(623 days)
The PMD-200 with the Nociception Level (NOL) Index is indicated for use in a clinical setting that requires assessment of changes in nociception levels in adult patients under general anesthesia receiving opioid or opioid-sparing analgesia as part of their care.
The PMD-200 should be used as an adjunct to clinical judgment. Clinical judgment should always be used when interpreting the NOL index in conjunction with other available clinical and vital signs.
The PMD-200 (device) is a nociception monitoring system which assists assessment of anaesthetized patient's physiological response to noxious stimuli and helps tailor analgesic administration to the patient's actual response to painful stimuli. The device provides quantification of the patient's response to noxious stimuli with the nociception level index (NOL).
The PMD-200 system consists of 4 main components:
- Monitor acquisition and display of physiological raw data signals and NOL . index and trend graph.
- . Software includes two main components:
- Calculation of the NOL index based on physiological parameters extracted from raw data signals.
- O User interface displays physiological raw data signals, NOL index and trend graph.
- Finger probe -includes the following sensors: .
- Photoplethysmogram (PPG or Pleth) o
- · Thermistor for peripheral temperature (TMP)
- · A 3-axis accelerometer for movement (ACC or Movement).
- Connectors for the Galvanic skin response sensor (GSR or Conductance)
- Single use sensor (connected to the finger probe) includes the following sensor: . o Bio-impedance Galvanic skin response sensor (GSR or Conductance)
The NOL index is a relative, non-linear measure with a range of 0-100, where 0 represents no pain /nociceptive response and 100 represents extreme pain/nociceptive response. The NOL index and trend are intended to support clinical decisions concerning the administration of analgesic medications.
Here's a breakdown of the acceptance criteria and study information for the Medasense Biometrics Ltd. PMD-200, based on the provided text:
PMD-200 Acceptance Criteria and Performance Studies
1. Table of Acceptance Criteria and Reported Device Performance
The acceptance criteria for the algorithm's performance are primarily detailed in the "Algorithm Verification" and "Algorithm Validation" sections. The device met all specified acceptance criteria.
Algorithm Verification Results (Table 1 from text):
| Test description | Test metrics | Acceptance criteria | Results |
|---|---|---|---|
| Algorithm overall predictability | Estimated vs reference CISA: mean +/- 95% CI | 95% CI < 1.0 CISA unit | Pass |
| NOL algorithm decision accuracy (binary testing) | Youden Index for NOL threshold of 25 | 25 +/- 3 NOL units | Pass |
| AUC | 0.85 (0.8 for low 95% CI) | Pass | |
| Specificity | 0.85 (0.75 for low 95% CI) | Pass | |
| Sensitivity | 0.85 (0.75 for low 95% CI) | Pass | |
| Accuracy | > 0.85 | Pass | |
| Characterization of NOL values at times of no noxious stimulus | Mean NOL value during periods where no nociception is reported | 97.7% of NOL samples should be below 25 | Pass |
Algorithm Validation Phase I Results (Table 2 from text):
| Test description | Test metrics | Acceptance criteria | Result |
|---|---|---|---|
| Algorithm overall predictability | Estimated vs reference CISA: mean +/- 95% CI | 95% CI < 1.0 CISA unit | Pass |
| NOL ability to correctly grade various nociceptive intensities | mean {NOL(POI)} (-/+ 95% CI) by stimulus groups: TP1: intubation, TP2: incision/trocar, TNP: non-nociceptive stimulus or no stimulus | mean {NOL(TP1)} > mean {NOL(TP2)} > mean {NOL(TNP)} (Wilcoxon signed-rank test applied) | Pass |
| NOL algorithm decision accuracy (binary testing) | Youden Index for NOL threshold of 25 | 25 +/- 3 NOL units | Pass |
| AUC | 0.85 (0.8 for low 95% CI) | Pass | |
| Specificity | 0.85 (0.75 for low 95% CI) | Pass | |
| Sensitivity | 0.85 (0.75 for low 95% CI) | Pass | |
| Accuracy | > 0.85 | Pass | |
| Clinical relevance score | > 0.8 | Pass | |
| Characterization of NOL values at times of no noxious stimulus | Mean NOL value during periods where no nociception is reported | 97.7% of NOL samples should be below 25 | Pass |
Algorithm Validation Phase II (Sub-group Analysis) (Table 3 from text):
All subgroups (Female, Male, Age < 65, Age > 65, BMI 18-25, BMI 25-30, BMI > 30, Remifentanil, Fentanyl, Desflurane, Sevoflurane, Propofol, ASA I, ASA II, ASA III) passed all 7 tests.
2. Sample Size Used for the Test Set and Data Provenance
The document describes three main types of studies for evaluating the PMD-200.
- Algorithm Verification: A multinational, multi-center dataset was used. The specific number of patients or data points for this dataset is not explicitly stated, but it covered a wide range of patient demographics and anesthetic drugs.
- Algorithm Validation: A separate multinational, multi-center dataset was used, distinct from the verification and training datasets.
- Phase I Validation: The exact number of patients or data points for Phase I validation is not explicitly stated for all tests; however, the sub-group analysis (Phase II) indicates that each sub-group contained at least 40 patients.
- Phase II Validation (Sub-group Analysis): The dataset used for Phase II combined both the verification and validation datasets.
- Female: 75 patients (retrospective study mentions 483 data points)
- Male: 75 patients (retrospective study mentions 219 data points)
- Age < 65: 81 patients (retrospective study mentions 476 data points)
- Age > 65: 48 patients (retrospective study mentions 217 data points)
- BMI 18-25: 39 patients
- BMI 25-30: 45 patients
- BMI > 30: 45 patients
- Remifentanil: 55 patients (retrospective study mentions 265 data points)
- Fentanyl: 67 patients (retrospective study mentions 395 data points)
- Desflurane: 155 data points (from retrospective study)
- Sevoflurane: 354 data points (from retrospective study)
- Propofol: 173 data points (from retrospective study)
- ASA I: 112 data points (from retrospective study)
- ASA II: 418 data points (from retrospective study)
- ASA III: 91 data points (from retrospective study)
- NOL Retrospective Clinical Validation Study: This study used a database comprising 500 adult patients with 702 data points total across all subgroups (summing N data points in the table), collected retrospectively between January 2015 to December 2020.
- Provenance: This multi-center dataset included data from:
- HMR, Montreal, Canada (datasets: CINAAMON, NOLGYN, Remi-Trach)
- Shaare Zedek Medical Center, Jerusalem, Israel (dataset: Abdomi-NOL)
- Leiden University Medical Center, Leiden, the Netherlands (datasets: NOLA, SOLAR)
- University of Vermont Medical Center, Larner College of Medicine, Burlington, Vermont (Observational study)
- Cleveland Clinic Foundation, Cleveland, USA (Fentanyl pilot study)
- Provenance: This multi-center dataset included data from:
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications
The document does not explicitly state the number of experts used to establish ground truth for the algorithm verification or validation datasets, nor does it specify their qualifications. The ground truth appears to be based on observed physiological responses to stimuli during anesthesia (e.g., intubation, incision) as recorded during surgical procedures.
For the human factors testing, the following was mentioned:
- Usability validation study in Israel: 18 participants representative of intended users.
- Usability validation study in Boulder, Colorado: Fifteen (15) US licensed anesthesiologists and CRNAs. Both are considered professional users with extensive clinical training.
4. Adjudication Method for the Test Set
The document does not describe a formal expert adjudication method (e.g., 2+1, 3+1) for establishing the ground truth of the physiological responses. The ground truth appears to be derived from the timing and nature of clinical events (e.g., intubation, incision) which are considered noxious stimuli. The retrospective study mentions "manual and automated data review" for excluding patients with incomplete records, which suggests some level of data quality assessment but not necessarily expert consensus on event labeling.
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, and Effect Size of Human Readers Improvement with AI vs. without AI Assistance
The document does not describe an MRMC study comparing human readers with and without AI assistance. Instead, it presents two clinical outcome studies (Abdomi-NOL and SOLAR) that compare NOL-guided analgesia (which implicitly means human clinicians using the PMD-200 for guidance) against standard of care monitoring (human clinicians using traditional methods like blood pressure and heart rate).
Effect Size (from Abdomi-NOL and SOLAR studies comparing NOL-guided vs. SOC):
- Abdomi-NOL Study:
- Median postoperative pain scores (NRS scale) at 60 minutes in PACU: 3 (NOL-guided) vs. 5 (SOC). Actual difference: 1.6 (95% CI 0.5-2.7). Corrected for sex distribution: 1.9 (95% CI 0.7-3.0).
- Median postoperative pain scores (NRS scale) at 90 minutes in PACU: 3 (NOL-guided) vs. 5 (SOC). Actual difference: 1.3 (95% CI 0.3-2.3). Corrected for sex distribution: 1.5 (95% CI 0.5-2.6).
- These reductions represent 30-33% improvement on the 11-point NRS scale.
- SOLAR Study:
- Median postoperative pain scores (NRS scale) during the first 90 minutes of PACU stay: 3.2 (NOL-guided) vs. 4.8 (control group). Actual difference: 1.6 (95% CI 0.5-2.7).
- Increased ACTH and cortisol levels (stress hormones) were 1.5 to 2-fold greater in the standard care group compared to the NOL-guided group.
These studies demonstrate an improvement in patient outcomes (reduced postoperative pain) when clinicians use the NOL index as an adjunct, but they do not isolate the improvement of human reader performance itself.
6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done
Yes, standalone performance (algorithm only) was assessed.
The "Algorithm Verification," "Algorithm Validation" (Phase I and II), and "NOL Retrospective Clinical Validation Study" sections describe the standalone performance of the PMD-200 algorithm. These studies evaluate the algorithm's ability to correctly identify and predict nociception based on its input physiological data, independent of direct clinician intervention. The metrics like AUC, sensitivity, specificity, and accuracy are measures of the algorithm's standalone diagnostic performance.
7. The Type of Ground Truth Used
The ground truth for both the algorithm verification, validation activities, and the retrospective study primarily relies on the occurrence of specific noxious stimuli during surgical procedures.
Examples of ground truth events indicating nociception include:
- Intubation (TP1)
- Incision/trocar placement (TP2)
- Periods of "no noxious stimulus" or "no nociception reported" (TNP)
These events represent discrete points in time during surgery where a nociceptive response is expected (or not expected), allowing for the classification of the PMD-200's NOL index against these clinical events.
8. The Sample Size for the Training Set
The document explicitly states that the recordings used for verification were not used in the training dataset, and similarly, validation data was unique, i.e., not used for training the algorithm or for verification purposes.
However, the specific sample size for the training set is not provided in the given text.
9. How the Ground Truth for the Training Set Was Established
While the document states that the system has a training dataset, it does not explicitly describe how the ground truth for the training set was established. It can be inferred that it would follow a similar methodology to the verification and validation datasets, likely based on recorded physiological responses to known noxious and non-noxious stimuli during general anesthesia, as observed in surgical procedures.
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DE NOVO CLASSIFICATION REQUEST FOR MEDASENSE BIOMETRICS LTD. PMD-200
REGULATORY INFORMATION
FDA identifies this generic type of device as:
Adjunctive nociception index. An adjunctive nociception index is a prescription device that uses a software algorithm(s) to analyze physiological sensor data and provide a quantitative measure of nociceptive response to painful stimuli in patients under general anesthesia. This device type is intended for adjunctive use to personalize analgesic administration to a patient's actual response to painful stimuli and is not intended to independently direct therapy decisions.
NEW REGULATION NUMBER: 21 CFR 868.2200
CLASSIFICATION: Class II
PRODUCT CODE: QVE
BACKGROUND
DEVICE NAME: PMD-200
SUBMISSION NUMBER: DEN210022
DATE DE NOVO RECEIVED: June 04, 20212
SPONSOR INFORMATION:
Medasense Biometrics, Ltd. 4 Hachilazon St., P.O. Box 3724 Ramat Gan 5213606 Israel
INDICATIONS FOR USE
The PMD-200 with the Nociception Level (NOL) Index is indicated for use in a clinical setting that requires assessment of changes in nociception levels in adult patients under general anesthesia receiving opioid or opioid-sparing analgesia as part of their care.
The PMD-200 should be used as an adjunct to clinical judgment. Clinical judgment should always be used when interpreting the NOL index in conjunction with other available clinical and vital signs.
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LIMITATIONS
The sale, distribution, and use of the PMD-200 are restricted to prescription use in accordance with 21 CFR 801.109.
The PMD-200 should be used as an adjunct to clinical judgment. Clinical judgment should always be used when interpreting the NOL index and trend line in conjunction with other available clinical and vital signs.
PLEASE REFER TO THE LABELING FOR A COMPLETE LIST OF WARNINGS, PRECAUTIONS AND CONTRAINDICATIONS.
DEVICE DESCRIPTION
The PMD-200 (device) is a nociception monitoring system which assists assessment of anaesthetized patient's physiological response to noxious stimuli and helps tailor analgesic administration to the patient's actual response to painful stimuli. The device provides quantification of the patient's response to noxious stimuli with the nociception level index (NOL).
Image /page/1/Picture/6 description: The image shows a Medasense monitor displaying a graph and the number 58. The monitor is white with red accents and has a screen that displays various signals and trends. The graph on the screen shows a fluctuating line, and the number 58 is prominently displayed in the upper right corner of the screen.
The PMD-200 system consists of 4 main components:
- Monitor acquisition and display of physiological raw data signals and NOL . index and trend graph.
- . Software includes two main components:
- Calculation of the NOL index based on physiological parameters extracted from raw data signals.
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- O User interface displays physiological raw data signals, NOL index and trend graph.
- Finger probe -includes the following sensors: .
- Photoplethysmogram (PPG or Pleth) o
- · Thermistor for peripheral temperature (TMP)
- · A 3-axis accelerometer for movement (ACC or Movement).
- Connectors for the Galvanic skin response sensor (GSR or Conductance)
- Single use sensor (connected to the finger probe) includes the following sensor: . o Bio-impedance Galvanic skin response sensor (GSR or Conductance)
The NOL index is a relative, non-linear measure with a range of 0-100, where 0 represents no pain /nociceptive response and 100 represents extreme pain/nociceptive response. The NOL index and trend are intended to support clinical decisions concerning the administration of analgesic medications. Clinical evidence 1-3.4 suggests the following guidelines for procedures under general anesthesia:
- . NOL above 25 for more than one minute may indicate the patient requires additional analgesic therapy. Higher values indicate a stronger nociceptive response. However, the magnitude above the NOL threshold of 25 does not provide guidance on the magnitude of the dose of analgesic, but rather indicates timing as to when additional analgesic dosing may be necessary, following a nociceptive response.
- NOL between 0-25 represents an appropriately suppressed physiological . response to noxious stimuli and suggests adequate analgesia.
- . The NOL index cannot anticipate noxious stimuli and thus a minimal level of analgesics should always be maintained.
SUMMARY OF NONCLINICAL/BENCH STUDIES
BIOCOMPATIBILITY
The PMD-200 includes components that are direct contact with patient skin during use. The finger probe and single-use sensor are categorized as surface contacting (intact skin) devices with prolonged contact in accordance with ISO 10993-1 referenced by the FDA guidance document, Use of International Standard ISO 10993-1, "Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process". The components were subjected to biocompatibility testing in accordance ISO 10993-1. The following tests were conducted to assess biocompatibility of the device for the surface, intact skin contacting components for prolonged duration:
1 Meijer, F et al/Reduced postoperative pain using Nocieption Level-guided fentany dosing during sevolurane anaesthesia: a randomised controlled trial/ British Journal of Anaesthesia 2020 September
2 Meijer F et al Nociception-guided Care during Remifentanil-Propofol Anesthesia: A Randomized Controlled Trial/Anesthesiology 2019 Feb.
8 Ledowski, T., Schheter, P. & Hall, N. Nociception level inter-operative values allow the prediction of acute postoperative pain?. J Clin Monit Comput (2021).
4 Martini CH et al Ability of the Nociception Level (NOL), a multiparameter composite of autonomic signals, to detect noxious stimuli during propofol-remifentanil anesthesia Anesthesiology 2015 Sept.
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- . Cytotoxicity
- Sensitization .
- . Irritation
All tests passed. The results demonstrated the biocompatibility of the device.
SHELF LIFE/REPROCESSING/STERILITY
The PMD-200 system is provided non-sterile and is not intended to be sterilized by the user. The monitor and finger probe components of the PMD-200 system are reusable and the single use sensor (disposable) has a three (3) year shelf-life. The labeling provides cleaning and disinfection procedures for the main unit and finger probe. The procedures for the reusable components were validated following the recommendations of the FDA Guidance Document "Reprocessing Medical Devices in Health Care Settings: Validation Methods and Labeling".
The shelf-life of the single use sensor was assessed by visual and functional testing following accelerated and real-time aging of three (3) years. The expected service life of the PMD-200 finger probe is 2 years (24 months) which is reflected by 600 procedures (300 per year) based on usage data in other jurisdictions in which the device is already in routine use. Service life testing with 600 simulated use cycles followed by functional testing is provided to validate the service life.
ELECTROMAGNETIC CAPABILITY & ELECTRICAL SAFETY
Electrical safety and electromagnetic compatibility testing has been performed and complies with the following standards:
- IEC 60601-1-2 Medical Electrical Equipment Part 1:2014+AMD1:2020: . General Requirements for Safety: Electromagnetic Compatibility Requirements and Tests (Edition 4.1).
- AAMI / ANSI ES60601-1:2005/(R)2012 + AMD1:2012, C1:2009/(R)2012 And . A2:2010/(R)2012 (Consolidated Text) Medical Electrical Equipment - Part 1: General Requirements For Basic Safety And Essential Performance (IEC 60601-1:2005+ AMD1:2012+AMD2:2020, edition 3.2.
- The device was also tested for requirements of IEC 60601-1-2:2014+AMD1:2020 . and AIM 7351731 for RFID to evaluate the effects of electrocautery and diathermy.
SOFTWARE
Software documentation including management of cybersecurity was provided in accordance with the FDA Guidance Document. "Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices," (issued May 11, 2005) for a Moderate Level of Concern (LOC). A Moderate LOC is deemed appropriate as
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malfunction of the device software or a latent design flaw in the device software may lead to erroneous information or a delay in the delivery of appropriate medical care. which would likely result in minor injury but would likely not result in serious injury or death due to the current practice of medicine
HUMAN FACTORS TESTING
The PMD-200 has been evaluated in a comprehensive human factor validation process in compliance with IEC 62366 and ANSI/AAMI 60601-1-6. The summative validation study of 18 participants representative of intended users conducted in Ramban hospital (Haifa, Israel) and Carmel Medical Center (Haifa, Israel) was intended to validate usability aspects of the device including operational validation and display validation. The testing activities performed endured that the test tasks confirm to the ended use of the device and to patient safety and defined user needs. In the operational validation each task was completed at a success rate of 94%. In no case did two participants repeat the same use errors. In the display validation most questions were answered with 100% success rate and a few with 94% success rate. No wrong answer was repeated by more than one participant.
Another summative validation study was conducted in a simulated use environment in Boulder, Colorado was intended to validate workflow and operational validation, clinical interpretation and troubleshooting validation, and knowledge tasks by US intended users . Fifteen (15) US licensed anesthesiologists and CRNAs were recruited to participate in this validation study. The study was conducted by testing the ability of the users to perform a set of real tasks and interpret various clinical conditions. Knowledge tasks were evaluated using questionnaires. Anesthesiologists and CRNAs are considered to be one user group, as their interactions with the device and the tasks they perform are identical. Both anesthesiologists and CRNAs are professional users, who underwent extensive clinical training qualifying them to manage anaesthetized patients including the routine use of patient monitors to inform clinical decision making. Both would use the device in the same manner, same use environment and for the same use population. Tasks evaluated during the study were categorized using task analysis technique, which systematically breaks down the device use process into discrete sequences of tasks. All critical tasks were identified. mitigated as far as possible, and evaluated in the human factor validation study. The participants received a short introduction and training to the system. This training was designed to approximate the training actual users are likely to receive. 45 minutes were allowed to elapse between the introductory & training session and the actual testing. Following the 45 minutes, participants were asked to perform a set of tasks for the operation of the device, interpret clinical conditions and troubleshooting scenarios and complete questionnaires. Data collection was followed by a debriefing interview, to enable the collection of users' perspectives of the device and its use. The results were scored by both the moderator and the observer, where primary data collection is performed by the moderator. The observer scoring was used as reference in case of any uncertainty regarding the result. No use errors were recorded in any of the test sessions.
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PERFORMANCE TESTING - BENCH
Signal Acquisition
The essential performance of the PMD-200 according to ANSI/AAMI 60601-1 is defined as the ability of the PMD-200 to continuously produce NOL values. This performance is evaluated in the electrical safety report where the PMD-200 demonstrates continuous performance under different constraints as defined by the standard. The PPG signal acquisition was validated by injecting a Sine wave into the PMD-200 using a signal generator, and then altering the signal frequency and viewing its effect on the Pleth signal displayed on the PMD-200 screen. The full range of the PPG signal acquisition was validated in the algorithm unit testing,
The GSR signal acquisition is validated by using a resistor substitute to simulate a signal and reviewing the signal on the PMD-200 screen. The single-use sensor is then disconnected and the GSR alert 'Conductance' is verified. The full range of the GSR signal acquisition was validated in the algorithm unit testing.
The temperature signal range was tested to verify the accuracy of the Finger Probe thermistor by comparing it to a reference calibrated thermometer, according to the requirements of ISO 80601-2-56, clause 201.101.2. All tests met the pre-defined acceptance criteria of the thermistor deviating < 2.5℃ from the reference thermometer measurement in compliance with the standard.
The accelerometer performance was validated during software testing for movement detection and Trendelenburg detection in the algorithm unit testing.
Algorithm Unit Testing
A total of 604 different test points and test vectors were used for the unit testing. testing the main units of the algorithm. Four (4) additional bench tests were used for the unit testing:
- Two (2) bench tests to validate algorithm model performance. .
- . One (1) bench test to validate finger probe movement detection.
- One (1) bench test to validate Trendelenburg detection. .
- . One (1) bench test to validate the accuracy of detecting low quality of PPG signal (too low a quality for reliable calculation of physiological parameters).
The sensitivity and specificity of the NOL Index in response to noxious stimulation should be above 75% for the low 95% CI, validated for nociception / no nociception levels. All tests included in the unit testing passed this pre-defined acceptance criteria.
Algorithm Verification
For the verification testing, a multinational, multi-center dataset, consisting of major abdominal/gynecological surgery recordings performed on adult patients under general
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anesthesia was used. None of the recordings used for verification were used in the training dataset or for validation activities. This dataset covers a wide range of patient demographics, such as age, sex, BMI, pre-existing conditions and ASA classification to ensure diversity. Anesthetic drugs included Remifentanil Fentanyl for analgesia and Propofol\volatile gas for anesthesia.
The verification process includes 3 different types of tests, incorporating different methodology and procedures. The tests, acceptance criteria and results are provided in Table 1.
| Test description | Test metrics | Acceptance criteria | Results |
|---|---|---|---|
| Algorithm overallpredictability | Estimated vs reference CISA:mean +/- 95% CI | 95% CI < 1.0 CISA unit | Pass |
| NOL algorithm decisionaccuracy (binary testing) | Youden Index for NOL thresholdof 25 | 25 +/- 3 NOL units | Pass |
| AUC | 0.85 (0.8 for low 95% CI) | Pass | |
| Specificity | 0.85 (0.75 for low 95% CI) | Pass | |
| Sensitivity | 0.85 (0.75 for low 95% CI) | Pass | |
| Accuracy | > 0.85 | Pass | |
| Characterization of NOLvalues at times of nonoxious stimulus | Mean NOL value during periodswhere no nociception is reported | 97.7% of NOL samplesshould be below 25 |
Table 1: Algorithm verification results
Algorithm Validation
For validation, a multinational, multi-center dataset, consisting of major abdominal/gynecological surgeries surgery recordings, performed on adult patients under general anesthesia was used. All data is unique, i.e., was not used for training the algorithm or for verification purposes. This dataset covers a wide range of patient demographics, such as age. sex. BMI, pre-existing conditions and ASA score to ensure diversity. Validation was divided into two phases. Phase I repeated and expanded the verification activities on a separate dataset. Phase II included sub-group analysis. The purpose of the sub-group analysis is to validate the accuracy of the NOL algorithm for its intended use population, and to demonstrate that NOL performance is not affected by specific populations or anesthetic techniques:
- Sex: Male/Female
-
- Age: 18-65/65+
-
- BMI: 18-25/25-30/30+
-
- Analgesic drug: Remifentanil/Fentanyl
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Each sub-group contained at least 40 patients.
Phase I validation results are provided in Table 2.
| Test description | Test metrics | Acceptance criteria | Result |
|---|---|---|---|
| Algorithm overallpredictability | Estimated vs referenceCISA: mean +/- 95%CI | 95% CI < 1.0 CISA unit | Pass |
| NOL ability to correctlygrade variousnociceptive intensitiesmean {NOL(POI)}(-/+ 95% CI) bystimulus groups:TP1: intubationTP2: incision/trocarTNP: non-nociceptivestimulus or no stimulus | mean {NOL(TP1)} > mean {NOL(TP2)} >mean {NOL(TNP)}Wilcoxon signed-rank test | Pass | |
| NOL algorithmdecision accuracy(binary testing) | Youden Index for NOLthreshold of 25 | 25 +/- 3 NOL units | Pass |
| AUC | 0.85 (0.8 for low 95% CI) | Pass | |
| Specificity | 0.85 (0.75 for low 95% CI) | Pass | |
| Sensitivity | 0.85 (0.75 for low 95% CI) | Pass | |
| Accuracy | > 0.85 | Pass | |
| Clinical relevance score | > 0.8 | Pass | |
| Characterization ofNOL values at times ofno noxious stimulus | Mean NOL valueduring periods where nonociception is reported | 97.7% of NOL samples should be below25 | Pass |
Table 2: Phase I validation results
Phase II validation results are provided in Table 3. For the subgroup analysis, both the verification and the validation data sets were used
Table 3: Phase II validation results
| Sub-group | Numberof | Test #1CISA | Test #2 | Test #3Youden | Test #4 | Test #5Specificity | Test #6Sensitivity | Test #7Accuracy |
|---|---|---|---|---|---|---|---|---|
| ----------- | ------------------ | ----------------- | --------- | ----------------------- | --------- | ---------------------------- | ---------------------------- | ------------------------- |
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| patients | err95%CI | TP1/TP2/TNP | index | AUC | ||||
|---|---|---|---|---|---|---|---|---|
| Female | 75 | Pass | Pass | Pass | Pass | Pass | Pass | Pass |
| Male | 75 | Pass | Pass | Pass | Pass | Pass | Pass | Pass |
| Age < 65 | 81 | Pass | Pass | Pass | Pass | Pass | Pass | Pass |
| Age > 65 | 48 | Pass | Pass | Pass | Pass | Pass | Pass | Pass |
| BMI18-25 | 39 | Pass | Pass | Pass | Pass | Pass | Pass | Pass |
| BMI25-30 | 45 | Pass | Pass | Pass | Pass | Pass | Pass | Pass |
| BMI > 30 | 45 | Pass | Pass | Pass | Pass | Pass | Pass | Pass |
| Remifentani1 | 55 | Pass | Pass | Pass | Pass | Pass | Pass | Pass |
| Fentanyl | 67 | Pass | Pass | Pass | Pass | Pass | Pass | Pass |
SUMMARY OF CLINICAL INFORMATION
Clinical Outcome Studies
Two outcome studies (SOLAR & Abdomi-NOL) demonstrate clinically meaningful reduction of pain scores in the NOL guided groups vs. the standard of clinical care group. These studies were conducted with patients receiving a sevoflurane / fentanyl anesthesia regimen, which is broadly used in US practice. The studies were designed as singleblinded, two-group randomized, superiority studies. In order to evaluate the adjunctive intended use of the PMD-200, patients were randomized to either NOL-guided analgesia (NOL groups) or standard of care monitoring only (SOC group). The instructions and guidance on how to use the output from the PMD-200 were pre-specified and provided to investigators, prior to patient enrollment. Subjects underwent common, elective, noncardiac procedures as would normally be conducted in routine clinical practice. Both outcome studies compared the effect of NOL-guided fentanyl dosing versus standard clinical care in patients undergoing major abdominal surgery under sevoflurane/fentany] anesthesia on postoperative pain scores. The study hypothesis was that objective NOLguided fentanyl dosing during surgery would result in superior pain scores compared to standard of care fentanyl dosing based on the hemodynamic indices, blood pressure and heart rate. A clinically meaningful reduction in post-operative pain scores was demonstrated in both the SOLAR study and the Abdomi-NOL study. In the SOLAR study a clinically meaningful reduction of 1.6 in the median pain score was reported throughout the 90 minutes. The Abdomi-NOL study was designed as a confirmatory study to confirm and support the results of the SOLAR study and a clinically meaningful reduction of 1.5 was maintained up to 90 minutes from PACU entrance. These reductions represent 30-33% improvement on the 11-point NRS scale in comparison to the standard of care control groups.
Table 1: Abdomi-NOL Clinical Study
| Title of Study | Impact of Nociceptive-Level (NOL) Intraoperative GuidedFentanyl Analgesia versus Standard Clinical Care (SOC) forElective Major Abdominal Surgery |
|---|---|
| ---------------- | ----------------------------------------------------------------------------------------------------------------------------------------------------------- |
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| Investigators | Dr. Rivka Fuica | ||||
|---|---|---|---|---|---|
| Study center | Shaare Zedek Medical Center, Jerusalem, Israel | ||||
| Patient Enrollment Period | November 2019 - March 2021 | ||||
| Objective | To guide intraoperative fentanyl dosing using Nociception Level(NOL) index and assess the effect of this guidance on thepostoperative pain scores in the post-anesthesia care unit (PACU) | ||||
| Primary Endpoint | Reduction of pain score in the PACU. (Time points: at arrival;every 15min; at discharge or following 3 hours, whichever comesfirst) | ||||
| Secondary Endpoints | 1. Reduction in the frequency of inadequate analgesia/anesthesiaevents (MAP $< 55$ mmHg (severe hypotension) and/or $< 60$mmHg (hypotension); Systolic blood pressure $>140$ mmHg;Heart rate $<45$ min-1; Heart rate $>90$ min-1) during themaintenance period until reversal in the NOL-guided group.2. Total intraoperative fentanyl consumption (in mcg). | ||||
| Exploratory Endpoints | Intraoperative Use of vasoactive medication (ephedrine, phenylephrine,norepinephrine, atropine) In the PACU Time to the first administration of morphine and/or non-opioidsystematically administered analgesics Post-operative opioid consumption from arrival to discharge Readiness to discharge from PACU (Aldrete score measured atarrival, every hour and at discharge) Post-operative sedation scores with Ramsay Sedation Score(Time points: at arrival; every 15 min) Respiratory Depression- defined as respiratory rate (RR) below8 respirations per minute (RPM) for 1 minute. Saturation of lessthan 90% for 1 minute under continuous monitoring. Nausea and vomiting incidence (PONV Score) Pruritis requiring treatment WARD - up to 24 hours post-surgery Pain scores (VAS or NRS Scale; Time points: ~every 8 hoursor according to the SOC)) 24 hours post-operative opioid consumption PONV medication consumption |
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| Methodology | Patients were randomized to receive NOL-guided anesthesia orstandard of care. In both groups, a NOL device was connected, butin the standard care group, the anesthesia team was blinded to thedevice. The anesthetic technique was identical in the two groupsand consisted of induction with a single dose of 1-2µg/kg fentanyl(analgesia), followed by maintenance boluses of 0.5 µg/kg,sevoflurane (anesthesia maintenance targeted at MAC 0.8-1.2) androcuronium (muscle relaxant). In the standard clinical care (SOC)arm, fentanyl boluses were given based on hemodynamic variablessuch as blood pressure and heart rate. In the NOL-guided analgesiaarm, fentanyl dosing was based on NOL values. |
|---|---|
| Number of Patients | 75 patients (ASA 1-3 patients undergoing elective majorlaparoscopic abdominal, urologic or gynecologic procedures undergeneral anesthesia) were enrolled and completed all studyprocedures. |
| Main Criteria forInclusion | 1. Age: 18 years and older;2. ASA I-III3. Elective major laparoscopic abdominal, urologic orgynecologic procedures under general anesthesia.4. Patient able to provide informed consent |
| Main Criteria forExclusion | 1. Use of any type of anesthesia other than general anesthesia(neuraxial, epidural analgesia or local regional anesthesia, e.g.transversus abdominal plane block).2. Non-sinus heart rate.3. Pregnancy/lactation.4. Central nervous system disorder (neurologic/headtrauma/uncontrolled epileptic seizures).5. Abuse of alcohol or illicit drugs within the last 6 months.6. Chronic pain conditions - pain in 1 or more anatomic regionsthat persists or recurs for longer than 3 months and isassociated with significant emotional distress or significantfunctional disability.7. Opioid tolerant - if for at least 1 week the patient has beenreceiving oral morphine 60 mg/day; transdermal fentanyl 25mcg/hour; oral hydromorphone 8 mg/day; oral oxymorphone25 mg/day; or an equianalgesic dose of any other opioids.8. Chronic use of psychoactive drugs within 90 days prior tosurgery.9. Allergy or intolerance to any of the study drugs.10. History of severe cardiac arrhythmias within the last 12months.11. Surgeries less than one hour (from incision toextubation).12. Current participation in another clinical study |
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| Statistical Methods | Confidence intervals for median values were obtained usinggeneralized linear models with the cluster bootstrap and biascorrected and accelerated (Bca) 95% confidence intervals (CI).Continuous variables showing normality such as age, height,weight, and BMI were analyzed using Student's t-test andexpressed as mean ± SD. |
|---|---|
| Continuous variables not showing normality such as frequency ofinadequate analgesia/ anesthesia events and total intraoperativefentanyl consumption were analyzed using the Mann-Whitney testand expressed as median (IQR). | |
| For the secondary outcomes, according to the study protocol, the pvalue 0.05, normally considered as the threshold for statisticalsignificance, should have been corrected using the Holm step-down procedure. | |
| As none of the secondary outcomes were found to be statisticallysignificant even before the correction, actual application of theHolm step-down procedure was deemed unnecessary. | |
| SUMMARY AND CONCLUSIONS | |
| Safety Results | No adverse events associated with the use of the device werereported. Three (3) non-device related adverse events were reportedduring the study. |
| Effectiveness Results | Primary Endpoint: |
| Median postoperative pain scores following 60 minutes in thePACU were 3 (inter-quartile range 0-5) and 5 (3-7) in NOL-guidedand SOC groups, respectively. | |
| Bootstrap analysis actual difference 1.6, 95% confidence interval0.5-2.7 or 1.9 corrected for differences in sex distribution, 95%confidence interval 0.7-3.0 | |
| Median postoperative pain scores following 90 minutes in thePACU were 3 (inter-quartile range 0-5) and 5 (3-6) in NOL-guidedand SOC groups, respectively. | |
| Bootstrap analysis actual difference 1.3, 95% confidence interval0.3-2.3 or 1.5 corrected for differences in sex distribution, 95%confidence interval 0.5-2.6. | |
| Secondary Endpoints: | |
| Mean intraoperative fentanyl dosing was not different betweengroups 351 mcg in the NOL group vs. 338 mcg in the SOC. (Mann-Whitney p=0.22). There were no differences in the prevalence of | |
| inadequate analgesia/anesthesia events between the NOL and theSOC groups. | |
| Exploratory Endpoints:There were no significant differences between groups in any of theexploratory endpoints. | |
| Conclusion | Despite absence of differences in fentanyl and morphineconsumption during and after surgery, a 1.5-1.9-pointimprovement in postoperative pain scores was observed in theNOL-guided group. This was attributed to NOL-guided ratherthan BP- and HR driven fentanyl dosing during anesthesia. |
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Table 2: SOLAR Clinical Study
| Title of Study | Sevoflurane/fentanyl anesthesia guided by Nociceptive-Level indexduring abdominal surgery in ASA 1-3 patients - a randomizedcontrolled trial on the effect of NOL-guidance on postoperative painscores |
|---|---|
| Investigators | Monique van Velzen PhD, Martijn Boon MD PhD, Chris MartiniMD, PhD, Maarten Honing MD, Paul Calis MD, Emre Almac MD,AlbertDahan MD PhD |
| Study centers | 1. Leiden University Medical Center, Leiden2. Alrijne Hospital, Leiderdorp |
| Study period | From: May 2019To: December 2019 |
| Objective | To guide the analgesic component of anesthesia using the NOLindex in ASA 1-3 patients under general anesthesia for electiveabdominal surgery |
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| Endpoints | Primary Endpoints |
|---|---|
| Postoperative pain scores in the post anesthetic care unit (PACU). | |
| Secondary Endpoints | |
| 1. Postoperative opioid consumption; | |
| 2. Fentanyl use during anesthesia; | |
| 3. Sevoflurane consumption during anesthesia; | |
| 4. Inadequate hemodynamic events; | |
| 5. Time between reversal of neuromuscular block and extubation/eyes open; | |
| 6. Occurrence of awareness; | |
| 7. Anesthesia and surgery times/PACU stay time. | |
| 8. Blood ACTH and cortisol levels during and following theprocedure. | |
| Methodology | Patients were randomized to receive NOL-guided anesthesia orstandard of clinical care. In both groups, a NOL device wasconnected, but in the standard of clinical care group, the anesthesiateam was blinded to the device. The anesthetic technique wasidentical in the two studies and consisted of 25-50 or 50-100 $ μ $ gfentanyl boluses (analgesia), sevoflurane (anesthesia maintenanceaimed at BIS values 50 ± 5) and rocuronium (muscle relaxant). Inthe standard of clinical care (SOC) arm, fentanyl boluses weregiven based on hemodynamic variables such as blood pressure andheart rate. In the NOL-guided analgesia arm, fentanyl dosingwas based on NOL values. |
| Number of patients | 50 ASA 1-3 patients undergoing elective open abdominal surgeryor laparoscopic/ robot-assisted abdominal surgery at two centers. |
| Main criteria for | 1. Age: 18 years and older; |
| inclusion | 2. ASA 1-3 |
| 3. Elective open abdominal surgery or robotic/laparoscopicabdominal surgery. | |
| Main criteria for | 1. Unable to give written informed consent; |
| exclusion | 2. Use of epidural analgesia or local anesthesia (e.g. transversus |
| abdominal plane block-TAP block) | |
| 3. Non-elective surgery | |
| 4. Pregnancy/lactation. | |
| 5. Uncontrolled preoperative hypo- or hypertension (Mean | |
| arterial pressure < 60 mmHg or systolic blood pressure > 160mmHg) | |
| 6. Preoperative Heart rate < 45/min or > 90/min; | |
| 7. Central nervous system disorder (neurologic/head trauma/uncontrolled epileptic seizures). | |
| Statistical Methods | The primary endpoint, PACU pain scores over time, was comparedbetween the two treatment groups using generalized linear modelwith the cluster bootstrap and bias corrected and accelerated (Bca)95% confidence intervals (CI) (Deen 2000). Analyses wereimplemented using R Cluster Bootstrap package v1.1.2. Modelsincluded group, time center and demographic characteristics. |
| For secondary endpoints, since statistical testing was exploratoryrather than confirmatory, power calculations were not performed.Data analysis of these data was performed using independent two-tailed-t-test, Mann-Whitney test, $\chi^2$ -test for continuous &categorical measurements respectively, for measurementsevaluated over time (morphine & stress hormones) ClusterBootstrap with Bca 95% confidence intervals were applied. | |
| Data are presented as mean ± SD, mean ± 95% confidenceinterval, median and interquartile range and counts & percentagesunless otherwise stated. | |
| Corrections for type one error were not performed as: | |
| The study included a single primary endpoint | |
| Sample size was not powered for secondary endpoints,and they are therefore considered as exploratory andnot confirmatory | |
| For assessment of the reproducibility of the study endpoints at thetwo hospitals (Leiden University Medical Center, Leiden andAlrijne Hospital, Leiderdorp), descriptive analysis was performedas well graphical representation using boxplots. |
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SUMMARY AND CONCLUSIONS
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| Safety Results | 4 of 50 (8%) of patients experienced serious adverse events(SAEs) not related to the study device. In the SOC group, two SAEs(one event of postoperative nausea/vomiting and constipation andthe other of bile leakage) were judged as unrelated to the studydevice. In addition, in the NOL-guided group, two SAEs (oneevent of anastomotic leak and one episode of postoperativebleeding) were judged to be also, unrelated to the study device.No adverse events (AE), or device related adverse events (ADE) orserious adverse device events (SADEs) were recorded throughoutthe study. |
|---|---|
| Effectiveness Results | During the first 90 minutes of PACU stay, the medianpostoperative pain scores were 3.2 [interquartile range 1.3 – 4.3]and 4.8 [3.0 – 5.3] in NOL-guided and control groups, respectively(actual difference 1.6, 95% confidence interval 0.5-2.7). As twoindependent centers were included in this study, center was addedto the Bootstrap model as a covariate, this addition did not impactthe results (actual difference 1.7, 95% confidence interval 0.8-2.8).Postoperative morphine consumption was 0.06 ± 0.07 mg/kg(NOL-guided group) and 0.09 ± 0.09 mg/kg (p=0.3) Duringsurgery, fentanyl dosing was not different between groups.ACTH and cortisol levels were analyzed using bias corrected andaccelerated cluster bootstrap intervals with time, center, sex, ageand BMI as covariates. Relative to baseline, the increase of ACTHand cortisol was 1.5 to 2-fold greater in the group that receivedstandard care compared to those that received Nociception Levelindex guided fentanyl dosing”. Mean difference 40.6 and 242.6 forcortisol and ACTH respectively (95% confidence interval 7.1 to -85.1 for cortisol and 39.4 to 513.5 for ACTH).The results demonstrated for morphine consumption and stresshormone levels are considered exploratory, representing a trendtowards reduction of morphine consumption in the PACU andreduced levels of stress hormones in the NOL guided group.Further confirmatory studies are required in order to assess thereproducibility and clinical relevance of these results.The remaining secondary endpoints did not demonstrate any |
| meaningful results. | |
| Conclusion | Patients receiving intraoperative NOL-guided fentanyladministration during sevoflurane anesthesia for abdominalsurgery demonstrated decreased pain in the PACU, likely as aresult of better objective intraoperative fentanyl management. |
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NOL Retrospective Clinical Validation Study
In addition, a retrospective study comparing the clinical performance of the PMD-200 monitor across multiple patient cohorts in order to assess the generalizability of the technology performance in clinical practice representative of the intended use environment was conducted. The patient cohorts include various anesthesia regimens and patients with different demographic characteristics. The study was performed on a database comprising 500 adult patients.
The hypothesis that the NOL index responds consistently to nociceptive stimuli in patients under general anesthesia over a broad range of patient demographic characteristics and physical health classifications, using different anesthesia and analgesia drugs was evaluated. The primary endpoint was the ability of the NOL index to discriminate between noxious and non-noxious stimuli in various subgroups of adult surgical patients. NOL recordings from elective surgery procedures using the PMD-200 monitor between January 2015 to December 2020 were selected. All data were shared with the company as deidentified datasets under data-sharing agreements appropriate for the purpose of this study:
-
- HMR, Montreal, Canada:
- . CINAAMON
- . NOLGYN
- . Remi-Trach
-
- Shaare Zedek Medical Center, Jerusalem, Israel
- . Abdomi-NOL
-
- Leiden University Medical Center, Leiden, the Netherlands
- · NOLA
- · SOLAR
-
- University of Vermont Medical Center, Larner College of Medicine, Burlington, Vermont
- . Observational study
-
- Cleveland Clinic Foundation, Cleveland, USA
- Fentanyl pilot study .
Adults who had elective general, gynecological, or urological surgery under general anesthesia (GA) with or without epidural analgesia were included. Patients with incomplete intraoperative medication listings or annotation records were excluded after
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manual and automated data review. The ability to discriminate between noxious and nonnoxious stimuli was assessed using descriptive statistics and receiver operating characteristics (ROC) curve of the NOL response within the 3 minutes post stimulus. The results of the retrospective study are provided in Table 3.
| Subgroup | N (datapoints) | NOLCutoffPoint | AUC | Specificity | Sensitivity | Accuracy | CRS | Pass/Fail |
|---|---|---|---|---|---|---|---|---|
| Sex | ||||||||
| Female | 483 | 25 | 0.97(0.95-0.98)p < 0.0001 | 0.93(0.89-0.96) | 0.92(0.88-0.95) | 0.92 | 0.87 | Pass |
| Male | 219 | 25 | 0.96(0.93-0.99)p < 0.0001 | 0.91(0.85-0.95) | 0.90(0.85-0.94) | 0.92 | 0.80 | Pass |
| Age | ||||||||
| Age < 65 | 476 | 25 | 0.96(0.95-0.98)p < 0.0001 | 0.94(0.90-0.96) | 0.90(0.85-0.94) | 0.92 | 0.86 | Pass |
| Age > 65 | 217 | 23 | 0.95(0.92-0.98)p < 0.0001 | 0.93(0.88-0.97) | 0.91(0.83-0.96) | 0.92 | 0.83 | Pass |
| BMI | ||||||||
| Overweight25-30 | 280 | 25 | 0.95(0.93-0.98)p < 0.0001 | 0.90(0.85-0.95) | 0.93(0.87-0.97) | 0.92 | 0.85 | Pass |
| Overweight25-30 | 255 | 25 | 0.95(0.92-0.98)p < 0.0001 | 0.96(0.91-0.99) | 0.93(0.87-0.97) | 0.91 | 0.85 | Pass |
| Obese30+ | 162 | 25 | 0.98(0.96-1.00)p < 0.0001 | 0.97(0.91-0.99) | .90(0.81-0.96) | 0.94 | 0.86 | Pass |
| Anesthesia | ||||||||
| Desflurane | 155 | 25 | 0.99(0.98-1.00)p < 0.0001 | 0.99(0.95-1.00) | 0.95(0.88-0.99) | 0.97 | 155 | Pass |
| Sevoflurane | 354 | 25 | 0.95(0.93-0.98)p < 0.0001 | 0.89(0.84-0.93) | 0.93(0.88-0.97) | 0.91 | 354 | Pass |
| Propofol | 173 | 25 | 0.98(0.97-1.00)p < 0.0001 | 0.96(0.89-0.99) | 0.89(0.82-0.96) | 0.92 | 173 | Pass |
| ASA Classification | ||||||||
| ASA I | 112 | 25 | 0.96(0.94-0.99)p < 0.0001 | 0.90(0.81-0.95) | 0.90(0.81-0.95) | 0.90 | 0.88 | Pass |
| ASA II | 418 | 25 | 0.95(0.93-0.98)p < 0.0001 | 0.95(0.91-0.97) | 0.89(0.84-0.94) | 0.92 | 0.84 | Pass |
| ASA III | 91 | 25 | 0.97(0.94-1.00)p < 0.0001 | 0.94(0.88-1.00) | 0.92(0.83-1.00) | 0.93 | 0.85 | Pass |
| Analgesia | ||||||||
| Remifentanil | 265 | 24 | 0.97(0.95-0.99)$p < 0.0001$ | 0.92(0.87-0.96) | 0.92(0.85-0.96) | 0.92 | 0.82 | Pass |
| Fentanyl | 395 | 25 | 0.96(0.94-0.98)$p < 0.0001$ | 0.90(0.85-0.94) | 0.94(0.89-0.97) | 0.92 | 0.88 | Pass |
Table 3: Retrospective study results
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The NOL algorithm met product requirements and behaved consistently across all tested subgroups. The performance of the NOL index was thus reliable, independent of patient characteristics and anesthetic approach, and generalizes well across the intended use population.
Pediatric Extrapolation
The device is intended for use in adults only.
LABELING
The labeling (User Instructions) meets the requirements of 21 CFR 801.109 for prescription devices and satisfies the special controls listed below:
- . A summary of the clinical validation data, including demographics and other relevant characteristics of the clinical study participants (including age, gender, race or ethnicity, and patient condition), the anesthetic regimen, including types (e.g., morphine, hydromorphone, fentanyl, etc.), and doses of opioids used, and a summary of validation result.
- . A description of what the device measures and outputs to the user.
- The type of sensor data used, including specification of compatible sensors for . data acquisition.
- Warnings identifying sensor signal-acquisition factors that may impact output. .
- . Warnings identifying situations that may create a safety risk to the patient or users.
- Information on the patient population(s) for which the device has been . demonstrated to be effective and for subpopulations (age, gender, race or ethnicity) which may experience disparate performance.
- . Guidance for clinical interpretation of the output, including warning(s) emphasizing the adjunctive use of the output measure(s).
RISKS TO HEALTH
The table below identifies the risks to health that may be associated with use of an adjunctive nociception index and the measures necessary to mitigate the risks
| Identified Risks to Health | Mitigation Measures |
|---|---|
| Delayed or incorrect treatment due toerroneous device output resulting | Technological characteristics for signal quality andnoisy/missing data handling mechanisms. |
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| from software malfunction or algorithm error | Software verification, validation, and hazard analysis |
|---|---|
| Non-clinical performance testing | |
| Clinical performance testing | |
| Labeling | |
| Delayed or incorrect treatment due to user misinterpretation or overreliance on indicator | Usability assessment |
| Labeling | |
| Adverse tissue reaction | Biocompatibility Evaluation |
| Electric shock/electromagnetic interference | Electrical safety testing |
| Electromagnetic compatibility testing |
SPECIAL CONTROLS
In combination with the general controls of the FD&C Act, the adjunctive nociception index device is subject to the following special controls:
-
- Technical characteristics/features of the device software/algorithm must include mechanisms for handling of noisy or missing data and poor signal quality.
-
- Software description, verification, and validation based on comprehensive hazard analysis must be provided.
- · Full characterization of technical parameters of the software, including any proprietary algorithm(s);
- · Description of the expected impact of all applicable sensor acquisition hardware characteristics on performance and any associated hardware specifications:
- · Specification of acceptable incoming sensor data quality control measures;
- Mitigation of impact of user error or failure of any subsystem components O (signal detection and analysis, data display, and storage) on output accuracy;
-
- Scientific justification for the validity of the index algorithm(s) must be provided (e.g., clinical relevance of decision threshold).
-
- Non-clinical performance must be provided:
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- Bench testing must demonstrate the ability of the device software/algorithm to o detect adequate input signal quality, handle noisy or missing data and poor signal quality, and perform as intended under anticipated conditions of use.
- Verification of algorithm calculations and bench/simulation testing of the o algorithm using a data set separate from the training data must support the validity of modeling.
-
- Usability assessment must be provided to demonstrate acceptable risk mitigation of misinterpretation of the index (output).
-
- The patient contacting components of the device must be demonstrated to be biocompatible.
-
- Testing must demonstrate electromagnetic compatibility (EMC) & electrical safety of hardware components of the device.
-
- Clinical data must be provided to validate the algorithm in support of the intended use. This clinical validation testing must be completed using a dataset that is separate from the training dataset and include the following:
- · A summary of the clinical data used, including source, patient demographics, and any techniques used for annotating and separating the data.
- Output measure(s) must be compared to an acceptable reference method to o demonstrate the required accuracy and/or sensitivity and specificity of the output measure(s):
- Clinical testing must demonstrate the consistency of the output and be o representative of the range of data sources and data quality likely to be encountered in the intended use population and relevant use conditions in the intended use environment.
- Clinical testing must support the type of pain (nociceptive, somatic, visceral, o neuropathic) that is within the scope of the indicated use.
-
- Labeling must include the following:
- A summary of the clinical validation data, including demographics and other relevant characteristics of the clinical study participants (including age. gender, race or ethnicity, and patient condition), the anesthetic regimen, including types (e.g., morphine, hydromorphone, fentanyl, etc.), and doses of opioids used, and a summary of validation result.
- A description of what the device measures and outputs to the user.
- The type of sensor data used, including specification of compatible sensors for o data acquisition.
- Warnings identifying sensor signal-acquisition factors that may impact output. o
- · Warnings identifying situations that may create a safety risk to the patient or users.
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- Information on the patient population(s) for which the device has been o demonstrated to be effective and for subpopulations (age, gender, race or ethnicity) which may experience disparate performance.
- Guidance for clinical interpretation of the output, including warning(s) o emphasizing the adjunctive use of the output measure(s).
BENEFIT-RISK DETERMINATION
The risks of the device include underdose and overdose of opioid during intraoperative procedures due to inaccurate NOL readings and allergic response to the material of the finger probe. Insufficient analgesia may result in temporary hypertension, tachycardia, postoperative pain, sensitization that may cause persistent post-operative pain and delayed postoperative recovery. Excessive analgesia may result in temporary respiratory depression, hypotension, bradycardia, opioid induced hyperalgesia, post-op nausea/vomiting and delayed postoperative recovery. During clinical study, there were no reports of any serious or minor adverse events related to the device, other than 3 isolated cases of minor pressure marks to the patient's finger, that self-resolved and did not require treatment.
The probable benefits of the device include reduction of postoperative pain which may reduce prolonged postsurgical opioid use. An additional probable benefit includes clinically relevant reduction in inadequate anesthesia events.
Patient Perspectives
This submission did not include specific information on patient perspectives for this device.
Benefit/Risk Conclusion
The risks of false positive or false negative results leading to under- or over-dosing are diminished due to the patient-specific nature of NOL values. The score provided is a relative score based on the patient's own normalized data. Further, the device is used as an adjunct to the traditional, surrogate measures of assessing nociception, such as blood pressure heart rate, and somatic signs (tearing, mydriasis etc.) Accordingly, the NOL information is provided only to supplement the physician's standard of care practices for guiding analgesic dosing. The patient remains under direct observation at all points in time.
In conclusion, given the available information above, for the following indication statement:
"The PMD-200 with the Nociception Level (NOL) Index is indicated for use in a clinical setting that requires assessment of changes in nociception levels in adult patients under general anesthesia receiving opioid or opioid-sparing analgesia as part of their care.
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The PMD-200 should be used as an adjunct to clinical judgment. Clinical judgment should always be used when interpreting the NOL index in conjunction with other available clinical and vital signs."
The probable benefits outweigh the probable risks for the PMD-200. The device provides benefits, and the risks can be mitigated by the use of general controls and the identified special controls.
CONCLUSION
The De Novo request for the PMD-200 is granted and the device is classified as follows:
Product Code: QVE Device Type: Adjunctive nociception index Regulation Number: 21 CFR 868.2200 Class: II
N/A