Search Results

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

Study Details

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

8. 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.

Ask a specific question about this device

The B.R.A.H.M.STM sFlt-1/PIGF KRYPTORTM Test System is comprised of the B . R . H . M S PIGF plus KRYPTOR assay and the B . A . H . M . S sFit-1 KRYPTOR assay.

The B R . A . H . M . S PIGF plus KRYPTOR is an automated immunofluorescent assay using Time-Resolved Amplified Cryptate Emission (TRACE™) technology for the quantitative determination of the concentration of Placental Growth Factor (PIGF) in human serum and plasma (K2 EDTA) on the B.R.A.H.M.S KRYPTOR analyzer.

The B · A · H · M · S s F t - 1 K R PTOR is an automated immunofluorescent assay using Time-Resolved Amplified Cryptate Emission (TRACE) technology for the quantitative determination of the concentration of soluble fms-like tyrosine kinase-1 (sFit-1), also known as VEGF receptor-1, in human serum and plasma (K2 EDTA) on the B.R.A.H:M:S KRYPTOR analyzer.

The B · A · H · M · S PIGF plus KRYPTOR is to be used in conjunction with the B · A · M · S sFlt-1 KRYPTOR along with other laboratory tests and clinical assessments to aid in the risk assessment of pregnant women (singleton pregnancies between gestational age 23+0 to 34+6/7weeks) hospitalized for hypertensive disorders of pregnancy (preeclampsia, chronic hypertension with or without superimposed preeclampsia, or gestational hypertension) for progression to preeclampsia with severe features (as defined by American College of Obstetricians and Gynecologists (ACOG) guidelines) within 2 weeks of presentation.

The B · A · H · M · S · F · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · PIGF plus KRYPTOR assay and the B.R.A.H.M.S sFlt-1 KRYPTOR assay.

B R . A H M . S PIGF plus KRYPTOR and B . R . H . M . STM sFit-1 KRYPTOR assays are supplied as two reagent kits that are run on the B-R-A-H-M-S KRYPTOR compact PLUS. Each kit is sufficient for 75 determinations, and is comprised of two bottled reagents:

PIGF
Cryptate conjugate: Lumi4®-Tb labeled, anti-human PlGF antibody, buffer, bovine albumin, rat immunoglobulins, bovine immunoglobulins, goat immunoglobulins, trehalose, mannitol.
XL conjugate: Cyanin 5.5 labeled, anti-human PlGF antibody, buffer, bovine albumin, rat immunoglobulins, bovine immunoglobulins, goat immunoglobulins.

sFlt-1
Cryptate conjugate: Lumi48-Tb labeled, anti-human sFlt-1 antibody, buffer, bovine albumin, bovine immunoglobulins, mouse immunoglobulins, dextran, preservative. XL conjugate: Cyanin 5.5 labeled, anti-human sFlt-1 antibody, buffer, bovine albumin, bovine immunoglobulins, mouse immunoglobulins, dextran, preservative.

The B · A · H · M · S KRYPTOR compact PLUS is an automated test platform. The analyzer consumables are:

B · R · A · H · M · S KRYPTOR compact Solution 1: ProClinTM 150 Solution
B · R · A · H · M · S KRYPTOR compact Solution 2: Potassium fluoride solution
B · R · A · H · M · S KRYPTOR compact Solution 3: Active chlorine and sodium hydroxide solution
B · R · A · H · M · S KRYPTOR compact Solution 4: Sodium hydroxide solution
B · R · A · H · M · S KRYPTOR BUFFER: Phosphate Buffer Saline
B · R · A · H · M · S KRYPTOR compact REACT: 60 plates

Also supplied and required are calibrators - single level B.R.A.H.M.S PIGF plus KRYPTOR CAL and two levels B. R. A. H. M.S sFlt-1 KRYPTOR CAL. The instrument is calibrated on a 15 day cycle, and re-calibrated with each new lot of reagents.

Also supplied and required are three levels of controls - B.R.A.H.M.S PIGF plus KRYPTOR OC Controls and B.R.A.H.M.S sFlt-1 KRYPTOR OC.

Here's a breakdown of the acceptance criteria and study details for the B.R.A.H.M.S sFlt-1/PIGF KRYPTOR Test System, based on the provided text:

Acceptance Criteria and Device Performance

The primary clinical performance acceptance criteria revolve around the device's ability to aid in the risk assessment of pregnant women for progression to preeclampsia with severe features. This is evaluated through its positive predictive value (PPV), negative predictive value (NPV), sensitivity, and specificity.

Table of Acceptance Criteria and Reported Device Performance:

Note: The document does not explicitly state numerical acceptance criteria prior to the study results. The granting of the De Novo request implies that the reported performance metrics were deemed acceptable by the FDA for the device's intended use.

Study Proving Device Meets Acceptance Criteria

The study described is the PRAECIS (Preeclampsia Risk Assessment: Evaluation of Cut-offs to Improve Stratification, Identification and Validation of a Cut-off for the Ratio of Soluble Fms-like Tyrosine Kinase-1 to Placental Growth Factor (sFlt-1/PlGF) to Stratify Risk in Pregnant Women with Hypertensive Disorders of Pregnancy) clinical study.

1. Sample Size Used for the Test Set and Data Provenance:

• Sample Size: 556 enrollments (from 520 patients, with some patients enrolled multiple times).
• Data Provenance: Prospective, multicenter, blinded, non-interventional study conducted across 18 sites in the US.

2. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts:

• Number of Experts: A panel of 3 independent obstetricians.
• Qualifications: "Obstetricians" is the only qualification mentioned. No specific experience levels (e.g., years of experience) are provided.

3. Adjudication Method for the Test Set:

• Method: A central adjudication committee (panel of 3 independent obstetricians) was assembled to review data and arrive at consensus regarding each patient's diagnoses for the development of sPE following the 2013 ACOG clinical practice guidelines. This indicates a consensus-based adjudication.

4. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was Done:

• No, an MRMC comparative effectiveness study was not done. This study evaluates an in vitro diagnostic (IVD) test system (measurement of sFlt-1 and PlGF levels and their ratio) rather than an AI-assisted imaging diagnosis system where human readers would be involved in interpreting images. Therefore, the concept of "human readers improving with AI vs. without AI assistance" does not apply here.

5. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done:

• Yes, in essence, a standalone evaluation was performed for the device's output. The "algorithm" here is the immunofluorescent quantitative assay that measures sFlt-1 and PIGF concentrations and calculates their ratio. The clinical performance (PPV, NPV, sensitivity, specificity) is based on comparing the device's calculated ratio (using a defined cutoff of >40 for 'high risk' and <40 for 'low risk') directly against the ground truth established by the clinical outcome adjudicated by the expert panel. There isn't a "human-in-the-loop" step in the device's output determination influencing the sFlt-1/PIGF ratio result itself, though the result is then used by a clinician for risk assessment.

6. The Type of Ground Truth Used:

• Expert Consensus + Outcomes Data: The ground truth for the clinical outcome ("progression to preeclampsia with severe features (sPE) within 2 weeks of presentation") was established by a central adjudication committee (panel of 3 independent obstetricians) who reviewed data and arrived at a consensus diagnosis following the 2013 ACOG guidelines. This relies on clinical outcomes and expert interpretation of those outcomes.

7. The Sample Size for the Training Set:

• The document implies a two-part study: "identification (part 1) and validation (part 2) of the cut-off".
• No explicit sample size is given for "Part 1" (the identification phase) for establishing the sFlt-1/PlGF ratio cutoff. The 556 enrollments refer to "Part 2" (the validation phase). It states the interpretation of results "determined in part 1".
• The PRAECIS study description focuses on the validation cohort (Part 2).

8. How the Ground Truth for the Training Set Was Established:

• As mentioned above, the sample size for the training/identification set (Part 1) is not explicitly detailed. However, the cut-off was "identified" in Part 1 of the PRAECIS study. It's reasonable to infer that the ground truth for establishing the cut-off in Part 1 would have been established similarly to Part 2, i.e., through clinical outcome assessment (development of sPE) adjudicated by experts, but on a separate cohort of patients used for discovery/derivation. The document doesn't provide details on the specific characteristics of the Part 1 cohort or its ground truth establishment process beyond stating it was used to derive the cutoff.

Ask a specific question about this device