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.

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, A. Hemolung Cartridge, and B. Hemolung Catheter.

AI/ML Overview

The acceptance criteria for the Hemolung Respiratory Assist System are not explicitly listed in a single table or section, but rather are distributed across sections describing Nonclinical/Bench Studies, Performance Testing - Animal, and Summary of Clinical Information, and further consolidated in the RISKS TO HEALTH and SPECIAL CONTROLS sections. The "device performance" is therefore interpreted as the results from the various tests conducted.

Here is a summary of the acceptance criteria and the device's reported performance based on the provided text:

Hemolung Respiratory Assist System Acceptance Criteria and Reported Performance

Acceptance Criteria Category	Specific Acceptance Criteria (Inferred)	Reported Device Performance and Study that Proves It
Nonclinical/Bench Studies
Pump Characterization	Pressure-flow characteristics consistent with intended use.	Study: Tested in a recirculation loop using a blood analogue at 37°C with various pump speeds and Hemolung 15.5 Fr Femoral and Jugular Catheters. Performance: Data from this testing supports the technological characteristics are consistent with the indication for use (implicit satisfaction of criterion).
Gas Exchange	Gas exchange performance (CO2 removal) across the full range of blood and sweep gas flow rates.	Study: Tested in a recirculation loop using heparinized bovine blood at 37°C. Measured gas exchange at blood flow rates (350, 450, 550 mL/min) and sweep gas flow rates (1, 5.5, 10 L/min room air), normalized for an inlet pCO2 of 45mmHg. Performance: All results implicitly met the requirements, as the study is cited to demonstrate consistency with the indication for use.
Heat Loss/Gain	Maintain appropriate blood temperature during operation (simulate worst-case conditions).	Study: Tested in a recirculation loop using heparinized bovine blood at 37°C with room air sweep gas. Temperatures measured at inlet and outlet of 6' blood lines. Performance: Testing performed to simulate worst case, implicitly met requirements.
Reliability & Physical Integrity	Physical integrity of the system in worst-case operating conditions over 14 days; no wear or corrosion.	Study: Recirculation loop (glycerol:water, NaCl solution at 37°C) for 14 days at max pump speed (1400 RPM), max sweep gas flow (10 LPM), and 1.5X max operating pressure. Evaluated blood/gas pathways, Cartridge, and Catheter for wear/corrosion. Performance: Implied satisfactory as it's included as evidence that consistency with indication for use was demonstrated.
Hemolysis	Acceptable levels of blood damage.	Study: Measured plasma free hemoglobin in a recirculation loop. Performance: Characterized blood damage, implicitly deemed acceptable.
Heparin Coating Leachability	Stable heparin coating over 7 days, with sustained heparin activity.	Study: PBS recirculated through Cartridge for 7 days (37°C, 1400 RPM, 550 mL/min). Eluted heparin quantified, and fiber mat heparin activity measured at conclusion. Performance: Implied satisfactory.
Catheter Performance	Flow characteristics, physical requirements (markings), kink resistance, antiseptic resistance, leak test (pressure/vacuum), force to break, corrosion resistance, ambulation-dislodgement, ambulation-weight, recirculation properties comparable to FDA-approved dialysis catheter.	Study: Various tests listed: Flow, Physical Req., Kink Resistance (5cm radium wheel, 25 bends), Antiseptic Resistance (24h soak with various antiseptics), Leak Test (2X max pressure/vacuum), Force to Break (tensile strain rate), Corrosion Resistance (NaCl soak, boiling water), Ambulation-Dislodgement (15N axial, transverse, upward, torque forces), Ambulation-Weight (extension tubes bent 25 times), Recirculation (vena cava simulated flow circuit, compared to FDA-approved dialysis catheter). Performance: All catheter performance criteria were met, implicitly indicating acceptable results for each test.
Biocompatibility	All patient-contacting components are biocompatible per ISO 10993-1.	Study: Performed on all patient contacting components in final, finished, sterilized form (2X EtO) as per ISO 10993-1. Included Cytotoxicity (MEM Extraction Assay with L929 fibroblasts), Sensitization (guinea pig maximization test), Irritation (intracutaneous reactivity), Systemic Toxicity (Acute/Sub Chronic Injection, Pyrogen test, large animal study leverage), Genotoxicity (Bacterial Mutagenicity, Mouse Lymphoma, Bone Marrow Micronucleus), Hemocompatibility (Hemolysis, Complement Activation, PTT, Platelet/Leukocyte count, Surface Morphology, In Vivo thrombogenicity), and Implantation (In Vivo animal study).Performance: All components passed the specified tests, indicating biocompatibility.
Shelf-Life Testing	Maintain sterility and device functionality for the identified shelf life (2 years).	Study: Real-Time Aging (2 years) and Accelerated Aging. Evaluable aspects included gas exchange, pump characterization, reliability, heparin stability, catheter performance, hemolysis, heat loss/gain, heparin uniformity/leachability, verification by analysis, catheter recirculation, in vivo animal study. Performance: Product performance confirmed to meet all requirements after 2-year real-time aging and accelerated aging, supporting the shelf life.
Sterilization Validation	Achieve 10-6 sterility assurance level (SAL) and acceptable EO residuals.	Study: In accordance with ANSI/AAMI/ISO 11135-1:2014/AMD1:2018 (including sublethal, half-cycle, cold conditioning, full cycle exposures). Performance: Confirmed 10-6 SAL for designated product load and acceptable EO residuals.
Packaging Validation	Maintain strength and integrity of sterile barriers after simulated shipping and aging.	Study: In accordance with ISO 11607-1, 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. Performance: Evaluated ability of packaging to maintain strength and integrity of sterile barriers, implicitly satisfactory.
Hardware & Software Verification	Functionality and safety of Hemolung CR4 Controller hardware and software.	Study: Tested interface with disposables, power, sweep gas generation/control/monitoring, CO2 monitoring, blood pump RPM control/monitoring, blood flow monitoring (ANSI/AMI/IEC 62304:2006 + AMDI: 2015). Performance: Verified functionality and safety.
Electrical Safety & Compliance	Compliance with IEC 60601-1 and IEC 60601-1-8 (alarm systems). Short circuit protection, AC Power indicator, air in blood lines detection, ventilation, enclosure temp measurement, label resistance to bleach/soap/water.	Study: Tested for IEC 60601-1:2015+ AM1: 2012, IEC 60601-1-2:2014, IEC 60601-1-6:2010+A1: 2013, IEC 60601-1-8: 2006 + AMD1:2012. Performance: Verified compliance with standards and tested various functionalities.
Electromagnetic Compatibility	Conformance with IEC 60601-1-2 and collateral standards, and AIM 7351731.	Study: Tested for 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. Performance: Verified conformance with standards.
Environmental Verification	Fluid ingress IPX1, shipping (ISTA 3E), corner/edge drop (60068-2-31), operating temperature/humidity (10-35C, 20-90% RH), storage temperature/humidity (-20-50C, 15-95% RH), altitude (sweep gas 10.0 SLPM ±0.3 SLPM up to 8000 ft).	Study: Tested for fluid ingress (IPX1), shipping (ISTA 3E), corner drop/edge drop (60068-2-31), operating/storage temp/humidity, and altitude requirements. Performance: Verified compliance with environmental conditions.
Usability	User interface components are safe and intuitive; critical tasks (e.g., priming, connection, replacement) can be performed correctly by trained users.	Study: According to IEC 62366-1:2015. Critical care nurses trained, followed by a decay period, then a summative test on disposable-related tasks. Performance: Validated all disposable-related tasks, implicitly satisfactory.
Animal Study (In Vivo)	Safe and effective performance under simulated clinical use for 7 days; no major clinical events, no procedural complications related to test article, no severe abnormalities (grade 3+), no clinical anemia/hemolysis, no excessive bleeding/inflammation/infection, no gross thrombi.	Study (Methods): 8 male calves implanted with Hemolung system for 7 days. Regularly tested blood chemistry, hematology, fibrinogen, plasma free hemoglobin, ACT, hematocrit. Veterinary observations, SOAPE exams, abnormality grading. Necropsy performed to examine implant site and organs for gross abnormalities and histopathology. Performance (Results/Conclusions): No major clinical events. Early therapy discontinuation in 2 calves due to low blood flow alarms (not health reasons). No procedural complications directly related to test article. No significant health concerns. Cartridge replacements not required. No clinical evidence of severe coagulation insufficiency. No grade 3+ abnormalities. No clinical anemia/hemolysis (one calf had increased PFH but clinically insignificant). No obvious excessive bleeding/inflammation/infection. No infection at catheter site. Overall, calves stable for 7 days.
Clinical Performance
Effectiveness	1) Correction of refractory hypercapnia and respiratory acidosis. 2) De-escalation of mechanical ventilatory support while preventing respiratory acidosis. Demonstrate clinically beneficial response (correction of respiratory acidosis). Avoidance of intubation/IMV in NIV patients.	Study: Analysis of data from 234 patients from prospective clinical trials, real-world use, and the Hemolung Post-market Registry. Patients included if they met 4 criteria: original patient-level efficacy data, pre-Hemolung pH/PaCO2, data for at least one additional time point during first 35 hours, received therapy for at least 6 hours. Data stratified by baseline pH (<7.35 for acidotic, >=7.35 for non-acidotic). Acute timepoint (first day) analyzed. Performance: - Demonstrated clinically and statistically significant correction of respiratory acidosis and de-escalation of mechanical ventilatory support. - 91% of Hemolung patients showed a clinically beneficial response (correction in respiratory acidosis after one day of 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 corrected respiratory acidosis (pH =7.24 -> pH=7.36).
Safety	Low incidence of therapy-related, procedural, operational, and component-related complications. Most complications should not result in patient harm, rarely permanent harm or death. Demonstrated characterization and mitigation of risks (bleeding, thrombocytopenia, hemolysis, thrombosis, infection, adverse tissue reaction, mechanical failure, hemodynamic instability, hypothermia, mechanical injury, inadequate gas exchange, hemodilution, gas embolism).	Study: Analysis of clinical complication data from 1,034 patients receiving Hemolung therapy (prospectively monitored AE data, US Expanded Access/EUA, OUS post-market Registry, OUS post-market surveillance). Performance: - Therapy-Related Complications (172 total in 121 patients): Bleeding (7.0%), Hemolysis (2.6%), Thrombocytopenia (2.1%), Thrombosis/coagulation disorder (1.3%), Hemodynamic instability (1.6%), Other (2.1%). 66 had no patient impact, 96 required medical intervention, 10 resulted in death. No unanticipated adverse device events. - Procedural, Operational, and Component-Related Complications (128 total): - Procedural: 62 (6.0%); 7 required intervention, 4 resulted in death, 51 no impact. - Operational: 33 (3.2%); 0 required intervention or death, 33 no impact. - Component-related: 33 (3.2%); 1 required intervention, 0 resulted in death, 32 no impact. - Overall, incidences were low, most did not result in patient harm, and rarely permanent harm or death. Risks are characterized and mitigated via non-clinical testing, animal studies, and special controls.

Additional Information on Studies:

Sample size used for the test set and the data provenance (e.g. country of origin of the data, retrospective or prospective)
- Clinical Effectiveness (Test Set): 234 patients. Data provenance included prospective clinical trials, real-world use, and the Hemolung Post-market Registry. It is implied to be a mix of retrospective and prospective data, but predominantly based on existing patient-level data. The text doesn't specify country of origin for the 234 patients, but mentions "OUS post-market Hemolung Registry" and "OUS post-market surveillance", suggesting international data.
- Clinical Safety (Test Set): 1,034 patients. Data derived from monitored and independently adjudicated adverse event data from prospective clinical trials, US Expanded Access or Emergency Use Authorization data collection and surveillance, the OUS post-market Hemolung Registry, and OUS post-market surveillance. This is a mix of prospective and retrospective (post-market surveillance) data, with both US and OUS (outside US) origins.
Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g. radiologist with 10 years of experience)
- For the clinical safety data (1,034 patients), adverse event data from prospective clinical trials were "monitored and independently adjudicated." The number and qualifications of these adjudicators (experts) are not specified.
- For clinical effectiveness data, the "ground truth" was established by measured clinical outcomes (pH, PaCO2, ventilatory support status). This does not explicitly involve human experts creating a ground truth label in the same way as, for example, image interpretation. The interpretation of these physiological parameters is standard medical practice carried out by treating physicians.
Adjudication method (e.g. 2+1, 3+1, none) for the test set
- For clinical safety, adverse events from prospective clinical trials were "independently adjudicated." The specific method (e.g., 2+1, 3+1) is not provided. For other data sources (real-world use, registries, surveillance), the text does not mention formal adjudication of events by a panel, but rather refers to data collection from treating physicians and surveillance procedures.
If a multi reader multi case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance
- No MRMC comparative effectiveness study was done. The device is not an AI-assisted diagnostic tool for human readers; it is a medical device providing extracorporeal CO2 removal. Therefore, questions regarding "human readers improve with AI vs without AI assistance" are not applicable.
If a standalone (i.e. algorithm only without human-in-the-loop performance) was done
- The Hemolung Respiratory Assist System is a device with hardware, software, and disposables that directly interacts with the patient's blood. Its performance is inherently "standalone" in the sense that its primary function (CO2 removal) is performed by the device itself, not by an algorithm providing information for a human to act on. The "clinical performance" study (234 patients) and "animal study" (8 calves) assess the device's standalone performance in a clinical or simulated clinical setting. The software within the device has undergone validation and verification.
The type of ground truth used (expert consensus, pathology, outcomes data, etc)
- Animal Study: Ground truth was established through direct physiological measurements (blood chemistry, hematology, etc.), veterinary observations, clinical scoring (abnormality grading), and detailed necropsy with histopathology. This is a combination of objective measurements and expert veterinary evaluation of animal health status and pathology.
- Clinical Effectiveness: Ground truth for effectiveness was based on physiological outcomes data, specifically pH and PaCO2 measurements, and the need for or de-escalation of mechanical ventilatory support. These are objective clinical parameters.
- Clinical Safety: Ground truth for safety was based on reported and, in some cases, adjudicated adverse events documented during clinical trials, real-world use, and post-market surveillance. This involves a combination of physician diagnoses, clinical observations, and in some cases, independent adjudication.
The sample size for the training set
- The document explicitly describes the studies conducted to support the de novo request (bench, animal, and clinical performance/safety). It does not mention a "training set" in the context of machine learning. The studies listed are for validation of the device's safety and performance. The device itself is not described as an AI/ML product developed with training data but rather a direct therapeutic device.
How the ground truth for the training set was established
- Not applicable, as no machine learning training set is mentioned for the device itself.

Summary

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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.

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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 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.

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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 whenconnected to Hemolung 15.5 Fr Femoral and Jugular Catheters
Gas exchange	Gas exchange testing was performed to characterize gas exchange performance of theHemolung system over the full range of blood and sweep gas flow rates. The system wastested in a recirculation loop using heparinized bovine blood at 37°C. At each blood flowrate (350 mL/min, 450 mL/min, 550 mL/min), gas exchange was measured at 1 L/min, 5.5L/min and 10 L/min room air sweep gas flow rates. All results are normalized for an inletpCO2 of 45mmHg.
Heat loss/gain	Heat loss/gain testing was performed to simulate worst case conditions for heat loss or gainduring normal operation of the Hemolung. The system was tested in a recirculation loopusing heparinized bovine blood at 37°C and room air sweep gas. Temperatures weremeasured at the inlet and outlet of the 6' blood lines to account for heat loss/gain across theentire extracorporeal circuit.
Reliability andPhysical Integrity	Reliability testing evaluated physical integrity of the Hemolung system under worst caseoperating 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 operatedat maximum pump speed (1400 RPM), maximum sweep gas flow (10 LPM), and 1.5X themaximum operating pressure. Following the 14-day simulated use, physical integrity of theblood and gas pathways were evaluated, and the Cartridge and Catheter were examined forany wear or corrosion
Hemolysis	Hemolysis testing was performed to characterize blood damage within the system bymeasuring plasma free hemoglobin in a recirculation loop.
Heparin coatingleachability	Phosphate buffered saline (PBS) was recirculated through each Cartridge for a period of 7days under worst case conditions (37°C, 1400 RPM, 550 mL/min). Eluted heparin wasquantified in the PBS solution throughout the test, and fiber mat heparin activity wasmeasured at the conclusion of the 7-day study.
Catheter PerformanceTesting	Flow Test	Characterize flows and pressures through the catheter inboth straight and bent configurations over a range of pumpspeeds in a recirculation loop using a bloodanalog at 37°C
	Physical Requirements	Ensure markings are present on catheters following asimulated soak for 2X the duration of use
	Kink Resistance	Distal top of the catheter was fixed to a 5cm radium wheeland bent around the wheel 25 times.
	Antiseptic Resistance	Antiseptics were placed on the catheter materials includingglue joints and soaked for 24 hours at 37 °C. The antisepticsused 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 andvacuum)	Catheters placed under vacuum and pressure representing2X the maximum vacuum and pressure of the system for 10min using DI water following simulated use.
	Force to Break Test	Measuring the force to break each distinct section of theCatheter using a tensile strain rate of 20mm/min/mm ofgauge length.
	Corrosion Resistance	Catheters soaked in a sodium chloride solution for fivehours, immersed in boiling distilled water for 30 min andthen placed in an oven at 37°C for 48 hours and theninspected for corrosion.
	Ambulation-Dislodgement	Ensure suture ring can secure the catheter during simulatedpatient ambulation of axial, transverse, and upward forcesof 15N and torque each applied for 15 seconds
	Ambulation-Weight onCatheter	Catheters placed in a water bath at 37°C and the extensiontubes were bent in all four directions 25 times to simulatepatient movement.
	Recirculation	Recirculation properties of the Catheter were tested in avena cava simulated flow circuit using both SVC and IVCflow conditions at the minimum and maximum catheterflow rates, as compared to an FDA-approved dialysiscatheter.
BiocompatibilityTesting	Biocompatibility testing was performed on all patient contacting components as specified inISO 10993-1 and Use of International Standard ISO 10993-1, "Biological evaluation ofmedical devices - Part 1: Evaluation and testing within a risk management process" -Guidance for Industry and Food and Drug Administration Staff. All components of thesystem 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 (ISO10993-11)	Acute Systemic Injection TestMaterial mediated rabbit pyrogen testSub Chronic Systemic Injection TestLeverage from functional large animal study
	Genotoxicity (ISO 10993-3)	Bacterial Mutagenicity Test - Ames AssayIn Vitro Mouse Lymphoma AssayIn Vivo Mouse Bone Marrow Micronucleus Assay
	Hemocompatibility (ISO10993-4/A1 & ASTM F756& ASTM F2382-18 &ASTM F2888-19)	Hemolysis; Saline ExtractHemolysis; Direct ContactComplement Activation - SC5b-9 AssayPartial Thromboplastin Time (PTT) with ComparisonArticleHeparinized Blood Platelet and Leukocyte Count withComparison ArticleSurface Morphology AssessmentIn 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 productfollowing 2-year real time aging to characterize any impactsfrom aging on device performance or safety. The agedproducts were used to confirm that the device met all of thefollowing product requirements: gas exchange, pumpcharacterization, reliability, heparin stability, catheterperformance.
	Accelerated Aging	Device performance testing was completed using 2-yearaccelerated aged product to support shelf-life where realtime aging is not expected to impact device performance.The aged products were used to confirm that the device metall of the following product requirements: hemolysis, heatloss/gain, heparin/uniformity and leachability, verificationby analysis, catheter recirculation, in vivo animal study.
SterilizationValidation	Sterilization validation was performed in accordance with ANSI/AAMI/ISO 11135-1:2014/AMD1:2018 including two sublethal exposures, four half-cycle exposures, coldconditioning, and one full cycle exposure. An ethylene oxide (EO) sterilization validationstudy was performed for the Hemolung family of sterile products to confirm a 10-6 sterilityassurance 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 Hemolungproduct sterile packaging configuration to maintain strength and integrity of the sterilebarriers' seals following simulated shipping and/or aging. Testing was conducted inaccordance with ISO 11607-1 Packaging for Terminally Sterilized Medical Devices - Part1: Requirements for materials, sterile barrier systems, and packaging systems.(ISTA 2A-2011, ISTA 3E:2017, ASTM D 4169-16, ASTM D 6653/D653M-13, ASTMF1980-16. ASTM F2096-11 (2019), ISO 11607-1: 2019, ASTM F 88/F 88M-15)
Hardware andSoftware Verification	The Hemolung CR4 Controller's hardware and software was tested to verify functionalityand safety before clinical testing. The following functional areas were tested: interface withdisposable components, power system, generation, control, and monitoring of sweep gasflow, CO2 monitoring, blood pump RPM control and monitoring, and blood flowmonitoring.(ANSI/AMI/IEC 62304:2006 + AMDI: 2015)
Electrical Safety andCompliance Testingand other safety-related requirements	Electrical Safety and Compliance Testing was conducted for the Hemolung CR4 Controllerto verify functionality and safety before clinical testing. This testing verified compliancewith IEC 60601-1 electrical safety standard and IEC 60601-1-8 alarm system standard. Thistesting consisted of verifying short circuit protection of all off-board connections andoperation of AC Power indicator. In addition, testing was conducted to verify detection ofair in blood lines.In addition, the testing was used to verify the following functional areas: ventilation toprevent battery damage, measurement of enclosure temperature, and label resistance tobleach, soap and water.(IEC 60601-1:2015+ AMI: 2012, IEC 60601-1-2:2014, IEC 60601-1-6:2010+A1: 2013, IEC60601-1-8: 2006 + AMD1:2012)
ElectromagneticCompatibility	Electromagnetic Compatibility Testing was conducted for the Hemolung CR4 Controller toverify conformance with IEC 60601-1-2 and collateral standards and conformance withAIM 7351731.(IEC 60601-1-2:2014, AIM 7351731, EN 55011:2009+A1:2010, IEC 61000-3-2:2014, IEC61000-3-3: 2013. IEC 61000-4-2: 2008. IEC 61000-4-3:2010, IEC 61000-4-4:2012, IEC61000-4-5:2014, IEC 61000-4-6:2013, IEC 61000-4-8:2019. IEC 61000-4-11:2010)
EnvironmentalVerification	Environmental Verification Testing was conducted for the Hemolung CR4 Controller toverify 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 environmentalconditions were verified in the testing: 1) operating temperature and humidity from 10C to35C 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: maintainsweep 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 userinterface components. In the testing, critical care nurses were trained in the use of thesystem 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).

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PERFORMANCE TESTING - ANIMAL

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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 recoveredand survived on therapy for 7 days. Blood chemistry, hematology, fibrinogen, plasma freehemoglobin, activated clotting time and hematocrit were regularly tested throughout the study.Calves were routinely observed by veterinary staff and Subjective Objective Assessment Planexaminations were performed by veterinarians. Clinical abnormalities were scored using anabnormality grading scale adapted from the Common Terminology Criteria for AdverseEvents.At the end of the therapy, the Hemolung system was shut down and the circuit was thoroughlyexamined for clots/thrombi. The calves were humanely euthanized, and a detailed necropsywas performed to examine implant site and organs for gross abnormalities, excisingrepresentative samples for histopathology. Histopathology was performed on naïve and testcatheter 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 eightcalves: one calf was taken off therapy on Day 1.7 post implant and terminated at Day 2 postimplant, and one calf was taken off therapy on Day 6.2 post implant but terminated as plannedon Day 7.
Conclusions:	There were no procedural complications directly related to the test article that put the calf'shealth at risk or created any significant clinical health concerns. There were adjustmentsrequired for the anticoagulation therapy as well as for routine maintenance and observation ofthe catheter. There were no significant health concerns to the calves resulting from theseadjustments. Cartridge replacements were not required and cessation of therapy in two calveswas due to decreases in blood flow through the test article. There was no clinical evidence ofsevere coagulation insufficiency in any of the calves. Based on the abnormality gradingsystem, none of the calves were found to have any severe abnormalities that required a grade 3or higher. The two calves that were taken off therapy were removed due the low blood flowalarms and were not removed for health reasons. Based on the daily PCV values none of thecalves were clinically anemic. There was no clinical evidence of hemolysis. Plasma freehemoglobin (PFH) was increased in one calf but was found to be clinically insignificant as thecalf did not have evidence of anemia, low hematocrit or hyperbilirubinemia. No obviousindications of excessive bleeding, inflammation, or infection were noted. No evidence ofinfection was observed at the test Catheter insertion site, and no gross thrombi were noted atthe site of the insertion. Overall, the calves remained stable throughout the 7-day time pointand did not have any clinical emergencies that threatened the life of the calf.

Methods:

Eight (8) male calves were implanted with the Hemolung system. Calves were to be recoveredand survived on therapy for 7 days. Blood chemistry, hematology, fibrinogen, plasma freehemoglobin, activated clotting time and hematocrit were regularly tested throughout the study.Calves were routinely observed by veterinary staff and Subjective Objective Assessment Planexaminations were performed by veterinarians. Clinical abnormalities were scored using anabnormality grading scale adapted from the Common Terminology Criteria for AdverseEvents.At the end of the therapy, the Hemolung system was shut down and the circuit was thoroughlyexamined for clots/thrombi. The calves were humanely euthanized, and a detailed necropsywas performed to examine implant site and organs for gross abnormalities, excisingrepresentative samples for histopathology. Histopathology was performed on naïve and testcatheter 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 eightcalves: one calf was taken off therapy on Day 1.7 post implant and terminated at Day 2 postimplant, and one calf was taken off therapy on Day 6.2 post implant but terminated as plannedon Day 7.

Conclusions:

There were no procedural complications directly related to the test article that put the calf'shealth at risk or created any significant clinical health concerns. There were adjustmentsrequired for the anticoagulation therapy as well as for routine maintenance and observation ofthe catheter. There were no significant health concerns to the calves resulting from theseadjustments. Cartridge replacements were not required and cessation of therapy in two calveswas due to decreases in blood flow through the test article. There was no clinical evidence ofsevere coagulation insufficiency in any of the calves. Based on the abnormality gradingsystem, none of the calves were found to have any severe abnormalities that required a grade 3or higher. The two calves that were taken off therapy were removed due the low blood flowalarms and were not removed for health reasons. Based on the daily PCV values none of thecalves were clinically anemic. There was no clinical evidence of hemolysis. Plasma freehemoglobin (PFH) was increased in one calf but was found to be clinically insignificant as thecalf did not have evidence of anemia, low hematocrit or hyperbilirubinemia. No obviousindications of excessive bleeding, inflammation, or infection were noted. No evidence ofinfection was observed at the test Catheter insertion site, and no gross thrombi were noted atthe site of the insertion. Overall, the calves remained stable throughout the 7-day time pointand 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:

1. Correction of refractory hypercapnia and respiratory acidosis

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OR

1. De-escalation of mechanical ventilatory support while preventing respiratory acidosis
  Data was stratified based on baseline (Pre-Hemolung) pH as follows: Acidotic patients (pH < 7.35) were analyzed for correction of refractory hypercapnia and respiratory acidosis; Nonacidotic patients (pH ≥ 7.35) were analyzed for de-escalation of mechanical ventilatory support while preventing respiratory acidosis. An acute timepoint (first day of Hemolung therapy) was chosen to analyze Hemolung clinical effectiveness as the physiologic response from Hemolung therapy is observed within hours of initiating treatment. The acute time frame also eliminates longer-term confounding effects from underlying illness, additional critical care support technologies and patient-specific titration of Hemolung therapy.

The benefits of Hemolung therapy from this clinical data analysis are summarized as follows:

. Extra-corporeal carbon dioxide removal using the Hemolung demonstrated clinically and statistically significant correction of respiratory acidosis and de-escalation of mechanical ventilatory support in patients who have not been on ventilatory support and primarily received standard of care therapy until the Hemolung therapy was initiated
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)

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 evaluationNon-clinical performance testingLabeling
Infection	In vivo evaluationSterilityShelf-life testingLabeling
Adverse tissue and/orhematologic reaction	In vivo evaluationBiocompatibilityLabeling
Mechanical failure	In vivo evaluationNon-clinical performance testingLabelingSoftware validation, verification, and hazardanalysis
Hemodynamic instability	In vivo evaluationNon-clinical performance testingLabeling
Hypothermia	In vivo evaluationNon-clinical performance testingLabeling
Mechanical injury to accessvessels	In vivo evaluationNon-clinical performance testingLabeling

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Inadequate gas exchange	In vivo evaluationNon-clinical performance testingLabeling
Hemodilution	In vivo evaluationNon-clinical performance testingLabeling
Gas embolism	In vivo evaluationNon-clinical performance testingLabeling

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:

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
1. 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
1. 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.
1. All patient contacting components of the device must be demonstrated to be biocompatible.
1. Performance testing must demonstrate the electrical safety and electromagnetic compatibility (EMC) of any electrical components.
1. Software validation, verification, and hazard analysis must be performed.
1. Performance testing must demonstrate the sterility of all patient-contacting components.
1. Performance testing must support the shelf life of the device by demonstrating continued sterility and device functionality over the identified shelf life.
1. 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:

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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

Regulation Number and Section

§ 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.