(254 days)
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No
The summary describes a mechanical system for extracorporeal CO2 removal and does not mention any AI or ML components in the device description, performance studies, or key metrics.
Yes
The device is indicated for respiratory support that provides extracorporeal carbon dioxide (CO2) removal from the patient's blood to treat acute, reversible respiratory failure, which is a therapeutic intervention.
No
The device is described as providing extracorporeal CO2 removal and respiratory support, which indicates a therapeutic function rather than a diagnostic one.
No
The device description explicitly states that the Hemolung RAS consists of three main components: a Controller, a Cartridge, and a Catheter. These are physical hardware components, not solely software. The performance studies also include extensive testing of hardware aspects like pump characterization, physical integrity, and catheter performance.
Based on the provided information, this device is not an IVD (In Vitro Diagnostic).
Here's why:
- Intended Use: The intended use clearly states that the device provides "extracorporeal carbon dioxide (CO2) removal from the patient's blood." This is a therapeutic intervention performed on the patient's blood outside the body, not a diagnostic test performed in vitro (in a lab setting) on a sample of blood or other bodily fluid to diagnose a condition.
- Device Description: The description details a system that circulates blood through a cartridge to remove CO2. This is consistent with an extracorporeal therapy device, not a diagnostic device.
- Lack of Diagnostic Function: There is no mention of the device analyzing blood or other samples to provide diagnostic information about a patient's condition. Its purpose is to treat a condition (respiratory failure) by removing CO2.
IVD devices are used to examine specimens derived from the human body (like blood, urine, tissue) to provide information for the diagnosis, monitoring, or treatment of a disease or condition. The Hemolung Respiratory Assist System performs a therapeutic function directly on the patient's blood.
N/A
Intended Use / Indications for Use
The Hemolung Respiratory Assist System is indicated for respiratory support that provides extracorporeal carbon dioxide (CO2) removal from the patient's blood for up to 5 days in adults with acute, reversible respiratory failure for whom ventilation of CO2 cannot be adequately or safely achieved using other available treatment options and continued clinical deterioration is expected.
Product codes (comma separated list FDA assigned to the subject device)
QOH
Device Description
The Hemolung RAS provides low blood flow, veno-venous extracorporeal carbon dioxide removal (ECCO2R) using a single, 15.5 French dual lumen catheter inserted percutaneously in the femoral or jugular vein. The Hemolung RAS is not intended to provide therapeutic levels of oxygenation. During Hemolung therapy, blood passing through the circuit is oxygenated via room air sweep gas; however, at ultra-low extracorporeal blood flows, the limited oxygen carrying capacity of blood precludes meaningful oxygenation of mixed venous blood.
The Hemolung RAS consists of three main components:
- C. Hemolung Controller is the mechanism for operating the Hemolung Respiratory Assist System. It controls the extracorporeal blood flow rate and the sweep gas flow rate.
- A. Hemolung Cartridge is an integrated extracorporeal gas exchanger and blood pump. Blood is circulated around the outside of the Cartridge's hollow fiber membranes while a sweep gas flows through the inside of the membranes. Carbon dioxide diffuses out of the blood and is swept away by the sweep gas while oxygen diffuses from the sweep gas into the blood. Blood tubing and other accompanying disposable products are included in the Hemolung Cartridge Kit.
- B. Hemolung Catheter is a dual lumen venous catheter designed specifically for use with the Hemolung RAS. It exhibits low resistance to flow while also resisting kinks. Individual femoral and jugular Hemolung Catheter Kits are available for use. Each kit includes a Catheter Insertion Kit.
Mentions image processing
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Mentions AI, DNN, or ML
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Input Imaging Modality
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Anatomical Site
Femoral or jugular vein
Indicated Patient Age Range
Adults
Intended User / Care Setting
Not Found
Description of the training set, sample size, data source, and annotation protocol
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Description of the test set, sample size, data source, and annotation protocol
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Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)
SUMMARY OF NONCLINICAL/BENCH STUDIES
- Pump characterization: The Hemolung system was tested in a recirculation loop using a blood analogue at 37°C. Pressure-flow characteristics were measured for the system at various pump speeds when connected to Hemolung 15.5 Fr Femoral and Jugular Catheters.
- Gas exchange: Gas exchange testing was performed to characterize gas exchange performance of the Hemolung system over the full range of blood and sweep gas flow rates. The system was tested in a recirculation loop using heparinized bovine blood at 37°C. At each blood flow rate (350 mL/min, 450 mL/min, 550 mL/min), gas exchange was measured at 1 L/min, 5.5 L/min and 10 L/min room air sweep gas flow rates. All results are normalized for an inlet pCO2 of 45mmHg.
- Heat loss/gain: Heat loss/gain testing was performed to simulate worst case conditions for heat loss or gain during normal operation of the Hemolung. The system was tested in a recirculation loop using heparinized bovine blood at 37°C and room air sweep gas. Temperatures were measured at the inlet and outlet of the 6' blood lines to account for heat loss/gain across the entire extracorporeal circuit.
- Reliability and Physical Integrity: Reliability testing evaluated physical integrity of the Hemolung system under worst case operating conditions. The test was performed in a recirculation loop of 40:60 glycerol: water, 0.9% NaCl solution at 37°C for a duration of 14 days. The Cartridges were operated at maximum pump speed (1400 RPM), maximum sweep gas flow (10 LPM), and 1.5X the maximum operating pressure. Following the 14-day simulated use, physical integrity of the blood and gas pathways were evaluated, and the Cartridge and Catheter were examined for any wear or corrosion.
- Hemolysis: Hemolysis testing was performed to characterize blood damage within the system by measuring plasma free hemoglobin in a recirculation loop.
- Heparin coating leachability: Phosphate buffered saline (PBS) was recirculated through each Cartridge for a period of 7 days under worst case conditions (37°C, 1400 RPM, 550 mL/min). Eluted heparin was quantified in the PBS solution throughout the test, and fiber mat heparin activity was measured at the conclusion of the 7-day study.
- Catheter Performance Testing:
- Flow Test: Characterize flows and pressures through the catheter in both straight and bent configurations over a range of pump speeds in a recirculation loop using a blood analog at 37°C.
- Physical Requirements: Ensure markings are present on catheters following a simulated soak for 2X the duration of use.
- Kink Resistance: Distal top of the catheter was fixed to a 5cm radium wheel and bent around the wheel 25 times.
- Antiseptic Resistance: Antiseptics were placed on the catheter materials including glue joints and soaked for 24 hours at 37 °C. The antiseptics used were: 10% povidone-iodine solution in water (i.e. Betadine®), 4% Chlorhexidine gluconate, 2% chlorhexidine gluconate in 70% isopropyl alcohol (i.e. Chloraprep®), Bacitracin zinc ointment (i.e. Polysporin®).
- Leak Test (Pressure and vacuum): Catheters placed under vacuum and pressure representing 2X the maximum vacuum and pressure of the system for 10 min using DI water following simulated use.
- Force to Break Test: Measuring the force to break each distinct section of the Catheter using a tensile strain rate of 20mm/min/mm of gauge length.
- Corrosion Resistance: Catheters soaked in a sodium chloride solution for five hours, immersed in boiling distilled water for 30 min and then placed in an oven at 37°C for 48 hours and then inspected for corrosion.
- Ambulation-Dislodgement: Ensure suture ring can secure the catheter during simulated patient ambulation of axial, transverse, and upward forces of 15N and torque each applied for 15 seconds.
- Ambulation-Weight on Catheter: Catheters placed in a water bath at 37°C and the extension tubes were bent in all four directions 25 times to simulate patient movement.
- Recirculation: Recirculation properties of the Catheter were tested in a vena cava simulated flow circuit using both SVC and IVC flow conditions at the minimum and maximum catheter flow rates, as compared to an FDA-approved dialysis catheter.
- Biocompatibility Testing: Biocompatibility testing was performed on all patient contacting components as specified in ISO 10993-1 and Use of International Standard ISO 10993-1, "Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process" - Guidance for Industry and Food and Drug Administration Staff. All components of the system were tested in their final, finished, and sterilized (2X EtO) form.
- Cytotoxicity (ISO-10993-5): MEM Extraction Assay with L929 mammalian fibroblasts.
- Sensitization (ISO 10993-10): Guinea pig maximization test.
- Irritation (ISO 109993-10): Intracutaneous Reactivity.
- Systemic Toxicity (ISO 10993-11): Acute Systemic Injection Test, Material mediated rabbit pyrogen test, Sub Chronic Systemic Injection Test, Leverage from functional large animal study.
- Genotoxicity (ISO 10993-3): Bacterial Mutagenicity Test - Ames Assay, In Vitro Mouse Lymphoma Assay, In Vivo Mouse Bone Marrow Micronucleus Assay.
- Hemocompatibility (ISO 10993-4/A1 & ASTM F756 & ASTM F2382-18 & ASTM F2888-19): Hemolysis; Saline Extract, Hemolysis; Direct Contact, Complement Activation - SC5b-9 Assay, Partial Thromboplastin Time (PTT) with Comparison Article, Heparinized Blood Platelet and Leukocyte Count with Comparison Article, Surface Morphology Assessment, In Vivo thrombogenicity; In Vivo animal study.
- Implantation (ISO 10993-6): In Vivo animal study.
- Shelf-Life Testing:
- Real-Time Aging: Device performance testing was completed using product following 2-year real time aging to characterize any impacts from aging on device performance or safety. The aged products were used to confirm that the device met all of the following product requirements: gas exchange, pump characterization, reliability, heparin stability, catheter performance.
- Accelerated Aging: Device performance testing was completed using 2-year accelerated aged product to support shelf-life where real time aging is not expected to impact device performance. The aged products were used to confirm that the device met all of the following product requirements: hemolysis, heat loss/gain, heparin/uniformity and leachability, verification by analysis, catheter recirculation, in vivo animal study.
- Sterilization Validation: Sterilization validation was performed in accordance with ANSI/AAMI/ISO 11135-1:2014/ AMD1:2018 including two sublethal exposures, four half-cycle exposures, cold conditioning, and one full cycle exposure. An ethylene oxide (EO) sterilization validation study was performed for the Hemolung family of sterile products to confirm a 10-6 sterility assurance level (SAL) for the designated product load and acceptable levels of EO residuals.
- Packaging Validation: A packaging validation study was performed to evaluate the ability of each Hemolung product sterile packaging configuration to maintain strength and integrity of the sterile barriers' seals following simulated shipping and/or aging. Testing was conducted in accordance with ISO 11607-1 Packaging for Terminally Sterilized Medical Devices - Part 1: Requirements for materials, sterile barrier systems, and packaging systems.
- Hardware and Software Verification: The Hemolung CR4 Controller's hardware and software was tested to verify functionality and safety before clinical testing. The following functional areas were tested: interface with disposable components, power system, generation, control, and monitoring of sweep gas flow, CO2 monitoring, blood pump RPM control and monitoring, and blood flow monitoring.
- Electrical Safety and Compliance Testing and other safety-related requirements: Electrical Safety and Compliance Testing was conducted for the Hemolung CR4 Controller to verify functionality and safety before clinical testing. This testing verified compliance with IEC 60601-1 electrical safety standard and IEC 60601-1-8 alarm system standard. This testing consisted of verifying short circuit protection of all off-board connections and operation of AC Power indicator. In addition, testing was conducted to verify detection of air in blood lines. In addition, the testing was used to verify the following functional areas: ventilation to prevent battery damage, measurement of enclosure temperature, and label resistance to bleach, soap and water.
- Electromagnetic Compatibility: Electromagnetic Compatibility Testing was conducted for the Hemolung CR4 Controller to verify conformance with IEC 60601-1-2 and collateral standards and conformance with AIM 7351731.
- Environmental Verification: Environmental Verification Testing was conducted for the Hemolung CR4 Controller to verify fluid ingress rating of IPX1, test shipping to ISTA 3E, and that the Corner drop / Edge drop are in compliance with 60068-2-31. In addition, the following environmental conditions were verified in the testing: 1) operating temperature and humidity from 10C to 35C at 20% to 90% non-condensing humidity, 2) storage temperature and humidity from -20C to 50C at 15% to 95% non-condensing humidity, and 3) altitude requirements: maintain sweep gas for of 10.0 SLPM ±0.3 SLPM at simulated altitudes up to 8000 ft (2500 m).
- Usability: Usability testing was conducted in accordance with IEC 62366-1:2015 to verify user interface components. In the testing, critical care nurses were trained in the use of the system and then after a decay period completed a summative test to validate all disposables-related tasks (unpacking disposables, system priming, recirculation, catheter unpackaging, patient connection, cartridge replacement, rinse back, and vacuum canister replacement).
PERFORMANCE TESTING - ANIMAL
- Study Type: In vivo Animal Study
- Sample Size: Eight (8) male calves
- Methods: Calves were implanted with the Hemolung system. Calves were to be recovered and survived on therapy for 7 days. Blood chemistry, hematology, fibrinogen, plasma free hemoglobin, activated clotting time and hematocrit were regularly tested throughout the study. Calves were routinely observed by veterinary staff and Subjective Objective Assessment Plan examinations were performed by veterinarians. Clinical abnormalities were scored using an abnormality grading scale adapted from the Common Terminology Criteria for Adverse Events. At the end of the therapy, the Hemolung system was shut down and the circuit was thoroughly examined for clots/thrombi. The calves were humanely euthanized, and a detailed necropsy was performed to examine implant site and organs for gross abnormalities, excising representative samples for histopathology. Histopathology was performed on naïve and test catheter implanted sections of the right jugular vein, lungs, heart, lymph nodes, adrenal glands, liver, kidney, spleen and any other tissue with abnormal observations.
- Key Results: There were no major clinical events. Therapy was discontinued early on two (2) of the eight calves: one calf was taken off therapy on Day 1.7 post implant and terminated at Day 2 post implant, and one calf was taken off therapy on Day 6.2 post implant but terminated as planned on Day 7.
- Conclusions: There were no procedural complications directly related to the test article that put the calf's health at risk or created any significant clinical health concerns. There were adjustments required for the anticoagulation therapy as well as for routine maintenance and observation of the catheter. There were no significant health concerns to the calves resulting from these adjustments. Cartridge replacements were not required and cessation of therapy in two calves was due to decreases in blood flow through the test article. There was no clinical evidence of severe coagulation insufficiency in any of the calves. Based on the abnormality grading system, none of the calves were found to have any severe abnormalities that required a grade 3 or higher. The two calves that were taken off therapy were removed due the low blood flow alarms and were not removed for health reasons. Based on the daily PCV values none of the calves were clinically anemic. There was no clinical evidence of hemolysis. Plasma free hemoglobin (PFH) was increased in one calf but was found to be clinically insignificant as the calf did not have evidence of anemia, low hematocrit or hyperbilirubinemia. No obvious indications of excessive bleeding, inflammation, or infection were noted. No evidence of infection was observed at the test Catheter insertion site, and no gross thrombi were noted at the site of the insertion. Overall, the calves remained stable throughout the 7-day time point and did not have any clinical emergencies that threatened the life of the calf.
Hemolung Clinical Performance
- Data Source: 234 patients from prospective clinical trials, real-world use, and the Hemolung Post-market Registry.
- Inclusion Criteria: All 4 of the following criteria were met: 1) Original patient level efficacy data was available, 2) Pre-Hemolung pH and PaCO2 data was available, 3) Data coinciding with at least one additional time point during the first 35 hours after commencement of Hemolung therapy was available, and 4) the patient received Hemolung therapy for at least 6 hours.
- Primary Clinical Outcomes:
-
- Correction of refractory hypercapnia and respiratory acidosis
-
- De-escalation of mechanical ventilatory support while preventing respiratory acidosis
-
- Analysis: Data was stratified based on baseline (Pre-Hemolung) pH: Acidotic patients (pH pH=7.36).
Hemolung Clinical Safety
- Data Source: 1,034 patients receiving Hemolung therapy from four primary sources: 1) monitored and independently adjudicated adverse event data from prospective clinical trials, 2) US Expanded Access or Emergency Use Authorization data collection and surveillance, 3) the OUS post-market Hemolung Registry, and 4) OUS post-market surveillance.
- Therapy-Related Complications:
- A total of 172 therapy-related complications were reported as being definitely, probably, or possibly related to use of the Hemolung, or with unknown determination of causality.
- Total number of patients who experienced therapy-related complications: 121 of 1,034 treatments.
- Of 172 total therapy-related complications: 66 had no patient impact, 96 required medical intervention, and 10 resulted in death.
- No reported unanticipated adverse device events.
- Breakdown of Therapy-Related Complications (n=1034 pts):
- Bleeding: 72 (7.0%)
- Hemolysis: 27 (2.6%)
- Thrombocytopenia: 22 (2.1%)
- Thrombosis/coagulation disorder: 13 (1.3%)
- Hemodynamic instability: 16 (1.6%)
- Other: 22 (2.1%)
- TOTAL # OF THERAPY-RELATED COMPLICATIONS: 172
- Required medical intervention: 96
- Resulted in death: 10
- No patient impact: 66
- Procedural, Operational and Component-Related Complications:
- A total of 128 procedural, operational, and component-related complications were reported.
- Of 128 total complications: 116 had no patient impact, 8 required medical intervention and 4 resulted in death.
- Breakdown of Complications (n=1,034 pts):
- Procedural-related complications: 62 (6.0%)
- Required medical intervention: 7
- Resulted in death: 4
- No patient impact: 51
- Operational-related complications: 33 (3.2%)
- Required medical intervention: 0
- Resulted in death: 0
- No patient impact: 33
- Component-related complications: 33 (3.2%)
- Required medical intervention: 1
- Resulted in death: 0
- No patient impact: 32
- Procedural-related complications: 62 (6.0%)
Key Metrics (Sensitivity, Specificity, PPV, NPV, etc.)
- 91% of Hemolung patients demonstrated a clinically beneficial response, where there was a correction in respiratory acidosis after one day of Hemolung therapy.
- 92% of non-invasively ventilated (NIV) patients avoided intubation and invasive mechanical ventilation (IMV) with Hemolung therapy.
- For acidotic patients failing NIV (n=43). Hemolung therapy resulted in correction of respiratory acidosis (pH =7.24 -> pH=7.36)
Predicate Device(s): If the device was cleared using the 510(k) pathway, identify the Predicate Device(s) K/DEN number used to claim substantial equivalence and list them here in a comma separated list exactly as they appear in the text. List the primary predicate first in the list.
Not Found
Reference Device(s): Identify the Reference Device(s) K/DEN number and list them here in a comma separated list exactly as they appear in the text.
Not Found
Predetermined Change Control Plan (PCCP) - All Relevant Information for the subject device only (e.g. presence / absence, what scope was granted / cleared under the PCCP, any restrictions, etc).
Not Found
§ 870.4150 Extracorporeal system for carbon dioxide removal.
(a)
Identification. An extracorporeal system for carbon dioxide removal is a system of devices and accessories that provides assisted extracorporeal carbon dioxide removal from the patient's blood in patients with acute respiratory failure, where other available treatment options have failed, and continued clinical deterioration is expected or the risk of death is imminent. The main devices and accessories of the system include, but are not limited to, the console (hardware), software, and disposables, including, but not limited to, a gas exchanger, blood pump, cannulae, tubing, filters, and other accessories (e.g., monitors, detectors, sensors, connectors).(b)
Classification. Class II (special controls). The special controls for this device are:(1) In vivo evaluation, which may include animal testing and clinical data, of the devices and accessories in the circuit must demonstrate their performance over the intended duration of use, including a detailed summary of the in vivo evaluation pertinent to the use of the devices and accessories to demonstrate their effectiveness.
(2) The technological characteristics of the device must ensure that the geometry and design parameters are consistent with the intended use, and that the devices and accessories in the circuit are compatible.
(3) Non-clinical performance testing of the devices and accessories in the circuit must demonstrate that the device performs as intended under anticipated conditions of use. The following performance characteristics must be tested:
(i) Mechanical integrity;
(ii) Durability; and
(iii) Reliability.
(4) All patient contacting components of the device must be demonstrated to be biocompatible.
(5) Performance testing must demonstrate the electrical safety and electromagnetic compatibility (EMC) of any electrical components.
(6) Software validation, verification, and hazard analysis must be performed.
(7) Performance testing must demonstrate the sterility of all patient-contacting components.
(8) Performance testing must support the shelf life of the device by demonstrating continued sterility and device functionality over the identified shelf life.
(9) Labeling must include the following:
(i) A detailed summary of the non-clinical and in vivo evaluations pertinent to use of the device and accessories in the circuit;
(ii) Adequate instructions with respect to circuit setup, performance characteristics with respect to compatibility among different devices and accessories in the circuit, and maintenance during a procedure; and
(iii) A shelf life.
0
DE NOVO CLASSIFICATION REQUEST FOR HEMOLUNG RESPIRATORY ASSIST SYSTEM
REGULATORY INFORMATION
FDA identifies this generic type of device as:
Extracorporeal system for carbon dioxide removal. An extracorporeal system for carbon dioxide removal is a system of devices and accessories that provides assisted extracorporeal carbon dioxide removal from the patient's blood in patients with acute respiratory failure, where other available treatment options have failed, and continued clinical deterioration is expected or the risk of death is imminent. The main devices and accessories of the system include, but are not limited to, the console (hardware), software, and disposables, including, but not limited to, a gas exchanger, blood pump, cannulae, tubing, filters, and other accessories (e.g., monitors, detectors, sensors, connectors).
NEW REGULATION NUMBER: 21 CFR 870.4150
CLASSIFICATION: Class II
PRODUCT CODE: QOH
BACKGROUND
DEVICE NAME: Hemolung Respiratory Assist System
SUBMISSION NUMBER: DEN210006
DATE DE NOVO RECEIVED: March 4, 2021
SPONSOR INFORMATION:
ALung Technologies, Inc. 2500 Jane Street. Suite 1 Pittsburgh, Pennsylvania 15203
INDICATIONS FOR USE
The Hemolung Respiratory Assist System is indicated for respiratory support that provides extracorporeal carbon dioxide (CO2) removal from the patient's blood for up to 5 days in adults
with acute, reversible respiratory failure for whom ventilation of CO2 cannot be adequately or safely achieved using other available treatment options and continued clinical deterioration is expected.
1
LIMITATIONS
The sale, distribution, and use of the Hemolung RAS are restricted to prescription use in accordance with 21 CFR 801.109.
Contraindications:
The Hemolung RAS is contraindicated for patients with known sensitivity to heparin (e.g., history of heparin-induced thrombocytopenia). The Hemolung Cartridge membranes are coated with heparin and systemic anticoagulation is required when using the device.
Use of the Hemolung 15.5 Fr Femoral Catheter is contraindicated for patients with an inferior vena cava filter.
PLEASE REFER TO THE LABELING FOR A COMPLETE LIST OF WARNINGS, PRECAUTIONS AND CONTRAINDICATIONS.
DEVICE DESCRIPTION
The Hemolung RAS provides low blood flow, veno-venous extracorporeal carbon dioxide removal (ECCO2R) using a single, 15.5 French dual lumen catheter inserted percutaneously in the femoral or jugular vein. The Hemolung RAS is not intended to provide therapeutic levels of oxygenation. During Hemolung therapy, blood passing through the circuit is oxygenated via room air sweep gas; however, at ultra-low extracorporeal blood flows, the limited oxygen carrying capacity of blood precludes meaningful oxygenation of mixed venous blood.
The Hemolung RAS consists of three main components:
Image /page/1/Figure/9 description: The image shows three different medical devices. Image A shows a cylindrical container with a clear top and bottom and a white filter inside. Image B shows two catheters with red and blue connectors. Image C shows a medical device on wheels with a screen displaying the word "HEMOLLUNG".
C. Hemolung Controller is the mechanism for operating the Hemolung Respiratory Assist System. It controls the extracorporeal blood flow rate and the sweep gas flow rate.
- A. Hemolung Cartridge is an integrated extracorporeal gas exchanger and blood pump. Blood is circulated around the outside of the Cartridge's hollow fiber membranes while a sweep gas flows through the inside of the membranes. Carbon dioxide diffuses out of the blood and is swept away by the sweep gas while oxygen diffuses from the sweep gas into the blood. Blood tubing and other accompanying disposable products are included in the Hemolung Cartridge Kit.
- B. Hemolung Catheter is a dual lumen venous catheter designed specifically for use with the Hemolung RAS. It exhibits low resistance to flow while also resisting kinks. Individual femoral and jugular Hemolung Catheter Kits are available for use. Each kit includes a Catheter Insertion Kit.
2
SUMMARY OF NONCLINICAL/BENCH STUDIES
The following bench studies were performed to demonstrate that the technological characteristics of the Hemolung system are consistent with the device's indication for use:
| Pump characterization | The Hemolung system was tested in a recirculation loop using a blood analogue at 37°C.
Pressure-flow characteristics were measured for the system at various pump speeds when
connected to Hemolung 15.5 Fr Femoral and Jugular Catheters | |
|------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Gas exchange | Gas exchange testing was performed to characterize gas exchange performance of the
Hemolung system over the full range of blood and sweep gas flow rates. The system was
tested in a recirculation loop using heparinized bovine blood at 37°C. At each blood flow
rate (350 mL/min, 450 mL/min, 550 mL/min), gas exchange was measured at 1 L/min, 5.5
L/min and 10 L/min room air sweep gas flow rates. All results are normalized for an inlet
pCO2 of 45mmHg. | |
| Heat loss/gain | Heat loss/gain testing was performed to simulate worst case conditions for heat loss or gain
during normal operation of the Hemolung. The system was tested in a recirculation loop
using heparinized bovine blood at 37°C and room air sweep gas. Temperatures were
measured at the inlet and outlet of the 6' blood lines to account for heat loss/gain across the
entire extracorporeal circuit. | |
| Reliability and
Physical Integrity | Reliability testing evaluated physical integrity of the Hemolung system under worst case
operating conditions. The test was performed in a recirculation loop of 40:60 glycerol:
water, 0.9% NaCl solution at 37°C for a duration of 14 days. The Cartridges were operated
at maximum pump speed (1400 RPM), maximum sweep gas flow (10 LPM), and 1.5X the
maximum operating pressure. Following the 14-day simulated use, physical integrity of the
blood and gas pathways were evaluated, and the Cartridge and Catheter were examined for
any wear or corrosion | |
| Hemolysis | Hemolysis testing was performed to characterize blood damage within the system by
measuring plasma free hemoglobin in a recirculation loop. | |
| Heparin coating
leachability | Phosphate buffered saline (PBS) was recirculated through each Cartridge for a period of 7
days under worst case conditions (37°C, 1400 RPM, 550 mL/min). Eluted heparin was
quantified in the PBS solution throughout the test, and fiber mat heparin activity was
measured at the conclusion of the 7-day study. | |
| Catheter Performance
Testing | Flow Test | Characterize flows and pressures through the catheter in
both straight and bent configurations over a range of pump
speeds in a recirculation loop using a blood
analog at 37°C |
| | Physical Requirements | Ensure markings are present on catheters following a
simulated soak for 2X the duration of use |
| | Kink Resistance | Distal top of the catheter was fixed to a 5cm radium wheel
and bent around the wheel 25 times. |
| | Antiseptic Resistance | Antiseptics were placed on the catheter materials including
glue joints and soaked for 24 hours at 37 °C. The antiseptics
used were:
• 10% povidone-iodine solution in water (i.e.Betadine®),
• 4% Chlorhexidine gluconate,
• 2% chlorhexidine gluconate in 70% isopropyl alcohol (i.e.
Chloraprep®),
• Bacitracin zinc ointment (i.e. Polysporin®) |
| | Leak Test (Pressure and
vacuum) | Catheters placed under vacuum and pressure representing
2X the maximum vacuum and pressure of the system for 10
min using DI water following simulated use. |
| | Force to Break Test | Measuring the force to break each distinct section of the
Catheter using a tensile strain rate of 20mm/min/mm of
gauge length. |
| | Corrosion Resistance | Catheters soaked in a sodium chloride solution for five
hours, immersed in boiling distilled water for 30 min and
then placed in an oven at 37°C for 48 hours and then
inspected for corrosion. |
| | Ambulation-Dislodgement | Ensure suture ring can secure the catheter during simulated
patient ambulation of axial, transverse, and upward forces
of 15N and torque each applied for 15 seconds |
| | Ambulation-Weight on
Catheter | Catheters placed in a water bath at 37°C and the extension
tubes were bent in all four directions 25 times to simulate
patient movement. |
| | Recirculation | Recirculation properties of the Catheter were tested in a
vena cava simulated flow circuit using both SVC and IVC
flow conditions at the minimum and maximum catheter
flow rates, as compared to an FDA-approved dialysis
catheter. |
| Biocompatibility
Testing | Biocompatibility testing was performed on all patient contacting components as specified in
ISO 10993-1 and Use of International Standard ISO 10993-1, "Biological evaluation of
medical devices - Part 1: Evaluation and testing within a risk management process" -
Guidance for Industry and Food and Drug Administration Staff. All components of the
system were tested in their final, finished, and sterilized (2X EtO) form. | |
| | Cytotoxicity (ISO-10993-5) | MEM Extraction Assay with L929 mammalian fibroblasts |
| | Sensitization (ISO 10993-10) | Guinea pig maximization test |
| | Irritation (ISO 109993-10) | Intracutaneous Reactivity |
| | Systemic Toxicity (ISO
10993-11) | Acute Systemic Injection Test
Material mediated rabbit pyrogen test
Sub Chronic Systemic Injection Test
Leverage from functional large animal study |
| | Genotoxicity (ISO 10993-3) | Bacterial Mutagenicity Test - Ames Assay
In Vitro Mouse Lymphoma Assay
In Vivo Mouse Bone Marrow Micronucleus Assay |
| | Hemocompatibility (ISO
10993-4/A1 & ASTM F756
& ASTM F2382-18 &
ASTM F2888-19) | Hemolysis; Saline Extract
Hemolysis; Direct Contact
Complement Activation - SC5b-9 Assay
Partial Thromboplastin Time (PTT) with Comparison
Article
Heparinized Blood Platelet and Leukocyte Count with
Comparison Article
Surface Morphology Assessment
In Vivo thrombogenicity; In Vivo animal study |
| | Implantation (ISO 10993-6) | In Vivo animal study |
| Shelf-Life Testing | Real-Time Aging | Device performance testing was completed using product
following 2-year real time aging to characterize any impacts
from aging on device performance or safety. The aged
products were used to confirm that the device met all of the
following product requirements: gas exchange, pump
characterization, reliability, heparin stability, catheter
performance. |
| | Accelerated Aging | Device performance testing was completed using 2-year
accelerated aged product to support shelf-life where real
time aging is not expected to impact device performance.
The aged products were used to confirm that the device met
all of the following product requirements: hemolysis, heat
loss/gain, heparin/uniformity and leachability, verification
by analysis, catheter recirculation, in vivo animal study. |
| Sterilization
Validation | Sterilization validation was performed in accordance with ANSI/AAMI/ISO 11135-1:2014/
AMD1:2018 including two sublethal exposures, four half-cycle exposures, cold
conditioning, and one full cycle exposure. An ethylene oxide (EO) sterilization validation
study was performed for the Hemolung family of sterile products to confirm a 10-6 sterility
assurance level (SAL) for the designated product load and acceptable levels of EO residuals.
(ISO 11135:2014, ISO 11138-1:2017, ISO 11138-2:2017, ISO 11737-1:2018, ISO 117737-
2: 2019, AAMI TIR No. 14 (2016), 15(2016), 16 (2017)) | |
| Packaging Validation | A packaging validation study was performed to evaluate the ability of each Hemolung
product sterile packaging configuration to maintain strength and integrity of the sterile
barriers' seals following simulated shipping and/or aging. Testing was conducted in
accordance with ISO 11607-1 Packaging for Terminally Sterilized Medical Devices - Part
1: Requirements for materials, sterile barrier systems, and packaging systems.
(ISTA 2A-2011, ISTA 3E:2017, ASTM D 4169-16, ASTM D 6653/D653M-13, ASTM
F1980-16. ASTM F2096-11 (2019), ISO 11607-1: 2019, ASTM F 88/F 88M-15) | |
| Hardware and
Software Verification | The Hemolung CR4 Controller's hardware and software was tested to verify functionality
and safety before clinical testing. The following functional areas were tested: interface with
disposable components, power system, generation, control, and monitoring of sweep gas
flow, CO2 monitoring, blood pump RPM control and monitoring, and blood flow
monitoring.
(ANSI/AMI/IEC 62304:2006 + AMDI: 2015) | |
| Electrical Safety and
Compliance Testing
and other safety-
related requirements | Electrical Safety and Compliance Testing was conducted for the Hemolung CR4 Controller
to verify functionality and safety before clinical testing. This testing verified compliance
with IEC 60601-1 electrical safety standard and IEC 60601-1-8 alarm system standard. This
testing consisted of verifying short circuit protection of all off-board connections and
operation of AC Power indicator. In addition, testing was conducted to verify detection of
air in blood lines.
In addition, the testing was used to verify the following functional areas: ventilation to
prevent battery damage, measurement of enclosure temperature, and label resistance to
bleach, soap and water.
(IEC 60601-1:2015+ AMI: 2012, IEC 60601-1-2:2014, IEC 60601-1-6:2010+A1: 2013, IEC
60601-1-8: 2006 + AMD1:2012) | |
| Electromagnetic
Compatibility | Electromagnetic Compatibility Testing was conducted for the Hemolung CR4 Controller to
verify conformance with IEC 60601-1-2 and collateral standards and conformance with
AIM 7351731.
(IEC 60601-1-2:2014, AIM 7351731, EN 55011:2009+A1:2010, IEC 61000-3-2:2014, IEC
61000-3-3: 2013. IEC 61000-4-2: 2008. IEC 61000-4-3:2010, IEC 61000-4-4:2012, IEC
61000-4-5:2014, IEC 61000-4-6:2013, IEC 61000-4-8:2019. IEC 61000-4-11:2010) | |
| Environmental
Verification | Environmental Verification Testing was conducted for the Hemolung CR4 Controller to
verify fluid ingress rating of IPX1, test shipping to ISTA 3E, and that the Corner drop /
Edge drop are in compliance with 60068-2-31. In addition, the following environmental
conditions were verified in the testing: 1) operating temperature and humidity from 10C to
35C at 20% to 90% non-condensing humidity, 2) storage temperature and humidity from -
20C to 50C at 15% to 95% non-condensing humidity, and 3) altitude requirements: maintain
sweep gas for of 10.0 SLPM ±0.3 SLPM at simulated altitudes up to 8000 ft (2500 m). | |
| Usability | Usability testing was conducted in accordance with IEC 62366-1:2015 to verify user
interface components. In the testing, critical care nurses were trained in the use of the
system and then after a decay period completed a summative test to validate all disposables-
related tasks (unpacking disposables, system priming, recirculation, catheter unpackaging,
patient connection, cartridge replacement, rinse back, and vacuum canister replacement). | |
3
4
PERFORMANCE TESTING - ANIMAL
5
The objective of the in vivo Animal Study was to perform a safety and performance evaluation of the Hemolung system under simulated clinical use.
| Methods: | Eight (8) male calves were implanted with the Hemolung system. Calves were to be recovered
and survived on therapy for 7 days. Blood chemistry, hematology, fibrinogen, plasma free
hemoglobin, activated clotting time and hematocrit were regularly tested throughout the study.
Calves were routinely observed by veterinary staff and Subjective Objective Assessment Plan
examinations were performed by veterinarians. Clinical abnormalities were scored using an
abnormality grading scale adapted from the Common Terminology Criteria for Adverse
Events.
At the end of the therapy, the Hemolung system was shut down and the circuit was thoroughly
examined for clots/thrombi. The calves were humanely euthanized, and a detailed necropsy
was performed to examine implant site and organs for gross abnormalities, excising
representative samples for histopathology. Histopathology was performed on naïve and test
catheter implanted sections of the right jugular vein, lungs, heart, lymph nodes, adrenal glands,
liver, kidney, spleen and any other tissue with abnormal observations. |
|--------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Results: | There were no major clinical events. Therapy was discontinued early on two (2) of the eight
calves: one calf was taken off therapy on Day 1.7 post implant and terminated at Day 2 post
implant, and one calf was taken off therapy on Day 6.2 post implant but terminated as planned
on Day 7. |
| Conclusions: | There were no procedural complications directly related to the test article that put the calf's
health at risk or created any significant clinical health concerns. There were adjustments
required for the anticoagulation therapy as well as for routine maintenance and observation of
the catheter. There were no significant health concerns to the calves resulting from these
adjustments. Cartridge replacements were not required and cessation of therapy in two calves
was due to decreases in blood flow through the test article. There was no clinical evidence of
severe coagulation insufficiency in any of the calves. Based on the abnormality grading
system, none of the calves were found to have any severe abnormalities that required a grade 3
or higher. The two calves that were taken off therapy were removed due the low blood flow
alarms and were not removed for health reasons. Based on the daily PCV values none of the
calves were clinically anemic. There was no clinical evidence of hemolysis. Plasma free
hemoglobin (PFH) was increased in one calf but was found to be clinically insignificant as the
calf did not have evidence of anemia, low hematocrit or hyperbilirubinemia. No obvious
indications of excessive bleeding, inflammation, or infection were noted. No evidence of
infection was observed at the test Catheter insertion site, and no gross thrombi were noted at
the site of the insertion. Overall, the calves remained stable throughout the 7-day time point
and did not have any clinical emergencies that threatened the life of the calf. |
SUMMARY OF CLINICAL INFORMATION
Hemolung Clinical Performance
The clinical performance data provided to support the de novo request included data from 234 patients treated with Hemolung therapies from prospective clinical trials, real-world use, and the Hemolung Post-market Registry. Patients were systematically evaluated for inclusion in the effectiveness analysis if all 4 of the following criteria were met: 1) Original patient level efficacy data was available, 2) Pre-Hemolung pH and PaCO2 data was available, 3) Data coinciding with at least one additional time point during the first 35 hours after commencement of Hemolung therapy was available, and 4) the patient received Hemolung therapy for at least 6 hours. The two primary clinical outcomes used to evaluate effectiveness of Hemolung therapy were:
-
- Correction of refractory hypercapnia and respiratory acidosis
6
OR
-
- De-escalation of mechanical ventilatory support while preventing respiratory acidosis
Data was stratified based on baseline (Pre-Hemolung) pH as follows: Acidotic patients (pH pH=7.36)
- De-escalation of mechanical ventilatory support while preventing respiratory acidosis
Hemolung Clinical Safety
Assessment of Hemolung safety was supported through analysis of clinical complication data from 1,034 patients that received Hemolung therapy Safety data was derived from four primary sources: 1) monitored and independently adjudicated adverse event data from prospective clinical trials, 2) US Expanded Access or Emergency Use Authorization data collection and surveillance, 3) the OUS post-market Hemolung Registry, and 4) OUS post-market surveillance. The Hemolung Registry Form was provided to treating physicians for all commercial therapies outside the US. For commercial therapies completed without a returned Registry Form, ALung post-market surveillance procedures were used to collect safety data directly from the treating physician where possible.
Therapy-Related Complications
A total of 172 therapy-related complications were reported as being definitely, probably, or possibly related to use of the Hemolung, or with unknown determination of causality (Table 1). The total number of patients who experienced therapy-related complications was 121 of the 1,034 treatments (i.e., 172 complications occurred in 121 patients). Of the 172-total therapyrelated complications, 66 had no patient impact, 96 required medical intervention and 10 resulted in death. There were no reported unanticipated adverse device events.
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| Therapy-Related Complications | TOTAL
(n=1034 pts) |
|------------------------------------------------|-----------------------|
| Bleeding (n, incidence) | 72 (7.0%) |
| Hemolysis (n, incidence) | 27 (2.6%) |
| Thrombocytopenia (n, incidence) | 22 (2.1%) |
| Thrombosis/coagulation disorder (n, incidence) | 13 (1.3%) |
| Hemodynamic instability (n, incidence) | 16 (1.6%) |
| Other (n, incidence) | 22 (2.1%) |
| TOTAL # OF THERAPY-RELATED COMPLICATIONS | 172 |
| Required medical intervention | 96 |
| Resulted in death | 10 |
| No patient impact | 66 |
Table 1. Summary of Hemolung therapy-related complications. Bleeding includes complications categorized as bleeding or anemia. Thrombosis/ coagulation disorder includes complications categorized as coagulation disorder, disseminated intravascular coagulopathy, pulmonary embolism, and vein thrombosis. Hemodynamic instability includes complications categorized as cardiac arrythmia, cardiac arrest, hemodynamic instability, hypovolemia, septic shock, and shock.
Procedural, Operational and Component-Related Complications
A total of 128 procedural, operational, and component-related complications were reported (Table 2). Of the 128 total complications, 116 had no patient impact, 8 required medical intervention and 4 resulted in death.
| | TOTAL
(n=1,034 pts) |
|--------------------------------------------------|------------------------|
| Procedural-related complications (n, incidence) | 62 (6.0%) |
| Required medical intervention | 7 |
| Resulted in death | 4 |
| No patient impact | 51 |
| Operational-related complications (n, incidence) | 33 (3.2%) |
| Required medical intervention | 0 |
| Resulted in death | 0 |
| No patient impact | 33 |
| Component-related complications (n, incidence) | 33 (3.2%) |
| Required medical intervention | 1 |
| Resulted in death | 0 |
| No patient impact | 32 |
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Table 2. Summary of Hemolung procedural-related, operational-related and component- related complications
Pediatric Extrapolation
In this De Novo request, existing clinical data were not leveraged to support the use of the device in a pediatric patient population.
LABELING
The Hemolung Respiratory Assist System labeling consists of Instructions for Use that includes a detailed summary of the non-clinical and in vivo evaluations pertinent to use of the device and accessories in the circuit. The Instructions for Use also includes adequate instructions with respect to circuit setup, performance characteristics with respect to compatibility among different devices and accessories in the circuit, and maintenance during a procedure.
RISKS TO HEALTH
The table below identifies the risks to health that may be associated with use of an extracorporeal system for carbon dioxide removal and the measures necessary to mitigate these risks.
| Identified Risks to Health | Mitigation Measures |
|---|---|
| Bleeding, thrombocytopenia, hemolysis, thrombosis | In vivo evaluation |
| Non-clinical performance testing | |
| Labeling | |
| Infection | In vivo evaluation |
| Sterility | |
| Shelf-life testing | |
| Labeling | |
| Adverse tissue and/or | |
| hematologic reaction | In vivo evaluation |
| Biocompatibility | |
| Labeling | |
| Mechanical failure | In vivo evaluation |
| Non-clinical performance testing | |
| Labeling | |
| Software validation, verification, and hazard | |
| analysis | |
| Hemodynamic instability | In vivo evaluation |
| Non-clinical performance testing | |
| Labeling | |
| Hypothermia | In vivo evaluation |
| Non-clinical performance testing | |
| Labeling | |
| Mechanical injury to access | |
| vessels | In vivo evaluation |
| Non-clinical performance testing | |
| Labeling |
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| Inadequate gas exchange | In vivo evaluation
Non-clinical performance testing
Labeling |
|-------------------------|--------------------------------------------------------------------|
| Hemodilution | In vivo evaluation
Non-clinical performance testing
Labeling |
| Gas embolism | In vivo evaluation
Non-clinical performance testing
Labeling |
SPECIAL CONTROLS
In combination with the general controls of the FD&C Act, the extracorporeal system for carbon dioxide removal is subject to the following special controls:
-
- In vivo evaluation, which may include animal testing and clinical data, of the devices and accessories in the circuit must demonstrate their performance over the intended duration of use, including a detailed summary of the in vivo evaluation pertinent to the use of the devices and accessories to demonstrate their effectiveness
-
- The technological characteristics of the device must ensure that the geometry and design parameters are consistent with the intended use, and that the devices and accessories in the circuit are compatible
-
- Non-clinical performance testing of the devices and accessories in the circuit must demonstrate that the device performs as intended under anticipated conditions of use. The following performance characteristics must be tested:
- a. Mechanical integrity:
- b. Durability; and
- c. Reliability.
-
- All patient contacting components of the device must be demonstrated to be biocompatible.
-
- Performance testing must demonstrate the electrical safety and electromagnetic compatibility (EMC) of any electrical components.
-
- Software validation, verification, and hazard analysis must be performed.
-
- Performance testing must demonstrate the sterility of all patient-contacting components.
-
- Performance testing must support the shelf life of the device by demonstrating continued sterility and device functionality over the identified shelf life.
-
- Labeling must include the following:
- a. A detailed summary of the non-clinical and in vivo evaluations pertinent to use of the device and accessories in the circuit; and
- b. adequate instructions with respect to circuit setup, performance characteristics with respect to compatibility among different devices and accessories in the circuit, and maintenance during a procedure; and
- c. A shelf life.
BENEFIT-RISK DETERMINATION
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The benefits and risks of the device are based on nonclinical bench and animal studies as well as clinical data collected in clinical studies described above and real-world evidence.
Hemolung benefits were consistent across primary diagnoses and data sources, demonstrating generalizability of the clinical benefits for numerous acute respiratory failure etiologies. The two primary clinical benefits that were observed were 1) Correction of refractory hypercapnia and respiratory acidosis and 2) De-escalation of mechanical ventilatory support while preventing respiratory acidosis. 91% of Hemolung patients demonstrated a clinically beneficial response to Hemolung therapy. 92% of non-invasively ventilated (NIV) patients avoided intubation and invasive mechanical ventilation (IMV) with Hemolung therapy. The observed benefits are clinically meaningful enough to outweigh the potential complications related to device therapy.
Complications that were Hemolung therapy-related, procedural-related, operational-related, and component-related, occurred with low incidences, most often did not result in any patient harm, and rarely resulted in permanent patient harm or death. Complications from Hemolung therapy included bleeding, thrombosis/ coagulation disorder, and hemodynamic instability. Complications from procedures referred to insertion of the Hemolung Catheter, which is performed using a percutaneous technique. Complications during normal operational use of the Hemolung included circuit thrombosis, low blood flow due to patient/catheter positioning or hypovolemia, air in circuit, catheter dislodgement, and incorrect system setup. These complications are all expected risks of extracorporeal blood circulation. Complications related to Hemolung component failure or malfunction were primarily due to hardware/software issues with the Hemolung Controller, the majority of which have since been resolved through software bug fixes and hardware improvements. All risks from the Hemolung therapy are characterized and mitigated through non-clinical testing, including biocompatibility, in vivo animal studies, sterilization and packaging validation, mechanical reliability, and functional performance and safety testing. In addition, all risks from Hemolung therapy are characterized in ALune's Risk Management System and are appropriately mitigated through special controls. These risks are clinically acceptable and consistent with other technologically similar devices. Overall, the clinical benefits of the Hemolung Respiratory Assist System outweigh the probable risks.
PATIENT PERSPECTIVES
This submission did not include specific information on patient perspectives for this device.
BENEFIT/RISK CONCLUSION
In conclusion, given the available information above, for the following indication statement:
The Hemolung Respiratory Assist System is indicated for respiratory support that provides extracorporeal carbon dioxide (CO2) removal from the patient's blood for up to 5 days in adults with acute, reversible respiratory failure for whom ventilation of CO2 cannot be adequately or safely achieved using other available treatment options and continued clinical deterioration is expected.
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The probable benefits outweigh the probable risks for the Hemolung Respiratory Assist System. 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 Hemolung Respiratory Assist System is granted, and the device is classified as follows:
Product Code: QOH Device Type: Cardiovascular Surgical Devices Regulation Number: 21 CFR 870.4150 Class: II