← Product Code OIR · P200018 # NeuRX Diaphragm Pacing System (DPS) (P200018) _Synapse Biomedical, Inc. · OIR · Mar 31, 2023 · Anesthesiology · APPR_ **Canonical URL:** https://fda.innolitics.com/device/P200018 ## Device Facts - **Applicant:** Synapse Biomedical, Inc. - **Product Code:** OIR - **Decision Date:** Mar 31, 2023 - **Decision:** APPR - **Device Class:** Class 3 - **Review Panel:** Anesthesiology - **Attributes:** Therapeutic ## Indications for Use The NeuRx DPS® is intended for use in patients with stable, high spinal cord injuries with stimulatable diaphragms, but who lack control of their diaphragms. The device is indicated to allow the patients to breathe without the assistance of a mechanical ventilator for at least 4 continuous hours a day. For use only in patients 18 years of age or older. ## Device Story NeuRx DPS is an intramuscular, percutaneous diaphragm stimulation system. It uses four intramuscular electrodes implanted into the diaphragm muscle near phrenic nerve motor points via laparoscopic surgery. Electrodes are tunneled to a percutaneous exit site on the chest and connected to an external pulse generator (EPG). The EPG delivers capacitively-coupled, charge-balanced, biphasic stimulation to recruit diaphragm muscle fibers, eliciting inspiratory effort. The system is used in home and clinical settings; operated by patients or caregivers. Clinicians program stimulation parameters (amplitude, duration, frequency, ramp, respiratory rate) via a clinical station. The device replaces or supplements mechanical ventilation, reducing reliance on tracheostomy-based positive pressure ventilation. Benefits include improved respiratory independence, potential survival advantages, and reduced pulmonary complications compared to standard mechanical ventilation. ## Clinical Evidence Pivotal IDE study (G920162) and pooled HDE data (n=196). Primary endpoint: proportion of patients breathing without mechanical ventilation for ≥4 continuous hours/day. Results: 96.2% (primary cohort), 89.6% (pooled), and 92.2% (meta-analysis) met the endpoint (p<0.001 vs 45% performance goal). Secondary endpoint: 24-hour ventilator independence achieved by 52.7% of patients in meta-analysis. Safety: No device-related SAEs in primary cohort. Common AEs included capnothorax (39%), external equipment failure (15%), and broken external wires (13%). Survival rates were comparable or superior to literature-reported ventilator-dependent SCI populations. ## Technological Characteristics System includes PermaLoc intramuscular electrodes (316LVM stainless steel, polypropylene core, PFA insulation), indifferent return electrode, and external pulse generator. Stimulation: 4-channel, capacitively-coupled, biphasic. Essential performance verified per IEC 60601-1 and 60601-1-11. Biocompatibility per ISO 10993-1. Sterilization: Ethylene oxide (implantables) and gamma (disposables). Connectivity: Standalone, battery-powered EPG with clinical station for programming. ## Regulatory Identification The device is intended for use in patients with stable, high spinal cord injuries with stimulatable diaphragms, but who lack control of their diaphragms. The device is indicated to allow the patients to breathe without the assistance of a mechanical ventilator for at least 4 continuous hours a day. For use only in patients 18 years of age or older. ## Reference Devices - Avery Diaphragm Pacemaker System ([P860026](/device/P860026.md)) - ValuTrode® Neurostimulation Electrodes ([K970426](/device/K970426.md), [K130987](/device/K130987.md)) - Intrathecal baclofen pump (Saval, 2010) - Enterra Gastric Electrical Stimulator (Medtronic) ## Submission Summary (Full Text) > This content was OCRed from public FDA records by [Innolitics](https://innolitics.com). If you use, quote, summarize, crawl, or train on this content, cite Innolitics at https://innolitics.com. > > Innolitics is a medical-device software consultancy. We help companies design, build, and clear FDA-regulated software and AI/ML devices, including [a PMA](https://innolitics.com/services/regulatory/), [a 510(k)](https://innolitics.com/services/510ks/), [a SaMD](https://innolitics.com/services/end-to-end-samd/), [an AI/ML medical device](https://innolitics.com/services/medical-imaging-ai-development/), or [an FDA regulatory strategy](https://innolitics.com/services/regulatory/). {0} SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED) I. GENERAL INFORMATION Device Generic Name: Diaphragm Pacing System Device Trade Name: NeuRx® Diaphragm Pacing System (NeuRx DPS®) Device Procode: OIR Applicant’s Name and Address: Synapse Biomedical, Inc. 300 Artino Street Oberlin, OH 44074 Date(s) of Panel Recommendation: None Premarket Approval Application (PMA) Number: P200018 Date of FDA Notice of Approval: March 31, 2023 Priority Review: N/A Breakthrough Device: N/A II. INDICATIONS FOR USE The NeuRx DPS® is intended for use in patients with stable, high spinal cord injuries with stimulatable diaphragms, but who lack control of their diaphragms. The device is indicated to allow the patients to breathe without the assistance of a mechanical ventilator for at least 4 continuous hours a day. For use only in patients 18 years of age or older. III. CONTRAINDICATIONS There are no known contraindications. IV. WARNINGS AND PRECAUTIONS The warnings and precautions can be found in the NeuRx Diaphragm Pacing System labeling. V. DEVICE DESCRIPTION The NeuRx Diaphragm Pacing System (NeuRx DPS®) is an intramuscular, percutaneous, motor point diaphragm stimulation system (Figure 1). The device intramuscular PMA P200018: FDA Summary of Safety and Effectiveness Data {1} electrodes are implanted using standard laparoscopic surgical techniques and are connected to a four-channel external pulse generator at a percutaneous exit site. The pulse generator provides a capacitively coupled, charge balanced, biphasic stimulation to each electrode with a common indifferent electrode that is placed subcutaneously. The pulse generator controls the charge delivered through clinician programmed parameters of pulse amplitude, pulse duration, pulse frequency, pulse ramp, inspiration time, and respiratory rate. The user connects the device and turns it on for use; no other controls are available or necessary for operation. ![img-0.jpeg](img-0.jpeg) Figure 1: NeuRx DPS® System The NeuRx DPS® System primary components include: Electrodes - Sterile PermaLoc Electrode - Sterile Indifferent Electrode - External Components - External Pulse Generator - Patient Cable - Electrode connector, connector holder & strain relief boot - Programmer and Accessories - Clinical station - Electrode delivery instrument, pressure sensor, pressure tube, cable set, surface anode, tunnelers, crimp tool, socket pusher, surface electrode and interconnect. PMA P200018: FDA Summary of Safety and Effectiveness Data {2} PMA P200018: FDA Summary of Safety and Effectiveness Data 3 of 62 # Device Operation The NeuRx DPS® is a percutaneous, motor point, stimulation device that is implanted in the diaphragm during an outpatient laparoscopic procedure. The locations for implantation are identified by electrically mapping the inferior aspect of the diaphragm. Using the laparoscopic electrode delivery instrument, the PermaLoc intramuscular electrodes are surgically implanted in the diaphragm muscle in proximity to branches of the phrenic nerve without making contact or manipulating the nerve. The PermaLoc electrodes are tunneled, subcutaneously, to a percutaneous exit site on the lateral chest region. An indifferent return electrode (anode) is placed subcutaneously and exits at the same chest location. These electrodes are connected to an external pulse generator (EPG) (stimulator) that controls the timing and level of diaphragm pacing stimulation. Each electrode may be controlled individually in terms of charge (pulse duration and pulse amplitude) delivered and grouped together to recruit the diaphragm muscle to elicit the desired level of inspiratory effort. # Implantable Components Stimulation is delivered to the phrenic nerve motor point through four intramuscular electrodes implanted into the diaphragm. Two electrodes are placed into each hemi-diaphragm at locations, found during surgical mapping, that elicit the greatest contraction of the diaphragm. This may be obtained by a single motor point, where the main trunk of the phrenic nerve enters the diaphragm, to produce a diffuse contraction or at two individual branches that recruit the anterior and posterior portions of the diaphragm. The electrodes are tunneled directly to the percutaneous exit site on the chest. # Intramuscular Electrode (PermaLoc® Electrode) The PermaLoc intramuscular electrode is a double helix wound lead with exposed 316LVM stainless steel stimulating surface and polypropylene reinforced core. The PermaLoc also has a barb at the implanted end composed of 14 pieces of polypropylene suture fused together. The body of the lead is insulated with PFA (perfluoroalkoxy) fluoropolymer coating and terminated in a 316L stainless steel pin with a silicon reinforcing sleeve. # Indifferent Electrode (Anode) The indifferent electrode provides a common return current path for all the electrodes implanted in the diaphragm. It is implanted in the subcutaneous tissue of the lateral chest region and is tunneled to the percutaneous exit site. The lead is fabricated of the same double helix wound 316LVM stainless steel as the intramuscular electrode and percutaneous extension lead. {3} # External Components # NeuRx DPS® External Pulse Generator (EPG) The patient external pulse generator (EPG) is an external four channel battery powered device that controls the stimulus output and respiratory timing. The four output channels are independently controlled, capacitively-coupled, biphasic outputs with a common return. The device is packaged in an impact resistant plastic enclosure with patient cable connector on the top, display, and power buttons on the front and replaceable battery compartment on the back. A programming connector is in the battery compartment for connection to the clinical station. ![img-1.jpeg](img-1.jpeg) Figure 2: External Pulse Generator The EPG has no controls that allow modification to any parameter settings. On-off power control consists of redundant switches that require actuation at the same time to provide protection from accidental actuation by incidental contact. The device is powered from a user replaceable primary battery and a secondary rechargeable battery. The internal secondary battery recharges from the primary battery upon replacement. This configuration always allows a charged backup battery in the unit to allow sufficient time for the user to replace the primary battery. The display will indicate when the device is operating from the internal backup battery and provide an audio indicator when the internal backup battery reaches low charge remaining. A patient cable is provided that connects from the external pulse generator to the electrode connector socket. A disposable connector holder secures the electrode connector socket on the chest. The external portion of the electrode leads are protected at the connector by a strain-relief boot. PMA P200018: FDA Summary of Safety and Effectiveness Data {4} # Surgical Instruments # Mapping Instrument The initial step in the surgical implementation involves laparoscopic mapping of the diaphragm. This may be performed by introducing and connecting to an available laparoscopic dissector for stimulation or using the optional $5\mathrm{mm}$ mapping instrument. Either instrument is used to stimulate the inferior surface of the diaphragm in a grid pattern to identify optimal implantation sites of the intramuscular electrodes. The connected laparoscopic dissector may be applied to sequential sites on the diaphragm by the surgeon and stimulated. Optionally, the mapping instrument may be applied to sequential sites on the diaphragm by the surgeon and secured by applying the operating room vacuum through the central lumen of the probe. Stimulation is applied in either a twitch or burst mode from the clinical station to elicit an abdominal pressure change. ![img-2.jpeg](img-2.jpeg) Figure 3: Available Laparoscopic Dissector or Optional Mapping Probe # Transducer to Trocar Pressure Tube A one-meter section of PVC tubing, with male Luer lock connectors on either end, is used to connect a Trocar port to the solid-state pressure sensor. The long length of the tube permits connection to the pressure sensor outside of the sterile field. The transducer to trocar pressure tube is packaged in Tyvek packaging and sterilized by ethylene oxide exposure. # Solid State Pressure Sensor A differential, 1 PSI full scale, pressure sensor transduces the abdominal pressure changes to an electrical signal for the clinical station. It connects to the pressure tube with a female Luer lock and to the clinical station with a positive locking medical grade connector. The electrical signal provides an indication of relative pressure change. # Cable Set A set of cables with touch-proof connectors are used to connect off the sterile field from the mapping instrument to the clinical station. A set of $3\mathrm{m}$ meter cables connect to the mapping instrument or clip leads to test implanted electrodes. Another cable connects from the surface anode to the clinical station. PMA P200018: FDA Summary of Safety and Effectiveness Data {5} # Surface Anode The surface anode is an adhesive electrode that is placed on the skin during the intraoperative procedure. The anode is manufactured by Axelgaard and uses a proprietary hydrogel adhesive to adhere the surface anode to the skin. # Electrode Delivery Instrument A single use, disposable laparoscopic electrode delivery instrument is used for implantation of the electrodes in the diaphragm. The barbed intramuscular electrode is loaded in the lumen of the instrument with the de-insulated barb extending out of the needle. The skirt of the polypropylene barb is loaded inside of the needle. When the needle is extended and inserted between the muscle fibers, parallel to the diaphragm surface, the de-insulated barb catches on the fibers and the lead is drawn out of the lumen as the instrument is withdrawn. # Tunnelers The lead tunnelers are used intraoperatively to guide the electrode to the implantation site. They are thin-walled tubes of stainless steel (304SS). The material composition of the lead tunnelers is similar to the mapping probe cannula. The lead tunnelers are packaged in Tyvek packaging and sterilized by ethylene oxide exposure. # Clinical Station The Clinical Station provides the following three primary aspects of the device implementation: - intra-operative mapping functionality, - incorporates NeuRx DPS® External Pulse Generator functionality, and - NeuRx DPS® External Pulse Generator programming capability ![img-3.jpeg](img-3.jpeg) Figure 4: Clinical Station PMA P200018: FDA Summary of Safety and Effectiveness Data {6} The Clinical Station provides intra-operative stimulation and sensing of stimulated response. This surgical mapping mode utilizes the surgical components listed above to provide twitch or burst stimulation to record and display the abdominal pressure response through the solid-state pressure sensor. A pulse generator mode is used to test the channels individually and in combination at the end of the surgery to make sure that all electrodes are intact and providing the anticipated response. The Clinical Station is also equipped with External Pulse Generator programming capability. The following parameters are adjustable by using the programmer: Table 1: Stimulation Parameters | Parameter Description | Range | Resolution | | --- | --- | --- | | ENABLE: Output Enable | Outputs 1 to 4 | n/a | | lc: Cathodic Current Amplitude | 5 to 25 mA | 1 mA | | PW: Cathodic Current Pulsewidth | 20 to 200 usec | 10 usec | | PER: Output Pulse Period | 50 to 200 msec | 1 msec | | BPM: Breaths Per Minute | 8 to 18 | 1 | | INSP: Inspiration Time | 0.8 to 1.5 sec | 0.1 sec | | PMOD: Pulse Modulation Count (First Pulsewidth = 20% PW) | 0 to 10 | 1 | The parameters listed below are programmable on a global output basis: - Output Pulse Period (PER) - Breaths Per Minute (BPM) - Inspiration Time (INSP) - Pulse Width Modulation Count (PMOD) The following parameters are programmable on an individual output basis: - Cathodic Current Amplitude (IC) - Cathodic Current Pulsewidth (PW) - Output Enable Control (ENABLE) ## Clinician Crimp Tool The electrode leads are terminated prior to installation into the connector socket block by using the Clinician Crimp Tool. The termination is of the electrode lead requires the crimping of a larger contact socket that is compatible with the connector socket block. ## Socket Pusher After the terminated electrode leads after terminated, the Socket Pusher is used to insert each terminated lead into the connector socket block PMA P200018: FDA Summary of Safety and Effectiveness Data 7 of 62 {7} VI. ALTERNATIVE PRACTICES AND PROCEDURES There are several other alternatives for the correction of high spinal cord injury. The standard therapy for high spinal cord injured patients is mechanical ventilation via a tracheostomy. Other approved surgical and medical alternatives include Avery Laboratories Mark IV device, Non-Invasive Positive Pressure Ventilation (NIPPV), pneumobelt and Rocker beds. Each alternative has its own advantages and disadvantages. A patient should fully discuss these alternatives with his/her physician to select the method that best meets expectations and lifestyle. **Mechanical ventilation via tracheostomy**: These devices periodically force air, via positive pressure, directly into a patient’s airway to inflate the lungs. Mechanical ventilation (MV) adversely effects quality of life and its use is associated with life-threatening complications including posterior lobe atelectasis, pneumonia, barotrauma and tracheomalacia. The associated issues with MV have led to the development of less invasive technologies to support respiration in SCI patients. **Avery Diaphragm Pacemaker System**: An alternative to positive pressure mechanical ventilation, for a subset of patients, is the Avery Diaphragm Pacemaker System, also known as Avery Breathing Pacemaker. The original PMA (P860026) for the device was approved on the November 26: 1986 with indications for ventilatory support for treatment of central alveolar hypoventilation (CAH) and upper motor neuron respiratory muscle paralysis (RMP) (P860026) and whose remaining phrenic nerve, lung and diaphragm function are sufficient to accommodate electrical stimulation. The Avery device is composed of four principal components: an external radio frequency (RF) transmitter, two external transmitter antenna coils, two RF receivers with a built-in coil and two nerve electrodes with insulated lead wires to connect the receiver to the electrode. Placement of each electrode is performed with meticulous dissection of the phrenic nerve in either the neck or thorax using an open thoracic procedure. The phrenic nerve is laid in the groove of the electrode and the electrode is sutured in place around the nerve. This is different from the Synapse device where the electrodes are implanted directly into the diaphragm muscle. The pacer operates on the principle of RF induction of energy and control through the intact skin. The transmitter and transmitting antenna are external to the body. The Synapse device is designed with a direct connection through a wire to the control mechanism. The Avery device uses an implanted RF receiver where none is required with the Synapse device. **Non-invasive positive pressure ventilation (NIPPV)**: Other alternatives to positive pressure mechanical ventilation consist of various forms of non-invasive ventilation. Non-invasive positive pressure ventilation (NIPPV) may be used for limited ventilatory support in some patients with spinal cord injury to provide periods of time off mechanical ventilation. PMA P200018: FDA Summary of Safety and Effectiveness Data 8 of 62 {8} NIPPV is delivered as: - continuous positive pressure ventilation (CPAP) or - bilevel positive pressure ventilation (BiPAP) via a mask, nasal occlusion device, or tracheostomy adapter. Other forms of non-invasive ventilation include the pneumobelt and rocking bed. Pneumobelt: inflates and deflates a bladder wrapped around the patient’s abdomen and lower chest. Inflation of the bladder forces the abdominal contents to rise, compressing the lung allowing expiration of gas; deflation of the bladder allows the abdominal contents to move downward and the lung to expand. This device is used in the sitting position. Rocker beds: used in the supine position and rely on the shifting of abdominal contents by positional changes in the patient. ## VII. MARKETING HISTORY NeuRx DPS® has been approved for distribution in the U.S. under Humanitarian Device Exemptions (HDE) H070003 for a spinal cord injury (SCI) indication and HDE H100006 for an amyotrophic lateral sclerosis (ALS) indication. The device has been distributed in Europe to treat diaphragm dysfunction which includes patients with spinal cord injury (SCI), amyotrophic lateral sclerosis (ALS), and other forms of diaphragm dysfunction under EC certificate number 518356. The device is also approved by the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan. In addition, the device has been approved and distributed in Canada, Australia, Brazil, Israel, Middle East, Scandinavian countries, South Africa, Switzerland, South America, and North Africa. To date, over 2,000 NeuRx DPS® devices have been implanted world-wide. The NeuRx DPS® has not been withdrawn from marketing for any reason relating to the safety and effectiveness of the device. ## VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH A list of potential adverse effects associated with the placement and use of the device are provided below: ### Implant Procedure Related - Capnothorax - Pneumothorax - Bleeding /Hemothorax - Nerve, tissue, or organ damage PMA P200018: FDA Summary of Safety and Effectiveness Data {9} PMA P200018: FDA Summary of Safety and Effectiveness Data 10 of 62 ## Device Related - Adverse biocompatibility reaction to the electrodes / leads - Infection - Skin sensitivity due to adhesive - Skin erosion from leads - Lead breakage, internal or external - Lead dislodgement ## Therapy Related - Airway obstruction - Aspiration - Cardiac interaction - Crosstalk with another implanted device - Diaphragm fatigue - Pain or discomfort due to stimulation - Insufficient stimulation ## Other Procedure, System or Therapy Related - Autonomic dysreflexia - Death - Spasms For the specific adverse events that occurred in the clinical study, please see Section X below. ## IX. SUMMARY OF NONCLINICAL STUDIES The NeuRx DPS® System testing shown in Table 2 demonstrated compliance with specification requirements and performance. Evaluations of functional performance, EMC, environmental and mechanical robustness, electrical safety, and international standards compliance confirmed that the NeuRx DPS® System is acceptable for human use. Table 2: Performance Testing | Test Name | Purpose | Result | | --- | --- | --- | | Mechanical Random Vibration Test | To simulate a mechanical shock environment the NeuRx DPS EPG would be exposed to during typical use when tested per the requirements of IEC 60068-2-64:2008 Broad-Band Random Vibration 10-2,000Hz @ 30 minutes per axis | PASS | {10} | Test Name | Purpose | Result | | --- | --- | --- | | Mechanical Impact Test | To simulate a mechanical impact environment the NeuRx DPS EPG would be exposed to during typical use when tested to the requirements of IEC 60601-1:2012 by conducting an impact test with a 50mm diameter steel ball weighing 500g falling from 1.3meters | PASS | | Environmental - Cold Transport and Storage | To simulate temperature extremes the NeuRx DPS EPG would be exposed to during typical transport and or storage when tested per the requirements of IEC 60601-1 General Safety requirements at -20C for 6 hours minimum and 55C for 6 hours minimum | PASS | | Battery Testing - Overload of battery at fuse rating | To mitigate the risk of a battery external short circuit, the NeuRx DPS EPG maximum surface temperatures were tested during an overloading event of the battery by operating at 110% of the maximum rated voltage per IEC 60601-1:2012 General Safety requirements | PASS | | Battery Testing - Unintentional reverse charging | To mitigate the risk of a battery external short circuit, the NeuRx DPS EPG maximum surface temperatures were tested during potential reverse charging of battery per IEC 60601-1:2012 General Safety requirements for single fault conditions | PASS | | Battery Life Testing - Battery life data | To verify NeuRx DPS EPG battery life meets expected user requirements and design specifications | PASS | | Battery Testing (Primary Lithium) - Thermal abuse (cells) and short circuit | To mitigate the risk of NeuRx DPS EPG primary lithium-metal battery cells internal short circuit, certification from the manufacture to be compliant with IEC 60601-1:2012 General Safety requirements and specifically IEC 60086-4 Primary batteries - Safety of Lithium Batteries requirements has been obtained | PASS | | Battery Testing (Secondary) - Thermal abuse (cells) and forced internal short | To mitigate the risk of NeuRx DPS EPG secondary lithium-ion battery cells internal short circuit, certification from the manufacture to be compliant with IEC 62133 has been obtained | PASS | # Software: The Software Level of Concern (LOC) is identified as MAJOR. Software documentation was provided in accordance with the Agency "Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices" Guidance document. Certain elements of the analysis were derived from the Agency recognized software standards IEC 62304:2006+A1:2015: Medical device software - Software life cycle processes. The Sponsor has performed the following software V&V activities: - Code Review - Examples of functions reviewed: Variable Allocation, Look-up tables (period and pulse modulation), Initialize Waveform Generator Shutdown, Display Breaths Per Minute, Message Process, Interrupt Service Routine, etc. - Software Unit Testing - The code for the software units was verified through white box testing using the software development environment known as MPLAB IDE. Preconditions or pre-requirements for testing were also verified. - Software Integration Testing - Evaluated that all software units, hardware items, and user interfaces, were properly integrated into the software system. Testing results successfully met the predefined specifications. PMA P200018: FDA Summary of Safety and Effectiveness Data {11} - Validation Testing - The system conforms to user needs and intended use. An evaluation of alarms Alarm testing test Report was performed in accordance with IEC 60601-1-8 during software verification and validation in accordance with the Software Integration Test Procedure. The EPG has temporal audio alarm patterns for high, medium, and low priority error conditions. The alarm harmonics were established based on the specific requirements of the IEC 60601-1-8 standard for a variety of use environments which includes the EPG environment (home and professional healthcare). The Sponsor has verified that the NeuRx DPS® System Cybersecurity Assessment was conducted in accordance with the current FDA guidance and draft guidance documents, "Content of Premarket Submissions for Management of Cybersecurity in Medical Devices" regarding cybersecurity in medical devices. ## EMC: The sponsor provided detailed descriptions of the essential performance and the pass/fail criteria of the immunity testing performed. EMC testing was performed and passed for the NeuRx DPS® System including EPG and Clinical Station. ## Essential Performance ### Clinical Station - Delivery of stimulation to the cable set (surgical) per the test evaluation parameters and verified by: - LCD displayed stimulus parameters remain unchanged during continuous operation. - Stimulus output is evident on LCD display with electrode continuity or test plug. - Monitoring of stimulus waveforms using test-load resistors. ### EPG - Delivery of stimulation to the Patient Cable per the test evaluation parameters and verified by: - Stimulus data array parameters remain unchanged during continuous operation when no changes are received from the Clinical Station. - Stimulus output is evident on display with electrode continuity or test plug. - Monitoring of stimulus waveforms using test-load resistors. The essential performance of the device and the acceptance range of device operation are reasonable. PMA P200018: FDA Summary of Safety and Effectiveness Data 12 of 62 {12} The device configuration and pass/fail criteria for the EMC immunity testing performed are listed below: ## IMMUNITY PASS/FAIL CRITERIA (Per Synapse Biomedical Inc.) ### Clinical Station Delivery of stimulation to the cable set (surgical) per the test evaluation parameters and verified by: - LCD displayed stimulus parameters remain unchanged during continuous operation. - Stimulus output is evident on LCD display with electrode continuity or test plug - Monitoring of stimulus waveforms using fixed test-load resistors. ### EPG Delivery of stimulation to the Patient cable per the test evaluation parameters and verified by: - Stimulus data array parameters remain unchanged during continuous operation when no changes are received from the Clinical Station. - Stimulus output is evident on display with electrode continuity or test plug. - Monitoring of stimulus waveforms using fixed test-load resistors Table 3: Stimulus parameters | | Range | Test Value | Tolerance | | --- | --- | --- | --- | | lc: Cathodic Current Amplitude | 5 to 25 mA | 25 mA | +/-1 mA | | PW: Cathodic Current Pulsewidth | 20 to 200 usec | 100 usec | +/-5 usec | | PER: Output Pulse Period | 20 to 250 msec | 50 msec | +/-5 msec | | BPM: Breaths per Minute | 8 to 18 | 12 (5.0 sec) | +/-100 msec | | INSP: Inspiration Interval (Time) | 0.8 to 1.5 sec | 1.1 sec | +/-50 msec | | PMOD: Pulse Modulation Count | 0 to 10 | 10 | Discrete Values | The device operation in the commercial aircraft environment has been verified with EMC immunity testing per RTCA DO-160 as category R. ### Applicable Standards: - AIM 7351731 – Medical Electrical Equipment and System Electromagnetic Immunity Test for Exposure to Radio Frequency Identification Readers - FDA Guidance – Information to Support a Claim of Electromagnetic Compatibility (EMC) of Electrically-Powered Medical Devices PMA P200018: FDA Summary of Safety and Effectiveness Data 13 of 62 {13} - FDA Guidance – Immunity to exposure to known sources of EMI: Electrosurgical devices, Electrocautery devices, diathermy, and electromagnetic security systems (e.g., metal detectors and Electronic Article Surveillance system (EAS or anti-theft). Table 4: EMI Test | EMI Source | Test Level | Results | Anomalies/Degradations | | --- | --- | --- | --- | | Diathermy (1.7 MHz to 2.3 MHz) | 50 V/m | Pass | None | | Electronic Article Surveillance (7.7 MHz to 8.7 MHz) | 40 V/m | Pass | None | | Electrosurgical Cut (1.7 MHz) | 500 V/m Pulsed | Pass | None | | Electrosurgical Coagulate (1.7 MHz) | 400 V/m Pulsed | Pass | None | | X-ray (30kHz) | 10 V/m | Pass | None | Appropriate test levels specified for the home environment were utilized for the EPG and provided the following setting and the acceptance criteria. Table 5: Test acceptance parameter values | Parameter | Value | Acceptance | | --- | --- | --- | | Breaths per minute | 15 | +/- 0.1 sec | | Inspiration Interval | 1.2 Sec | +/- 50 msec | | Pulse Frequency | 20 Hz | +/- 5 msec | | Pulse Amplitudes (Outputs 1 to 4) | 20 mA | +/- 1 mA | | Pulse Widths (Outputs 1 to 4) | 100 usec | +/-5 usec | | All Outputs | Active | Yes | | Impedance Display | * | * | ## A. Laboratory Studies The NeuRx DPS® includes several device components with patient-contact: 1) PermaLoc Electrode, 2) Indifferent Electrode, 3) Connector Holder, 4) Patient Cable, 5) Surface Anode, 6) Mapping Probe, 7) Electrode Delivery Instrument, and 8) Lead Tunneler Set. Device materials and categorization was carried out according to ISO 10993-1 and Table A.1 of the FDA’s Biocompatibility Guidance document. According to “Use of International Standard ISO 10993-1, ‘Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process’”. PMA P200018: FDA Summary of Safety and Effectiveness Data 14 of 62 {14} Table 6: Patient-Contacting Device Components | Component | Body Contact | Material | Duration | | --- | --- | --- | --- | | Indifferent and PermaLoc Electrodes | | | | | Insulated electrode wire | implanted | 316LVM stainless steel & Perfluoroalkoxy fluoropolymer (PFA) | Long-term | | Anchoring suture | | Polypropylene | | | Reinforcing sleeve | | NuSil MED-4750 silicone rubber | | | Adhesive | | NuSil MED-2000 silicone adhesive | | | Connector Holder | | | | | Spun lace tape | Surface | MED5322 • spunlace polyester cloth • acrylic pressure-sensitive adhesive • paper backing | Long-term | | Patient cable | | | | | Cable cover | Surface | C6-265 Silicone | Long-term | | Surgical Components Surface Anode | | | | | Cloth top neurostimulation rectangular electrode | Surface | Proprietary hydrogel | Limited | | Surgical Components Mapping probe | | | | | Cannula (6 G) | Externally Communicating | 304SS | Limited | | Ferrule (16 G) | | 304SS | | | Silicone Tubing | | NuSil MED-4750 silicone rubber | | | Heat shrink Tubing | | 3527 polyolefin (PO) acrylate | | | PVC Tubing | | Clearflo® Tygon® polyvinyl chloride (PVC) | | | Mapping probe tip (10 G) | | 304SS | | | PFA Insulated Wire | | 316LVM stainless steel & Perfluoroalkoxy fluoropolymer (PFA) | | | Electrode delivery instrument | | | | | Tube tip w/main | Externally Communicating | 304SS | Limited | | Rack, actuator | | 303SS | | | Needle (16 G) | | 304SS | | | Chromium coating | | MEDCOAT 2000™ | | | Lead Tunneler Set | | | | | Lead tunneler (15 G) | Externally Communicating | 15 GA 304SS | Limited | The PermaLoc Electrode and Indifferent Electrode are implant devices in contact with tissue for long-term contact duration (>30 days). Biocompatibility testing on the PMA P200018: FDA Summary of Safety and Effectiveness Data {15} final finished PermaLoc Electrode was performed and biocompatibility test reports for the PermaLoc electrode, included cytotoxicity, sensitization, intracutaneous reactivity, acute systemic toxicity, material-mediated pyrogenicity, muscle implantation (30 day and 26 week), and genotoxicity (bacterial reverse mutation assay and in vitro mouse lymphoma assay) following the appropriate standards and the results support that the device is non-sensitizing, non-irritating, and non-toxic (acute). Biocompatibility testing, including Cytotoxicity testing with MEM elution, was performed on the Connector Holder in its final form. A review of the Connector Holder categorization per ISO 10993-1:2018 determined the component to be long-term (>30 days) surface contact on intact skin. Test results support that the device is non-cytotoxic, non-sensitizing, and non-irritating. The Disposable Electrode Delivery Tool is categorized as an Externally Communicating Device which contacts tissue/bone for a limited duration (< 24 hours). Patient Cable categorization per ISO 10993-1:2018 determined the component to be long-term (>30 days) surface contact on intact skin. results support that the device is non-cytotoxic, non-sensitizing, and non-irritating. The Mapping Probe is an external communicating device in contact with tissue for limited contact duration (<24 h). The biocompatibility testing provided on the Mapping Probe is adequate to support that the device is non-cytotoxic, non-sensitizing, non-irritating, non-pyrogenic, and non-toxic (acute). The Lead Tunneler is an external communicating device in contact with tissue for limited contact duration (<24 h). The biocompatibility data is leveraged from the Mapping Probe for the Lead Tunneler and deemed acceptable based on the same materials/manufacturing and patient contact. The sponsor has leveraged biocompatibility for the Surface Electrodes of the NeuRx DPS® proposed for the IDE as they are identical to a U.S. marketed device (ValuTrode® Neurostimulation Electrodes, K970426 and K130987, Axelgaard Manufacturing Co, Ltd.) with the same type and duration of patient contact. ## Standards Followed for Component Testing for Biocompatibility: ISO 10993-1 and Table A.1 of the FDA guidance "Use of International Standard, ISO 10993-1, 'Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process'". NeuRx RA/4 Diaphragm Pacing System Peterson-Type Electrodes and Leads, NeuRx RA/4 Diaphragm Pacing System Mapping Probe, Electrode Delivery Instrument (MEDCOAT 2000) -ISO 10993-5:2009, "Biological evaluation of PMA P200018: FDA Summary of Safety and Effectiveness Data 16 of 62 {16} medical devices — Part 5: Tests for in vitro cytotoxicity”- Cytotoxicity MEM Elution NeuRx RA/4 Diaphragm Pacing System Peterson-Type Electrodes and Leads, “NeuRx RA/4 Diaphragm Pacing System Mapping Probe”, patient Cable, Electrode Delivery Instrument (MEDCOAT 2000) - ISO 10993-10 2002. Biological evaluation of medical devices — Part 10: Tests for irritation and skin sensitization- Guinea Pig Maximization test NeuRx RA/4 Diaphragm Pacing System Peterson-Type Electrodes and Leads, “NeuRx RA/4 Diaphragm Pacing System Mapping Probe, Electrode Delivery Instrument (MEDCOAT 2000) -” ISO 10993-10 2002. Biological evaluation of medical devices — Part 10: Tests for irritation and skin sensitization Intracutaneous Reactivity in rabbits NeuRx RA/4 Diaphragm Pacing System Peterson-Type Electrodes and Leads": ISO 10993-11 “Biological evaluation of medical devices – Part 11: Tests for systemic toxicity”, NeuRx RA/4 Diaphragm Pacing System Mapping Probe, Electrode Delivery Instrument (MEDCOAT 2000)- Acute Systemic Toxicity ISO 10993-11:2017 Biological evaluation of medical devices — Part 11: Tests for systemic toxicity NeuRx RA/4 Diaphragm Pacing System Peterson-Type Electrodes and Leads, NeuRx RA/4 Diaphragm Pacing System Mapping Probe, Electrode Delivery Instrument (MEDCOAT 2000):” ISO 10993-11:1993 “Material-Mediated Pyrogenicity”-Rabbit Pyrogen Test (Material-Mediated) NeuRx RA/4 Diaphragm Pacing System Peterson-Type Electrodes and Leads “SO 10993-6: 1994 “Implantation”-Intramuscular Implantation in Rabbits– 30 days and 26 weeks NeuRx RA/4 Diaphragm Pacing System Peterson-Type Electrodes and Leads: ISO 10993-3:2003 “Biological evaluation of medical devices — Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity”- Bacterial Reverse Mutation- Bacterial Mutagenicity Test (Ames) Assay Sterile PermaLoc Electrode: ISO 10993-3:2003 “Biological evaluation of medical devices — Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity”- Bacterial Reverse Mutation- In Vitro Mouse Lymphoma Assay PMA P200018: FDA Summary of Safety and Effectiveness Data 17 of 62 {17} Genotoxicity testing in accordance with ISO 10993-3:2014 and ISO/TR 10993-33:2015 has been conducted and included two in vitro assays, one in bacterial cells (Ames) and one in mammalian cells (MLA). It should be noted that genotoxicity potential as determined from biological testing of device extracts may not be leveraged to waive the need to demonstrate acceptable genotoxicity risk of extractables identified by exhaustive chemical characterization analyses (conducted in accordance with ISO 10993-18) to be potential leachables that may be released from the subject implant device under worst case clinical use conditions. The Sponsor's toxicological risk assessment of NeuRX Diaphragm Pacing System may support acceptable toxicological risk of exposure to potential device leachables that may be released from the subject device during its intended use under worst-case clinical-use conditions provided chemical characterization did not underestimate exposure (as determined by the chemical characterization review). Table 7: NeuRx DPS® Biocompatibility Testing | Test | Description | Results | | --- | --- | --- | | Cytotoxicity | MEM Elution Test | Grading from 1-4 was used. The test sample article graded 0 while the positive controls graded 4. | | Sensitization | Guinea Pig Maximization Test | The test criteria of grades 1 or better are presumed to be due to sensitization. The grading was 0 for all experimental articles and 1, 2 or 3 for the positive controls | | Intracutaneous Reactivity | ISO Method of Intracutaneous Reactivity Test | The average reaction was not appreciably greater than the reaction to the blank. | | Systemic Injection Test | ISO Method of Systemic Injection Test | There was not a significant difference in biological reactivity between test groups and their corresponding negative controls. | | Pyrogen Test | Material Mediated Rabbit Pyrogen Test | The individual temperature rise of each individual rabbit was below the test criteria of 0.5 degrees C. The test material was demonstrated to be non-pyrogenic. | | Implantation Test | Thirty Day Muscle Implantation Test | The results indicate that the negative control and test article mean scores are in the same overall Toxicity rating (Not exceeding 1). | | Implantation Test | Twenty-Six Week Muscle Implantation Test | The results indicated that the negative control and the test article mean scores were in the same overall toxicity rating. | | Mutagenicity | Ames Assay Test | As none of the tester strains treated with the test article extract showed mean revertant frequencies greater than two-fold when compared to the concurrent negative control, the test article was considered non-mutagenic. | PMA P200018: FDA Summary of Safety and Effectiveness Data {18} # B. Animal Studies Pre-clinical animal testing of the NeuRx device was performed to support IDE approval (G920162). Proof of Concept, assessment of tissue encapsulation and surgical procedure testing was conducted as noted in Table 8. These pre-clinical studies followed standard university research laboratory protocols accepted by a peer review panel of the Case Western Reserve University School of Medicine. Table 8: NeuRx DPS® Pre-Clinical Animal Testing | Purpose | Animal | Number | Results | | --- | --- | --- | --- | | Demonstration that this procedure could produce the same maximum tidal volumes as phrenic nerve cuff electrodes | Dogs | 7 dogs, 32 intramuscular electrodes | The tidal volume induced 167% of the ventilation required for basal metabolic needs without fatiguing the diaphragm. | | To study the nature of tissue encapsulation surrounding the implanted electrode | Rats | 4 electrodes in each Rat. 3 rats to a group | No encapsulation of the implanted electrode was observed. | | Test new vacuum probing device | Dogs | 2 dogs, device placed in multiple diaphragmatic locations for 1 to 5 minutes | Exposure damage at 5 minutes is minimal and limited to area of application. | # C. Additional Studies # Electrical: - Classification information against electric shock is provided as the Stimulation Module is classified as internally powered and Clinical Station as Class II. - The Clinical Station is disabled and can't be used on the patient when it is connected to the live power for battery charging. - Applied parts of this device are classified as BF. - Subject device water leak protection has been evaluated. The Clinical Station is rated IP20 (no ingress protection), and Pulse Generator is rated IPX4 per the IEC 60601-1 test report and IP24 per IEC 60601-1-11. - Stimulation Module intended to operate in home environment. IEC60601-1-11 test report # Compliance with basic electrical safety required by IEC 60601-1-11 (Stimulation Module only): Sufficient information is provided to demonstrate that the subject Pulse Generator Module meets the electrical safety related requirements for home use collateral standard. PMA P200018: FDA Summary of Safety and Effectiveness Data {19} For the electrical safety in home use environment, manufacturer has provided test report showing that the subject pulse generator meets following IEC 60601-1-11 clauses. Table 9: Essential Performance | List of ESSENTIAL PERFORMANCE functions | MANUFACTURER'S document number reference or reference from this standard or collateral or particular standard(s) | Remarks | | --- | --- | --- | | Stimulus data array parameters remain unchanged | Within NeuRx DPS® Risk Management Plan 20-0000-6.1 Rev 10 there is a section titled “Essential Performance”. | P | | Stimulus output is evident on display with electrode continuity or test plug. | | P | | Delivery of stimulation to the Patient cable at the stimulus data array settings. | The Essential Performance items are evaluated in the NeuRx DPS® Risk Management Detail 20-0000-05 Rev A19. | P | | Parameter Data Ranges for the NeuRx External Pulse Generator | | P | | Supplementary Information: ESSENTIAL PERFORMANCE is performance, the absence or degradation of which, would result in an unacceptable risk. | | | ## Battery safety summary: The subject stimulator utilizing two alkaline primary and two lithium-ion rechargeable batteries. The alkaline batteries are the main power source for the Stimulation Module. They are rated to provide proximately 96 hours of power to this module. Rechargeable lithium-ion batteries are serving as backup power source and can provide power to this module for approximately 8 hours for device normal operation. These batteries connecting to the device power input when the primary batteries fail to provide powered to the device. Lithium-ion batteries are charged from primary alkaline batteries. The surface temperature of Tadiran battery has been measured under its maximum discharge load (i.e., loaded with $300\,\Omega$ resistor). ## Stimulation module battery safety: The risk of battery premature failure is mitigated by backup batteries, visual and audio alarm - Lithium-ion battery pack that is utilized with the stimulation module, includes overcharge, over discharge and over current protection circuit. The manufacturer claims that this battery follows IEC62133. The compliance with this standard and the imbedded battery pack safety circuit, provides adequate means to prevent internal short circuit. PMA P200018: FDA Summary of Safety and Effectiveness Data 20 of 62 {20} - IEC60601-1 test report includes information demonstrating adequate venting for alkaline batteries. - Information is provided to demonstrate that the reverse charge of nonchargeable batteries is mitigated by design. - Switch polarity of Primary Battery and Short circuit of rechargeable battery has been tested per the requirements of IEC60601-1:2005 MOD. Documentation provided supports subject device’s compliance with applicable electrical safety sections of IEC60601-1:2005 MOD. In addition, risk hazard analysis provided demonstrates that the hazards risk associated with the device essential performance are adequately mitigated per ISO 14971. The rechargeable battery in compliance with both IEC 60086-4 and IEC62133. ## Sterilization/Shelf Life and Packaging: Table 10: Shelf Life and Packaging: | Test | Acceptance Criteria | Results | Analysis Type | | --- | --- | --- | --- | | Sterilization | | | | | One year Aging Study-Packaging | No Test Method Acceptance Criteria-Sponsor specified: sponsor seal must withhold a minimum of 1.0 pounds of pressure. | Passed | From 3 boxes (60 samples), a one-inch segment of the seal was cut to connect sufficient material on each side of the seal to the instrument. Standard Method Based On: ASTM: F1980 and ISO 11607 | | X-Ray Energy Dispersion Spectroscopy (EDS) from samples in Scanning Electron Microscope (SEM) | None Stated | debris materials from the package snap and the shaft to the base package film. white residues identified as PET polyester. | 2 test articles disposable medical tool in blister package; tested per ASTM E1252-98(13)e1 | | Transportation and Distribution Tests | No test method acceptance criteria | Passed | test articles (10 boxes) were dropped from a Longmont PDT80 drop tester. Per ASTM D4169 (DC13 Assurance Level II) distribution cycle. | The implantable portions of the device are sterilized by ethylene oxide (EO). The EO Sterilization process was revalidated most frequently in 2018 and has not been altered, although additional electrodes have been added using product adoption evaluation and procedures. Sterility met the assurance level of $10^{-6}$ and all sterilized components were demonstrated to have a useful shelf life of two years from the date of sterilization. The Shelf life, 2 years, for the EO sterilized products (all use the same sterile barrier system) was initially validated based on accelerated aging of PMA P200018: FDA Summary of Safety and Effectiveness Data 21 of 62 {21} product; shelf life was confirmed in 2010 with the results of testing after real time aging of packaged product. The EO sterilization validation, revalidation, and shelf life/packaging validation for the electrodes and other components that are provided sterile was provided and is acceptable. The single patient use, disposable instrument is provided sterile to the hospital (gamma sterilization) and has a useful shelf life of one year from the date of sterilization. The VDmax method was selected for determining the the average bioburden of the device and sterilization dose for this disposable device. This method requires determination of which was performed. The sterility assurance level (SAL) established was 10-6. Documentation supporting the sterilization validation of the single-patient use electrode delivery system was provided and is acceptable. PermaLocThese electrodes are provided sterile and single use only. Visual inspection for debris at 1X and at 10X magnification of all packages on hand was performed and noted no dislodgement or debris. Additional ASTM 4169 distribution and transportation testing on 30 device packages in the 2-pack boxes is has been performed. ## Human Factors: All applicable standards including guidance, Applying Human Factors and Usability Engineering to Medical Devices documents were taken into consideration when developing the Synapse Human Factors and Usability Engineering process. Regarding the Agency's 2016 guidance, Applying Human Factors. The Human Factors and Usability Engineering processes used a Formative and Summative evaluation with 4 user test groups with 15 participants in each test group. The survey results are summarized in the following tables. Table 11: Usability Tasks | USER GROUPS | Surgeons (15) | Surgical Nurses (15) | Technicians (15) | Caregivers (15) | Totals (60) | | --- | --- | --- | --- | --- | --- | | Formative Evaluation | 180 tasks | 105 tasks | 330 tasks | 195 tasks | 810 tasks | | Summative Evaluation | 150 tasks | 45 tasks | 375 tasks | 255 tasks | 825 tasks | | Totals | 330 tasks | 150 tasks | 705 tasks | 450 tasks | 1,635 tasks | Table 12: Usability Response | USER GROUPS | Surgeons (15) | Surgical Nurses (15) | Technicians (15) | Caregivers (15) | Totals (60) | | --- | --- | --- | --- | --- | --- | PMA P200018: FDA Summary of Safety and Effectiveness Data 22 of 62 {22} | Response | A | B | C | A | B | C | A | B | C | A | B | C | A | B | C | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | Formative Evaluation | 169 | 8 | 3 | 94 | 9 | 2 | 326 | 4 | 0 | 189 | 5 | 1 | 778 | 26 | 6 | | Summative Evaluation | 141 | 4 | 5 | 42 | 2 | 0 | 370 | 5 | 0 | 254 | 1 | 0 | 807 | 13 | 5 | | Totals | 310 | 12 | 8 | 136 | 11 | 2 | 696 | 9 | 0 | 443 | 6 | 1 | 1,585 | 39 | 11 | Note: A-Acceptable B-Acceptable with feedback C-Could be Improved In addition, the alarm harmonics for the EPG comply based with the specific requirements of the IEC 60601-1-8 standard for a variety of use environments which includes the EPG environment (home and professional healthcare). The EPG alarms were compliant to this standard as evidenced by the validation report, results analysis, and test report. Based on these real-world observations of task performance and occurrences of use errors, close calls, and use problems including the feedback from interviews with test participants regarding device use, critical tasks, use errors, and problems, it was determined that the device is safe and effective for the intended users, uses and use environments. All USE associated residual risk hazards have an acceptable risk rating and acceptable mitigations to make the device to be safe and effective for the intended users, uses and use environments. ## X. SUMMARY OF PRIMARY CLINICAL STUDY **Summary IDE G920162 and data from patients implanted with the NeuRx device after HDE approval.** The applicant performed a one-armed pivotal clinical study to establish a reasonable assurance of safety and effectiveness of NeuRx DPS® implanted via a laparoscopic surgical procedure. The NeuRx Diaphragm Pacing System is intended for use in patients with stable, high spinal cord injuries with stimulatable diaphragms, but who lack control of their diaphragms (G920162). The device is indicated to allow the patients to breathe without the assistance of a mechanical ventilator for at least 4 continuous hours a day. It is indicated for use only in patients 18 years of age or older in the US. This clinical study summary describes data collected in IDE G920162 as well as data from patients implanted with the NeuRx device after HDE approval. To support this PMA, the sponsor presents the data analysis of 3 cohorts: 1. The primary cohort of 53 patients in the IDE trial (G920162) PMA P200018: FDA Summary of Safety and Effectiveness Data {23} 2. A 106-patient cohort—comprised of 53 patients from the primary cohort pooled with 53 HDE patients in the secondary cohort (Onders et. al where the total $n = 92$ , 39 of which were included in the IDE primary cohort) 3. A 196-patient cohort – 106 pooled patients plus 90 patients from 3 tertiary studies (the tertiary cohorts are comprised of additional HDE patients $(n = 40, n = 31$ and $n = 29)$ . These 5 groups of patients comprise the clinical population used in the statistical analyses for this PMA. Of note, the clinical protocol notes that “p-values are provided for comparative purposes only, to update the original study report results, and not for labeling purposes per the Statistical Analysis Plan”. # Effectiveness Data: # Primary Endpoint Proportion of patients not requiring MV 4hrs/day. FDA agreed that this is a clinically meaningful endpoint. The performance goal was $45\%$ and was based on the efficacy results of the Avery diaphragm pacing system. # Cohort 1 Table 13: Primary Endpoint, Primary Analysis Cohort (n=53) | Event | % (n/N) | 95% confidence interval | p-value* | | --- | --- | --- | --- | | Primary endpoint (proportion of subjects using the NeuRx DPS® to breathe without the assistance of a mechanical ventilator for at least 4 continuous hours a day) | 96.2% (51/53) | (87.0%, 99.5%) | <0.001 | * Exact two-sided binomial test against performance goal of 45% (0.45) The survival endpoint of the primary cohort was not identified as feasible to be analyzed in the original one-year follow-up at the time of the study. The survival analysis was added based on the follow-up at the time of Onders et al. 2018 publication, which was 18 years after the first patient was implanted in the primary analysis cohort. Thus, survival also appears to be improved with DPS although this was not a pre-specified endpoint. PMA P200018: FDA Summary of Safety and Effectiveness Data {24} ![img-4.jpeg](img-4.jpeg) Figure 5: SCI Survival (years since injury for Primary Analysis Cohort n=53) # Cohort 2 Table 14: Primary Endpoint, Secondary Analysis Cohort (n=106) | Event | %(n/N) | 95% confidence interval | p-value* | | --- | --- | --- | --- | | Primary endpoint (proportion of subjects using the NeuRx DPS® to breathe without the assistance of a mechanical ventilator for at least 4 continuous hours a day) | 89.6% (95/106) | (82.2%, 94.7%) | <0.001 | * Exact two-sided binomial test against performance goal of 45% (0.45) # Cohort 3 Table 15: Primary Endpoint, Secondary Analysis Cohort(n=196) | Event | %(n/N) | 95% confidence interval | p-value | | --- | --- | --- | --- | | Primary endpoint (Proportion of subjects using the NeuRx DPS® without the assistance of a mechanical ventilator 24 hours a day) | 92.2% | 82.6%, 96.7 | <0.001 | Secondary Endpoint = Tidal Volume in Chronic Use # Cohort 1 Table 16: Tidal Volume All Subjects | Characteristic | Mean ± SD (N) [Median] (IOR) | p-value (Vt vs basal requirements) | | --- | --- | --- | PMA P200018: FDA Summary of Safety and Effectiveness Data {25} | Basal requirement | 524.3 ± 146.1 (53) [518.01] (441.0,637.0) | | | --- | --- | --- | | Stimulated Vt | 745.6 ± 217.7 (53) [700.0] (605.0,865.0) | | | Percentage of tidal volume over basal requirements (PTOVB) | 48.4 ±41.5 (53) [51.51] (26.1,68.1) | <0.001 | Cohort 2 = N/A Cohort 3 = N/A Secondary Endpoint = Use of NeuRx DPS® without MV 24hrs/day An objective of the NeuRx therapy is to replace mechanical ventilation for patients on a chronic use basis; a surrogate secondary indicator of this objective is tidal volume (Vt) during chronic stimulation. Standard of care for ventilated patients indicates that the basal Vt requirements for an adult male are typically 7ml / kg of body weight and 6ml / kg for adult females. Due to ventilator circuit dead space, tracheotomy leakage, and duration/volume of speech concerns, spinal cord patients are typically mechanically ventilated at much higher settings than their basal Vt requirements. The tables below display basal requirements, stimulated Vt, and the computed percentage of tidal volume over basal requirements (PTOVB) along with a hypothesis test against μ (PTOVB)=0 as provided in the original IDE Pivotal Study report; data are analyzed from the primary analysis cohort only (the IDE Pivotal Study) as this is the only source providing tidal volume data (Table 17). p-values are provided for comparative purposes only, to update the original study report results, and not for labeling purposes per the Statistical Analysis Plan. # Cohort 1 Table 17: Tidal Volume All Subjects | Characteristic | Mean ± SD (N) [Median] (IQR) | p-value (Vt vs basal requirements) | | --- | --- | --- | | Basal requirement | 524.3 ± 146.1 (53) [518.0] (441.0,637.0) | | | Stimulated Vt | 745.6 ± 217.7 (53) [700.0] (605.0.865.5.0) | | | Percentage of tidal volume over basal requirements (PTOVB) | 48.4 ± 41.5 (53) [51.5] (26.1,68.1) | <0.001 | Further analysis by gender, an also performed in the pm or IDE Pivotal Study report, shown sufficient PTQYB performance in both males (Table 18) md females (Table 19). Table 18: Tidal Volume Males PMA P200018: FDA Summary of Safety and Effectiveness Data {26} | Characteristic | Mean ± SD (N) [Median] (IOR) | p-value (Vt vs. basal requirements) | | --- | --- | --- | | Basal requirement | 575.4 ± 119.1 (41) [556.0] (476.0,058.0) | | | Stimulated Vt | 793.9 ± 219.4 (41) [800.0] (660.0,900.0) | | | Percentage of tidal volume over basal requirements (PTOVB) | 42.0 ± 41.5 (41) [47.5] (11.8,61 9] | <0.001 | Table 19: Tidal Volume Females | Characteristic | Mean ± SD (N) [Median] (IOR) | p-value (Vt vs basal requirements) | | --- | --- | --- | | Basal requirement | 349.8 ± 80.2 (12) [336.0] (300.0,373.5) | | | Stimulated Vt | 580.4 ± 102.5(12) [602.5] (507.5,650.0) | | | Percentage of tidal volume over basal requirements (PTOVB) | 70.1 ± 35.2 (12) [65.5] (47.1,84.7) | <0.001 | Use of NeuRx DPS® to breathe without the assistance of a mechanical ventilator for 24 continuous hours a day As with the primary endpoint, the primary analysis cohort for this secondary endpoint is defined to be data collected from the Primary Study, for which $58.5\%$ (31/53) of subjects achieved at least 24 hours daily use (Table 20). A two-sided $95\%$ confidence interval is provided for descriptive purposes, but no formal statistical test is conducted, in keeping with the Statistical Analysis Plan. Ultimately, this represents full independence from mechanical ventilation and ability to support natural negative pressure respiration for the $58.5\%$ of patients that have reached this endpoint. Table 20: 24 hour/daily use - Primary Analysis Cohort (n=53) | Event | %(n/N) | 95% confidence interval | | --- | --- | --- | | Secondary endpoint (proportion of subjects using the NeuRx DPS® to breathe without the assistance of a mechanical ventilator 24 hours a day) | 58.5% (31/53) | (44.1%,74.9%) | # Cohort 2 Table 21: Secondary Endpoint (24 hr/daily use), Secondary Analysis Cohort (n=106) | Event | %(n/N) | 95% confidence interval | | --- | --- | --- | | Secondary endpoint (proportion of subjects using the NeuRx DPS® to breathe without the assistance of a mechanical ventilator 24 hours a day) | 56.6% (60/106) | (46.6%, 66.2%) | PMA P200018: FDA Summary of Safety and Effectiveness Data {27} PMA P200018: FDA Summary of Safety and Effectiveness Data 28 of 62 # Cohort 3 Table 22: Secondary Endpoint (24hr/daily use), Secondary Analysis Cohort (n=196) | Event | %(n/N) | 95% confidence interval | | --- | --- | --- | | Secondary endpoint (Proportion of subjects using the NeuRx DPS® without the assistance of a mechanical ventilator 24 hours a day) | 52.7% | (36.2, 68.6) | # Safety Endpoints: In no case was the patient required to return to the operating room for device repair. In the IDE Pivotal Trial, none of the commonly tracked peri-operative complications, including venous thrombosis, pulmonary embolus, wound infections, and pulmonary infections were reported. The most common peri-operative adverse event was a capnothorax, which is a common side-effect of laparoscopic surgery, was tracked and involved 21 out of 54 patients (39%). In the IDE Pivotal Trial there were no perioperative deaths. This device met the predefined primary endpoint by allow 90% of patients to breathe without a ventilator for at least four hours per day. A secondary endpoint of breathing without a ventilator for 24 h per day was achieved in 50% - 60% of subjects. # A. Study Design IDE Pivotal Study– G920162 The Pivotal Study of the NeuRx DPS® system was conducted at 5 investigational sites as a prospective, non-randomized, multi-center study to demonstrate the safety and effectiveness of the NeuRx device utilizing a patient as their own control. Patients were implanted between March 2000 and March 2008. The primary effectiveness endpoint was defined as use of the NeuRx DPS® to breathe without the assistance of a mechanical ventilator for at least 4 continuous hours a day. It was reported that 96.2% (51/53) of patients achieved at least 4 continuous hours daily use compared to the performance goal (PG) of 45% (p<0.001). In addition, it is found that 58% of subjects achieved at least 24 hours daily use. Safety: There was no specific safety hypothesis, but the sponsor provided a detailed summary of all adverse events (AEs). The sponsor claimed that safety of the NeuRx device was comparable to patients on mechanical ventilation with no apparent increase due to the device. Survival rates of patients using the NeuRx device were at least comparable if not better than patients on mechanical ventilation. {28} The clinical study data was collected and analyzed per the protocol. The clinical data were collected on the final design of the device except changes enumerated in Supplements since approval of H070003. The study population selected matches the device IFU and the endpoints are clinically relevant. According to the study results described in this PMA (P200018), there is strong evidence that the NeuRx device can benefit SCI patients in terms of breathing without the assistance of a mechanical ventilator for at least 4 continuous hours a day. ## Data Safety Monitoring A Data and Safety Monitoring Board consisting of a pulmonologist, spinal cord rehabilitative specialist and surgeon was formed to regularly review study progress and adjudicate adverse events. Members of the DSMB were not employees or major shareholders of Synapse, Inc. and did not participate as investigators. The committee’s purposes were to review and classify all serious adverse events including death occurring in treated patients, to determine if the rate of adverse events was acceptable, to evaluate data analysis results, and to provide related advice to Synapse, Inc., on study management and progress. Meetings were held on a basis determined appropriate for this study. ## 1. Clinical Inclusion and Exclusion Criteria Enrolment in the NeuRX -RA/4 Neuromuscular Stimulator study was limited to patients who met the following inclusion criteria Inclusion: - Age 18 years or older - Cervical spinal cord injury with dependence on mechanical ventilation - Clinically stable following acute spinal cord injury - Bilateral phrenic nerve function clinically acceptable as demonstrated with EMG recordings and nerve conduction times - Diaphragm movement with stimulation visible under fluoroscopy - Clinically acceptable oxygenation on room air (>90% 02 saturation) - Hemodynamically stable - No medical co-morbidities that would interfere with the proper placement or function of the device - Committed primary caregiver - Negative pregnancy test in females of child-bearing potential - Informed consent from patient or designated representative PMA P200018: FDA Summary of Safety and Effectiveness Data 29 of 62 {29} Patients were not permitted to enroll in the NeuRX -RA/4 Neuromuscular Stimulator study if they met any of the following exclusion criteria: - Co-morbid medical conditions that preclude surgery - Active lung disease (obstructive, restrictive or membrane diseases) - Active cardiovascular disease - Active brain disease - Hemodynamic instability or low oxygen levels on room air - Hospitalization for, or a treated active infection, within the last 3 months - Significant scoliosis or chest deformity - Marked obesity - Anticipated poor compliance with protocol by either patient or primary caregiver - Currently breastfeeding The study population matches the device intended use. 2. Follow-up Schedule The 52 subjects, and their caregivers, agreed to a follow-up schedule that could last 12 months. Follow-up was scheduled on subjects who had not achieved steady state use of the system at 3 months, 6 months, and 12 months. Once a subject achieved steady state use of the system, follow-up was performed on an as-requested basis or at the discretion of the Investigator Postoperatively, following the implant procedure, conditioning was started when patients were stable after surgery and when it was convenient for the patient's caregiver. Each electrode was characterized over the range of stimulus parameters using the Clinical Station. The objective parameters after initiation of stimulation measured during the study included tidal volumes which were recorded with a calibrated Wrights Spirometer and oxygen saturation was monitored with a pulse oximeter. It should be noted that the tidal volumes were measured with the patient's tracheotomy, which in many cases was a cuffless tracheal tube. This means that tidal volumes recorded (and subsequently reported in the results) with the Wrights Spirometer were lower than the actual inspired air volume due to air leaks around the patient's stoma and through their upper airway. An EKG rhythm strip was recorded at maximal stimulus parameters to assure that there was no capture of the cardiac waveform. Initial parameter settings were determined, and the external stimulator was programmed. Initial conditioning sessions were performed while the patient was at the hospital to assure the patient and their caregivers understood and were comfortable with the operation of the DPS. The patient returned home and logged his/her use of the NeuRx DPS® and the improvement in tidal volume as determined with the Wrights PMA P200018: FDA Summary of Safety and Effectiveness Data 30 of 62 {30} Spirometer. Pulse oximetry and a rank scale indication of respiratory effort were recorded along with any comments with each use of the DPS. All patients were scheduled to return for follow-up examinations during the initial weeks of DPS use, the clinical team assessed the patient's progress on a weekly basis by reviewing the log sheets and making any changes to parameters as necessary. Log sheets were maintained until the patient had reached, or was capable of, full time use. If the patient had not reached a steady-state plateau or full time use of the system by 3, 6, and 12-month intervals post-surgery, the electrodes were characterized again. Once the patient had achieved full time use of the DPS or was using it at a level that was consistent with their desired level of activity, they were free to use the system as desired. Adverse events and complications were recorded at all visits. The key timepoints are shown below in the tables summarizing safety and effectiveness. ## Additional Supporting Studies After ten years of real-world experience under the HDE, additional sources of evidence of effectiveness have been independently published which support the use of DPS. Each of these supporting studies, designated as studies #2 - #5 are summarized in Table 23. These studies were used to support the efficacy endpoints as described below. Table 23: Published Supporting Data of NeuRx DPS® | Study ID | Study Population Study Type Subject Number Characteristics | Efficacy Results as Published | Safety Results as Published | | --- | --- | --- | --- | | Study #2 - Onders et al. (2018) | Single center, single arm, open label, retrospective review N=92 39 IDE and 53 HDE tetraplegic patients with viable phrenic nerves and diaphragm muscles; including pediatric pts. (15%). Mean time on MV = 47.5m (range 6d-25y) | • 88% (81/92) achieved 4 hours of DPS pacing • 60.8% (56/92) used DPS 24 h/d • 5 pts (5.4%) had full recovery of volitional breathing • Five patients (5.4%) were not successfully weaned from MV • Subgroup analysis showed a trend that earlier DPS implantation leads to a greater number of patients utilizing DPS for 24 hours. | • Median survival was 22.2 years (95% CI 14.0 - not reached) with only 31 deaths. • 4/5 (80%) of patients unable to be weaned from MV died a mean of 9.9 months post-injury. • 17 patients with causes of death available, none were attributable to the device. | PMA P200018: FDA Summary of Safety and Effectiveness Data 31 of 62 {31} | Study ID | Study Population Study Type Subject Number Characteristics | Efficacy Results as Published | Safety Results as Published | | --- | --- | --- | --- | | Study #3 - Kerwin et al (2018) | Single center, single arm, retrospective matched cohort analysis (NeuRx DPS® vs MV). N=40 HDE patients with early DPS implants vs 61 matched pts w/o DPS implant. Mean time to implant=14d | • The DPS patients that developed VAP (26/40) had significantly shorter vent days as compared to the control patients that developed VAP (39/61): 24.5 ± 15.2d vs. 33.2 ± 23.3d; p=0.05 | Mortality and length of hospital stay were significantly higher in the control group: • Mortality significantly higher in the MV group (15% vs 3%; p=0.04) • Length of hospital stay significantly higher in the MV group (65±61 vs 43±24d; p=0.03) | PMA P200018: FDA Summary of Safety and Effectiveness Data 32 of 62 {32} | Study ID | Study Population Study Type Subject Number Characteristics | Efficacy Results as Published | Safety Results as Published | | --- | --- | --- | --- | | Study #4 - Larmmertse et al (2016) | 6 centers, prospective experience report of SCI and implanted with DPS: N=31 patients, (predominantly commercial HDE); with follow-up data on 28 pts. Outcomes collected 2011- 2016 on pts., 78% had C1 or C2 SCI, with implants 2007- 2014, and mean implant time post-injury: 4.5y (<1 month to 28y) | • 24/26 pts. (86%) were still using DPS at the lime of the follow-up (mean 16h/d) • 7/28 pts. (25%) were pacing 24h/d • 4/28 pts. (14%) were not pacing due to: “medical issues”, adverse reaction to pacing, shoulder pain, or need for pressure support via ventilator • Patients (n =28) initiated DPS at mean of 2.5d and a median of 1d (range 0-7d) post-implant. Achieved pacing for 6h/d after a median of 7d (range 0- 60d) and 24h/d after a median of 5d (range 0- 30d). Mean follow-up: 3.2y (range 15d-7.4y) | Device-related adverse effects reported were. • infection Issues at the electrode wire exit site (17%), • pain with pacing (14%), and • electrode wire issues involving hospitalization (13%) | | Study #5 - Posluszny et al (2014) | 10 centers, retrospective analysis of SCI pts. implanted with DPS. N=29 patients; 22 implanted, 7 nonresponsive diaphragms. Patients included at median 33d post injury (range 3- 112d) | • 73% (16/22) implanted were free of MV at a mean of 10.2d after DPS • 36% (8/22) had complete recovery of respiration and DPS wires were removed | • 1 patient, withdrawal of care and death • 3 (14%) partial wean and/or use with MV | ## 3. Clinical Endpoints ### Safety Endpoints: - Assessment of device-related adverse events in the NeuRx DPS® population, compared to a similar patient population without DPS use. - All-cause mortality in the NeuRx DPS® population, compared to a similar patient population without DPS use. ### Primary Effectiveness Endpoint: The primary effectiveness endpoint was defined as use of the NeuRx DPS® to breathe without the assistance of a mechanical ventilator for at least 4 continuous hours a day. This endpoint is reported as the proportion of subjects achieving the endpoint and assessed using binomial methods for the primary cohort (IDE PMA P200018: FDA Summary of Safety and Effectiveness Data {33} population n=53), the secondary cohort of the pooled data between the Primary cohort and Onders HDE patients (n=106), and then using mixed models for the meta-analysis of all data sources (n=196). The three hypothesis tests specified above are tested hierarchically in the order indicated, with the analysis of the primary cohort alone first, the pooled secondary cohort second, and the meta-analysis results from all data sources third. Each test is only performed if the prior test in the sequence meets statistical significance against the performance goal at the 0.05 two-sided level, thereby preserving overall Type I error at 0.0. ## Secondary Effectiveness Endpoints: - Tidal volume (VT) during chronic stimulation is a secondary indicator of the objective to replace mechanical ventilation for patients on a chronic use basis. Standard of care for ventilated patients indicates that the basal VT requirements for an adult male are typically 7ml / kg of body weight and 6ml / kg for adult females. - Use of NeuRx DPS® to breathe without the assistance of a mechanical ventilator for 24 continuous hours a day. ## B. Accountability of PMA Cohort The IDE (G920162) that was in progress at the time of HDE submission, and used in support of the HDE approval, continued with enrollment up to the inclusion of 50 subjects enrolled at U.S. centers. Three additional subjects were implanted (all three included in the HDE analysis) at investigational sites outside of the U.S. and one subject was a compassionate use patient that was approved by FDA with instructions from FDA that “data from this patient should be clearly distinguished from the study data” and not combined. Thus, a total of 54 subjects gave informed consent and the analysis cohort has 53 subjects. One subject, in the analysis cohort, had an unresponsive diaphragm at implant and thus never actively used the device. The remaining 52 subjects, and their caregivers, agreed to a follow-up schedule that could last 12 months. Follow-up was scheduled on subjects who had not achieved steady state use of the system at 3 months, 6 months, and 12 months. Once a subject achieved steady state use of the system, follow-up was performed on an as-requested basis or at the discretion of the Investigator. All subjects were allowed to continue device use once HDE approval was received PMA P200018: FDA Summary of Safety and Effectiveness Data 34 of 62 {34} Table 24: Primary Cohort Demographics and Injury History | Period | Analysis Cohort | Active During Period | Reached 4 continuous hour milestone | Exclusion or Withdrawal | | | --- | --- | --- | --- | --- | --- | | Enrolled | 54 | 54 | — | 1 | 1 compassionate use excluded | | Implanted | 53 | 52 | — | 1 | 1 unresponsive diaphragm at surgery | | 3 months | 53 | 52 | 36 | 0 | | | 6 months | 53 | 52 | 43 | 0 | | | 12 months | 53 | 50 | 50 | 2 | Two deaths between 6 & 12 months | One subject suspended conditioning because of a malfunctioning baclofen pump. Conditioning resumed but the subject did not achieve 4 continuous hours by the date of HDE approval. One subject achieved 4 hours of use after six months but died before 12 months. Table 25: Deaths reported during the IDE study, prior to HDE approval | Subject | Age at Injury (years) | Date of Implant | Date of Death | Months After Implant | Months After Injury | | --- | --- | --- | --- | --- | --- | | 01-03 | 42.7 | 2/28/03 | 10/10/04 | 19.3 | 112.4 | | 01-15 | 20.3 | 2/16/05 | 8/28/05 | 6.4 | 167.9 | | 01-17 | 69.7 | 5/18/05 | 3/24/06 | 10.2 | 38.5 | | 01-20 | 14.6 | 1/23/06 | 10/10/07 | 20.6 | 73.3 | The sponsor presents the data analysis of 3 cohorts: 1. the primary cohort of 53 patients in the IDE trial (G920162) 2. 106 patients – 53 from the primary cohort pooled with 53 HDE patients in the secondary cohort (Onders et. al where the total n= 92, 39 of which were included in the IDE primary cohort) 3. 196 patients – 106 pooled patients plus 90 patients from 3 tertiary studies (the tertiary cohorts are comprised of additional HDE patients (n=40, n=31 and n=29). ## C. Study Population Demographics and Baseline Parameters The demographics of the study population are typical for a pivotal study performed in the US. Per the National Spinal Cord Injury Statistical Center (NSCISC), the average age at injury has increased from 29 years during the 1970s to 43 since 2015. About 78% of new SCI cases are male. Vehicle crashes are the most recent leading cause of injury, closely followed by falls. Acts of violence (primarily gunshot wounds) and sports/recreation activities are also relatively common causes for SCI. PMA P200018: FDA Summary of Safety and Effectiveness Data {35} About $24\%$ of injuries have occurred among non-Hispanic blacks, which is higher than the proportion of non-Hispanic blacks in the general population $(13\%)$ . Table 26 provides the consolidated values for the demographics and injury history of the primary cohort (the IDE Pivotal Study). On average, 65.1 months had elapsed from injury to implant, and the mean age at the time of injury was 30.6 years. The most frequent causes of injury were motor vehicle accident and sporting activities, each occurring $37.7\%$ (20/53) of the time. The most common level of injury was C2, with $45.3\%$ (24/53) of cases, followed by C1/C2 with $30.2\%$ (16/53). Table 26: Primary Cohort Demographics and Injury History | Characteristic | Mean ± SD (N) [Median] (IQR) or % (n/N) | | --- | --- | | Age at implant | 36.1 ± 16.9 (52) [28.4] (22.6,50.5) | | Gender | | | Female | 22.6% (12/53) | | Male | 77.4% (41/53) | | Age at injury | 30.6 ± 18.6 (52) [23.2] (17.9,43.6) | | Time from injury (months) | 65.1 ± 81.0 (53) [28.3] (12.1,83.3) | | Cause of injury | | | Assault | 1.9% (1/53) | | Bicycle | 1.9% (1/53) | | Fall | 13.2% (7/53) | | Industrial | 1.9% (1/53) | | Meningitis | 1.9% (1/53) | | MVA | 37.7% (20/53) | | SP. Infarct | 1.9% (1/53) | | Sports | 37.7% (20/53) | | TM | 1.9% (1/53) | | Level of injury | | | C1 | 7.5% (4/53) | | C1/C2 | 30.2% (16/53) | | C2 | 45.3% (24/53) | | C2/C3 | 1.9% (1/53) | | C3 | 5.7% (3/53) | | C3/C4 | 5.7% (3/53) | | C4 | 1.9% (1/53) | | C4/C5 | 1.9% (1/53) | Table 27 displays subject demographics and injury history for the secondary cohort (Onders et al.). Of the 92 patients implanted, 39 were included in the IDE primary cohort; 53 HDE patients were analyzed as part of the pooled secondary cohort. Table 27 information is restricted to the 53 HDE patients. PMA P200018: FDA Summary of Safety and Effectiveness Data {36} Table 27: Onders et al. Demographics and Injury History | Characteristic | Mean ± SD (N) [Median] (IQR) or % (n/N) | | --- | --- | | Age at implant | 29.1 ± 17.8 (53) [25.0] (17.0,40.0) | | Gender | | | Female | 24.5% (13/53) | | Male | 75.5% (40/53) | | Age at injury | 26.3 ± 18.8 (53) [23.0] (16.0,38.0) | | Time from injury (months) | 35.9 ± 54.2 (53) [13.9] (4.3,49.6) | | Cause of injury | | | Crush | 5.7% (3/53) | | Electrocution | 1.9% (1/53) | | Fall | 15.1% (8/53) | | Forceps Delivery | 3.8% (2/53) | | GSW | 13.2% (7/53) | | MVA | 50.9% (27/53) | | Sports | 9.4% (5/53) | | Level of injury | | | C1 | 7.5% (4/53) | | C1-2 | 13.2% (7/53) | | C1-4 | 1.9% (1/53) | | C2 | 17.0% (9/53) | | C2-3 | 11.3% (6/53) | | C2-4 | 1.9% (1/53) | | C3 | 13.2% (7/53) | | C3-4 | 5.7% (3/53) | | C3-7 | 1.9% (1/53) | | C4 | 1.9% (1/53) | | C4-5 | 9.4% (5/53) | | C5 | 1.9% (1/53) | | C5-6 | 3.8% (2/53) | | C5-7 | 3.8% (2/53) | | C6 | 1.9% (1/53) | | C6-7 | 3.8% (2/53) | PMA P200018: FDA Summary of Safety and Effectiveness Data {37} D. Safety and Effectiveness Results 1. Safety Results Safety of the Primary Cohort Adverse Events There were 165 adverse events recorded during the study, from the first patient implant on 3/6/2000 until the study patients were converted to HDE patients with the approval of the HDE on 6/17/2008. Thirty-eight (38) of the 54 implanted patients (including the compassionate use patient that is excluded from the efficacy analysis) had adverse events recorded. Thus, 16 of the 54 patients had no adverse events recorded during the study. There were 72 device related adverse events reported in 35 patients. Thus, 19 of the 54 patients had no device related adverse events. Of the 72 device related events, 30 were due to equipment malfunctions (external lead breaks or stimulator malfunctions) and another 21 were due to procedure related capnothorax, which is a side-effect of laparoscopic surgery and discussed in more detail below. Eliminating those categories, 11 patients had device related adverse events. Table 28 lists the adverse events for patients in the primary cohort. Device related events are identified and placed into categories with respect to being device related, unanticipated or serious adverse events. There were four deaths during the study, none of them were device related. The full reports, as provided to the institutional review boards for the four deaths, are in Appendix 11.9. There was no device related serious adverse events (SAEs). There were 23 non-device related SAEs with several of them related to a root incident. With the… --- **Source:** [https://fda.innolitics.com/device/P200018](https://fda.innolitics.com/device/P200018) **Published by [Innolitics](https://innolitics.com)** — a medical-device software consultancy. We help companies design, build, and clear FDA-regulated software and AI/ML devices. If you're preparing [a PMA](https://innolitics.com/services/regulatory/), [a 510(k)](https://innolitics.com/services/510ks/), [a SaMD](https://innolitics.com/services/end-to-end-samd/), [an AI/ML medical device](https://innolitics.com/services/medical-imaging-ai-development/), or [an FDA regulatory strategy](https://innolitics.com/services/regulatory/), [get in touch](https://innolitics.com/contact). **Cite:** Innolitics at https://innolitics.com