0457 |
| Contact | Dr. Jane PhillipsPhone: (317) 521-3338Email: jane.phillips@roche.com |
| Date Prepared | February 2nd, 2025 |
| Proprietary Name | Elecsys sFlt-1 and Elecsys PIGF |
| Common Name | Elecsys PE Assays |
| Classification Name | Prognostic test for development or progression of preeclampsia |
| Product Codes,Regulation Numbers | QWH, 21CFR862.1602 |
| Predicate Devices | B·R·A·H·M·S sFlt-1/ PIGF KRYPTOR Test System (DEN220027) |
| Establishment Registration | Roche Diagnostics GmbH Mannheim, Germany: 9610126Roche Diagnostics GmbH Penzberg, Germany: 9610529Roche Diagnostics Indianapolis, IN United States: 1823260 |
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DEVICE DESCRIPTION 1.
1.1. Elecsys sFlt-1
The Elecsys sFlt-1 employs a sandwich principle. The total duration of the assay is 18 minutes.
1st incubation: 20 µL of sample, a biotinylated monoclonal sFlt-1 specific antibody, and a monoclonal sFlt-1 specific antibody labeled with a ruthenium complex (Tris(2.2'bipyridyl)ruthenium(II)-complex (Ru(bpy)s') 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 via a calibration curve which is instrument-specifically generated by 2point calibration and a master curve provided via the reagent barcode.
The Elecsys sFlt-1 reagents "M", "R1" and "R2" are combined in the so-called "rackpack", a bundle of the three reagent bottles, which is placed on the instrument as a single unit. The reagent rackpack is labeled as SFLT-1.
- M: Streptavidin-coated microparticles (transparent cap), 1 bottle, 6.5 mL: . Streptavidin-coated microparticles 0.72 mg/mL; preservative.
- R1: Anti-sFlt-1-Ab~biotin (gray cap), 1 bottle, 9 mL: Biotinylated monoclonal anti . sFlt-1 antibody (mouse) 0.5 mg/L; phosphate buffer 100 mmol/L, pH 7.2; preservative.
- R2: Anti-sFlt-1-Ab~Ru(bpy) (black cap), 1 bottle, 9 mL: Monoclonal anti sFlt-1 . antibody (mouse) labeled with ruthenium complex 1.0 mg/L, biotin scavenger antibody 1.0 mg/mL; phosphate buffer 100 mmol/L, pH 7.2; preservative.
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Elecsys sFlt-1 will be marketed with the following devices:
- CalSet sFlt-1; secondary, calibrator; JIT, 862.1150 Class II, exempt ●
- Elecsys PreciControl Multimarker (cleared in K102157); multi-analyte controls, all . kinds (assayed); JJY, 862.1660 – Class I, exempt
1.2. Elecsys PIGF
The Elecsys PIGF employs a sandwich principle. The total duration of the assay is 18 minutes.
1 st incubation: 50 µL of sample, a biotinylated monoclonal PIGF specific antibody and a monoclonal PlGF specific antibody labeled with a ruthenium complex (Tris(2.2'bipyridyl)ruthenium(II)-complex (Ru(bpy)) 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 via a calibration curve which is instrument-specifically generated by 2point calibration and a master curve provided via the reagent barcode.
The Elecsys PlGF reagents "M", "RI" and "R2" are combined in the so-called "rackpack", a bundle of the three reagent bottles, which is placed on the instrument as a single unit. The reagent rackpack is labeled as PLGF.
- M Streptavidin-coated microparticles (transparent cap). 1 bottle. 6.5 mL: . Streptavidin-coated microparticles 0.72 mg/mL; preservative.
- R 1 Anti-PlGF-Ab~biotin (gray cap), 1 bottle, 8 mL: Biotinylated monoclonal anti . PlGF antibody (mouse) 0.6 mg/L; phosphate buffer 50 mmol/L, pH 6.0; preservative.
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-
. R2 Anti-PlGF-Ab~Ru(bpy) (black cap), 1 bottle, 8 mL: Monoclonal anti PlGF antibody (mouse) labeled with ruthenium complex 4.0 mg/L, biotin scavenger antibody 1.0 mg/mL; phosphate buffer 50 mmol/L, pH 6.0; preservative.
Elecsys PlGF will be marketed with the following devices: -
CalSet PlGF; secondary, calibrator; JIT, 862.1150 Class II, exempt .
-
. PreciControl Multimarker (cleared in K102157); multi-analyte controls, all kinds (assayed); JJY, 862.1660 - Class I, exempt
Both assays contain a blocking agent for exogenous biotin from supplements.
INDICATIONS FOR USE 2.
Immunoassays for the in vitro quantitative determination of the soluble fms like tyrosine kinase-1/placental growth factor (sFlt-1/PlGF) ratio in human serum.
The sFlt-1/PlGF ratio is indicated as an aid in the risk assessment of pregnant women, with a singleton pregnancy (23+0 to 34+6/7 weeks' gestation) hospitalized for hypertensive disorders of pregnancy (preeclampsia, chronic hypertension with or without superimposed preeclampsia, or gestational hypertension), to develop preeclampsia with severe features within two weeks from testing. The sFit-1/PlGF ratio should be used in conjunction with clinical assessment and routine laboratory testing.
The electrochemiluminescence immunoassay "ECLIA" is intended for use on cobas e immunoassay analyzers.
3. IMMUNOASSAY ANALYZERS.TECHNOLOGICAL CHARACTERISTICS
The following tables compare the Elecsys sFlt-1 and PlGF with its predicate device, B·R·A·H·M·S sFlt-1/ PlGF KRYPTOR Test System (DEN220027).
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| Feature | Candidate DeviceElecsys sFlt-1 and PIGF | Predicate DeviceB·R·A·H·M·S sFlt-1/ PIGFKRYPTOR Test SystemDEN220027 |
|---|---|---|
| Intended Use | Immunoassays for the in vitroquantitative determination ofthe soluble fms like tyrosinekinase-1/placental growthfactor (sFlt-1/PIGF) ratio inhuman serum.The sFlt-1/PIGF ratio isindicated as an aid in the riskassessment of pregnantwomen, with a singletonpregnancy (23+0 to 34+6/7weeks' gestation)hospitalized for hypertensivedisorders ofpregnancy (preeclampsia,chronic hypertension with orwithout superimposedpreeclampsia, or gestationalhypertension), to developpreeclampsia with severefeatures within two weeksfrom testing. The sFlt-1/PIGFratio should be used inconjunction with clinicalassessment and routinelaboratory testing.Theelectrochemiluminescenceimmunoassay "ECLIA" isintended for use on cobas eimmunoassay analyzers. | The B·R·A·H·M·STM sFlt-1/PIGF KRYPTOR Test Systemis comprised of theB·R·A·H·M·S PIGF plusKRYPTOR assay and theB·R·A·H·M·S sFlt-1KRYPTOR assay.The B·R·A·H·M·S PIGF plusKRYPTOR is an automatedimmunofluorescent assay usingTime-Resolved AmplifiedCryptate Emission (TRACE)technology for the quantitativedetermination of theconcentration of PlacentalGrowth Factor (PlGF) inhuman serum and plasma (K2EDTA) on the B·R·A·H·M·SKRYPTOR analyzer.The B·R·A·H·M·S sFlt-1KRYPTOR is an automatedimmunofluorescent assay usingTime-Resolved AmplifiedCryptate Emission (TRACE)technology for the quantitativedetermination of theconcentration of soluble fms-like tyrosine kinase-1 (sFlt-1), also known as VEGFreceptor-1, in human serum andplasma (K2 EDTA) on theB·R·A·H·M·S KRYPTORanalyzer.The B·R·A·H·M·S PIGF plusKRYPTOR is to be used inconjunction with theB·R·A·H·M·S sFlt-1KRYPTOR along withother laboratory tests andclinical assessments to aid inthe risk assessment of pregnantwomen (singleton pregnancies |
| between gestational age 23+0to 34+6/7 weeks) hospitalizedfor hypertensive disorders ofpregnancy (preeclampsia,chronic hypertension with orwithout superimposedpreeclampsia, or gestationalhypertension) for progressionto pre-eclampsia with severe features(as defined by AmericanCollege of Obstetricians andGynecologists guidelines)within 2 weeks of presentation. | ||
| Assay Method | Sandwich immunoassay | Same |
| Detection Method | Electrochemiluminescence"ECLIA" | Time-Resolved AmplifiedCryptate Emission(TRACETM) technology |
| Applications/Test Time | 18 minute | 9 minute |
| Sample Type/Matrix | Human serum | Human serum/plasma |
| Sample Anticoagulants | N/A | K2-EDTA |
| Handling of R1 and R2 | Liquid, ready to use | Same |
| Buffer composition R1 | Phosphate buffer | Bovine albumin |
| Calibrator | sFlt-1 CalSet and PIGF CalSet | B·R·A·H·M·S sFlt-1KRYPTOR CAL andB·R·A·H·M·S PIGFKRYPTOR CAL |
| Calibration Method | 2-point calibration | Same |
| Calibration Interval | Calibration must be performedonce per reagent lot using freshreagent (i.e. not more than 24hours since the reagent kit wasregistered on the analyzer).Calibration interval may beextended based on acceptableverification of calibration bythe laboratory.Renewed calibration isrecommended as follows:• After 28 days using thesame reagent lot• After 7 days (whenusing the same reagentkit on the analytzer)• As required: e.g.quality control findings | Calibration must be carried outbefore the first use of each newB·R·A·H·M·S sFlt-1 and PIGFKRYPTOR lot, thenrepeated on a regular basisautomatically managed by theB·R·A·H·M·S KRYPTORanalyzer in order to readjust thestandard curve. Controls mustbe run after each calibration. |
| outside the definedlimits | ||
| Controls | PreciControl Multimarker | B·R·A·H·M·S sFlt-1KRYPTOR QC kit andB·R·A·H·M·S PIGFKRYPTOR QC kit |
| Traceability/Standardization | Elecsys sFlt-1 assay: Thismethod has been standardizedagainst theQuantikine ELISA HumanVEGFR1/Flt-1 Immunoassay.• Elecsys PIGF assay: Thismethod has been standardizedagainst theQuantikine ELISA HumanPIGF Immunoassay. | An international PIGFreference preparation is notavailable. Therefore, the assayis calibrated using a referencepreparation of recombinanthuman PIGF as the "HighestAvailable Standard". Thiscalibration is verified on aregular basis by regressionanalysis and comparison totheoretically expected results.The PIGF assay results aregiven in pg/mL. |
| Reagent Stability | Reagent stability for onanalyzer is now 28 days. | unopened at 2-8 °C: upto the stated expirationdate after opening at 2-8 °C:12 weeks on analyzers: 8 weeks |
| Measuring Range | sFlt-1 80-85000 pg/mLPIGF 10-5400 pg/mL | sFlt-1 315-90,000 pg/mLPIGF 7.6 – 4,000 pg/mL |
| Biotin Tolerance | Up to 1200 ng/mL | N/A |
Table 1: Technical Characteristics Comparison Table between Elecsys sFlt-1 and PIGF and B·R·A·H·M·S sFlt-1/ PlGF KRYPTOR Test System
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NON-CLINICAL PERFORMANCE EVALUATION 4.
Non-clinical performance evaluation for Elecsys sFit-1 and Elecsys P1GF assay executed with the study briefly summarized.
4.1. Precision
Precision measurements were conducted to evaluate repeatability (within-run precision) and intermediate precision (within-laboratory precision) according the CLSI guideline EP05-A3. Precision of the Elecsys sFlt-1 and PlGF assays was evaluated on a single cobas e 411 immunoassay analyzer according to CLSI EP5-A3 guideline. One reagent lot was evaluated. The precision study was conducted using the study design of testing 2 aliquots of each control
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(PC (=PreciControl) Multimarker) and human sera (HS) in single determinations per run, 2 runs per day for 21 days. Assay calibration was performed as specified in the package insert. The samples were run in randomized order on the cobas e 411 analyzer.
| Mean | Repeatability | Intermediate precision | ||||
|---|---|---|---|---|---|---|
| Sample | pg/mL | SD(pg/mL ) | CV (%) | SD(pg/mL ) | CV (%) | n |
| Human serum 1 | 46.3 | 1.03 | 2.2 | 1.51 | 3.3 | 84 |
| Human serum 2 | 89.9 | 1.18 | 1.3 | 2.03 | 2.3 | 84 |
| Human serum 3 | 441 | 4.46 | 1.0 | 7.27 | 1.7 | 84 |
| Human serum 4 | 11.8 | 0.670 | 5.7 | 1.17 | 9.9 | 83 |
| Human serum 5 | 74.0 | 1.87 | 2.5 | 4.11 | 5.6 | 84 |
| Human serum 6 | 39.4 | 1.06 | 2.7 | 2.09 | 5.3 | 84 |
| Human serum 7 | 96.0 | 1.58 | 1.6 | 2.38 | 2.5 | 84 |
| Human serum 8 | 74.7 | 1.34 | 1.8 | 2.28 | 3.1 | 84 |
| Human serum 9 | 4923 | 78.4 | 1.6 | 116 | 2.4 | 84 |
| Human serum 10 | 8894 | 141 | 1.6 | 178 | 2.0 | 84 |
| PCa) Multimarker 1 | 96.9 | 1.47 | 1.5 | 2.26 | 2.3 | 84 |
| PC Multimarker 2 | 950 | 8.68 | 0.9 | 17.1 | 1.8 | 84 |
Table 2: Summary of 21-Day Precision for Elecsys PlGF on the cobas e 411 analyzer
a)
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| Mean | Repeatability | Intermediate precision | ||||
|---|---|---|---|---|---|---|
| Sample | pg/mL | SD(pg/mL ) | CV (%) | SD(pg/mL ) | CV (%) | n |
| Human serum 1 | 1690 | 21.1 | 1.2 | 28.2 | 1.7 | 84 |
| Human serum 2 | 632 | 6.45 | 1.0 | 11.1 | 1.8 | 84 |
| Human serum 3 | 3867 | 43.0 | 1.1 | 74.1 | 1.9 | 84 |
| Human serum 4 | 89.3 | 2.02 | 2.3 | 3.15 | 3.5 | 83 |
| Human serum 5 | 36992 | 682 | 1.8 | 1287 | 3.5 | 84 |
| Human serum 6 | 76873 | 1870 | 2.4 | 2842 | 3.7 | 84 |
| Human serum 7 | 18037 | 246 | 1.4 | 405 | 2.2 | 84 |
| Human serum 8 | 2522 | 28.6 | 1.1 | 46.0 | 1.8 | 84 |
| Human serum 9 | 78.6 | 1.85 | 2.3 | 2.77 | 3.5 | 84 |
| Human serum 10 | 90.7 | 2.02 | 2.2 | 3.32 | 3.7 | 84 |
| PCa) Multimarker 1 | 106 | 2.13 | 2.0 | 2.98 | 2.8 | 84 |
| PC Multimarker 2 | 1044 | 9.46 | 0.9 | 17.3 | 1.7 | 84 |
Table 2: Summary of 21-Day Precision for Elecsys sFlt-1 on the cobas e 411 analyzer
Table 3: 21-Day Precision Results Ratio Summary
| Sample | Mean | Repeatability | Intermediate precision | |||
|---|---|---|---|---|---|---|
| Ratio | SD | CV (%) | SD | CV (%) | n | |
| Human serum 1 | 37 | 0.736 | 2.0 | 0.985 | 2.7 | 84 |
| Human serum 2 | 7 | 0.118 | 1.7 | 0.133 | 1.9 | 84 |
| Human serum 3 | 9 | 0.094 | 1.1 | 0.123 | 1.4 | 84 |
| Human serum 4 | 8 | 0.369 | 4.9 | 0.528 | 7.0 | 83 |
| Human serum 5 | 501 | 17.9 | 3.6 | 27.4 | 5.5 | 84 |
| Human serum 6 | 1957 | 71.8 | 3.7 | 101 | 5.1 | 84 |
| Human serum 7 | 188 | 2.95 | 1.6 | 3.92 | 2.1 | 84 |
| Human serum 8 | 34 | 0.497 | 1.5 | 0.798 | 2.4 | 84 |
| Human serum 9 | 0.016 | 0.0005 | 2.9 | 0.0005 | 3.4 | 84 |
| Human serum 10 | 0.01 | 0.0003 | 2.5 | 0.0004 | 3.7 | 84 |
| PC Multimarker 1 | 1 | 0.025 | 2.3 | 0.026 | 2.3 | 84 |
| PC Multimarker 2 | 1 | 0.015 | 1.4 | 0.017 | 1.5 | 84 |
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4.2. Linearity/Assay Reportable Range
The linearity study was conducted with the Elecsys sFlt-1 and PIGF assays on the cobas e 411 analyzer to demonstrate that measurements across the claimed measuring range for each parameter are linear. This was done according to CLSI EP06-Ed2. Study Design B. The linearity study was performed with more than two sets of panel members with each set partially covering the proposed linearity interval. The main reason for this study design is the large measuring range and limitations in the number of dilutions of each high sample. The concentration ranges of the diluted samples cover the entire measuring range of the assays. Samples were assayed in 4-fold determination within a single run, on one instrument. SD and CVs were calculated for each 4-fold determination.
Reportable ranges were established as:
- Elecsys sFlt-1 is 80-85000 pg/mL. .
- . Elecsys PlGF is 10-5400 pg/mL.
Attention: For the Elecsys sFlt-1 assay, please use the PreciControl Multimarker controls with the lowest control level for sFlt-1 being approximately 100 pg/mL.
Analytical Sensitivity 4.3.
Limit of Blank (LoB) 4.3.1.
LoB of the Elecsys sFlt-1 and PlGF assays on the cobas e 411 analyzer was determined according to CLSI EP17-A2. Limit of Blank determines the highest observed measurement values for samples free of analyte. The Limit of Blank was determined as the 95th percentile of measurements of blank samples. The zero-level (blank) sample used was a human serum sample from pregnant female diluted with horse serum.
In total 60 determinations for analyte free samples have been obtained. Limit of Blank determines the highest observed measurement values for samples free of analyte. The Limit of Blank was determined as the 95th percentile of measurements of blank samples.
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Table 4. LoB for PIGF
| Reagent lot | LoB (pg/mL) |
|---|---|
| 1 | 0.732 |
| 2 | 0.946 |
| 3 | 0.482 |
All lots met the predetermined acceptance criterion. The LoB claim in the labeling will be set to ≤ 2 pg/mL.
Table 5. LoB for sFLT-1
| Reagent lot | LoB (pg/mL) |
|---|---|
| 1 | 4.00 |
| 2 | 3.51 |
| 3 | 2.92 |
All lots met the predetermined acceptance criterion. The LoB claim in the labeling will be set to < 6 pg/mL.
Limit of Detection (LoD) 4.3.2.
LoD of the Elecsys sFlt-1 and PlGF assays on the cobas e 411 analyzer was determined according to CLSI EP17-A2. The LoD determines the lower limit for samples with analyte. The LoD was determined as the lowest amount of analyte in a sample that can be detected with a 95% probability.
Experimental Design:
- Three reagent lots ●
- One cobas e 411 analyzer ●
- Six runs on ≥ three days
- Two replicates per sample per run ●
- Five samples .
- 60 replicates per sample per reagent lot .
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Five low-analyte serum samples (non-pregnant female from single donor) were measured in twofold determination, six runs over at least three days. In total, 60 determinations per reagent lot were performed. A pooled estimate of the precision (SD total) for the 5 low level samples was calculated. The LoD was established according to the following EP17-A2 calculation:
LoD = LoB + 1.653 x SD total (of low analyte samples)
Table 6. LoD for PlGF
| Reagent Lot | LoD (pg/mL) |
|---|---|
| 1 | 2.19 |
| 2 | 2.19 |
| 3 | 1.65 |
All lots met the predetermined acceptance criterion. The LoD claim in the labeling will be set to < 3 pg/mL.
Table 7. LoD for sFLT-1
| Reagent Lot | LoD (pg/mL) |
|---|---|
| 1 | 6.03 |
| 2 | 4.95 |
| 3 | 4.44 |
All lots met the predetermined acceptance criterion. The LoD claim in the labeling will be set to < 10 pg/mL.
4.3.3. Limit of Quantitation (LoQ)
The LoQ of the Elecsys sFlt-1 and PlGF assays was determined on the cobas e 411 analyzer according to CLSI Guideline EP17-A2. LoQ determines the lowest amount of analyte that can be quantitatively determined with stated accuracy and stated experimental conditions. The LoQ was determined as the lowest concentration of analyte which can be quantified with an intermediate precision CV of no more than 20%.
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Experimental Design:
- . Three reagent lots
- One cobas e 411 analyzer .
- Five days .
- One run per day ●
- Five replicates per sample per run ●
- ≥ four low level serum samples .
- . 20 replicates per sample per reagent lot
A set of four human serum samples (non-pregnant female or pregnant female from single donor diluted with horse serum) with concentrations in the specified LoQ-area were evaluated. The mean value and the intermediate precision (CV) and standard deviation (SD) for each LoQ sample were calculated.
LoO samples were sorted according to the concentration of their measured mean value. LoO is defined as the mean value of that sample which is the first that fulfills the specification for the intermediate precision and for which no sample with higher concentration exists that exceeds this specification. Data are summarized in a table and a graphic is generated plotting the measured mean values versus the intermediate precision (CV) of the LoQ samples.
Table 8. LoQ for PIGF
| Reagent Lot | LoQ (pg/mL) |
|---|---|
| 1 | 8.97 |
| 2 | 7.77 |
| 3 | 7.48 |
All lots met the predetermined acceptance criterion. The LoQ claim in the labeling will be set to < 10 pg/mL.
{17}------------------------------------------------
Table 9. LoQ for sFLT-1
| Reagent Lot | LoQ (pg/mL) |
|---|---|
| 1 | 10.2 |
| 2 | 12.6 |
| 3 | 11.8 |
All lots met the predetermined acceptance criterion. The LoO claim in the labeling will be set to < 15 pg/mL.
4.4. High-Dose Hook Effect
The high-dose hook effect (HDHE) of the Elecsys sFlt-1 and PlGF assays was assessed on one cobas e 411 analyzer using a dilution series.
There is no high-dose hook effect at sFlt-1 concentrations up to 200000 pg/mL. There is no high-dose hook effect at PIGF concentrations up to 100000 pg/mL.
4.5. Human Anti-Mouse Antibodies (HAMA)
The effect of the presence of human anti-mouse antibodies (HAMA) on the Elecsys sFlt-1 and
Elecsys PIGF assays was assessed on one cobas e 411 analyzer. The differentiation between
HAMA- negative and HAMA-positive samples was assessed.
Heterophilic human anti-mouse antibodies (HAMA) interference was tested up to a HAMA concentration of 81 u g/L. No HAMA interference for Elecsys PlGF was found. For samples with sFit-1 concentrations ≤ 2190 pg/mL, HAMA was shown to interfere, resulting in sFit-1/P1GF ratios with ≥10% positive bias"
{18}------------------------------------------------
4.6. Interferences
For each interfering substance four human serum samples with four different concentrations of PIGF and sFLT-1 were tested.
Biotin:
One aliquot of each serum sample was spiked with the interfering substance; another aliquot was spiked with the same volume of isotonic NaCl solution (dilution pool). The interfering pool was then diluted into the dilution pool in 11 increments. The recovery for each sample was calculated by comparison to the reference (unspiked) sample.
Lipemia (Intralipid):
One aliquot of each serum sample was spiked with the interfering substance; another aliquot was spiked with the same volume of isotonic NaCl solution (dilution pool). The interfering pool was then diluted into the dilution pool in 10% increments. The recovery for each sample was calculated by comparison to the reference (unspiked) sample.
Hemoglobin:
Fresh hemolysate was prepared from fresh EDTA plasma. One aliquot of each serum sample was spiked with the hemolysate (interfering pool), another aliquot was spiked with the same volume of isotonic NaCl solution (dilution pool). The interfering pool was then dilution pool in 10% increments. The recovery for each sample was calculated by comparison to the reference (unspiked) sample.
Bilirubin (90 % unconjugated / 10 % conjugated bilirubin):
One aliquot of each serum sample was spiked with the interfering substance, and another aliquot was spiked with the same volume of the solvent (0.1 mol/L NaOH) of the interfering substance
{19}------------------------------------------------
(dilution pool). The interfering pool was then dilution pool in 10% increments. The recovery for each sample was calculated by comparison to the reference (unspiked) sample.
Rheumatoid Factor (RF):
One aliquot of each serum sample was spiked with the interfering substance, and another aliquot with the same volume of the solvent (buffer matrix) of the interfering substance (dilution pool). The interfering pool was then diluted into the dilution pool in 6 increments 6 dilution steps were prepared respectively 0, 10, 30, 50, 60 and 100%. The recovery for each sample was calculated by comparison to the reference sample.
| Table 10: Interferences |
|---|
| Compound | Highest concentration tested |
|---|---|
| Bilirubin | 451.4 µmol/L or 26.4 mg/dL |
| Hemoglobin | 0.621 mmol/L or 1000 mg/dL |
| Intralipid | 2000 mg/dL |
| Rheumatoid factors | 1200 IU/mL |
| Biotin | 1200 ng/mL |
Bilirubin concentrations at >26.4 mg/dL in the samples can result in an up to 10 % decrease of the sFlt-1/PlGF ratio around the cutoff of 38 as shown in a spiking experiment.
Heterophilic human anti-mouse antibodies (HAMA) in human specimens can react with reagent antibodies, interfering with in vitro immunoassays. Patients routinely exposed to animals or animal serum products for diagnosis or therapies can be prone to this interference and anomalous values may be observed. Specimens from patients who have received mouse monoclonal antibodies for diagnosis or therapy may contain human anti-mouse antibodies and may interfere in assays that employ mouse monoclonal antibodies. Additional information may be required for diagnosis.
In rare cases, interference due to extremely high titers of antibodies to analyte-specific antibodies, streptavidin or ruthenium can occur. These effects are minimized by suitable test design. sFlt-1 and PlGF values determined on patient samples using other manufacturers' assays
{20}------------------------------------------------
may result in significantly different ratios, which could lead to wrong diagnostic conclusions. Therefore, only the Elecsys sFlt-1 and Elecsys PlGF assays should be used to calculate the ratio.
Analytical Specificity/Cross-Reactivity 4.7.
A cross-reactivity study was conducted with Elecsys sFit-1 and PIGF assays on the cobas e 411 analyzer to evaluate the potential cross-reacting compounds using human serum samples. Samples were measured in the presence and absence of the potential cross-reactants and crossreactivity was calculated with one lot of reagent.
Elecsys sFlt-1 assay
The monoclonal antibodies used are highly specific against human sFlt-1. The following cross-reactivities were found in samples with sFlt-1 levels between 1300 and 9000 pg/mL.
| Substance | Concentration tested(pg/mL) | Cross-reactivity(%) |
|---|---|---|
| VEGFR2 | 11000000 | < 0.01 % |
| VEGFR3 | 1430000 | < 0.01 % |
| VEGF-B | 10000 | < 2.1 % |
Table 11. sFlt-1 Cross Reactivity
Elecsys PIGF assay
The monoclonal antibodies used are highly specific against human PIGF. The following cross-reactivities were found in samples with PIGF levels between 65 and 180 pg/mL.
Table 12. PIGF Cross Reactivity
| Substance | Concentration tested(pg/mL) | Cross-reactivity(%) |
|---|---|---|
| VEGF-B | 10000 | < 0.1 % |
| VEGF 165 | 10000 | < 0.2 % |
| VEGF/PIGF-1 | 10000 | < 0.9 % |
Recombinant PIGF-2 protein shows up to 42 % cross-reactivity and interferes with the Elecsys PIGF assay (please see section on Precautions and warnings).
{21}------------------------------------------------
Limitations - interference
Pharmaceutical substances Exogenous Interferences – Drugs 4.8.
Elecsys sFlt-1 and Elecsys PIGF assays
In vitro tests were performed on 15 commonly used pharmaceuticals. No interference with the Elecsys sFlt-1 and Elecsys PIGF assays was found.
| Compound | Concentration(mg/L) |
|---|---|
| Acetaminophen | 260 |
| Acetylcysteine | 150 |
| Acetylsalicylic acid | 1000 |
| Ampicillin-Na | 1000 |
| Ascorbic acid | 300 |
| Cefoxitin | 2500 |
| Cyclosporine | 5 |
| Doxycycline | 50 |
| Heparin | 5000 U/L (sFlt-1)500 U/L (PIGF)* |
| Ibuprofen | 500 |
| Levodopa | 20 |
| Metronidazole | 200 |
| Phenylbutazone | 400 |
| Rifampicin | 60 |
| Theophylline | 100 |
Table 13. Common Drugs Tested
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*Heparin interference with Elecsys PIGF was found for heparin concentrations > 500 U/L (see section Precautions and warnings).
13 additional pharmaceuticals and substances were tested with the Elecsys sFlt-1 and Elecsys PIGF assays. No interference with the Elecsys sFit-1 and Elecsys PIGF assays was found.
| Compound | Concentration(mg/L) |
|---|---|
| Albumin | 60000 |
| Caffeine | 59 |
| Calcium | 200 |
| Dihydralazin | 200 |
| Ethanol | 5 % (v/v) |
| Folic Acid | 2.4 |
| Gentamicin | 10 |
| Iron | 72 |
| Labetalol | 1.5 |
| Magnesium Sulfate | 252 |
| Methyldopa | 7.2 |
| Metroprolol | 5 |
| Nifedipine | 0.6 |
Table 14. Additional Substances Tested
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CLINICAL PERFORMANCE EVALUATION 5.
Praecis "Preeclampsia Risk Assessment: Evaluation of Cut-offs to Improve Stratification"
PRAECIS is a validation of the Roche sFlt-1/PlGF ratio cut-off of 38 as an aid in the risk assessment of pregnant women with a singleton pregnancy (23+0 to 34+6/7 weeks' gestation) with a hypertensive disorder of pregnancy to develop preeclampsia with severe features within two weeks from testing.
Study population included pregnant women (≥18 years of age) and gestational age 23+0 to 34+6/7 weeks who are admitted to the hospital with (or develop while hospitalized) a hypertensive disorder of pregnancy (preeclampsia, chronic hypertension with or without superimposed preeclampsia, or gestational hypertension).
Clinical Performance criteria of NPV and PPV were met for sFlt-1/PIGF ratio at a cutoff of 38 for the Intended Use and the Intended Use (Study Target) population. The primary study objective was fulfilled.
{24}------------------------------------------------
| Assay | N of sPE a) | N of non-sPE | Total N | Prevalence(%) | Sensitivity(%) (95% CI) | Specificity(%) (95% CI) | NPV b)(%) (95% CI) | Assay | N of sPE | N of non-sPE | Total N | PPV c)(%) (95% CI) | Accuracy(%) (95% CI) | LR- d)(95% CI) | LR+ e)(95% CI) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ratio > 38 | 170 | 84 | 254 | 91.40 | 77.30 | 94.70 | ratio > 38 | 170 | 84 | 254 | |||||
| ratio ≤ 38 | 16 | 286 | 302 | 33.45 | 91.40(86.41, 95.00) | 77.30(72.68, 81.47) | 94.70(91.54, 96.94) | ratio ≤ 38 | 16 | 286 | 302 | 66.93(60.77, 72.68) | 82.01(78.56, 85.12) | 0.11(0.07, 0.18) | 4.03(3.32, 4.88) |
| Total | 186 | 370 | 556 | Total | 186 | 370 | 556 |
Table 15: Performance of the sFLT-1 and PIGF Assays in the Intended Use Population
sPE = preeclampsia with severe features a)
NPV = negative predictive value b)
PPV = positive predictive value c)
LR- = negative likelihood ratio d)
LR+ = positive likihood ratio e)
Table 16: Impact of hypertensive disorder at presentation on the prognostic performance of Roche Elecsys sFlt-1/PIGF ratio at cutoff of 38
| Hypertensivedisorders | n | Sensitivity(%) (95% CI) | Specificity(%) (95% CI) | PPV(%) (95%CI) | NPV(%) (95%CI) |
|---|---|---|---|---|---|
| Preeclampsia | 142 | 95.06(87.84, 98.64) | 72.13(59.17, 82.85) | 81.91(72.63,89.10) | 91.67(80.02,97.68) |
| SuperimposedPreeclampsia | 68 | 93.75(79.19, 99.23) | 55.56(38.10, 72.06) | 65.22(49.75,78.65) | 90.91(70.84,98.88) |
{25}------------------------------------------------
| Hypertensivedisorders | n | Sensitivity(%) (95% CI) | Specificity(%) (95% CI) | PPV(%) (95%CI) | NPV(%) (95%CI) |
|---|---|---|---|---|---|
| ChronicHypertension | 232 | 87.76(75.23, 95.37) | 82.51(76.22, 87.72) | 57.33(45.38,68.69) | 96.18(91.87,98.58) |
| GestationalHypertension | 114 | 83.33(62.62, 95.26) | 78.89(69.01, 86.79) | 51.28(34.78,67.58) | 94.67(86.90,98.53) |
Table 17: Impact of maternal age at presentation on the prognostic performance of Roche Elecsys sFlt-1/PIGF ratio at cutoff of 38
| Maternalage | n | Sensitivity(%) (95% CI) | Specificity(%) (95% CI) | PPV(%) (95% CI) | NPV(%) (95% CI) |
|---|---|---|---|---|---|
| < 35 years | 370 | 90.91(84.66, 95.21) | 81.51(75.99, 86.23) | 73.17(65.70, 79.78) | 94.17(90.05, 96.95) |
| ≥ 35 years | 186 | 92.59(82.11, 97.94) | 69.70(61.10, 77.39) | 55.56(44.70, 66.04) | 95.83(89.67, 98.85) |
Table 18: Impact of gestational age at presentation on the prognostic performance of of Roche Elecsys sFlt-1/PlGF ratio at cutoff of 38
| Gestational | n | Sensitivity | Specificity | PPV | NPV |
|---|---|---|---|---|---|
| age | (%) (95% CI) | (%) (95% CI) | (%) (95% CI) | (%) (95% CI) | |
| < 30 weeks | 188 | 100.00(95.14, 100.00) | 81.58(73.23, 88.22) | 77.89(68.22, 85.77) | 100.00(96.11,100.00) |
| ≥ 30 weeks | 368 | 85.71(77.84, 91.61) | 75.39(69.64, 80.54) | 60.38(52.33, 68.04) | 92.34(87.87, 95.56) |
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REFERENCE RANGE STUDY 6.
Expected values
Roche completed a study to collect samples from apparently healthy pregnant women in the US, to test them for sFlt-1 and PlGF to calculate normal reference ranges. Subjects were enrolled at 9 sites across the US. Women enrolled were representative of the US population in terms of race and ethnicity and were currently within gestational weeks 23 weeks + 0 days - 34 weeks + 6 days. Within the gestational time ranges there were 380 evaluable subjects with 78 % Caucasian, 14 % African American, 6 % Asian and 2 % other.21 In a population of 380 healthy pregnant women between week 23+0 up to week 34+6, the sFlt-1/P1GF ratio median was established at 3.21, the 2.5th percentile at 0.857 and the 97.5th percentile at 13.5.
Expected values in the healthy population are for information only, the clinical application of the sFlt-1/PlGF ratio in the intended use population is outlined in the section titled "Interpretation of the sFlt-1/PlGF ratio" above.
CONCLUSIONS 7.
The information provided in this 510(k) Premarket Notification supports the determination that the Elecsys sFlt-1 and PlGF assay is substantially equivalent to the predicate device, B·R·A·H·M·S sFlt-1/ PlGF KRYPTOR Test System (DEN220027).
N/A