Organ Care System (OCS™) Lung System

{0} # SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED) # I. GENERAL INFORMATION | Device Generic Name: | Portable Ex-Vivo Organ Perfusion System for Donor Lung Preservation | | --- | --- | | Device Trade Name: | Organ Care System (OCS™) Lung System | | Device Procode: | QBA, PHO | | Applicant's Name and Address: | TransMedics Inc. 200 Minuteman Road, Suite 302 Andover, MA 01810 | | Date of Panel Recommendation: | None | | Premarket Approval Application (PMA) Number: | P160013/S002 | | Date of FDA Notice of Approval: | May 31, 2019 | The original PMA (PMA P160013) was approved on March 22, 2018 and is indicated for the preservation of standard criteria donor lungs in a near physiologic, ventilated, and perfused state for double lung transplantation. The SSED to support the indication is available on the CDRH website (https://www.accessdata.fda.gov/cdrh_docs/pdf16/P160013b.pdf) and is incorporated by reference here. The current supplement was submitted to expand the indication for the OCS™ Lung System to include the "preservation of donor lung pairs initially deemed unacceptable for procurement and transplantation based on limitations of cold static preservation." # II. INDICATION FOR USE The TransMedics Organ Care System (OCS) Lung is a portable, normothermic organ perfusion, ventilation and monitoring medical device indicated for preservation of standard criteria donor lung pairs and for preservation of donor lung pairs initially deemed unacceptable for procurement and transplantation based on limitations of cold static preservation. The device allows for ex vivo assessment of donor lungs prior to transplantation. # III. CONTRAINDICATIONS Moderate to severe traumatic donor lung injury with air leak (as seen on radiological studies, bronchial examination or final visual assessment in donor's chest) to avoid: - Perfusate leakage from injury site into the airways and potential edema formation - Inability to recruit donor lungs due to air leak PMA P160013/S002: FDA Summary of Safety and Effectiveness Data Page 1 {1} # IV. WARNINGS AND PRECAUTIONS PRECAUTIONS— Safety and effectiveness of the OCS™ Lung System is based upon clinical evaluations ≤ 5 years after organ preservation and transplantation. The impact of OCS™ Lung System organ preservation on longer-term clinical outcomes (e.g., incidence of bronchiolitis obliterans syndrome (BOS) and longer-term post-transplantation survival) is unknown. Users are advised to carefully review the available clinical data in Appendix A and B of the Clinical User Guide when considering use of the OCS™ Lung System for any donor organs and recipients. Safety and effectiveness of the OCS™ Lung System for the preservation of isolated single-lung donor organs has not been evaluated. This Clinical User Guide only includes instructions intended for the preservation of en-bloc double-lung donor organs. The safety and effectiveness of the OCS™ Lung System has not been studied in recipients with the following: - Single lung transplant - Prior solid organ or bone marrow transplant - Multi-organ transplants - Chronic use of hemodialysis or diagnosis of chronic renal failure requiring dialysis. Safety and effectiveness of the OCS™ Lung System has not been studied for donor organs with the following: - Hepatitis B and Hepatitis C. - Confirmed active pneumonia or persistent purulent secretions on repeated bronchoscopy evaluation or endotracheal (ET) suction. A device malfunction or user error could lead to a potential loss of a donor organ. Only trained users are allowed to use the OCS™ Lung System. # V. DEVICE DESCRIPTION The TransMedics® OCS™ Lung System consists of the following major components: - Lung Console: The Lung Console is a non-sterile, reusable, portable enclosure that houses an electronic display and non-sterile mechanical and electrical elements required to warm, pump, ventilate, and manage gas content of the perfusate. - Lung Perfusion Set (LPS): The Lung Perfusion Set includes a sterile, single-use perfusion module (Lung Perfusion Module or LPM) and various accessories. The perfusion module consists of an organ chamber and a circulatory system to perfuse and ventilate the lung. The supplied accessories connect the lung to the organ chamber and facilitate the management of fluids within the perfusion module. PMA P160013/S002: FDA Summary of Safety and Effectiveness Data Page 2 {2} - OCS™ Lung Solution: This is the high oncotic solution used for ex-vivo flush and perfusion of donor lungs when combined with packed red blood cells (pRBCs). Figure 1: Major Components of OCS™ Lung System  The OCS™ Lung System performs two primary functions to achieve its intended use: ### 1. Perfusion and Ventilation The OCS™ Lung System preserves ventilated lungs using warm oxygenated cellular perfusate. The system supports several ventilator modes to ensure both preservation and assessment of lung function during retrieval. Ventilator modes of the lung system include the following: Pause Preservation; Preservation; Continuous Monitoring; Bronchoscope Monitoring; and OFF Mode. Figure 2 below shows an overview of the circulation and ventilation. ### 2. Monitoring Capabilities The OCS™ Lung System was designed to provide a means to allow the transplantation team to evaluate the preservation conditions and the function of the organ during transport. The OCS™ Lung System incorporates a number of sensors to assess organ function and the preservation conditions during transportation. Specifically, it monitors lung perfusion flow rates, airway pressure, vascular resistance, temperature, arterial and venous oxygen saturation, and hematocrit (HCT) levels. Please refer to the Clinical User Guide for additional details. PMA P160013/S002: FDA Summary of Safety and Effectiveness Data Page 3 {3} **Figure 2: Conceptual Diagram of the OCS™ Lung System**  ## **VI. ALTERNATIVE PRACTICES AND PROCEDURES** The conventional method for preservation of donor lungs is cold static storage in a preservation solution prior to transplantation. There is one other approved normothermic machine perfusion device for use with initially unacceptable excised donor lungs. ## **VII. MARKETING HISTORY** The OCS™ Lung System was approved for marketing by the FDA on March 22, 2018 for the preservation of standard criteria donor lungs. In December 2011, TransMedics began distribution of the OCS™ Lung System in the European Union under CE-mark authorization. The OCS™ Lung System is classified as a Class IIa device under the European Medical Device Directive 93/42/EEC. The OCS™ Lung System is commercially available and marketed in Australia. The OCS™ Lung System has not been withdrawn from marketing for any reason related to the safety and effectiveness of this system. PMA P160013/S002: FDA Summary of Safety and Effectiveness Data Page 4 {4} ## **VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH** Potential adverse effects of the device on health are related to any deleterious effects to subsequent lung transplantation after a harvested donor organ is preserved or attempted to be preserved using the device. These potential adverse effects include, but are not limited to: - Injury to the donor organ during device instrumentation that - will complicate the transplantation surgical procedure; - necessitates conversion to an alternative preservation strategy, prolonging ischemic preservation time; - leads to loss of the donor organ. - Malfunction of the device that - leads to physiological conditions (e.g., warm ischemia, undesirable ventilatory parameters, or undesirable perfusion parameters) which could adversely affect clinical outcomes of the allograft; - leads to a clinical decision not to proceed with transplantation. - Unknown longer-term outcomes (e.g., survival or BOS occurrence) that could be less clinically desirable than if an alternative preservation strategy had been utilized. Adverse events that were observed in subjects treated with the OCS™ Lung System in the EXPAND clinical trial were numerous, but typical of those that generally do occur with lung transplantation recipients regardless of donor organ preservation. The adverse events included: respiratory failure; pleural effusion; pneumothorax; hemothorax; bronchostenosis; pulmonary embolism; bronchial secretion retention; chylothorax; acute respiratory failure; diaphragmatic paralysis; emphysema; pulmonary edema; pneumonia; lung infection; bronchopneumonia; infection; bronchitis; lung infection pseudomonal; respiratory tract infection; diverticulitis; aspergillosis; fungaemia; parainfluenzae virus infection; postoperative wound infection; pseudomonas infection; toxoplasmosis; atrial fibrillation; cardiac arrest; cardiac failure congestive; tachycardia; myocardial ischaemia; pericarditis; right ventricular failure; ventricular fibrillation; acute renal failure; renal failure; hemorrhage; deep vein thrombosis; ischaemia; haemodynamic instability; orthostatic hypotension; shock; post-procedural hemorrhage; wound dehiscence; complications of transplant surgery; procedural complications; drug toxicity; weaning failure; wound complications; impaired gastric emptying; dysphagia; gastrointestinal haemorrhage; large intestine perforations; diarrhea; duodenal perforation; gastric ulcers; gastritis; gastrointestinal disorder; gastrointestinal ulcer hemorrhage; nausea; pancreatitis; lung transplant rejection; cerebrovascular accident; encephalopathy; brain edema; convulsion; cerebellar ischaemia; cerebral infarction; hypoxic encephalopathy; chest pain; impaired healing; leukopenia; coagulopathy; hyponatremia; myopathy; rhabdomyolysis; mechanical ventilation; transfusion; pyloric stenosis; antibiotic resistant staphylococcus test positive; angioedema; and death. Potential adverse events that may occur but were not observed in the EXPAND Trial include: anemia; cough; gastroesophageal reflux disease; malignancy (post-transplant lymph proliferative disorder (PTLD)); mucus plug; neurological dysfunction; pleural bleeding; and pulmonary infarction. PMA P160013/S002: FDA Summary of Safety and Effectiveness Data Page 5 {5} The rates of adverse events observed in subjects treated with the OCS™ Lung System in the EXPAND are provided in Section X below. ## **IX. SUMMARY OF NONCLINICAL STUDIES** Nonclinical studies were performed on the OCS™ Lung System. Testing was provided in the original P160013. No additional preclinical studies were conducted to support the proposed indication. A summary of previously reported preclinical studies can be found in the Summary of Safety and Effectiveness Data (SSED) for the original PMA (see Section I above). ## **X. SUMMARY OF CLINICAL STUDY** TransMedics conducted the EXPAND clinical study to establish a reasonable assurance of safety and effectiveness of the OCS™ Lung System for the proposed indication under IDE G130019. Data from this clinical study were the basis for the PMA Panel Track supplement approval decision. A summary of the clinical study is presented below. Please refer to the Clinical User Guide of the OCS™ Lung System for additional information on the EXPAND Trial. ### **A. Study Design** EXPAND was a single-arm, multi-center, international, prospective clinical trial to evaluate the safety and effectiveness of the OCS™ Lung System to preserve donor lungs with one or more of the following characteristics: - Donor PaO₂/FiO₂ ≤ 300 mmHg; or - Expected ischemic time > 6 hours; or - Donor after Cardiac Death (DCD donor); or - Donor age ≥ 55 years old. This trial was conducted at 8 institutions in the United States and Europe and included 79 transplanted lung recipients (55 in the US and 24 in Europe). The planned sample size of up to 55 subjects was to be enrolled at a maximum of 15 participating sites in the USA and Europe. Perfusion solution used in the preservation was OCS™ Lung Solution. Only bilateral donor lungs (as opposed to single donor lungs) were included in the study. The EXPAND Trial had oversight by a Data Safety Monitoring Board and utilized a medical monitor for the adjudication of adverse events and Primary Graft Dysfunction (PGD) grading. #### **1. Clinical Inclusion and Exclusion Criteria** Separate inclusion and exclusion criteria were used for prospective donor organs and consented recipients. PMA P160013/S002: FDA Summary of Safety and Effectiveness Data Page 6 {6} # Donor Eligibility Criteria # Inclusion At least one of the following: - Donor PaO₂/FiO₂ ≤ 300 mmHg; or - Expected total ischemic time > 6 hours; or - Donor after Cardiac Death (DCD donor); or - Donor age ≥55 years old. # Exclusion - Presence of moderate to severe traumatic lung injury with air and/or blood leak - Presence of confirmed active pneumonia or persistent purulent secretions on repeated bronchoscopy evaluation or ET suction - Previous history of pulmonary disease - Multiple transfusions of >10 pRBCs units - ABO incompatibility - Tobacco history of >20 packs per year. # Recipient Eligibility Criteria # Inclusion – Day of Transplant - Registered male or female primary double lung transplant candidate - Age ≥18 years old - Signed: 1) written informed consent document and 2) authorization to use and disclose protected health information. # Exclusion – Day of Transplant - Prior solid organ or bone marrow transplant - Single lung recipient - Chronic use of hemodialysis or diagnosis of chronic renal insufficiency. # Donor Lung Acceptance for Transplantation - All donor lungs preserved on OCS Lung must meet the following standard clinical criteria for transplantation at final assessment on OCS Lung: - PaO₂/FiO₂ ≥ 300 mmHg at the end of OCS perfusion - Stable perfusion parameters (PAP, PVR, and PAWP): defined as stable or < 20% worsening of each of these parameters from beginning to end of OCS perfusion. - Clinically acceptable by the center's trial Principle Investigator (PI). PMA P160013/S002: FDA Summary of Safety and Effectiveness Data Page 7 {7} - Any decision to turn down lungs after the lungs have been retrieved, preserved and assessed on OCS™ Lung should be done with notification to the Site PI. ## 2. Follow-up Schedule Follow-up data collection was conducted through the initial 7 days, hospital discharge, 30 days, and 6 months post-transplant, with additional long-term data collection at 12 and 24 months. ## 3. Clinical Endpoints ### Primary Effectiveness Endpoint PGD is a form of acute lung injury that is a known serious complication of lung transplantation. The most severe form, PGD Grade 3 (PGD3), has been shown to be correlated with poor short and long-term outcomes, including reduced survival and increased incidence of Bronchiolitis Obliterans Syndrome (BOS). PGD Grade 2 (PGD2) is also correlated with worse clinical outcomes, though to a lesser degree than PGD3. The effectiveness endpoints evaluated the rates of PGD and survival. The primary effectiveness endpoint was a composite of patient survival at Day 30 post-transplant and absence of PGD3 at all time points up to 72 hours post-transplant (T0T72 hours), with a performance goal of 65%. PGD in this study was graded according to the International Society for Heart and Lung Transplantation (ISHLT) 2005 consensus statement (Appendix A). The primary hypothesis for this trial was that the true proportion of transplanted recipients with composite patient survival at Day 30 post transplantation and freedom of PGD3 at any time point up to 72 hours post-transplant, is greater than 65%. TransMedics based the EXPAND trial performance goal on published data available for PGD3 within the initial 72 hours post-transplant in mostly standard criteria donor lungs (Diamond, et al., 2013). The primary statistical hypotheses were as follows: $$H0: \pi \leq 65\%$$ $$H1: \pi > 65\%,$$ where $\pi$ is the true proportion of transplanted recipients with patient survival at Day 30 and freedom from PGD Grade 3 at any time point up to 72 hours post-transplant. To claim success on this endpoint, the lower bound of the 95% confidence interval must be > 65%. PGD grading, serious adverse events and cause of death were adjudicated by a Medical Monitor. PGD adjudication utilized the ISHLT criteria as outlined in Appendix A. PMA P160013/S002: FDA Summary of Safety and Effectiveness Data Page 8 {8} # Secondary Effectiveness Endpoints - Incidence of ISHLT PGD2 or 3 at T72 hours post-lung transplantation. - Incidence of ISHLT PGD3 at T72 hours post-lung transplantation # Other Endpoints - Duration of initial post-transplant invasive mechanical ventilation - Length of initial post-transplant Intensive Care Unit (ICU) stay - Length of initial post-transplant hospital stay - PGD Scores at T0, T24, T48, and T72 hours - Incidence of BOS at 6, 12, and 24 months post-transplantation. # Safety Endpoint The safety endpoint was the number of lung-graft-related serious adverse events (LGRSAE) through the 30 days post-transplantation per subject. A LGRSAE is defined as the occurrence of any of the following four categories of adverse events that are also serious. Reporting of the safety endpoint included the average number of LGRSAEs per patient, with multiple occurrences of SAE of the same category on the same subject within 30 days counted as one LGRSAE. - Acute rejection (biopsy-proven) - Respiratory failure - Bronchial anastomotic complication - Major pulmonary-related infection. # B. Accountability of PMA Cohort The analysis population in the EXPAND Trial consists of all patients who were transplanted in the trial with an eligible donor lung that had been preserved with OCS. At the time of database lock, of 79 patients (recipients) enrolled in the PMA study, 79 patients (100%) were available for analysis at the completion of the study (the 12-month post-transplantation visit) and all could be determined to be dead or alive at that time point. There were no patients lost to follow-up in this period. In the EXPAND trial, 93 donor lungs were preserved and assessed on the OCS™ Lung System. Of those, 12 donor lungs (13%) were turned down for transplantation due to failing to meet the clinical transplantability criteria while on the OCS™ Lung System. The clinical reasons for discarding the perfused lungs were: - N= 6 – Donor lung contusion and open lung injury resulting in air and perfusate leakage into the bronchoalveolar space - N= 4 – Unstable OCS™ Lung perfusion parameters and persistent low P/F ratio - N=1 – Persistent lung edema - N=1 – Persistent purulent secretions. PMA P160013/S002: FDA Summary of Safety and Effectiveness Data Page 9 {9} Eight-one (81) donor lungs (87%) met the EXPAND defined clinical transplantability criteria on OCS Lung System. Two (2) of the donor lungs that met transplantability criteria were not transplanted: - N=1 – Recipient was determined to have lung cancer on day of transplantation. - N=1 – Surgical team was not available to perform the transplant due to surgical emergency. This resulted in 79 transplants in the EXPAND trial. The donor lung disposition is presented in Figure 3 below. Figure 3: Donor Lung Disposition in the EXPAND Trial  ### C. Study Population Demographics and Baseline Parameters Donor demographic baseline characteristics and risk factors for donor lungs transplanted in EXPAND are shown in Table 1 below. The retrieved donor lungs met several eligibility criteria including donor age ≥ 55 years (39%), expected cross clamp time > 6 hours for the second lung (32%), PaO₂/FiO₂ ≤ 300 mmHg at final offer (25%) and DCD (33%). Twenty-one (21) of the 79 donors (26.6%) had more than one donor inclusion criterion met. Table 2 shows the donor demographic baseline characteristics and risk factors for donors in EXPAND with one donor inclusion criteria met. Note that in the sections that follow, the overall transplanted recipient population (N=79) includes recipients who received donor lungs with multiple inclusion criteria met (N=21) and recipients of donors with a single inclusion criterion met (N=58). PMA P160013/S002: FDA Summary of Safety and Effectiveness Data Page 10 {10} **Table 1: Donor Demographics by Inclusion Criteria – ALL Donors (N=79)** | | PaO_{2}/FiO_{2} Ratio ≤ 300 mmHg (N=20) mean ± SD Median Range | Expected Cross Clamp Time > 6 hours (N=25) mean ± SD Median Range | DCD Donor (N=26) mean ± SD Median Range | Donor Age ≥ 55 (N= 31) mean ± SD Median Range | All Donors (N=79) mean ± SD Median Range | | --- | --- | --- | --- | --- | --- | | PaO_{2}/FiO_{2} Ratio (mmHg) | 239 ± 47 254 (135-295) | 378 ± 122 376 (190 – 624) | 407 ± 81 416 (250 – 624) | 398 ± 106 400 (144 – 663) | 378 ± 110 383 (135 – 663) | | Observed Cross Clamp Time (min) | 603 ± 88 593 (452 – 800) | 643 ± 124 608 (432 – 864) | 608 ± 146 599 (359 – 899) | 604 ± 134 581 (353 – 1047) | 609 ± 127 590 (353 – 1047) | | Donor Age (Years) | 42 ± 16 45 (17 – 68) | 38 ± 14 40 (17 – 62) | 40 ± 14 41 (17 – 69) | 63 ± 6 62 (55 – 76) | 47 ± 16 50 (17 – 76) | | **Additional Demographics & Risk Factors** | | | | | | | Female gender: % (n/N) | 25.0% (5/20) | 28.0% (7/25) | 34.6% (9/26) | 54.8% (17/31) | 41.8% (33/79) | | Abnormal Findings on Inspection and Palpation % (n/N) | 30.0% (6/20) | 12.0% (3/25) | 26.9% (7/26) | 50.0% (15/30) | 32.1% (25/78) | | Abnormal Imaging Findings % (n/N) | 75.0% (15/20) | 75.0% (18/24) | 57.7% (15/26) | 67.7% (21/31) | 65.4% (51/78) | **Table 2: Donor Demographics by Inclusion Criteria for Donors with a Single Inclusion Criteria met (N=58)** | Parameter | Donor PaO_{2}/FiO_{2} ratio ≤ 300 mmHg (N=9) mean ± SD Median Range | Expected total ischemic time > 6 hours (N=11) mean ± SD Median Range | Donor experienced cardiac death (DCD donor) (N=16) mean ± SD Median Range | Donor ≥ 55 years old (N=22) mean ± SD Median Range | All Donors (N=58) mean ± SD Median Range | | --- | --- | --- | --- | --- | --- | | PaO_{2}/FiO_{2} Ratio (mmHg) | 240.6 ± 48.6 245.4 135.0 - 295.0 | 426.70 ± 85.0 399.7 307.0 - 559.0 | 407.6 ± 51.4 426.7 312.0 - 492.0 | 442.5 ± 84.0 429.5 305.0 - 663.0 | 398.4 ± 99.4 401.0 135.0 - 663.0 | | Observed Cross Clamp Time (min) | 610.6 ± 92.0 588.0 524 - 761 | 637.1 ± 106.9 640.0 432 - 821 | 565.1 ± 140.9 513.5 359 - 899 | 606.7 ± 147.0 581.0 353 - 1047 | 601.6 ± 130.5 584.5 353 - 1047 | | Donor Age (Years) | 34.7 ± 12.5 34.0 17.0 - 53.5 | 36.3 ± 11.8 40.2 17.5 - 52.7 | 41.8 ± 10.3 43.8 25.1 - 54.0 | 63.7 ± 6.5 62.5 55.1 - 76.0 | 48.0 ± 15.8 49.9 17.0 - 76.0 | PMA P160013/S002: FDA Summary of Safety and Effectiveness Data Page 11 {11} | Parameter | Donor PaO2/FiO2 ratio ≤ 300 mmHg (N=9) mean ± SD Median Range | Expected total ischemic time > 6 hours (N=11) mean ± SD Median Range | Donor experienced cardiac death (DCD donor) (N=16) mean ± SD Median Range | Donor ≥ 55 years old (N=22) mean ± SD Median Range | All Donors (N=58) mean ± SD Median Range | | --- | --- | --- | --- | --- | --- | | **Additional Demographics & Risk Factors** | | | | | | | Female gender % (n/N) | 22.2% (2/9) | 54.5% (6/11) | 50.0% (8/16) | 59.1% (13/22) | 50.0% (29/58) | | Abnormal Findings on Inspection and Palpation % (n/N) | 33.3% (3/9) | 18.2% (2/11) | 18.8% (3/16) | 52.4% (11/21) | 33.3% (19/57) | | Abnormal Imaging Findings % (n/N) | 66.7% (6/9) | 80.0% (8/10) | 50.0% (8/16) | 59.1% (13/22) | 61.4% (35/57) | The EXPAND recipient demographic and baseline characteristics are shown in Table 3 below. Mean Lung Allocation Score (LAS) was 42 and median 37. There were 22.8% (18/79) of recipients diagnosed with idiopathic pulmonary fibrosis (IPF) and 27.8% (22/79) were diagnosed with secondary pulmonary hypertension. Table 3: Recipient Demographic and Baseline Characteristics | | OCS EXPAND Lung Recipients (n=79) | | --- | --- | | Age (Years): Mean ± SD | 55.56 ± 10.58 | | Gender (% Female) | 41.8 | | BMI (kg/m²) Mean ± SD | 24.49 ± 4.57 | | LAS Score (n=70) Mean ± SD | 42.0 ± 13.49 | | Median | 37.0 | | **Primary Diagnosis** | | | • Chronic obstructive pulmonary disease/Emphysema | 34.2% (27/79) | | • Idiopathic pulmonary fibrosis (IPF) | 22.8% (18/79) | | • Cystic Fibrosis | 15.2% (12/79) | | • Nonspecific interstitial pneumonia | 6.3% (5/79) | | • Bronchiectasis | 5.1% (4/79) | | • Sarcoidosis | 2.5% (2/79) | | • Other | 13.9% (11/79) | | **Secondary Pulmonary Hypertension** | 27.8% (22/79) | PMA P160013/S002: FDA Summary of Safety and Effectiveness Data Page 12 {12} TransMedics obtained match run data from the United Network for Organ Sharing (UNOS)/Organ Procurement and Transplantation Network (OPTN) database on the number of donor offers that were turned down by other transplant centers, prior to the organ being accepted into the EXPAND trial and being instrumented on the OCS™ Lung System. Of the 93 lungs instrumented on OCS, 67 were in the U.S. and UNOS/OPTN data are available on 66 of these 67 U.S. donor lungs. No match run data is available on Outside the United States (OUS) donor lungs. The 66 donor lungs were refused by other centers an average of 35.3 times (median 21, 25% percentile 6.25 times and 75% percentile 49.75 times), with a range of 0 to 197 rejections prior to the donor lung acceptance in the EXPAND trial and instrumentation on the OCS™ Lung System. #### **D. Donor Lung Preservation Characteristics** Donor Lung preservation characteristics are shown in Figure 4 below. Note that total out of body time (also referred to as cross-clamp time) is the time from aortic cross clamp application in the donor to the pulmonary artery (PA) cross-clamp removal in the recipient. During OCS perfusion, the donor lung is perfused with oxygenated blood perfusate and ischemic times are limited to small windows of time during donor procurement and during surgical re-implantation into the recipient. Thus, the ischemic time is different from the total cross clamp time. The total out of body time averaged 8.5 and 10.2 hours for the first and second lung respectively, while the average ischemic times for the first and second donor lungs was 2.6 and 3.9 hours, respectively. **Figure 4: Total Out of Body Time and Ischemic Time for First and Second Lung in EXPAND Trial**  PMA P160013/S002: FDA Summary of Safety and Effectiveness Data Page 13 {13} A comparison of the perfusion and ventilation parameters at initial and final assessments on the OCS™ Lung System are shown in Figure 5 below for Vascular Resistance and Peak Airway Pressure. A comparison between the average final PaO₂/FiO₂ ratio in donor chest and PaO₂/FiO₂ ratio at final assessment on the OCS™ Lung System on room air is also shown. Note that the timepoint of “initial” PaO₂/FiO₂ ratio differs from that of “initial” perfusion and ventilation parameters, with the former occurring prior to donor organ procurement and the latter occurring after the resected organ has been stabilized on the device. Figure 5: Comparison of Initial and Final Mean OCS Assessments for EXPAND Donor Lungs  ### E. Safety and Effectiveness Results #### 1. Safety Results The EXPAND trial safety endpoint was defined as the number of LGRSAEs up to 30 days follow-up after lung transplantation, consisting of the following categories: - acute rejection (biopsy proven); - respiratory failure; - bronchial anastomotic complications; - and major pulmonary-related infection. Multiple occurrences of the same category of events in one patient were counted once only, and thus the safety endpoint did not necessarily reflect the overall burden of LGRSAEs. The safety endpoint’s average for the EXPAND subjects was 0.3 ± 0.47. The safety outcomes for this study are presented below in Table 4. Adverse effects are reported in Tables 5 to 6. PMA P160013/S002: FDA Summary of Safety and Effectiveness Data Page 14 {14} **Table 4: Safety Endpoint for Lung EXPAND Trial and Listing of LGRSAEs** | Number of lung-graft-related serious adverse (LGRSAE) events up to the 30-day follow-up after transplantation (at most one per type)^{1} | OCS EXPAND (N= 79) | | --- | --- | | Mean ± SD | 0.3 ± 0.47 | | Median | 0.0 | | Min.-Max. | 0.0 - 2.0 | | 95% Confidence Interval of mean^{2} | (0.1, 0.4) | | Type of LGRSAEs n (%) | OCS EXPAND (N= 79) | | Acute Rejection | 0 (0%) | | Respiratory Failure^{3} | 12 (15.2%) | | Bronchial Anastomotic Complication | 0 (0%) | | Major Pulmonary-Related Infection | 7 (8.9%) | | ^{1} Multiple occurrences of the same category of events on one patient are counted once only. ^{2} Confidence interval calculated based on the t-distribution. ^{3} Need for re-intubation, tracheostomy or the inability to discontinue ventilator support within 4 days post-transplant. | | There were 12 patients in the EXPAND trial who had the LGRSAE of respiratory failure. Six of these 12 patients (50%) with respiratory failure had DCD donors. Eight of the 12 patients had PGD3 within 72 hours, but only two of these had PGD3 that persisted through 72 hours (one patient did not have PGD results available at T72). None of the patients developed BOS. One of these patients died at Day 352 post-transplant and another patient died at Day 393 post-transplant. The LGRSAE of respiratory failure for both EXPAND and INSPIRE was defined as: impairment of respiratory function requiring re-intubation, tracheostomy or the inability to discontinue invasive ventilatory support within 4 days (96 hours) post-transplant. Reintubation does not necessarily mean the transplanted lung is functioning poorly. # **Adverse effects that occurred in the PMA clinical study:** Table 5 below shows the adverse events by type that were observed in the EXPAND trial, and Table 6 below shows the adjudicated SAEs by System Organ Class and Preferred term for EXPAND subjects. **Table 5: Adverse Events by Type in EXPAND Trial** | Parameter | OCS Expand N = 79 | | --- | --- | | Subjects with Any Type of Adverse Events | 67 (84.8%) | | Subjects with Adverse Events Probably or Definitely Related to OCS^{1} | 0 (0.0%) | | Subjects with Unanticipated Adverse Device Effect (UADE) | 0 (0.0%) | | Subjects with at least one Serious Adverse Event | 61 (77.2%) | | Deaths up to 12 months | 7 (8.9%) | | ^{1} Relatedness determined by site investigators | | PMA P160013/S002: FDA Summary of Safety and Effectiveness Data Page 15 {15} **Table 6: List of Adjudicated SAEs By System Organ Class and Preferred Term – Transplanted Recipient Population through 30 days of follow up in EXPAND Trial** | System Organ Class/Preferred Term | OCS (N=79) | | | --- | --- | --- | | | Subjects n (%) | Events n (%) | | Total | 61 (77.2%) | 121 (100.0%) | | **Cardiac disorders** | **9 (11.4%)** | **9 (7.4%)** | | Arrhythmia supraventricular | 1 (1.3%) | 1 (0.8%) | | Atrial fibrillation | 5 (6.3%) | 5 (4.1%) | | Atrial flutter | 1 (1.3%) | 1 (0.8%) | | Supraventricular tachycardia | 2 (2.5%) | 2 (1.7%) | | **Gastrointestinal disorders** | **1 (1.3%)** | **1 (0.8%)** | | Pancreatitis | 1 (1.3%) | 1 (0.8%) | | **General disorders and administration site conditions** | **1 (1.3%)** | **1 (0.8%)** | | Multi-organ failure | 1 (1.3%) | 1 (0.8%) | | **Hepatobiliary disorders** | **1 (1.3%)** | **1 (0.8%)** | | Haemobilia | 1 (1.3%) | 1 (0.8%) | | **Immune system disorders** | **2 (2.5%)** | **2 (1.7%)** | | Anaphylactic shock | 1 (1.3%) | 1 (0.8%) | | Lung transplant rejection | 1 (1.3%) | 1 (0.8%) | | **Infections and infestations** | **27 (34.2%)** | **38 (31.4%)** | | Bronchitis | 1 (1.3%) | 1 (0.8%) | | Bronchopneumonia | 1 (1.3%) | 1 (0.8%) | | Bronchopulmonary aspergillosis | 2 (2.5%) | 2 (1.7%) | | Candida pneumonia | 1 (1.3%) | 1 (0.8%) | | Clostridial infection | 2 (2.5%) | 2 (1.7%) | | Cytomegalovirus infection | 1 (1.3%) | 1 (0.8%) | | Device related infection | 1 (1.3%) | 1 (0.8%) | | Enterobacter tracheobronchitis | 1 (1.3%) | 1 (0.8%) | | Fungal infection | 1 (1.3%) | 1 (0.8%) | | Infection | 3 (3.8%) | 3 (2.5%) | | Lung infection pseudomonal | 2 (2.5%) | 2 (1.7%) | | Oesophageal infection | 1 (1.3%) | 1 (0.8%) | | Pneumonia | 8 (10.1%) | 8 (6.6%) | | Pneumonia bacterial | 1 (1.3%) | 2 (1.7%) | | Pneumonia klebsiella | 2 (2.5%) | 3 (2.5%) | | Pneumonia staphylococcal | 2 (2.5%) | 2 (1.7%) | | Pseudomonas infection | 3 (3.8%) | 3 (2.5%) | | Pulmonary tuberculosis | 1 (1.3%) | 1 (0.8%) | | Respiratory syncytial virus infection | 1 (1.3%) | 1 (0.8%) | | Respiratory tract infection | 1 (1.3%) | 1 (0.8%) | | **Injury, poisoning and procedural complications** | **16 (20.3%)** | **18 (14.9%)** | | Arterial injury | 2 (2.5%) | 2 (1.7%) | | Bronchial anastomosis complication | 1 (1.3%) | 1 (0.8%) | PMA P160013/S002: FDA Summary of Safety and Effectiveness Data Page 16 {16} | | OCS (N=79) | | | --- | --- | --- | | System Organ Class/Preferred Term | Subjects n (%) | Events n (%) | | Deep vein thrombosis postoperative | 1 (1.3%) | 1 (0.8%) | | Endotracheal intubation complication | 1 (1.3%) | 1 (0.8%) | | Nerve injury | 1 (1.3%) | 1 (0.8%) | | Operative haemorrhage | 2 (2.5%) | 2 (1.7%) | | Post procedural haemorrhage | 6 (7.6%) | 6 (5.0%) | | Post procedural pulmonary embolism | 1 (1.3%) | 1 (0.8%) | | Postoperative thoracic procedure complication | 1 (1.3%) | 1 (0.8%) | | Procedural complication | 1 (1.3%) | 1 (0.8%) | | Wound dehiscence | 1 (1.3%) | 1 (0.8%) | | **Investigations** | **1 (1.3%)** | **1 (0.8%)** | | Clostridium test positive | 1 (1.3%) | 1 (0.8%) | | **Metabolism and nutrition disorders** | **2 (2.5%)** | **2 (1.7%)** | | Hypernatraemia | 2 (2.5%) | 2 (1.7%) | | **Musculoskeletal and connective tissue disorders** | **2 (2.5%)** | **2 (1.7%)** | | Compartment syndrome | 1 (1.3%) | 1 (0.8%) | | Osteopenia | 1 (1.3%) | 1 (0.8%) | | **Nervous system disorders** | **1 (1.3%)** | **1 (0.8%)** | | Horner's syndrome | 1 (1.3%) | 1 (0.8%) | | **Psychiatric disorders** | **6 (7.6%)** | **6 (5.0%)** | | Delirium | 6 (7.6%) | 6 (5.0%) | | **Renal and urinary disorders** | **4 (5.1%)** | **4 (3.3%)** | | Renal failure | 3 (3.8%) | 3 (2.5%) | | Renal failure acute | 1 (1.3%) | 1 (0.8%) | | **Respiratory, thoracic and mediastinal disorders** | **28 (35.4%)** | **31 (25.6%)** | | Acute respiratory failure | 1 (1.3%) | 1 (0.8%) | | Bronchial secretion retention | 2 (2.5%) | 2 (1.7%) | | Chylothorax | 2 (2.5%) | 2 (1.7%) | | Haemothorax | 2 (2.5%) | 2 (1.7%) | | Hypercapnia | 1 (1.3%) | 1 (0.8%) | | Hypoxia | 2 (2.5%) | 2 (1.7%) | | Pleural effusion | 2 (2.5%) | 2 (1.7%) | | Pneumonia aspiration | 2 (2.5%) | 2 (1.7%) | | Pneumothorax | 3 (3.8%) | 3 (2.5%) | | Respiratory failure | 12 (15.2%) | 14 (11.6%) | | **Vascular disorders** | **4 (5.1%)** | **4 (3.3%)** | | Deep vein thrombosis | 2 (2.5%) | 2 (1.7%) | | Iliac artery occlusion | 1 (1.3%) | 1 (0.8%) | | Lymphocele | 1 (1.3%) | 1 (0.8%) | | Notes: Number of subjects refers to the number of subjects with at least one serious adverse event of the indicated type. Number of events refers to all events of the indicated type. Percentages are calculated based on the total number of subjects in the Transplanted Recipient Population, or the total number of events, as appropriate. For number of subjects, subjects experiencing multiple events under the same system organ class/preferred term are counted only once for that system organ class/preferred term. | | | PMA P160013/S002: FDA Summary of Safety and Effectiveness Data Page 17 {17} ## 2. Primary Effectiveness Endpoint The primary effectiveness endpoint of patient survival at Day 30 post-transplant and freedom from PGD3 within initial 72 hours for the EXPAND trial did not meet the pre-specified performance goal of 65%, as the 95% lower confidence interval was 42.8%. Table 7 below shows the results of the primary effectiveness endpoint. **Table 7: Results for Primary Effectiveness Endpoint for the EXPAND Trial** | Results for Primary Effectiveness Endpoint | Transplanted Recipients (N= 79) | | --- | --- | | **Patient survival at Day 30 post-transplantation and absence of ISHLT PGD grade 3 in the first 72 hours** | | | Number (n) | 43 | | Proportion (%) (n/N) | 54.4% (43/79) | | 95% CI (%) for Proportion^{1} | (42.8%, 65.7%) | | Performance Goal^{2} | 65% | | p-value^{3} | 0.9663 | | ^{1} Clopper-Pearson exact confidence interval for a binomial proportion. | | | ^{2} The primary effectiveness endpoint is not met since the lower bound of the 95% confidence interval is 42.8%, which is lower than the Performance Goal of 65%. | | | ^{3} The p-value is based on a one-sided exact binomial test, testing the null hypothesis that the true proportion is less than or equal to 65% versus the alternative hypothesis that the true proportion is greater than 65% (Performance Goal). | | A comparison of the primary endpoint results stratified by donor inclusion criteria is provided in Section X(E)(6), and a comparison of survival and PGD3 results for the overall EXPAND population compared to INSPIRE control is shown in Section X(E)(7). ### 2.1 Day 30 Survival Component of the Primary Effectiveness Endpoint The results for the patient survival at Day 30 post-transplantation component of the primary effectiveness endpoint for the EXPAND trial are shown in Table 8 below. **Table 8: Results for components of Primary Effectiveness Endpoint for the EXPAND trial: Patient Survival at Day 30 Post-Transplant** | | Transplanted Recipients (N= 79) | | --- | --- | | **Patient survival at Day 30 post-transplantation** | | | Number (n) | 78 | | Proportion ^{1} (%) (n/N) | 98.7% (78/79) | | 95% CI (%) for Proportion^{2} | (93.1%, 100%) | | ^{1} Observed proportion = n/N *100%. | | | ^{2} Clopper-Pearson exact confidence interval for a binomial proportion. | | PMA P160013/S002: FDA Summary of Safety and Effectiveness Data Page 18 {18} 2.2 PGD3 within 72 Hours Component of the Primary Effectiveness Endpoint The results for the PGD3 within 72 Hours component of the primary effectiveness endpoint for the EXPAND trial are shown in Table 9 below. Table 9: Results for components of Primary Effectiveness Endpoint for the EXPAND trial: Absence of PGD3 within 72 hours post-transplant | | Transplanted Recipients (N= 79) | | --- | --- | | **Absence of ISHLT PGD grade 3 in the first 72 hours post-transplantation** | | | Number (n) | 44 | | Proportion ^{1} (%) (n/N) | 55.7% (44/79) | | 95% CI (%) for Proportion^{2} | (44.1%, 66.9%) | | ^{1} Observed proportion = n/N *100%. ^{2} Clopper-Pearson exact confidence interval for a binomial proportion. | | 3. Secondary Effectiveness Endpoints The results for the secondary endpoints, i.e., PGD2 or PDG3 at T72 and PDG3 at T72, are shown in Table 10 below for the EXPAND transplanted recipient population overall. One patient was ungradable at T48 and T72 due to missing arterial blood gas (ABG) and/or chest X-ray (CXR). A comparison of the Secondary Endpoint results stratified by donor inclusion criteria are provided in Section X(E)(6). A comparison of the secondary endpoint results for the overall population compared to INSPIRE control are shown in Section X(E)(7). Table 10: Results for Secondary Effectiveness Endpoints in EXPAND Trial | | Transplanted Recipients (N= 79) | | --- | --- | | **Incidence of PGD2 or PGD3 at T72 hours post-transplantation** | | | Number (n) | 13 | | Proportion ^{1} (%) (n/N) | 16.7% (13/78) | | 95% CI (%) for Proportion^{2} | (9.2%, 26.8%) | | **Incidence of PGD3 at T72 hours post-transplantation** | | | Number (n) | 5 | | Proportion ^{1} (%) (n/N) | 6.4% (5/78) | | 95% CI (%) for Proportion^{2} | (2.1%, 14.3%) | | ^{1} Observed proportion = n/N *100%. ^{2} Clopper-Pearson exact confidence interval for a binomial proportion. | | 4. Other Endpoints ICU, Ventilation, and Hospitalization Times The duration of initial post-transplant ventilation, the length of initial post-transplant ICU time and length of initial post-transplant hospital stay are shown in Table 11 below. PMA P160013/S002: FDA Summary of Safety and Effectiveness Data Page 19 {19} **Table 11: ICU, Ventilation, and Hospitalization Times** | | Transplanted Recipients (N=79) | | --- | --- | | **Duration of Initial Post-Transplant Mechanical Ventilation (Hours)** | | | Mean ± SD | 180.6 ± 397.2 | | Median | 37.0 | | Min.-Max. | 5.2 – 2620.5 | | **Length of Initial Post-Transplant ICU Stay (Hours)** | | | Mean ± SD | 266.8 ± 292.0 | | Median | 155.7 | | Min.-Max. | 32.3 – 1370.5 | | **Length of Initial Post-Transplant Hospital Stay (Days)** | | | Mean ± SD | 30.9 ± 26.1 | | Median | 23.0 | | Min.-Max. | 10-151 | # ISHLT PGD Grades at T0, T24, T48, and T72 Hours Post-transplant The PGD grades at T0, T24, T48 and T72 for EXPAND subjects are listed in Table 12 below. Note that one patient was ungradable at T48 and T72 due to missing ABG and/or CXR. In the PMA review of INSPIRE (see P160013’s SSED), evaluation of the primary effectiveness endpoint included both PGD3 at T72 and PGD3 within 72 hours (i.e., T0, T24, T48, and T72). In EXPAND, only PGD3 within 72 hours was assessed for the primary effectiveness endpoint. **Table 12: Listing of ISHLT PGD Grades at T0, T24, T48, and T72 Hours for Transplanted Recipients in EXPAND Trial** | PGD Grade | Transplanted OCS Recipients (N=79) | | --- | --- | | **T0 hour** | | | 0 | 17.7% (14/79) | | 1 | 16.5% (13/79) | | 2 | 25.3% (20/79) | | 3 | 40.5% (32/79) | | **T24 hour** | | | 0 | 26.6% (21/79) | | 1 | 38.0% (30/79) | | 2 | 19.0% (15/79) | | 3 | 16.5% (13/79) | | **T48 hour** | | | 0 | 29.5% (23/78) | | 1 | 50.0% (39/78) | | 2 | 11.5% (9/78) | | 3 | 9.0% (7/78*) | PMA P160013/S002: FDA Summary of Safety and Effectiveness Data Page 20 {20} | PGD Grade | Transplanted OCS Recipients (N=79) | | --- | --- | | **T72 hour** | | | 0 | 35.9% (28/78) | | 1 | 47.4% (37/78) | | 2 | 10.3% (8/78) | | 3 | 6.4% (5/78*) | | *one patient was ungradable at T48 and T72 due to missing ABG and/or CXR. | | #### Incidence of BOS at 6 and 12 Months BOS is the most common long-term complication after lung transplantation and is the leading cause of long-term graft failure. As shown in Table 13 below, the incidence of BOS diagnosis for the EXPAND trial was 0% and 1.4% (1/74) at 6- and 12-months follow-up timepoints, respectively. Longer-term Freedom from BOS for EXPAND subjects is shown in Section X(E)(7), along with a comparison to INSPIRE control subjects. **Table 13: BOS through 12 months for EXPAND transplanted recipients** | | EXPAND Transplanted Recipient Population (N=79) | | --- | --- | | **BOS by 6 months** | | | Incidence of BOS, n/N (%) | 0/78^{1} (0.0%) | | 95% CI* | (0.0%, 4.6%) | | **BOS by 12 months** | | | Incidence of BOS, n/N (%) | 1/74^{2} (1.4%) | | 95% CI* | (0.0%, 7.3%) | | *Clopper-Pearson exact confidence interval for a binomial proportion | | | ^{1}Excludes one patient who died before 6 months | | | ^{2}Excludes five patients who died before 12 months | | #### 5. Adjunct Effectiveness Analyses ##### Patient Survival The results for patient survival at 30 days, 6 months, 12 months, and 24 months in the EXPAND study are shown in Figure 6. The OPTN/Scientific Registry of Transplant Patient (SRTR) national averages for the same time periods are 96.2%, 90.2%, 85% and 76%, respectively (Valapour, et al. 2018). Longer-term survival of EXPAND subjects compared to survival of INSPIRE control subjects and UNOS National averages is described in Section X(E)(7). PMA P160013/S002: FDA Summary of Safety and Effectiveness Data Page 21 {21} **Figure 6: Patient Survival for all EXPAND recipients (N=79) through 24 Months Post-transplant**  #### Utilization Rate In the EXPAND trial, 93 donated lungs were instrumented and assessed on the OCS™ Lung System. Twelve (13%) donor lungs failed to meet the trial’s transplantation criteria on OCS™ Lung System, resulting in 81 (87%) donor lungs designated as appropriate for transplantation. Two (2.2%) donor lungs were not transplanted due to recipient and logistics screen failures. Utilization rate for the Lung EXPAND study is shown in Table 14 below. **Table 14: Donor Lung Utilization in the EXPAND trial** | Donor Lung Utilization in the EXPAND Trial | Number of donor Lungs | | --- | --- | | OCS Perfused Lungs | 93 | | Did not meet transplant criteria after OCS perfusion | 12 | | Met transplant criteria after OCS perfusion | 81 | | Recipients transplanted with the OCS lungs | 79 | | OCS perfused lungs not transplanted | 2 | | | **Rate % (n/N)** | | Rate of transplanted lungs among OCS perfused lungs % (n/N) | 85% (79/93) | | 95% Confidence Interval | (76.0%, 91.5%) | | Rate of utilizable lungs after OCS perfusion, % (n/N) | 87% (81/93) | | 95% Confidence Interval | (78.6%, 93.2%) | #### 6. Post-hoc Subgroup Analyses of EXPAND Results Stratified by Donor Inclusion Criteria The types of donor lungs studied in EXPAND were heterogeneous in their characteristics. The aggregate results primarily reflect a donor population defined PMA P160013/S002: FDA Summary of Safety and Effectiveness Data Page 22 {22} more by clinicians' decisions to avoid cold static preservation than by the donor lungs *per se* being clinically sub-optimal as 'extended-criteria' donors. The majority of donor lungs were accepted into the study because of meeting a solitary inclusion criterion. Post-marketing use of the device is also expected to be dominated by donor organs with solitary (not multiple) criteria prompting physicians' decisions to choose the device. Therefore, FDA requested post hoc analyses of effectiveness endpoint assessments in the subgroups of patients who received donor organs accepted into the study on the basis of a solitary donor inclusion criterion. FDA believes these analyses provide important information about the safety and effectiveness of the device for real-world applications. Although caution is needed when interpreting *post hoc* analyses with relatively small sample sizes, a reasonable inference is that clinical results may vary depending upon the reason(s) for which donor organs have been initially deemed unacceptable for procurement and transplantation. Post-hoc subgroup results for the primary effectiveness endpoint are displayed in Table 15 below for recipients of donors with a single criterion met (N=58), recipients of donors with multiple criteria met (N=21) and all recipients (all donors, N=79), stratified by donor inclusion criteria. Analogous results for the components of the primary effectiveness endpoint, patient survival at Day 30 and freedom from PGD3 within 72 hours post-transplant are shown in Table 16 and Table 17, respectively. **Table 15: Post-hoc subgroup analyses of Primary Effectiveness Endpoint stratified by donor inclusion criteria for recipients of donors with a single criterion met (N=58), recipients of donors with multiple inclusion criteria met (N=21) and for all transplanted recipients (all donors, N=79).** | | Survival at Day 30 Post-Transplant and Freedom from PGD3 within 72 hours post-transplant | | --- | --- | | **Recipients of Donors with a Single Criterion Met (N=58)** | **58.6% (34/58)** | | • PaO_{2}/FiO_{2} ≤ 300 mm Hg (N=9) | 55.6% (5/9) | | • Donor Age ≥ 55 (N=22) | 63.6% (14/22) | | • Expected Cross-Clamp Time > 6 hr (N=11) | 63.6% (7/11) | | • DCD (N=16) | 50.0% (8/16) | | **Recipients of Donors with Multiple Criteria Met (N=21)** | **42.9% (9/21)** | | • PaO_{2}/FiO_{2} ≤ 300 mm Hg (N=11) | 63.6% (7/11) | | • Donor Age ≥ 55 (N=9) | 44.4% (4/9) | | • Expected Cross-Clamp Time > 6 hr (N=14) | 35.7% (5/14) | | • DCD (N=10) | 20.0% (2/10) | | **All Recipients – All Donor Inclusion Criteria (N=79)** | **54.4% (43/79)** | | • PaO_{2}/FiO_{2} ≤ 300 mm Hg (N=20) | 60% (12/20) | | • Donor Age ≥ 55 (N=31) | 58.1% (18/31) | | • Expected Cross-Clamp Time > 6 hr (N=25) | 48% (12/25) | | • DCD (N=26) | 38.5% (10/26) | PMA P160013/S002: FDA Summary of Safety and Effectiveness Data Page 23 {23} **Table 16: Post-hoc subgroup analyses of component of Primary Effectiveness Endpoint: Patient Survival at Day 30 Post-Transplant stratified by donor inclusion criteria for recipients of donors with a single criterion met (N=58), recipients of donors with multiple inclusion criteria met (N=21) and for all transplanted recipients (all donors, N=79).** | | Patient Survival at Day 30 Post-Transplant | | --- | --- | | **Recipients of Donors with a Single Criterion Met (N=58)** | **98.3% (57/58)** | | • PaO_{2}/FiO_{2} ≤ 300 mm Hg (N=9) | 100% (9/9) | | • Donor Age ≥ 55 (N=22) | 100% (22/22) | | • Expected Cross-Clamp Time > 6 hr (N=11) | 90.9% (10/11) | | • DCD (N=16) | 100.0% (16/16) | | **Recipients of Donors with Multiple Criteria Met (N=21)** | **100% (21/21)** | | • PaO_{2}/FiO_{2} ≤ 300 mm Hg (N=11) | 100% (11/11) | | • Donor Age ≥ 55 (N=9) | 100% (9/9) | | • Expected Cross-Clamp Time > 6 hr (N=14) | 100% (14/14) | | • DCD (N=10) | 100% (10/10) | | **All Recipients – All Donor Inclusion Criteria (N=79)** | **98.7% (78/79)** | | • PaO_{2}/FiO_{2} ≤ 300 mm Hg (N=20) | 100% (20/20) | | • Donor Age ≥ 55 (N=31) | 100% (31/31) | | • Expected Cross-Clamp Time > 6 hr (N=25) | 96.0% (24/25) | | • DCD (N=26) | 100% (26/26) | **Table 17: Post-hoc subgroup analyses of Component of Primary Effectiveness Endpoint: Freedom from PGD3 within 72 hours post-transplant, stratified by donor inclusion criteria for recipients of donors with a single criterion met (N=58), recipients of donors with multiple inclusion criteria met (N=21) and for all transplanted recipients (all donors, N=79).** | | Freedom from PGD3 within 72 hours post-transplant | | --- | --- | | **Recipients of Donors with a Single Criterion Met (N=58)** | **60.3% (35/58)** | | • PaO_{2}/FiO_{2} ≤ 300 mm Hg (N=9) | 55.6% (5/9) | | • Donor Age ≥ 55 (N=22) | 63.6% (14/22) | | • Expected Cross-Clamp Time > 6 hr (N=11) | 72.7% (8/11) | | • DCD (N=16) | 50.0% (8/16) | | **Recipients of Donors with Multiple Criteria Met (N=21)** | **42.9% (9/21)** | | • PaO_{2}/FiO_{2} ≤ 300 mm Hg (N=11) | 63.6% (7/11) | | • Donor Age ≥ 55 (N=9) | 44.4% (4/9) | | • Expected Cross-Clamp Time > 6 hr (N=14) | 35.7% (5/14) | | • DCD (N=10) | 20.0% (2/10) | | **All Recipients – all Donor Inclusion Criteria (N=79)** | **55.7% (44/79)** | | • PaO_{2}/FiO_{2} ≤ 300 mm Hg (N=20) | 60.0% (12/20) | | • Donor Age ≥ 55 (N=31) | 58.1% (18/31) | | • Expected Cross-Clamp Time > 6 hr (N=25) | 52.0% (13/25) | | • DCD (N=26) | 38.5% (10/26) | PMA P160013/S002: FDA Summary of Safety and Effectiveness Data Page 24 {24} The results for the secondary endpoints (PGD2 or 3 at T72 and PGD3 at T72) are shown in Figure 7 below, stratified by donor inclusion criteria. **Figure 7: Secondary Endpoint Results (PGD2 or PGD3 at T72 post-transplant and PGD3 at T72 post-transplant) for EXPAND Trial Overall Population (N=79) and Stratified by Donor Inclusion Criteria**  # Post-hoc Subgroup Analysis of Donation after Circulatory Death (DCD) and Donation after Brain Death (DBD) Donors In the EXPAND trial, the incidence of PGD3 at T0 for DCD Transplants was 62% (16/26) compared to the incidence of PGD3 at T0 for DBD Transplants which was 30% (16/53) (see Figure 8). **Figure 8: Incidence of PGD3 at each timepoint for EXPAND Recipients stratified by DCD vs DBD Donor lungs**  PMA P160013/S002: FDA Summary of Safety and Effectiveness Data Page 25 {25} ### Post-hoc Subgroup Analyses of BOS In the EXPAND trial, there were 35 subjects with PGD3 and 44 subjects without PGD3 in the first 72 hours post-transplant. The results for Kaplan-Meier (K-M) Analysis of Freedom from BOS for EXPAND subjects with and without PGD3 in the first 72 hours post-transplant are shown in Figure 9. As expected, subjects with PGD3 showed a higher incidence of BOS compared to subjects without PGD3. Note that data at 36 months post-transplant is available for 57% of EXPAND subjects since follow-up is on-going. **Figure 9: K-M Analysis of BOS for EXPAND Recipients with PGD3 vs. without PGD3 within 72 Hours Post-Transplant**  The results for the K-M analyses of BOS through 36 months, stratified by donor inclusion criteria is shown in Figure 10 below for recipients of donor lungs with a single donor criterion met (N=58), respectively. Note that data at 36 months post-transplant is available for 57% of EXPAND subjects since follow-up is on-going. PMA P160013/S002: FDA Summary of Safety and Effectiveness Data Page 26 {26} Figure 10: K-M Analysis of Freedom from BOS for EXPAND Stratified by Donor Inclusion Criteria for Recipients with Single Donor Inclusion Criterion Met (N=58)  ### Post-hoc Subgroup Analyses of Patient Survival The results for the K-M analyses of patient survival through 36 months, stratified by donor inclusion criteria are shown in Figure 11 below for recipients of donor lungs with a single donor criterion met (N=58), respectively. Note that data at 36 months post-transplant is available for 57% of EXPAND subjects since follow-up is on-going. PMA P160013/S002: FDA Summary of Safety and Effectiveness Data Page 27 {27} **Figure 11: K-M Analysis of Survival of EXPAND Subjects Stratified by Donor Inclusion Criteria for Transplanted Recipients who had a Single Donor Inclusion Criterion (N=58)**  ## 7. Comparison of Lung EXPAND Results to INSPIRE Control Group EXPAND was a single-arm study. However, the recipient enrollment criteria in EXPAND were the same as those of the contemporaneous, randomized and controlled INSPIRE trial. Additionally, although the studies were designed to evaluate different types of donor lungs, there was in fact overlap between the two studies in the characteristics of the donor lungs used. Accordingly, FDA had pre-specified that an adjunctive analysis compare the EXPAND results to those of the INSPIRE Control group (see SSED for original P160013). FDA believes this large group of subjects who received standard criteria lungs preserved using standard of care cold static storage can serve as an informative benchmark comparator when drawing inferences from EXPAND’s clinical results Table 18 below compares the demographic data for donors and recipients in the EXPAND trial and the INSPIRE control group, who received standard criteria donor lungs preserved on cold static storage, including various donor and recipient factors as identified in Diamond, et al. (2013). Although the recipient inclusion/exclusion criteria were the same for the two trials, some differences were observed. The percentage of recipients with BMI > 25 was 50.6% (40/79) for EXPAND compared to 34.2% (63/184) for INSPIRE control. The mean LAS Score was 42 for the EXPAND recipients and 48 for the INSPIRE Control group. The prevalence of secondary pulmonary hypertension PMA P160013/S002: FDA Summary of Safety and Effectiveness Data Page 28 {28} was 28% (22/79) in the EXPAND recipients compared to 32% (59/184) in the INSPIRE control group. For donor risk factors, 23.0% (42/184) of INSPIRE donors had a history of smoking > 20 pack-years compared to 1.3% (1/79) of donors for EXPAND (Note: Smoking > 20 pack-years was an exclusion criterion in EXPAND, but not INSPIRE). 39.2% (31/79) EXPAND donors had age ≥ 55 years compared to 17.5% (32/184) for INSPIRE control, 25.3% (20/79) EXPAND Donors had PaO₂/FiO₂ ≤ 300 mmHg compared to 0% (0/0) for INSPIRE control and 65.4% (51/79) EXPAND donors had abnormal findings on chest X-ray compared to 48.3% (85/184) for INSPIRE control. **Table 18: Comparison of Recipient and Donor Demographics for EXPAND Trial Recipients and INSPIRE Control Recipients (Standard criteria donors, preserved on cold storage)** | | EXPAND Transplanted Recipients N=79 | INSPIRE Control Recipients N=184 | | --- | --- | --- | | **Donor Characteristics** | | | | Donor Age ≥ 55 years, n (%) | 31 (39.2%) | 32 (17.5%) | | Female Gender, n (%) | 33 (41.8%) | 73 (39.7%) | | Smoking > 20 pack years, n (%) | 1 (1.3%) | 42 (23.0%) | | PaO₂/FiO₂ ratio ≤ 300 mmHg, n (%) | 20 (25.3%) | 0 (0.0%) | | History of Aspiration, n (%) | 3 (3.8%) | 19 (10.4%) | | Head trauma as cause of death, n (%) | 8 (10.1%) | 50 (27.2%) | | Abnormal findings on chest X-ray, n (%) | 51 (65.4%) | 85 (48.3%) | | **Recipient Characteristics** | | | | Cardiopulmonary bypass, n (%) | 38 (48.1%) | 70 (38.0%) | | BMI > 25, n (%) | 40 (50.6%) | 63 (34.2%) | | Diagnosis of COPD, n (%) | 27 (34.2%) | 53 (28.8%) | | Diagnosis of sarcoidosis, n (%) | 2 (2.5%) | 9 (4.9%) | | Diagnosis of cystic fibrosis, n (%) | 12 (15.2%) | 43 (23.4%) | | Diagnosis of idiopathic pulmonary fibrosis (IPF), n (%) | 18 (22.8%) | 64 (34.8%) | | Diagnosis of secondary pulmonary hypertension, n (%) | 22 (27.8%) | 59 (32.2%) | | Use of pre-transplant ECMO, n (%) | 1 (1.3%) | 10 (5.5%) | | Use of pre-transplant mechanical ventilation, n (%) | 3 (3.8%) | 10 (5.5%) | | History of heart failure, n (%) | 1 (1.3%) | 13 (7.2%) | | History of insulin dependent diabetes, n (%) | 19 (24.1%) | 40 (21.7%) | | LAS – Mean ± SD (n/N) | 42 ± 14 (70/79) | 48 ± 18 (125/184) | #### Comparison of PGD for EXPAND and INSPIRE Control Recipients The results for PGD3 within 72 hours post-transplant in the EXPAND transplanted recipient population are higher than the INSPIRE control population, but the results for PGD3 at T72 are comparable to those observed for the PMA P160013/S002: FDA Summary of Safety and Effectiveness Data Page 29 {29} INSPIRE Control group. Similarly, results for PGD2 or PGD3 at T72 post-transplant were higher in the EXPAND recipients compared to the INSPIRE control recipients (See Table 19). **Table 19: Comparison of PGD post-transplant for EXPAND trial recipients and INSPIRE control group (standard criteria donor lungs preserved on cold storage)** | | EXPAND Trial Transplanted Recipients N=79 | INSPIRE Trial Control Group N=184 | | --- | --- | --- | | PGD3 within T72 post-transplant (T0, T24, T48 and T72) | 35/79 (44.3%) | 53/184 (28.8%) | | PGD3 at T0 post-transplant | 32/79 (40.5%) | 38/184 (20.7%) | | PGD3 at T24 post-transplant | 13/79 (16.5%) | 20/184 (10.9%) | | PGD3 at T48 post-transplant | 7/78 (9.0%) | 12/183 (6.6%) | | PGD3 at T72 post-transplant | 5/78 (6.4%) | 10/183 (5.5%) | | PGD2 or PGD3 at T72 post-transplant | 13/78 (16.7%) | 20/183 (10.9%) | A post-hoc analysis of PGD3 within the initial 72 hours was performed using logistic regression to adjust for the identified differences. Terms were included for treatment, donor age $\geq 55$ years, donor smoking $> 20$ pack years, donor P/F ratio $\leq 300$ mmHg, donor head trauma as cause of death, donor abnormal findings on chest X-ray, and recipient BMI $> 25$. Regarding PGD3, the adjusted rates are higher in the EXPAND group when compared to the INSPIRE control group regardless of the other variables. #### Comparison of Patient Survival through 36 Months for EXPAND and INSPIRE Control Recipients Figure 12 below shows the K-M post-transplant patient survival results through 36 months in the EXPAND trial compared to the recipients of standard donor lungs preserved on cold storage in the Control arm of the INSPIRE trial. Analyses at 36 months are based on available data. Figure 13 compares the results for the EXPAND trial to the results of the OPTN/SRTR national average statistics for patient survival post-lung transplantation through 24 months post-transplant. PMA P160013/S002: FDA Summary of Safety and Effectiveness Data Page 30 {30} **Figure 12: K-M Overall Survival through 36 Months Post-transplant for EXPAND Subjects Compared to INSPIRE Control**  **Figure 13: Comparison of Patient survival in the EXPAND trial overall population (N=79) to INSPIRE Control Group (N=184) and to US National Average post-lung transplantation (Valapour, et al. 2018).**  PMA P160013/S002: FDA Summary of Safety and Effectiveness Data Page 31 {31} # Comparison of Freedom from BOS through 36 months post-transplant for EXPAND and INSPIRE Control Recipients The results for K-M analyses for Freedom from BOS for EXPAND recipients compared to INSPIRE control group through 36 months post-transplant are shown in Figure 14. The comparative K-M analysis for BOS-free survival (Survival and Freedom from BOS) through 36 months is shown in Figure 15. The analyses at 36 months are based on available data. TransMedics will continue to evaluate this trend for 5 years post-transplant in a post-market study of EXPAND subjects. **Figure 14: K-M Analysis of Freedom from BOS through 36 Months Post-transplant, EXPAND Recipients Compared to INSPIRE Control**  PMA P160013/S002: FDA Summary of Safety and Effectiveness Data Page 32 {32} **Figure 15: K-M Analysis of BOS-free Survival through 36 Months Post-transplant, EXPAND Recipients Compared to INSPIRE control** | Follow-up Timepoint | Patient Accounting | | | | | | --- | --- | --- | --- | --- | --- | | | Month 0 | Month 6 | Month 12 | Month 24 | Month 36 | | EXPAND – OCS – Patients at Risk | 79 | 74 | 71 | 59 | 22 | | Patient Censored | -- | 0 | 0 | 2 | 32 | | Patient with BOS or Died | -- | 5 | 8 | 18 | 25 | | INSPIRE – Standard of Care (SOC) – Patients at Risk | 184 | 165 | 155 | 137 | 95 | | Patient Censored | -- | 0 | 0 | 0 | 29 | | Patient with BOS or Died | -- | 19 | 29 | 47 | 60 | ### Subgroup Analyses Comparing EXPAND and INSPIRE Control Recipients Table 20, Table 21, Table 22, and Table 23 below provide post-hoc subgroup analyses comparing various subgroups in the Lung EXPAND trial with similar post-hoc subgroups in the INSPIRE control group. Enrollment criteria for recipients in INSPIRE and EXPAND were the same, and there was overlap in donor organ characteristics (see below). The types of donor lungs studied in EXPAND were heterogeneous in their characteristics. The aggregate results primarily reflect a donor population defined more by clinicians' decisions to avoid cold static preservation than by the donor lungs *per se* being clinically sub-optimal as "extended-criteria" donors. The majority of donor lungs were accepted into the study because of meeting a solitary inclusion criterion. FDA requested *post hoc* comparison analyses in the subgroups of patients who received donor organs accepted into EXPAND on the basis of recipient LAS and on the basis of a solitary donor inclusion criterion; clinically analogous *post hoc* subgroups from INSPIRE Control were identified as comparators. FDA believes these analyses provide important information about the safety and effectiveness of the device for real-world applications. Although caution is needed when interpreting *post hoc* analyses with relatively small sample sizes, a reasonable inference is that clinical results may vary depending upon the reason(s) for which donor organs have been initially deemed unacceptable for procurement and transplantation. PMA P160013/S002: FDA Summary of Safety and Effectiveness Data Page 33 {33} **Table 20: Post-hoc Subgroup comparisons of EXPAND trial transplanted recipients and INSPIRE control group (standard criteria donor lungs preserved using cold storage): LAS ≥ 50** | | OCS EXPAND (Donor Lungs Initially Deemed Unacceptable) (N= 79) | INSPIRE Control (Standard Criteria Lungs, Cold Storage) (N = 184) | | --- | --- | --- | | **Recipient LAS Score ≥ 50** | **N=11** | **N=37** | | LAS Score, Mean ± SD | 67.5 ± 16.6 | 71.3 ± 16.5 | | Primary Effectiveness Endpoint, n/N (%) | 3/11 (27.3%) | 21/37 (56.8%) | | • Survival at Day 30 post-transplant, n/N (%) | 10/11 (90.9%) | 37/37 (100%) | | • Freedom from PGD3 within 72 hours post-transplant, n/N (%) | 4/11 (36.4%) | 21/37 (56.8%) | | Incidence of PGD2 or PGD3 at T72, n/N (%) | 4/10 (40%) | 5/37 (13.5%) | | Incidence of PGD3 at T72, n/N (%) | 2/10 (20%) | 2/37 (5.4%) | **Table 21: Post-hoc Subgroup comparisons of EXPAND trial transplanted recipients and INSPIRE control group (standard criteria donor lungs preserved using cold storage): LAS < 50** | | OCS EXPAND (Donor Lungs Initially Deemed Unacceptable) (N= 79) | INSPIRE Control (Standard Criteria Lungs, Cold Storage) (N = 184) | | --- | --- | --- | | **Recipient LAS Score < 50** | **N=59** | **N = 88** | | LAS Score, Mean ± SD | 37.3 ± 4.9 | 37.6 ± 5.2 | | Primary Effectiveness Endpoint, n/N (%) | 35/39 (59.3%) | 69/88 (78.4%) | | • Survival at Day 30 post-transplant, n/N (%) | 59/59 (100%) | 88/88 (100%) | | • Freedom from PGD3 within 72 hours post-transplant, n/N (%) | 35/39 (59.3%) | 69/88 (78.4%) | | Incidence of PGD2 or PGD3 at T72, n/N (%) | 7/59 (11.9%) | 6/87 (6.9%) | | Incidence of PGD3 at T72, n/N (%) | 3/59 (5.1%) | 4/87 (4.6%) | PMA P160013/S002: FDA Summary of Safety and Effectiveness Data Page 34 {34} **Table 22: Post-hoc Subgroup comparisons of EXPAND trial transplanted recipients and INSPIRE control group (standard criteria donor lungs preserved using cold storage): Donor Age ≥ 55 years** | | OCS EXPAND (Donor Lungs Initially Deemed Unacceptable) | INSPIRE Control (Standard Criteria Lungs, Cold Storage) | | --- | --- | --- | | **Donor Age ≥ 55 years** | **Donors enrolled with single criterion Age ≥ 55 N=22** | **All Donors with Age ≥ 55^{1} N=32** | | Donor Age, mean ± SD | 63.7 ± 6.5 | 58.1 ± 2.4 | | Primary Effectiveness Endpoint, n/N (%) | 14/22 (63.6%) | 22/32 (68.8%) | | • Survival at Day 30 post-transplant, n/N (%) | 22/22 (100%) | 32/32 (100%) | | • Freedom from PGD3 within 72 hours post-transplant, n/N (%) | 14/22 (63.6%) | 22/32 (68.8%) | | Incidence of PGD2 or PGD3 at T72, n/N (%) | 5/22 (22.7%) | 5/32 (15.6%) | | Incidence of PGD3 at T72, n/N (%) | 2/22 (9.1%) | 3/32 (9.4%) | $^{1}$Donor age ≥ 55 was not an enrollment criterion for INSPIRE **Table 23: Post-hoc Subgroup comparisons of EXPAND trial transplanted recipients and INSPIRE control group (standard criteria donor lungs preserved using cold storage): Expected and Observed Cross-Clamp Time > 6 hours** | | OCS EXPAND (Donor Lungs Initially Deemed Unacceptable) | INSPIRE Control (Standard Criteria Lungs, Cold Storage) | | --- | --- | --- | | **Cross-Clamp Time > 6 hr** | **Donors with single criterion of expected cross-clamp time > 6 hr N = 11** | **All donors with observed cross-clamp time > 6 hr N=99** | | Observed Cross-Clamp Time (min), Mean ± SD | 637.1 ± 106.9 | 488.1 ± 103.9 | | Primary Effectiveness Endpoint, n/N (%) | 7/11 (63.6%) | 76/99 (76.8%) | | • Survival at Day 30 post-transplant, n/N (%) | 10/11 (90.9%) | 99/99 (100%) | | • Freedom from PGD3 within 72 hours post-transplant, n/N (%) | 8/11 (72.7%) | 76/99 (76.8%) | | Incidence of PGD2 or PGD3 at T72, n/N (%) | 2/10 (20.0%) | 10/98 (10.2%) | | Incidence of PGD3 at T72, n/N (%) | 0/10 (0.0%) | 5/98 (5.1%) | PMA P160013/S002: FDA Summary of Safety and Effectiveness Data Page 35 {35} ### Comparison of Safety Endpoint between EXPAND and INSPIRE Control The EXPAND trial and the INSPIRE trial utilized the same safety endpoint, as defined in Section X(A)(3). The results for EXPAND recipients for this endpoint compared to INSPIRE control group are shown in Table 24 below. The mean number of LGRSAEs and the type of LGRSAEs are similar for the two studies. **Table 24: Number of LGRSAEs during the first 30 days post-transplantation in the EXPAND Trial, with Comparison to INSPIRE Control group as a Benchmark** | Number of lung-graft-related serious adverse events (LGRSAEs) up to the 30-day follow-up after transplantation (at most one per type)^{1} | OCS EXPAND (Donor Lungs Initially Deemed Unacceptable) (N= 79) | INSPIRE Control (Standard Criteria Lungs, Cold Storage) (N = 184) | | --- | --- | --- | | Mean ± SD | 0.3 ± 0.47 | 0.3 ± 0.54 | | Median | 0.0 | 0.0 | | Min.-Max. | 0.0 - 2.0 | 0.0 – 2.0 | | 95% Confidence Interval of mean^{2} | (0.1, 0.4) | (0.21, 0.37) | | **Type of LGRSAEs n(%)** | | | | Acute Rejection | 0 (0%) | 4 (2.2%) | | Respiratory Failure^{3} | 12 (15.2%) | 16 (8.7%) | | Bronchial Anastomotic Complication | 0 (0%) | 4 (2.2%) | | Major Pulmonary-Related Infection | 7 (8.9%) | 29 (15.8%) | | ^{1} Multiple occurrences of the same category of events on one patient are counted once only. ^{2} Confidence interval calculated based on the t-distribution. ^{3} Need for re-intubation, tracheostomy or the inability to discontinue ventilator support within 4 days post-transplant. | | | ### 8. Device Malfunctions A summary of the device malfunctions that occurred during the EXPAND Trial is provided in Table 25. Four malfunctions occurred. Three of the 4 malfunctions occurred prior to initiation of preservation. All four patients who experienced the device malfunctions were transplanted with the OCS-preserved lungs and were analyzed in the study. None of the malfunctions led to a loss of a donor organ. **Table 25: Summary of Device Malfunctions and User Errors** | Malfunctions/User Error | Total N (4) | Loss of Lung | Treated and Analyzed in EXPAND | | --- | --- | --- | --- | | Ventilator subsystem failure | 2 | 0 | 2 | | LPM with out-of-range values for PAP prior to preservation | 1 | 0 | 1 | | Pump failure prior to preservation | 1 | 0 | 1 | | TOTAL | 4 | 0 | 4 | PMA P160013/S002: FDA Summary of Safety and Effectiveness Data Page 36 {36} TransMedics has addressed the observed malfunctions with design and/or manufacturing process improvements, in accordance with FDA Quality System Regulations. 9. Pediatric Extrapolation In this premarket panel track supplement application, existing clinical data were not leveraged to support approval of a pediatric patient population. F. Financial Disclosure The Financial Disclosure by Clinical Investigators regulation (21 CFR 54) requires applicants who submit a marketing application to include certain information concerning the compensation to, and financial interests and arrangement of, any clinical investigator conducting clinical studies covered by the regulation. The EXPAND clinical study included 8 investigators. None of the clinical investigators had disclosable financial interests/arrangements as defined in sections 54.2(a), (b), (c), and (f). The information provided does not raise any questions about the reliability of the data. G. Summary of Supplemental Clinical Information: EXPAND II Study TransMedics also conducted the EXPAND II study, which is an ongoing study of the OCS™ Lung System for the same types of donor lungs enrolled in the Lung EXPAND study (e.g., donor lung pairs initially deemed unacceptable for procurement and transplantation based on limitations of cold static preservation). The EXPAND II trial was designed with two co-primary endpoints: utilization rate and patient survival at Day 30 or at hospital discharge if longer than 30 days. The study was approved for 90 subjects at 20 sites. At the time of this review, data were available on 40 transplanted recipients. Donor characteristics are shown in Table 26 below. Thirty (30) of the 40 subjects (75%) received donor lungs with a single donor criterion met: - 6 patients – Donor PaO₂/FiO₂ ≤ 300 mm Hg - 7 patients – Expected Cross-Clamp Time > 6 hours - 13 patients – DCD - 4 patients – Donor Age ≥ 55. Ten (10) of the 40 subjects (25%) received donor lungs with multiple donor inclusion criteria met: - 3 patients - Donor Age ≥ 55 and Donor PaO₂/FiO₂ ≤ 300 mm Hg - 3 patients - DCD and Donors with Expected Cross-Clamp time > 6 hours - 1 patient - Donor with Expected Cross-Clamp time > 6 hours and Donor PaO₂/FiO₂ ≤ 300 mm Hg - 1 patient - DCD and Donor PaO₂/FiO₂ ≤ 300 mm Hg - 1 patient - Donor with Expected Cross-Clamp time > 6 hours and Donor Age ≥ 55 - 1 patient – DCD and Donor PaO₂/FiO₂ ≤ 300 mm Hg and Donor Age ≥ 55. PMA P160013/S002: FDA Summary of Safety and Effectiveness Data Page 37 {37} **Table 26: Donor Demographics by Inclusion Criteria for EXPAND II transplanted donors to date (N=40)** | | PaO_{2}/FiO_{2} Ratio ≤ 300 mmHg (N=12) Mean ± SD Median (Range) | Expected Cross Clamp Time > 6 hours (N=12) Mean ± SD Median (Range) | DCD Donor (N=18) Mean ± SD Median (Range) | Donor Age ≥ 55 (N= 9) Mean ± SD Median (Range) | All Donors (N=40) Mean ± SD Median (Range) | | --- | --- | --- | --- | --- | --- | | PaO_{2}/FiO_{2} Ratio (mmHg) | 254 ± 32 262 (201-296) | 414 ± 77 402 (288 – 553) | 399 ± 82 386 (253 – 602) | 360 ± 124 382 (201 – 520) | 375 ± 100 381 (201 – 602) | | Observed Cross Clamp Time (min) | 624 ± 150 583 (411 – 927) | 725 ± 94 695 (617-919) | 609 ± 157 614 (330 – 851) | 571 ± 123 546 (411 – 762) | 631 ± 145 617 (330 – 927) | | Donor Age (Years) | 47 ± 12 50 (27 – 61) | 41 ± 13.0 43 (23 – 65) | 40 ± 12 43 (15 – 61) | 60 ± 3 61 (59 – 65) | 44 ± 13 44 (15 – 65) | | **Additional Demographics & Risk Factors** | | | | | | | Female gender: % (n/N) | | | | | 50.0% (20/40) | | Abnormal Findings on Inspection and Palpation % (n/N) | | | | | 59.0% (23/39) | | Abnormal Imaging Findings % (n/N) | | | | | 77.5% (31/40) | The EXPAND II trial enrolled lung transplant recipients as shown in Table 27 below. **Table 27: Recipient Demographic and Baseline Characteristics for EXPAND II subjects to date (N=40)** | | OCS EXPAND II (n=40) | | --- | --- | | Age (Years): Mean ± SD | 55 ± 14 | | Gender (% Female) | 40.0 | | BMI (kg/m^{2}) Mean ± SD | 25 ± 4 | | LAS Score | 43 ± 9 (39/40) | | Primary Diagnosis | | | Chronic obstructive pulmonary disease/Emphysema | 13% (5/40) | | Idiopathic pulmonary fibrosis | 38% (15/40) | PMA P160013/S002: FDA Summary of Safety and Effectiveness Data Page 38 {38} | | **OCS EXPAND II (n=40)** | | --- | --- | | Cystic Fibrosis | 13% (5/40) | | Bronchiectasis | 0% (0/40) | | Sarcoidosis | 5% (2/40) | | Interstitial Lung Disease other than IPF | 25% (10/40) | | Other | 8% (3/40) | | Secondary Pulmonary Hypertension | 30% (12/40) | #### EXPAND II Results to Date A total of 46 eligible lungs were preserved on OCS to date and of these, 40 were transplanted, giving a utilization rate, defined as the number of donated lungs instrumented on OCS™ that meet inclusion/exclusion criteria for the trial and acceptance criteria for transplantation after OCS™ Lung assessment divided by the total eligible donor lungs instrumented on the OCS™ Lung System, of 87.0%. Patient survival at 30 days was 95%, while patient survival at 30 days and hospital discharge (if longer than 30 days) was 84%. The results for the co-primary and secondary endpoints for EXPAND II subjects to date are shown in Table 28 below. **Table 28: Co-primary and Secondary Endpoints for Lung EXPAND II trial based on available adjudicated data (N=40)** | **Lung EXPAND II Primary and Secondary Endpoints** | **n/N (%) (range)** | | --- | --- | | **Co-primary Endpoint 1:** Patient survival at Day 30 or Post-transplant Hospital Discharge (whichever is later) | 32/38 (84%) | | • Patient Survival at Day 30 post-transplant | 37/39 (95%) | | **Co-primary Endpoint 2:** Utilization rate | 40/46 (87%) | | **Secondary Endpoints** | | | Incidence of Primary Graft Dysfunction (PGD) Grade 3 at T72 hours | 5/37 (13.5%) (4.5%, 28.8%) | | Incidence of PGD Grade 3 within the initial 72 hours post-transplantation. | 22/35 (62.9%) (44.9%, 78.5%) | | Incidence of Primary Graft Dysfunction (PGD) Grades 2 or 3 at T72 hours | 6/37 (16.2%) (6.2%, 32.0%) | | Incidence of PGD Grades 2 or 3 within the initial 72 hours post-transplantation | 27/35 (77.1%) (59.9%, 89.6%) | #### **XI. PANEL MEETING RECOMMENDATION AND FDA'S POST-PANEL ACTION** In accordance with the provisions of section 515(c)(3) of the act as amended by the Safe Medical Devices Act of 1990, this PMA was not referred to the Gastroenterology and Urology Devices Panel, an FDA advisory committee, for review and recommendation because the information in the PMA substantially duplicates information previously reviewed by this panel. PMA P160013/S002: FDA Summary of Safety and Effectiveness Data Page 39 {39} ## **XII. CONCLUSIONS DRAWN FROM PRECLINICAL AND CLINICAL STUDIES** ### **A. Effectiveness Conclusions** In EXPAND, there were four donor inclusion criteria in EXPAND that specified donor organs deemed initially unacceptable for procurement and transplantation: one was based upon observed donor function (Pa/FiO2 < 300), one was based upon donor age (≥ 55 years), one was based upon donor procurement method (DCD), and one was based upon investigators' estimation of prolonged cold ischemic time (> 6 hours) if cold static preservation were to be used. Among those donor lungs transplanted after preservation with the device, 73% had a single donor inclusion criterion allowing enrollment into EXPAND, while 27% had more than one criterion. Donor age ≥ 55 years was the most frequent donor inclusion criterion. The primary effectiveness endpoint evaluated a composite of survival at Day 30 post-transplantation and freedom from PGD3 within 72 hours post-transplantation. Unlike the randomized, controlled trial INSPIRE, which was used to support approval of this device for standard-criteria donor lungs, the current principal clinical study, EXPAND, was single-arm, with the primary effectiveness endpoint to be a comparison to a pre-specified performance goal of 65%. Because clinical outcomes with the types of lungs expected to be enrolled were unknown, FDA had recommended comparison, with an appropriate clinical effectiveness margin, to a concurrent, non-randomized control arm of standard criteria donor lungs preserved using cold static storage. The primary effectiveness endpoint was not met (95% lower confidence interval was 42.8% for the observed primary effectiveness endpoint rate). Survival at Day 30 post-transplantation was high (98.7%), and the failure to meet the composite endpoint was a function of the observed rate of PGD3 within 72 hours (55.7%). Assessment of PGD at only the 72-hour timepoint is another clinically validated metric of lung injury after preservation and transplantation. The observed rate of PGD3 at T72 (a pre-specified secondary effectiveness endpoint) was 6.4%, whereas the observed rate of PGD2 or PGD3 at T72 (also a pre-specified secondary effectiveness endpoint) was 16.7%. Taken together, these results indicate that the principal driver of the primary effectiveness endpoint finding was early PGD3, whose clinical manifestation dissipated in some donor organs by later time points. Peri-operative PGD has been correlated with mid- and long-term graft dysfunction (e.g., BOS) and decreased recipient and/or graft survival. One-year patient survival was 91%, and two-year survival was 85%. Overall, BOS developed in 1.4%, of recipients by one year, a figure that is consistent with the known pattern of BOS generally being a later-presenting complication of lung transplantation. Freedom from BOS at two years (Kaplan-Meier estimate) is 89%, while survival at two years in the absence of BOS is estimated at 77%. ---PMA P160013/S002: FDA Summary of Safety and Effectiveness Data Page 40 {40} *Post hoc* analyses requested by FDA included effectivene…