(149 days)
The DeltaScan Monitor provides the binary DeltaScan Output based on a technical index of polymorphic delta (PMD) waveshape detections made in the EEG from the bipolar Fp2 and Pz channel on adult patients (over 60 years of age) to aid in the diagnosis of acute encephalopathy.
DeltaScan should only be used by a healthcare provider as a component of a complete clinical evaluation or as support for the clinician's decision to pursue further testing. The device is NOT to be used as a stand-alone method in the evaluation or diagnosis of acute encephalopathy.
The intended patient is a hospitalized, awake adult, who is at risk of acute encephalopathy and delirium as decided by the responsible licensed healthcare physician or a medical professional working under the responsibility of a licensed healthcare physician.
The use environment is in hospitals:
· non-sterile environments;
· ICUs, wards, and other patient evaluation locations;
The DeltaScan Monitor is intended to be used in combination with the DeltaScan Patch (K222671) through a proprietary connector design.
The DeltaScan Monitor provides EEG signal acquisition and analysis technology intended for use as an adjunct to clinical judgment. The DeltaScan Monitor provides support in clinical decision-making by providing an assessment for a patient having acute encephalopathy or not, based on a measure of the detected polymorphic delta (PMD) waves in the EEG.
The DeltaScan Monitor consists of a Monitor and a Patch connector. The Patch connector contains the EEG amplifier hardware. The Monitor contains electronics for galvanic isolation to the EEG cable with Patch connector, storage of EEG recording and log files (eMMC memory chip), processing capacity to run software (DeltaScan Monitor Application, or DMA), user interface elements (e.g., screen, keys, recording button), battery (FEY PA-IEC-LNB162Q.R001), and the charging circuitry. EEG data is collected by the DeltaScan Monitor using a DeltaScan Patch. Collected EEG signals are amplified, digitized, and then processed by the software algorithms to provide the user with the DeltaScan Output. The DeltaScan Monitor Application is stand-alone software running on an Embedded Linux OS.
This document describes the acceptance criteria and the study that proves the device (DeltaScan Monitor R2) meets these criteria.
1. Table of Acceptance Criteria and Reported Device Performance
| Acceptance Criteria (Pre-specified Criteria) | Reported Device Performance (Study Result) | Pass/Fail | Discussion and Sensitivity Analysis | Rationale for Safety and Effectiveness |
|---|---|---|---|---|
| ICU | ||||
| Null hypothesis: NPV < 0.80 (lower bound of CI ≥ 0.8) | NPV = 0.85 CI = [0.77, 0.92] | Fail | The reasons why the end-point for NPV was missed is clear: 1) due to COVID-19 restriction, the number of patients on ICUs is less than aimed for, resulting in larger confidence intervals, and 2) the prevalence estimates were too low in the power calculation, resulting in too high pre-specified criteria. A sensitivity analysis that adjusts the prevalence to the study protocol estimate for prevalence (35%) shows that: NPV = 0.89 [0.85, 0.94]. Under these conditions, the end-points would have been met. | We conclude that reasons for the missed end-point on NPV are clear and understood. Overall, NPV values are reasonably high, while NPV+PPV values exceed the pre-specified criterium. Both NPV and PPV results are robust for some variation in study assumptions (sensitivity analysis). When considering both NPV and PPV, the performance shows safety and effectiveness. |
| NPV + PPV ≥ 1 | NPV + PPV = 1.62 CI = [1.50, 1.72] | Pass | ||
| Ward | ||||
| Null hypothesis: NPV < 0.85 (lower bound of CI ≥ 0.85) | NPV = 0.83 CI = [0.76, 0.89] | Fail | The reason why the end-point for NPV was missed is clear: the prevalence estimates were too low in the power calculation, resulting in too high pre-specified criteria. A sensitivity analysis that adjusts the prevalence to the study protocol estimate for prevalence (25%) shows that: NPV = 0.90 [0.87, 0.93]. Under these conditions, the end-points would have been met. | We conclude that reason for the missed end-point on NPV are clear and understood. Overall, NPV values are reasonably high, while NPV+PPV values exceed the pre-specified criterium. Both NPV and PPV results are robust for some variation in study assumptions (sensitivity analysis). When considering both NPV and PPV, the performance shows safety and effectiveness. |
| NPV + PPV ≥ 1 | NPV + PPV = 1.66 CI = [1.55, 1.75] | Pass | ||
| ICU + Ward (pooled) | ||||
| Null hypothesis: NPV < 0.80 (lower bound of CI ≥ 0.8) | NPV = 0.84 CI = [0.79, 0.88] | Fail | The reason why the end-point for NPV was missed is clear: the prevalence estimates were too low in the power calculation, resulting in too high pre-specified criteria. A sensitivity analysis that adjusts the prevalence to the study protocol estimate for prevalence on the ICU (35%) shows that: NPV = 0.87 [0.84, 0.90]. Under these conditions, the end-points would have been met. | We conclude that reason for the missed end-point on NPV are clear and understood. Overall, NPV values are reasonably high, while NPV+PPV values exceed the pre-specified criterium. Both NPV and PPV results are robust for some variation in study assumptions (sensitivity analysis). When considering both NPV and PPV, the performance shows safety and effectiveness. |
| NPV + PPV ≥ 1 | NPV + PPV = 1.63 CI = [1.55, 1.71] | Pass |
2. Sample Size Used for the Test Set and Data Provenance
- Sample Size for Test Set: 434 patients (195 on ICUs and 239 on wards) fulfilled inclusion, but not exclusion, criteria.
- Data Provenance:
- Country of Origin: The Netherlands (geographically distinct clinics: 6 ICUs and 15 wards).
- Retrospective or Prospective: Prospective. The study "DeltaStudy" was designed to evaluate diagnostic performance and repeatability, involving the collection of EEGs with DeltaScan and clinical data on ICUs and wards.
3. Number of Experts Used to Establish Ground Truth for the Test Set and Their Qualifications
- Acute Encephalopathy (EEG reference standard): 3 separate EEG experts. Qualifications are not explicitly detailed beyond being "EEG experts." They visually assessed 4-minutes of EEG data for the presence of polymorphic delta activity.
- Delirium (clinical reference standard): 3 clinical delirium experts. Qualifications are not explicitly detailed beyond being "clinical delirium experts." They assessed clinical data including researcher's interview based on DSM-5 criteria A-C, Electronic Health Record data, and description of patient behavior.
4. Adjudication Method for the Test Set
The ground truth for both acute encephalopathy and delirium was established using consensus (majority vote) among the experts.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
No MRMC study comparing human readers with and without AI assistance was reported. The study focused on the standalone diagnostic performance of the DeltaScan Monitor in comparison to expert consensus (ground truth).
6. Standalone (Algorithm Only) Performance
Yes, a standalone performance study was conducted. The "DeltaScan Output" (binary positive/negative for acute encephalopathy) was determined by the DeltaScan Monitor from EEG recordings, and these outputs were compared against the expert committee's estimated diagnoses for acute encephalopathy and delirium.
7. Type of Ground Truth Used
- Acute Encephalopathy: Expert consensus from 3 EEG experts visually assessing EEG data for polymorphic delta activity.
- Delirium: Expert consensus from 3 clinical delirium experts assessing clinical data and DSM-5 criteria.
8. Sample Size for the Training Set
The document mentions that the DeltaScan was calibrated based on a "previous clinical calibration dataset" from Numan et al., 2019, BJA. This dataset contained 321 EEG recordings. This is the sample size for the calibration dataset, which effectively serves as a training or development set for the algorithm's scoring and thresholding.
9. How the Ground Truth for the Training Set Was Established
For the calibration dataset (Numan et al., 2019, BJA), the ground truth for acute encephalopathy and delirium was established through expert labels. The document states that the calibration dataset contained "321 EEG recordings with expert labels for acute encephalopathy and delirium." This suggests a similar expert review process to the test set, where experts provided their diagnoses to create the ground truth.
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February 2, 2023
Image /page/0/Picture/1 description: The image shows the logo of the U.S. Food and Drug Administration (FDA). On the left is the Department of Health & Human Services logo. To the right of that is a blue square with the letters "FDA" in white. To the right of the blue square is the text "U.S. FOOD & DRUG ADMINISTRATION" in blue.
Prolira B.V. % Dr. Paul Manberg Corolla Clin/Reg Consulting 481 Spindrift Trail #696 Corolla, North Carolina 27927
Re: K222680
Trade/Device Name: DeltaScan Monitor R2 Regulation Number: 21 CFR 882.1440 Regulation Name: Neuropsychiatric Interpretive Electroencephalograph Assessment Aid Regulatory Class: Class II Product Code: NCG Dated: December 16, 2022 Received: January 3, 2023
Dear Paul Manberg:
We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database located at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.
If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.
Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part
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801); medical device reporting of medical device-related adverse events) (21 CFR 803) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-products); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4. Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.
For comprehensive regulatory information about mediation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).
Sincerelv.
Jay R. Gupta -S
Jay Gupta Assistant Director DHT5A: Division of Neurosurgical, Neurointerventional and Neurodiagnostic Devices OHT5: Office of Neurological and Physical Medicine Devices 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) K222680
Device Name DeltaScan Monitor R2
Indications for Use (Describe)
The DeltaScan Monitor provides the binary DeltaScan Output based on a technical index of polymorphic delta (PMD) waveshape detections made in the EEG from the bipolar Fp2 and Pz channel on adult patients (over 60 years of age) to aid in the diagnosis of acute encephalopathy.
DeltaScan should only be used by a healthcare provider as a component of a complete clinical evaluation or as support for the clinician's decision to pursue further testing. The device is NOT to be used as a stand-alone method in the evaluation or diagnosis of acute encephalopathy.
The intended patient is a hospitalized, awake adult, who is at risk of acute encephalopathy and delirium as decided by the responsible licensed healthcare physician or a medical professional working under the responsibility of a licensed healthcare physician.
The use environment is in hospitals:
· non-sterile environments;
· ICUs, wards, and other patient evaluation locations;
The DeltaScan Monitor is intended to be used in combination with the DeltaScan Patch (K222671) through a proprietary connector design.
Please refer to the Instructions for Use and the Instructions for Use on the Primary packaging of the DeltaScan Patch for more information.
| Type of Use (Select one or both, as applicable) | |
|---|---|
| Prescription Use (Part 21 CFR 801 Subpart D) | Over-The-Counter Use (21 CFR 801 Subpart C) |
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510(k) Summary
This summary of 510(k) safety and effectiveness information is being submitted in accordance with 21 CFR 807.92.
SUBMITTER l.
Prolira BV
Padualaan 8 Utrecht, The Netherlands NL-3584CH Phone Number: +31 6 47762936 Email: r.vanmerkerk@prolira.com
Contact Person: Rutger van Merkerk Date Prepared: February 2nd, 2023
II. DEVICE
Name of Device: DeltaScan Monitor Common or Usual Name: DeltaScan Monitor R2 Classification Name: Neuropsychiatric interpretive electroencephalograph assessment aid (21 CFR 882.1440) Regulatory Class: II Product Code: NCG
III. PREDICATE DEVICE
| Name | Manufacturer | De novo # |
|---|---|---|
| NEBA system | NEBA HEALTH, LLC | DEN110019 |
IV. DEVICE DESCRIPTION
Acute encephalopathy and delirium are extremely common in hospitalized patients, for example, one third of general medical patients aged 70 years or older has delirium (Marcantonio et al., 2017, NEJM). Acute encephalopathy and delirium are, by definition, the consequence of the same underlying medical condition (Slooter et al., 2020, Intensive Care Med). Acute encephalopathy can present as subsyndromal delirium, or delirium. Acute encephalopathy can be assessed with EEG (Palanca et al., 2017, BJA). Delirium is determined by clinical examination (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition). Acute encephalopathy and delirium occur in the same patient. Many patients with acute encephalopathy (i.e., EEG alterations) develop delirium (i.e., behavioral changes). Patients with acute encephalopathy and/or delirium should therefore also be seen as the same
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patient population. Clinically, there is a clear relation between the two, which is important to understand. The figure below presents the relationship between underlying conditions, acute encephalopathy, and delirium.
Image /page/4/Figure/3 description: The image shows a flow chart of medical conditions. The first box at the top says "Underlying condition" and has an arrow pointing down to a box that says "Acute Encephalopathy EEG change". There is an arrow pointing down to a box that says "Delirium Behavioral change". The arrows are labeled "Can cause" and "Can present as".
Figure 5-1: the relation between acute encephalopathy and delirium
In everyday care, standard 21-lead EEG as well as delirium expert assessments are not routinely feasible. Therefore, checklists were developed for routine screening. The diagnostic performance in routine care settings, however, is found to be low as these tests have subjective elements. Patient can be best cared for when acute encephalopathy is assessed with an objective tool that helps to detect acute encephalopathy as early as possible, followed by further clinical assessment.
Specific delta activity (PolyMorphic Delta activity; PMD) occurs in the EEG of patients with acute encephalopathy and delirium (i.e., PMD waves are a known characteristic of acute encephalopathy and delirium). PMD is considered a sensitive and specific biomarker for acute encephalopathy and delirium in awake adults (over 60 years of age) without dementia, neurological trauma, or other causes of PMD in the awake state.
The DeltaScan Monitor provides EEG signal acquisition and analysis technology intended for use as an adjunct to clinical judgment. The DeltaScan Monitor provides support in clinical decision-making by providing an assessment for a patient having acute encephalopathy or not, based on a measure of the detected polymorphic delta (PMD) waves in the EEG.
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The DeltaScan Monitor consists of (see Figure 5-2 below):
Image /page/5/Figure/3 description: The image shows a medical device and its components. The device includes a monitor, a patch connector, and a recording button, labeled as 1, 2, and 3 respectively. Additionally, a charger for the monitor is shown and labeled as 4.
Figure 5-2 DeltaScan Monitor components
The Patch connector contains the EEG amplifier hardware. The Monitor contains electronics for galvanic isolation to the EEG cable with Patch connector, storage of EEG recording and log files (eMMC memory chip), processing capacity to run software (DeltaScan Monitor Application, or DMA), user interface elements (e.g., screen, keys, recording button), battery (FEY PA-IEC-LNB162Q.R001), and the charging circuitry.
EEG data is collected by the DeltaScan Monitor using a DeltaScan Patch (see Figure 5-3). The DeltaScan Patch requires separate 510(k) clearance as a Class II device under Classification Name Cutaneous electrode (21 CFR 882.1320).
In designing the DeltaScan Patch, the International 10-20 System was used as a basis for electrode placement. Two recording electrodes are placed on the Fp2 and Pz locations, and the reference electrode is placed at the Fpz location. The electrodes are individually packaged and pregelled. The DeltaScan Monitor should only be used in combination with a DeltaScan Patch.
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Image /page/6/Figure/2 description: The image shows a diagram of a brain scanning device. The device consists of a headset with sensors that is connected to a control unit. The control unit has a display screen and buttons for operation. The headset is worn on the head and the sensors are positioned to measure brain activity.
Figure 5-3 Artist impression of the DeltaScan Monitor used with a DeltaScan Patch
Collected EEG signals are amplified, digitized, and then processed by the software algorithms to provide the user with the DeltaScan Output. The DeltaScan Monitor Application is stand-alone software running on an Embedded Linux OS.
To understand Prolira's technology, first the basic concept of EEG power spectrum analysis is explained. Kooi et al. (2015, Chest) explain that a relative delta measure presents the relative amount of energy that is present in the EEG spectrum between 0.5Hz and 4Hz, divided by the energy in the whole spectrum of interest that lies between 0.5Hz and 30Hz. Kooi et al. used EEG segments that are handpicked by the researcher and that are relatively free of artefacts to perform their analysis. But, as with any automatically derived parameter, artefacts and poor signal quality may lead to inappropriate results. For example, eye movements are commonly present in a typical EEG segment (even in eyes closed EEG data). Furthermore, eye movements can present as waveshapes in the same frequency range as the waveshapes that are characteristic of acute encephalopathy and delirium (i.e., energy in the delta frequency band). Therefore, a general relative delta measure will also count the energy of eye movements when automated algorithms provide the result in a clinical setting.
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To deal with this situation, Prolira's technology specifically detects EEG waveshapes that are characteristic for acute encephalopathy and delirium, allowing to calculate a specific (rather than general) measure based on the amount of detected PMD waves in the EEG. In this, Prolira uses several artifact detection and segregation approaches:
-
- State-of-the-art signal conditioning and signal quality quantification technology are applied to minimize the disturbance of artefacts, removing as many artefacts as possible, for example due to poor skin contact (high impedance), muscle activity or rigidity, head and body motion, improper sensor placement, and unusual or excessive electrical interference.
-
- Specific EEG waveshapes in the delta frequency range (polymorphic delta waves; PMD) are detected. Using advanced waveshape recognition technology, the chance of detecting the target waveshapes is increased, and the chance to include artefacts in the resulting measure is reduced. In addition, the algorithm also specifically detects eye artifact, which allows for additional scrutiny of detected PMD waves in the case that eye artifact and PMD waves are situated close together (see Figure 5-4 for an example of PMD wave and eye artifact detections in the EEG).
Image /page/7/Figure/5 description: The image shows a graph of voltage over time. The x-axis represents time in seconds, ranging from 82 to 92. The y-axis represents voltage in microvolts, ranging from -100 to 100. There are two lines plotted on the graph, one in blue and one in red, showing the voltage fluctuations over time.
Figure 5-4: examples of a polymorphic delta (PMD) wave detection (red line) and eye artifact detections (turquoise line)
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The detected and analyzed PMD waveshapes in the EEG are then translated into the 5-point DeltaScan Score, which is the DeltaScan's calibrated technical index.
The DeltaScan Output is NEGATIVE for acute encephalopathy for DeltaScan Score 1 or 2. The DeltaScan Output is POSITIVE for acute encephalopathy for DeltaScan Score 3, 4 or 5. See below in the section Clinical Studies for details on the clinical validation thereof.
Table 5-1 below indicates the clinical meaning of the DeltaScan Output and the technical meaning of the 5-point DeltaScan Score.
| DeltaScan result | Clinical meaning ofDeltaScan Output | Technical meaning ofDeltaScan Score |
|---|---|---|
| NEGATIVE1 2 3 4 5 | NEGATIVE test for acuteencephalopathy | For Score 1 and 2,PMD waveshapes arenot or hardly detected inthe EEG |
| NEGATIVE1 2 3 4 5 | ||
| POSITIVE1 2 3 4 5 | POSITIVE test for acuteencephalopathy | For Score 3, 4 and 5,the amount ofdetected PMDwaveshapes in theEEG increases |
| POSITIVE1 2 3 4 5 | ||
| POSITIVE1 2 3 4 5 |
Table 5-1 Technical and clinical meaning of a DeltaScan result
The technical 5-point scale and clinical threshold for acute encephalopathy are calibrated based on a previous clinical calibration dataset (the dataset is presented in Numan et al., 2019, BJA) containing of 321 EEG recordings with expert labels for acute encephalopathy and delirium. The following calibration steps were performed:
- . For each recording in the calibration dataset, the number of PMD detections and the PMD power (detected PMD waveshapes / unit time) was calculated.
- . The clinical threshold for acute encephalopathy, NEGATIVE (score 1-2) and POSITIVE (score 3-5), is determined on the calibration dataset by finding an optimum for sensitivity, specificity and NPV using the expert labels for acute encephalopathy and delirium.
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- The cut-offs between score 3 and 4, and score 4 and 5, were chosen to maximize repeatability of the score points. The number of patients from the calibration dataset with a POSITIVE result are equally divided over the score bins 3, 4, and 5. This sets the boundaries in terms of the PMD power.
- . The cut-off between score 1 and 2 is determined by the number of detections; none or one detection always leads to DeltaScan Score 1, two detections always lead to DeltaScan Score 2, regardless of the power in those detections.
Note: the measure based on the detected PMD waveshapes underlying the 5-point scale is nonlinear.
V. INDICATIONS FOR USE
The DeltaScan Monitor provides the binary DeltaScan Output based on a technical index of polymorphic delta (PMD) waveshape detections made in the EEG from the bipolar Fp2 and Pz channel on adult patients (over 60 years of age) to aid in the diagnosis of acute encephalopathy.
DeltaScan should only be used by a healthcare provider as a component of a complete clinical evaluation or as support for the clinician's decision to pursue further testing. The device is NOT to be used as a stand-alone method in the evaluation or diagnosis of acute encephalopathy.
The intended patient is a hospitalized, awake adult (over 60 years of age), who is at risk of acute encephalopathy and/or delirium as decided by the responsible licensed healthcare physician or a medical professional working under the responsibility of a licensed healthcare physician.
The use environment is in hospitals:
- · in non-sterile environments;
- · in departments like ICUs, wards, and other patient evaluation locations;
The DeltaScan Monitor is intended to be used in combination with the DeltaScan Patch (K222671) through a proprietary connector design.
Please refer to the Instructions for Use and the Instructions for Use on the Primary packaging of the DeltaScan Patch for more information.
VI. COMPARISON OF TECHNOLOGICAL CHARACTERISTICS WITH THE PREDICATE DEVICE
The DeltaScan Monitor is an EEG acquisition device with an integrated computer module that runs the DeltaScan Monitor Application (DMA) to provide the User Interface and runs automated processing modules to determine the DeltaScan Output on an EEG recording. Although standard EEG devices could also be used by a trained physician to detect elevated slow wave activity (high relative delta measure), the DeltaScan Monitor has been designed to provide a more practical, consistent, and easy to interpret measure of elevated low frequency waveforms associated with acute encephalopathy. In recognition of this more focused clinical application, a standard EEG device may not be the most appropriate predicate device for a 510(k) regulatory pathway.
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Instead, the NEUROPSYCHIATRIC EEG-BASED ASSESSMENT AID FOR ADHD (NEBA) SYSTEM with De Novo # DEN110019 is suggested as the most appropriate predicate device.
A technology comparison between the DeltaScan Monitor and the NEBA System is provided in Table 5-2 below.
| NEBA System | DeltaScan Monitor |
|---|---|
| Intended Use | Intended Use |
| Neuropsychiatric Interpretive | Neuropsychiatric Interpretive |
| Electroencephalograph Assessment Aid. | Electroencephalograph Assessment Aid. |
| The Neuropsychiatric Interpretive | The Neuropsychiatric Interpretive |
| Electroencephalograph Assessment Aid is a | Electroencephalograph Assessment Aid is a |
| prescription device that uses a patient's | prescription device that uses a patient's |
| electroencephalograph (EEG) to provide an | electroencephalograph (EEG) to provide an |
| interpretation of the patient's neuropsychiatric | interpretation of the patient's neuropsychiatric |
| condition. | condition. |
| The Neuropsychiatric Interpretive EEG | The Neuropsychiatric Interpretive EEG Assessment |
| Assessment Aid is used only as an assessment aid | Aid is used only as an assessment aid for a medical |
| for a medical condition for which there exists | condition for which there exists other valid |
| other valid methods of diagnosis. | methods of diagnosis. |
| Indications for Use | Indications for Use |
Table 5-2 Technology comparison
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| NEBA System | DeltaScan Monitor |
|---|---|
| The Neuropsychiatric EEG-Based ADHD | The DeltaScan Monitor provides the binary |
| Assessment Aid (NEBA®) uses the theta/beta | DeltaScan Output based on a technical index of |
| ratio of the EEG measured at electrode CZ on a | polymorphic delta (PMD) waveshape detections |
| patient 6-17 years of age combined with a | made in the EEG from the bipolar Fp2 and Pz |
| clinician's evaluation to aid in the diagnosis of | channel on adult patients (over 60 years of age) to |
| ADHD. | aid clinicians in the diagnosis of acute |
| NEBA should only be used by a clinician as | encephalopathy. |
| confirmatory support for a completed clinical | DeltaScan should only be used by a clinician as a |
| evaluation or as support for the clinician's | component of a complete clinical evaluation or as |
| decision to pursue further testing following a | support for the clinician's decision to pursue |
| clinical evaluation. The device is NOT to be used | further testing. The device is NOT to be used as a |
| as a stand-alone in the evaluation or diagnosis of | stand-alone method in the evaluation or diagnosis |
| ADHD. | of acute encephalopathy. |
| The intended patient is a hospitalized, awake adult | |
| (over 60 years of age), who is at risk of acute | |
| encephalopathy and/ or delirium as decided by the | |
| responsible licensed healthcare physician or a | |
| medical professional working under the | |
| responsibility of a licensed healthcare physician. | |
| The use environment is in hospitals: | |
| • in non-sterile environments; | |
| • in departments like ICUs, wards, and other | |
| patient evaluation locations; | |
| The DeltaScan Monitor is intended to be used in | |
| combination with the DeltaScan Patch (K222671) | |
| through a proprietary connector design. | |
| Please refer to the Instructions for Use and the | |
| Instructions for Use on the Primary packaging of | |
| the DeltaScan Patch for more information | |
| NEBA System | DeltaScan Monitor |
| LIMITATIONS | LIMITATIONS |
| For prescription use only. | For prescription use only. |
| The NEBA cannot be used in an individual for whom anEEG recording is not valid, specifically a patient with:a history of EEG abnormalities; a history of a seizure disorder; on anticonvulsant medication(s); a metal plate in the head; or a metal device in the head. | The DeltaScan Monitor cannot be used in an individualfor whom an EEG recording is not valid, specifically apatient:on sedation (RASS -4 or -5); persons under 60 years of age; with a history of brain injury; using Lithium/Clozapine; with a metal or plastic implant in the upperhemisphere of the head; with an active medical device in the head |
| The NEBA system cannot be used in subjects who areunable to remain still for a minimum of 30 seconds forEEG recording. | The DeltaScan system cannot be used in subjects whoare unable to follow three measurement instructions;the patient should (1) be awake, (2) be relaxed, and (3)keep the eyes closed. |
| For patients on sedatives with a RASS -3, with dementia(MMSE $\le$ 24), and with (acute) brain injury, the DeltaScanOutput can be higher than expected. For more severeand/or acute cases (i.e., of sedation, dementia and braininjury), it becomes less likely that a POSTIVE DeltaScanOutput relates to an acute encephalopathic brain state.The meaning of NEGATIVE DeltaScan Output for thesepatients is most likely not altered. The DeltaScan Outputfor these patients should be interpreted accordingly. | |
| The NEBA system should only be used by medicalprofessionals qualified to assess psychiatric disordersand experienced in diagnosing ADHD. To ensureproper device performance, the user must firstperform a diagnostic evaluation per the standard oftheir practice. NEBA interpretations are based on theclinician's initial diagnostic evaluation, the subject'sage and the EEG results. | The DeltaScan Monitor should only be used by licensedhealthcare physicians or medical professionals qualifiedto assess inpatient disorders and who are experiencedin diagnosing acute encephalopathy and/ or delirium, orby other medical professionals working under theresponsibility of a licensed healthcare physician. Toensure proper device performance, the user mustperform a diagnostic evaluation per the standard oftheir practice. DeltaScan interpretations are based onthe clinician's initial diagnostic evaluation, the subject'sresponse to questioning and the EEG results. |
| The device should not be used as a stand-alonediagnostic device. | The device should not be used as a stand-alonediagnostic device. |
| PLEASE REFER TO THE LABELING FOR A MORECOMPLETE LIST OF WARNINGS, PRECAUTIONS ANDCONTRAINDICATIONS. | PLEASE REFER TO THE LABELING FOR A MORECOMPLETE LIST OF WARNINGS, PRECAUTIONS ANDCONTRAINDICATIONS. |
| Primary EEG Feature/Electrode position | |
| Theta/Beta Ratio | A binary DeltaScan Output based on a technicalindex of polymorphic delta (PMD) waveshape |
| NEBA System | DeltaScan Monitor |
| detections made in the EEG | |
| CZ | Fp2 and Pz |
| Software | |
| Software for the device consisted of bothproprietary software and off-the- shelf (OTS)software. | DeltaScan Monitor Application developedaccording to "EN 62304:2006+A1:2015 Medicaldevice software - Software life-cycle processes". |
| Software class according toEN62304:2006+A1:2015: Class B. | |
| The software was reviewed and the provideddocumentation was found adequate andconsistent with a 'MODERATE' level of concern.,as discussed in the FDA document, "Guidance forthe Content of Premarket Submissions forSoftware Contained in Medical Devices," issuedMay 11, 2005. | The software was reviewed and the provideddocumentation was found adequate andconsistent with a 'MODERATE' level of concern., asdiscussed in the FDA document, "Guidance for theContent of Premarket Submissions for SoftwareContained in Medical Devices," issued May 11,2005. |
| Device output | |
| Three categoriesLOW TBR = Strongly Recommend Further ClinicalTesting (other conditions)MODERATE TBR = Suggest Further Clinical Testing(other conditions)HIGH TBR = Confirmatory Support for ADHD asprimary diagnosis | Two categories based on a threshold of theamount of PMD waveshapes detected in the EEG:- NEGATIVE for acute encephalopathy- POSITIVE for acute encephalopathy |
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VII. PERFORMANCE DATA
The following performance data were provided in support of the substantial equivalence determination.
Biocompatibility testing
The biocompatibility evaluation for the DeltaScan Monitor was assessed in accordance with the FDA's guidance document titled, "Use of International Standard ISO 10993-1, 'Biological Evaluation of Medical Devices Part 1: Evaluation and testing within a risk management process", June 16, 2016.
The DeltaScan Monitor, its EEG cable, the Recording button, and the medical-grade Power adapter have transient contact with the patient's and/ or user intact skin (i.e., finger contact while setting up and using the device).
If there is contact between the patient and a part of the DeltaScan Monitor at all, this would be with the Patch connector, see Figure 5-2 above.
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None of the components are "attached" to skin, all contact is handling contact. The material of DeltaScan Monitor is generally used in combination with intact skin of the user, and the materials used are identical as in widespread use applications.
Based on the above, there is no biocompatibility testing needed for the DeltaScan Monitor.
Electrical safety and electromagnetic compatibility (EMC)
Electrical safety and EMC testing were conducted on the DeltaScan Monitor. The DeltaScan Monitor complies with the IEC 60601-1:2005+A1:2012 standard for safety and the IEC 60601-1-2:2014 standard for EMC.
Software verification and validation testing
Software verification and validation testing were conducted, and documentation was provided as recommended by FDA's Guidance for Industry and FDA Staff, "Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices" and "Content of Premarket Submissions for Management of Cybersecurity in Medical Devices". The software for this device was considered a "moderate" level of concern, since a failure or latent flaw in the software could lead to a delay in delivery of appropriate medical care that could lead to minor injury.
Performance bench testing
Thorough bench testing is provided in the file which are considered adequate. This included, but is not limited to:
- Usability testing demonstrated compliance to EN 62366-1:2015+A1:2020
- . The labeling was tested to be legible, durable, compliant with regulations, and compatible with the packaging.
- . The packaging was tested to verify it is compatible with the labeling and can be shipped without damage.
- Mechanical Strength testing demonstrated compliance to IEC 60601-1:2005+A1:2012 (cl.15.3).
- Bench testing showed >95% reliability for the technical 5-point DeltaScan Score for increasing amounts of polymorphic delta activity (PMD) present in sample EEGs.
These verification and validation activities all show that the device complies to the preset requirements.
Clinical Studies
Diagnostic Performance testing of DeltaScan was done in the multi-center DeltaStudy, which ran between Q1 2018 and Q3-2021.
The study has been designed to comply with ISO 14155:2011 Clinical investigation of medical devices for human subjects - Good clinical practice, and in the European Medical Device Regulation (MDR)
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2017/745 Annex XV Chapter II, and to comply with the United States Food and Drug Administration's special control 21 CFR 882.1440.
In respect to 21 CFR 812.28(a)(1) Good Clinical Practice. Although the rule does not identify a specific GCP standard, by following ISO 14155:2011 in the conduct of clinical investigations the requirement in § 812.28(a)(1) of this rule (as well as the local laws and regulations of the countries where the investigations are conducted) are met.
SUMMARY OF CLINICAL TESTS
DeltaScan was developed based on clinical datasets described in 1) Kooi et al. (2015, Chest) and 2) Numan et al. (2019, BJA; clinicaltrials.gov # NCT02404181).
Registration study: clinical study design
The objective of the study presented here, called DeltaStudy (clinicaltrials.gov # NCT03966274), was to evaluate the diagnostic performance of the DeltaScan Monitor according to the Indications for Use and to evaluate repeatability.
The clinical investigation included the collection of EEGs with DeltaScan and clinical data on ICUs and wards. An EEG expert panel reviewed the DeltaScan EEGs and a clinical expert panel reviewed the clinical data to determine consensus (majority vote) for acute encephalopathy and delirium, respectively.
For acute encephalopathy, the reference standard was defined by the assessment by 3 separate EEG experts of 4-minutes of EEG data recorded with DeltaScan. The EEG data was visually assessed by the EEG experts, for the presence of polymorphic delta activity to determine acute encephalopathy.
For delirium, the reference standard was defined by the assessment of clinical data by 3 clinical delirium experts separately. Clinical data included a researcher's interview based on DSM-5 criteria A-C through an extensive test battery, Electronic Health Record data, and description of the behavior of the patient. Clinical data were assessed on individual DSM-5 criteria, the presence of delirium, and the probability of delirium.
All EEG and clinical assessments were blinded to DeltaScan Output, prospectively planned, and performed as reviews of anonymized patient data. As the estimated diagnosis of acute encephalopathy and delirium we used the majority vote of 3 EEG experts, and 3 clinical delirium experts, respectively.
Subjects were adults on the ICU (avg. age 64 years; std = 13) and elderly on wards (avg. age 80 years; std = 7) in geographically distinct clinics (6 ICUs and 15 wards) in the Netherlands. It shall be noted that some Study Data in the ICU population does contain patients in the 18-60 range; however, the majority of the study population was 60, or above.
In total, 606 patients were enrolled in the study of whom 434 patients (195 on ICUs and 239 on wards) fulfilled inclusion, but not exclusion, criteria. Due to COVID-19 restriction, the number of patients on ICUs is less than aimed for and that resulted in larger confidence bounds than anticipated.
A DeltaScan Output for each subject was determined from the DeltaScan EEG recording in the locked databases (ICUs and wards). To evaluate performance, the DeltaScan Outputs were compared with the estimated diagnosis of the two expert panels (references for acute encephalopathy and delirium).
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Results: diagnostic performance of DeltaScan
The diagnosis of acute encephalopathy (EEG reference standard) was based upon the best estimate diagnosis results by consensus of the expert panel and was blinded to the DeltaScan Output.
Table 5-3 tabulates the primary objectives and the results. We see that the pre-specified values for the lower bound of the Cl for the ICU (≥0.8) and on wards (≥0.85) are just missed The main reason is that the found prevalence of AE on the ICU was 44% (vs. the expected 35% in the study protocol) and on the ward was 39% (vs. the expected 25% in the study protocol), which resulted in lower values for the lower bound of the CI for NPV than anticipated.
A sensitivity analysis that adjusts the prevalence to the expected prevalence showed that under these conditions, the end-points would have been met (see Table 5-3 for details). When pooling the ICU and ward patients, we see the same result when adjusting the prevalence to the expected prevalence for the ICU.
So, the main reason why the end-point for NPV was missed is clear: the prevalence estimates were too low in the power calculation, resulting in too high pre-specified criteria.
Specifically for the ICU, the included number of patients (n) was less than aimed for due to COVID-19 restriction, resulting in larger confidence intervals.
Table 5-3 Results on primary hypothesis on acute encephalopathy (EEG labels) for adults on the ICU and elderly patients on wards. We are also showing the results when pooling the ICU and ward patients.
| Department | Pre-specifiedcriteria | Study result | Pass/Failon pre-specifiedcriteria | Discussion and Sensitivityanalysis | Rationale for safety andeffectiveness |
|---|---|---|---|---|---|
| ICU | Nullhypothesis:NPV < 0.80(lower boundof CI ≥ 0.8) | NPV = 0.85CI = [0.77,0.92] | Fail | The reasons why the end-point for NPV was missed isclear: 1) due to COVID-19restriction, the number ofpatients on ICUs is less thanaimed for, resulting in largerconfidence intervals, and 2)the prevalence estimates weretoo low in the powercalculation, resulting in toohigh pre-specified criteria. | We conclude that reasons forthe missed end-point on NPVare clear and understood.Overall, NPV values arereasonably high, whileNPV+PPV values exceed thepre-specified criterium. |
| NPV + PPV ≥ 1 | NPV + PPV =1.62CI = [1.50,1.72] | Pass | Both NPV and PPV results arerobust for some variation instudy assumptions (sensitivityanalysis). | ||
| A sensitivity analysis thatadjusts the prevalence to thestudy protocol estimate forprevalence (35%) shows that:NPV = 0.89 [0.85, 0.94]PPV = 0.69 [0.61, 0.77]NPV+PPV = 1.59 [1.47, 1.70]Under these conditions, theend-points would have beenmet. | When considering both NPVand PPV, the performanceshows safety andeffectiveness | ||||
| Ward | Nullhypothesis:NPV < 0.85(lower boundof CI ≥ 0.85)NPV + PPV ≥ 1 | NPV = 0.83CI = [0.76,0.89]NPV + PPV =1.66CI = [1.55,1.75] | FailPass | The reason why the end-pointfor NPV was missed is clear:the prevalence estimates weretoo low in the powercalculation, resulting in toohigh pre-specified criteria.A sensitivity analysis thatadjusts the prevalence to thestudy protocol estimate forprevalence (25%) shows that:NPV = 0.90 [0.87, 0.93]PPV = 0.71 [0.62, 0.82]NPV+PPV = 1.62 [1.50, 1.74]Under these conditions, theend-points would have beenmet. | We conclude that reason forthe missed end-point on NPVare clear and understood.Overall, NPV values arereasonably high, whileNPV+PPV values exceed thepre-specified criterium.Both NPV and PPV results arerobust for some variation instudy assumptions (sensitivityanalysis).When considering both NPVand PPV, the performanceshows safety andeffectiveness |
| ICU +Ward(pooled) | Nullhypothesis:NPV < 0.80(lower boundof CI ≥ 0.8)NPV + PPV ≥ 1 | NPV = 0.84CI = [0.79,0.88]NPV + PPV =1.63CI = [1.55,1.71] | FailPass | The reason why the end-pointfor NPV was missed is clear:the prevalence estimates weretoo low in the powercalculation, resulting in toohigh pre-specified criteria.A sensitivity analysis thatadjusts the prevalence to thestudy protocol estimate forprevalence on the ICU (35%)shows that:NPV = 0.87 [0.84, 0.90]PPV = 0.75 [0.69, 0.81]NPV+PPV = 1.62 [1.53, 1.70]Under these conditions, theend-points would have beenmet. | We conclude that reason forthe missed end-point on NPVare clear and understood.Overall, NPV values arereasonably high, whileNPV+PPV values exceed thepre-specified criterium.Both NPV and PPV results arerobust for some variation instudy assumptions (sensitivityanalysis).When considering both NPVand PPV, the performanceshows safety andeffectiveness |
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Suggested clinical interpretation
The clinician will typically have a DeltaScan Output and his/her clinician's evaluation for clinical signs (behavioral changes) that could indicate delirium. Table 5-4 indicates how the additional information from the DeltaScan Monitor can be used with other existing clinical information.
Table 5-4 Suggested clinical interpretation for combined clinician's evaluation and DeltaScan Output
| DeltaScan Output: NEGATIVE (green) | DeltaScan Output: POSITIVE (red) | |
|---|---|---|
| Clinicianpositive fordelirium signs | Negative result for acute encephalopathy,but with clinical signs of delirium | DeltaScan confirms clinician's evaluation |
| Further evaluate other causes of theobserved clinical behavior to determinethe correct diagnosis | ||
| Cliniciannegative fordelirium signs | DeltaScan confirms clinician's evaluation | Positive result for acute encephalopathywithout clinical signs of deliriumFurther evaluate causes for the presenceof PMD in the EEG to determine thecorrect diagnosis |
Table 5-4 indicates that, especially when there is a difference in the clinician's evaluation and the DeltaScan Output, the combination aids the clinician in finding the correct diagnosis. Either by considering an alternative for the positive delirium signs (e.g., psychosis or hallucinations without delirium), or by providing evaluation that explains the presence of PMD waves in the EEG (e.g., a bladder infection, or acute kidney failure).
Repeatability of DeltaScan results
The repeatability (test-retest reliability) of the DeltaScan Score was estimated from a set of DeltaScan EEG recordings in which each patient or volunteer was recorded 3 times within 30 minutes. There were 9 patients (same inclusion criteria as the main DeltaStudy as presented above) and 30 volunteers included in this analysis. The intraclass correlation coefficient (ICC) of repeated DeltaScan Scores includes the 1-5 scale. The calculated ICC is 0.799 and p = 0.0000, which satisfies the pre-specified criteria of ICC > 0.75 and p < 0.05. The calculated ICC for the binary DeltaScan Output: ICC is 0.829, p = 0.0000.
Conclusions on clinical study results
- . Acute encephalopathy
- O Diagnostic performance in acute encephalopathy assessment is good, almost meeting the pre-specified criterium for NPV. the NPV end-point is just missed due to a higher than anticipated prevalence, both on the ICU and on wards. Under the condition where the prevalence is adjusted to the expected values, the pre-specified criteria are met. The results for NPV+PPV for both the ICU and the ward exceed the
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pre-specified criterium.
- On the 67% subgroup of patients who had congruent results using the reference O EEG and Clinical assessments, the found NPV was especially high at 0.94.
- Repeatability
- O Repeatability testing for the 5 point DeltaScan Scale satisfied the pre-specified criteria (ICC ≥ 0.75) and resulted in an ICC of 0.799. The ICC for the binary DeltaScan Output is higher at 0.829.
- Generalizability
- O The patients in this study are a good representation of the intended use population. From site to site, department to department, and between US and OUS, the prevalence of the condition can vary. Our sensitivity analysis on prevalence shows that performance remains strong regardless.
- Safety ●
- O Safety of the DeltaScan Monitor has been established. Physical use of the device has been shown to be safe. EEG collection is a safe, non-invasive procedure. No adverse device events and no unanticipated adverse device events were reported in the clinical investigation.
- Suggested clinical interpretation
- o It is suggested that differences in a clinician's evaluation and a DeltaScan Output can lead to further evaluation to determine the correct diagnosis.
These results present convincing evidence to justify the Indications for Use of the DeltaScan Monitor.
The clinical data demonstrate that the DeltaScan Monitor performs as intended, is safe and effective for its intended use, and provides similar safety and effectiveness results to the predicate device.
VIII. CONCLUSION
The DeltaScan Monitor has the same Intended Use and similar Indication for Use and substantially equivalent technological characteristics as the identified predicate device.
Both the DeltaScan Monitor and predicate devices are EEG based applications as support for the clinician's decision.
Based on the Intended Use, technological characteristics, and performance data provided in this premarket notification, the subject device has been shown to be substantially equivalent to the currently marketed predicate device.
§ 882.1440 Neuropsychiatric interpretive electroencephalograph assessment aid.
(a)
Identification. The neuropsychiatric interpretive electroencephalograph assessment aid is a prescription device that uses a patient's electroencephalograph (EEG) to provide an interpretation of the patient's neuropsychiatric condition. The neuropsychiatric interpretive EEG assessment aid is used only as an assessment aid for a medical condition for which there exists other valid methods of diagnosis.(b)
Classification. Class II (special controls). The special controls for this device are:(1) The technical parameters of the device, hardware and software, must be fully characterized and must demonstrate a reasonable assurance of safety and effectiveness.
(i) Hardware specifications must be provided. Appropriate verification, validation, and hazard analysis must be performed.
(ii) Software, including any proprietary algorithm(s) used by the device to arrive at its interpretation of the patient's condition, must be described in detail in the software requirements specification and software design specification. Appropriate software verification, validation, and hazard analysis must be performed.
(2) The device parts that contact the patient must be demonstrated to be biocompatible.
(3) The device must be designed and tested for electrical safety, electromagnetic compatibility, thermal, and mechanical safety.
(4) Clinical performance testing must demonstrate the accuracy, precision, reproducibility, of determining the EEG-based interpretation, including any specified equivocal zones (cutoffs).
(5) Clinical performance testing must demonstrate the ability of the device to function as an assessment aid for the medical condition for which the device is indicated. Performance measures must demonstrate device performance characteristics per the intended use in the intended use environment. Performance measurements must include sensitivity, specificity, positive predictive value, and negative predictive value per the device intended use. Repeatability of measurements must be demonstrated using interclass correlation coefficients and illustrated by qualitative scatter plot(s).
(6) The device design must include safeguards to prevent use of the device as a stand-alone diagnostic.
(7) The labeling must include the following information:
(i) A warning that the device is not to be used as a stand-alone diagnostic.
(ii) A detailed summary of the clinical performance testing, including any adverse events and complications.
(iii) The qualifications and training requirements for device users including technicians and clinicians.
(iv) The intended use population and the intended use environment.
(v) Any instructions technicians should convey to patients regarding the collection of EEG data.
(vi) Information allowing clinicians to gauge clinical risk associated with integrating the EEG interpretive assessment aid into their diagnostic pathway.
(vii) Where appropriate, validated methods and instructions for reprocessing of any reusable components.