← Product Code QQK · P200031

# Organ Care System (OCS™) Liver (P200031)

_TransMedics, Inc. · QQK · Sep 28, 2021 · Gastroenterology, Urology · APPR_

**Canonical URL:** https://fda.innolitics.com/device/P200031

## Device Facts

- **Applicant:** TransMedics, Inc.
- **Product Code:** QQK
- **Decision Date:** Sep 28, 2021
- **Decision:** APPR
- **Device Class:** Class 3
- **Review Panel:** Gastroenterology, Urology
- **Attributes:** Therapeutic

## Indications for Use

The TransMedics® Organ Care System (OCSTM) Liver is a portable extracorporeal liver perfusion and monitoring system indicated for preservation and monitoring of hemodynamics and metabolic function which allows for ex vivo assessment of liver allografts from donors after brain death (DBD) or liver allografts from donors after circulatory death (DCD) ≤55 years old and with ≤30 mins of warm ischemic time, macrosteatosis ≤15%, in a near-physiologic, normothermic and functioning state intended for a potential transplant recipient.

## Device Story

The OCS Liver is a portable, electromechanical platform maintaining donor livers in a near-physiologic, normothermic, perfused state. It utilizes a pulsatile pump, perfusate warmer, and oxygenator to circulate a warm, nutrient-enriched, pRBC-based perfusate through the hepatic artery and portal vein. The system includes a sterile, single-use Liver Perfusion Module (LvPM) with embedded sensors for monitoring perfusion parameters (flow, pressure) and metabolic function (lactate, bile production). Used in the clinical setting by trained operators, the system provides real-time data via a wireless monitor, allowing surgeons to assess liver viability ex vivo. This assessment informs clinical decision-making regarding transplant suitability, potentially reducing ischemic biliary complications and early allograft dysfunction compared to cold static storage. The device benefits patients by enabling the use of donor organs that might otherwise be discarded and by mitigating cold ischemic injury.

## Clinical Evidence

PMA approval based on the prospective, multi-center, randomized PROTECT trial (N=300 randomized). Primary endpoint: Early Allograft Dysfunction (EAD) incidence within 7 days. Results: OCS arm showed non-inferiority and superiority in EAD reduction (18% vs 31%, p=0.009). Secondary endpoints included successful ex vivo assessment (93% success rate). Safety endpoint (LGRSAEs) met non-inferiority. No significant difference in patient/graft survival at 12/24 months. Additional data from PROTECT CAP (N=74) supported findings. Bench and animal studies (porcine model) validated performance and safety.

## Technological Characteristics

Integrated electromechanical console with pulsatile perfusion pump, perfusate warmer, and sensors. Components: OCS Liver Console, single-use Liver Perfusion Module (LvPM), and OCS Liver Bile Salts (sodium taurocholate). Perfusate: pRBC-based with electrolytes and additives. Connectivity: Peer-to-peer Bluetooth between console and wireless monitor. Sterilization: ETO (LvPS) and gamma irradiation (bile salts). Complies with IEC 60601-1 (electrical safety) and IEC 60601-1-2 (EMC).

## Regulatory Identification

The device is intended for machine preservation of donor livers prior to transplantation.

## Submission Summary (Full Text)

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SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)

I. GENERAL INFORMATION

Device Generic Name: Ex Vivo Portable Organ Perfusion System for Donor Livers

Device Trade Name: Organ Care System (OCSTM) Liver

Device Procode: QQK

Applicant's Name and Address: TransMedics, Inc.
200 Minuteman Road, Suite 302
Andover, MA 01810

Date of Panel Recommendation: July 14, 2021

Premarket Approval Application (PMA) Number: P200031

Date of FDA Notice of Approval: TBD

II. INDICATIONS FOR USE

The TransMedics® Organ Care System (OCSTM) Liver is a portable extracorporeal liver perfusion and monitoring system indicated for preservation and monitoring of hemodynamics and metabolic function which allows for ex vivo assessment of liver allografts from donors after brain death (DBD) or liver allografts from donors after circulatory death (DCD) ≤55 years old and with ≤30 mins of warm ischemic time, macrosteatosis ≤15%, in a near-physiologic, normothermic and functioning state intended for a potential transplant recipient.

III. CONTRAINDICATIONS

The OCS Liver should not be used for:

- Livers with moderate or severe traumatic injury
- Livers with active bleeding (e.g., hematomas)
- Split livers
- Livers with accessory arterial blood supply requiring back table anastomosis.

IV. WARNINGS AND PRECAUTIONS

A device malfunction or user error could lead to loss of a donor organ. Only trained users should use the OCS Liver System.

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Please refer to the TransMedics® Organ Care System OCS Liver User Guide for additional applicable warnings and precautions.

## V. DEVICE DESCRIPTION

The OCS Liver is an integrated, portable platform designed to maintain donor livers in a near-physiologic, normothermic, and perfused state. The OCS Liver is comprised of three major components as described below.

**OCS Liver Console (Liver Console):** This is a compact, electromechanical device that contains an integrated, pulsatile perfusion pump, batteries, perfusate warmer, and pressure, flow, and saturation meters. In addition, it has an integrated Wireless Monitor that allows the clinical operator to control and display critical perfusion parameters of the preserved donor livers.

**OCS Liver Perfusion Set (LvPS):** The LvPS consists of the Liver Perfusion Module (LvPM) and LvPS Accessories.

The LvPM is a sterile, single-use perfusion module that maintains the organ's physiologic environment and has embedded sensors to control and monitor the perfusion parameters and bile production. In addition, the perfusion module enables perfusate sampling to monitor the liver's metabolic condition.

The LvPS Accessories are sterile, disposable accessories necessary to instrument the liver and manage the perfusate. The LvPS Accessories are as follows:

- OCS Liver Perfusion Initiation Set
- OCS Liver Instrumentation Tool Set
- OCS Liver Solution Infusion Set
- OCS Liver Perfusion Termination Set.

**OCS Liver Bile Salts Set:** The OCS Liver Bile Salts are composed of sodium taurocholate, which is infused to the circulating perfusate to replenish bile salt levels during ex-vivo perfusion on the OCS Liver.

These three major components are shown in Figure 1 below.

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Figure 1: Components of the OCS Liver

|  OCS Liver Console | OCS Liver Perfusion Set | OCS Liver Bile Salts  |
| --- | --- | --- |
|  TransMedics |  |   |

Note: The Liver Console figure (left) shows the LvPM mounted into the system. The LvPS figure (middle) only shows the LvPM.

The OCS Liver preserves the liver in a near-physiological, functioning state by perfusing the liver with a continuously-circulating mixture of warm packed red blood cells (pRBC)-based perfusate supplemented with nutrients and oxygen in a controlled and protected environment referred to as the circuit.

The perfusate consists of user-supplied multiple-electrolytes solution (PlasmaLyte® or equivalent), albumin, pRBCs, and other additives.

Figure 2 below illustrates the circulation of perfusate through the LvPM circuit. The perfusate is pumped from the reservoir by the Circulatory Pump (labeled as the pulsatile pump in the figure below) and then directed through the oxygenator (labeled as the gas exchanger). The perfusate then passes through the warmer to reach the desired temperature. The path is then split so that the perfusate is delivered to both the Hepatic Artery (HA) and the Portal Vein (PV). The PV leg of the circuit contains the PV compliance chamber and the PV clamp. The configuration of these two legs of the circuit results in a pulsatile flow of perfusate delivered to the HA and a non-pulsatile flow of perfusate to the PV. Deoxygenated perfusate exits the liver from the Inferior Vena Cava (IVC). The perfusate from the IVC is directed to the reservoir through the drain in the liver chamber. Additionally, the liver circuit directs bile produced by the liver through a bile cannula to a collection bag.

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![img-0.jpeg](img-0.jpeg)
Figure 2: Schematic of OCS Liver Fluid Flow

To adequately maintain the liver, the OCS Liver controls and monitors the preservation environment. The user can adjust the perfusate flow rate, delivery rate of solutions and additives, gas flow rate, and perfusate temperature within specified ranges. The OCS Liver calculates and displays pertinent organ status parameters, and provides alarms for parameters out of expected ranges, alarms for low gas, battery, and solution capacity, and alarms for sensor failures.

# VI. ALTERNATIVE PRACTICES AND PROCEDURES

Liver transplantation is the only curative treatment for end stage liver failure. Standard of care preservation for donor livers is cold, static storage of the donor liver in a commercially available hypothermic preservation solution prior to transplantation. There are no other legally marketed devices in the U.S. that are designed to provide donor liver preservation in a near physiologic, normothermic, and perfused state.

# VII. MARKETING HISTORY

The OCS Liver Console and Liver Perfusion Set (LvPS) have CE mark authorization. However, the OCS Liver has not been commercially distributed in the United States or any foreign country.

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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 liver 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; or
- leads to loss of the donor organ; and
- malfunction of the device that
- leads to physiological conditions (e.g., warm ischemia, or undesirable perfusion parameters) that could adversely affect clinical outcomes of the allograft; or
- leads to a clinical decision not to proceed with transplantation.

Below is a list of the potential adverse effects (e.g., complications) associated with receiving a donor liver preserved using the OCS Liver, which are typical of the liver transplant procedure:

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- Early liver allograft dysfunction (EAD)
- Acute rejection
- Anastomotic site complications; narrowing, bleeding or occlusion
- Biliary strictures and bile leaks
- Liver primary non-function
- Renal dysfunction and/or failure
- Death
- Bleeding
- Drug Toxicity
- Atrial fibrillation
- Fever
- Delirium, confusion and neurological complications
- Hepatic artery thrombosis
- Pleural effusion
- Convulsion
- Respiratory failure
- Anemia
- Wound Infection
- Ascites
- Aspiration
- Bowel obstruction
- Bowel thromboembolic complications and gangrene
- Cerebrovascular accident
- Cholangitis

- Coagulopathy
- Hemodynamic instability
- Hepatic coma
- Hepatic psychosis
- Hyperacute rejection
- Hyperammonemia
- Ileus
- Liver abscess
- Malignancy
- Multiple organ failure
- Pancreatitis
- Peptic ulceration
- Phrenic nerve injury
- Portal vein thrombosis
- Protamine and other anti-heparin medication reaction
- Sepsis
- Stroke
- Transfusion reaction
- Venous thromboembolism (deep venous thrombosis [DVT])
- Abdominal wound dehiscence
- Diaphragmatic injury
- Gastritis
- Gastro esophageal reflux disease (GERD)
- GI Bleeding (upper or lower)

For the specific adverse events that occurred in the clinical studies, please see Section X.

## IX. SUMMARY OF NONCLINICAL STUDIES

TransMedics conducted the following nonclinical studies to evaluate the OCS Liver: (A) engineering bench testing; (B) biocompatibility and biological safety; (C) software verification and validation; (D) cybersecurity; (E) electrical and medical device safety; (F) electromagnetic compatibility; (G) wireless technology; (H) sterilization; (I) shelf life; and (J) animal functional testing.

## A. Engineering Bench Testing

TransMedics performed engineering bench testing on the complete OCS Liver, as well as the Liver Console and the LvPS, to demonstrate that the device meets its product requirements and specifications. In cases when testing was performed on an earlier version of the device, the later design changes did not affect the functions or

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specifications under evaluation.

## B. Biocompatibility and Biological Safety - LvPS

TransMedics performed a series of biocompatibility studies to demonstrate the safety of the materials of the LvPS. All studies were conducted in compliance with 21 CFR Part 58 - Good Laboratory Practice for Nonclinical Laboratory Studies (GLPs).

The LvPS has been categorized for its body contact and duration of contact according to ISO 10993-1, Biological Evaluation of Medical Devices - Part 1: Evaluation and Testing, to select the appropriate biocompatibility testing program.

Biocompatibility tests and results are provided in Table 1 below.

Table 1: Summary of the Biocompatibility Testing on LvPS

|  Biocompatibility Test | ISO Test Standard | Results  |
| --- | --- | --- |
|  Cytotoxicity Test | 10993-5 | Non-cytotoxic  |
|  Material-Mediated Pyrogenicity | 10993-11 | Non-pyrogenic  |
|  Hemocompatibility (direct/indirect) | 10993-4 | Non-hemolytic  |
|  Sensitization | 10993-10 | No delayed dermal contact sensitization  |
|  Intracutaneous Reactivity | 10993-10 | No irritation  |
|  Acute Systemic Toxicity | 10993-11 | No systemic toxicity observed  |
|  Genotoxicity (complete test battery) | 10993-3 | Non-mutagenic  |
|  USP Physicochemical Tests | USP<661> Containers, Plastics | Meets USP limits; no significant extractables  |

To support the biological safety of Sodium Taurocholate (OCS Liver Bile Salts), TransMedics provided the information consistent with the FDA guidance entitled, "Medical Devices Containing Materials Derived from Animal Sources (Except for In Vitro Diagnostic Devices)." This information included the control of animal tissue collection, manufacturing controls, the assessment for need for virus validation studies, and the exposure to Transmissible Spongiform Encephalopathies (TSE) risk.

## Biocompatibility and Biological Safety – Perfusion Solution

To support the biocompatibility of the recommended perfusion solution, TransMedics conducted the tests in Table 2 below. A Biological risk assessment of Bile Salts/sodium taurocholate was also conducted.

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Table 2: Summary of the Biocompatibility Testing for the Perfusion Solution* Mixed with OCS Liver Bile Salts and PlasmaLyte

|  Biocompatibility Test | ISO Test Standard | Results  |
| --- | --- | --- |
|  Cytotoxicity Test (MEM Elution, with PlasmaLyte) | 10993-5 | Non-cytotoxic  |
|  Hemocompatibility, direct contact** (using PlasmaLyte) | 10993-4 | Non-hemolytic  |
|  Intracutaneous Reactivity (using PlasmaLyte) | 10993-10 | No irritation  |
|  Acute Systemic Toxicity (using PlasmaLyte) | 10993-11 | No systemic toxicity observed  |
|  Pyrogenicity (USP <151> Rabbit Pyrogen, using PlasmaLyte) | 10993-11 | Non-pyrogenic  |
|  Sensitization (Guinea Pig Maximization Sensitization, using PlasmaLyte) | 10993-10 | No delayed dermal contact sensitization  |
|  *The perfusion solution is not sold with the device, but a formulation is included in Section 4.3 of the OCS Liver User Guide. **Indirect hemocompatibility was not considered applicable, because the test was performed on the bile salt solution that was used as the extract, rather than the typical application of indirect testing intended for materials through which fluids pass before entry into the body.  |   |   |

## C. Software Verification and Validation

TransMedics performed software verification and validation testing to demonstrate the OCS Liver performs as intended. The device passed all testing and met its requirements. Software documentation was provided in accordance with the FDA guidance document entitled "Guidance for the Contents of Premarket Submissions for Software Contained in Medical Devices." Verification and validation testing included unit tests, static analysis, system level verification tests (which included functional testing to demonstrate the device met its requirements), code review, and validation testing.

## D. Cybersecurity

The OCS Liver does not contain the hardware or software required for many common network interfaces such as USB, Ethernet or Wi-Fi. The OCS Liver incorporates a Wireless Monitor dedicated to the Liver Console. The Wireless Monitor communicates with the OCS Console using one of two redundant communication interfaces; hard-wired serial and Bluetooth.

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A cybersecurity incident affecting an OCS could not directly result in harm to multiple organs, because the OCS is not connected to any other device, network, or the internet. Accordingly, because the OCS does not connect to a network, the internet or another medical device/product coupled with the fact that a cybersecurity incident cannot result in harm to multiple organs, it is considered Tier 2 (Standard Cybersecurity Risk).

To address potential cybersecurity risks, TransMedics provided information according to FDA guidance entitled, "Content of Premarket Submissions for Management of Cybersecurity in Medical Devices." This information included, among other things, a Cybersecurity Threat Model and Assessment, validation/verification testing (which included penetration testing), and a plan for identifying and responding to emerging cybersecurity issues. Collectively, this information demonstrated that TransMedics has appropriate controls in place to identify, protect, detect, respond, and recover from cybersecurity threats per the FDA guidance.

# E. Electrical and Medical Device Safety

The OCS Liver was tested to demonstrate that it meets the requirements for medical device safety, including electrical safety. The system was tested by an outside laboratory according to the Edition 3.1 of the IEC 60601-1 standard, as well as the ANSI/AMMI and CSA versions of the standard. The results are shown in Table 3 below.

Table 3: Summary of Electrical, Thermal, and Mechanical Safety Testing

|  Test Description | IEC/ANSI/AAMI 60601-1: 2005 +A1:2012 Clause | Result  |
| --- | --- | --- |
|  General Requirements | 4 | Pass  |
|  General Requirements for Testing ME Equipment | 5 | Pass  |
|  Classification of ME Equipment and ME Systems | 6 | Pass  |
|  ME Equipment, Identification Marking and Documents | 7 | Pass  |
|  Protection Against Electrical Hazards from ME Equipment | 8 | Pass  |
|  Protection Against Mechanical Hazards of ME Equipment and ME Systems | 9 | Pass  |
|  Protection Against Unwanted and Excessive Radiation Hazards | 10 | Pass  |
|  Protection Against Excessive Temperatures and Other Hazards | 11 | Pass  |
|  Accuracy of Controls and Instruments and Protection Against Hazardous Outputs | 12 | Pass  |
|  Hazardous Situations and Fault Conditions | 13 | Pass  |
|  Programmable Electrical Medical Systems (PEMS) | 14 | Pass  |

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|  Construction of ME Equipment | 15 | Pass  |
| --- | --- | --- |
|  ME Systems | 16 | Pass  |

# F. Electromagnetic Compatibility (EMC)

The OCS Liver was tested to demonstrate that it meets the requirements for radio frequency emissions and radio frequency susceptibility (together, EMC). The system was tested by an outside laboratory according to standards for EMC requirements of electrical equipment (IEC 60601-1-2 ( $4^{\text{th}}$  edition) – Group 1, Class A, non-life supporting equipment, CISPR 25, and RTCA DO-160G). The OCS Liver met the requirements of the standards. The results are shown in Table 4 below.

Table 4: Summary of Emission and Immunity Testing

|  Test | Standard | Results  |
| --- | --- | --- |
|  Radiated Emissions | EN 55011/FCC 47 Part 15C (CISPR 11) | Pass  |
|  AC Mains Conducted Emissions | EN 55011/FCC 47 Part 15C (CISPR 11) | Pass  |
|  Harmonics Emissions | IEC 61000-3-2 | Pass  |
|  Voltage Fluctuation/Flicker | IEC 61000-3-3 | Pass  |
|  Electrostatic Discharge Immunity | IEC 61000-4-2 | Pass  |
|  Immunity to proximity fields from RF wireless communications equipment | IEC 60601-1-2 Clause 8.10 | Pass  |
|  Radiated RF Immunity | IEC 61000-4-3 | Pass  |
|  Electrical Fast Transients Immunity | IEC 61000-4-4 | Pass  |
|  Surge Immunity | IEC 61000-4-5 | Pass  |
|  Conducted RF Immunity | IEC 61000-4-6 | Pass  |
|  Magnetic Field Immunity | IEC 61000-4-8 | Pass  |
|  Voltage Dips/Interrupts | IEC 61000-4-11 | Pass  |
|  Radiated Immunity | RTCA DO 160G | Pass  |
|  Radiated Emissions | RTCA DO 160G | Pass  |
|  Radiated Emissions | CISPR 25 | Pass  |
|  Spurious Emissions | FCC 47 CFR Part 15C | Pass  |

# G. Wireless Technology

The wireless connection between the OCS Console and Wireless Monitor is a peer-to-peer Bluetooth connection. The Bluetooth communications between the OCS Console and the Wireless Monitor are achieved using two off-the-shelf Bluetooth-to-serial

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adapters - one in the OCS Console and one in the Wireless Monitor. TransMedics addressed the recommendations presented in the FDA guidance entitled, "Radio Frequency Wireless Technology in Medical Devices," and performed successful wireless coexistence testing according to the IEEE article, "An Experimental Method for Evaluating Wireless Coexistence of a Bluetooth Medical Device."

## H. Sterilization

The LvPS is sterilized using Ethylene Oxide (ETO). ETO sterilization validation was performed per ISO 11135-1:2007 and demonstrated a minimum sterility assurance level (SAL) of $10^{-6}$. The lethality of the ETO sterilization process was demonstrated utilizing the overkill concept of sterilization.

The OCS Liver Bile Salts are sterilized by gamma irradiation. The sterilization cycle was validated to achieve a minimum SAL of $10^{-6}$ in accordance with EN ISO 11137-2:2013.

ETO and ethylene chlorohydrin (ECH) residuals were evaluated on the entire LvPS, LvPM, LvPS accessories and the bile salts together and determined to be below the maximum allowable limits per ISO 10993-7: 2008, Biological evaluation of medical devices – Part 7: Ethylene oxide sterilization residuals.

## I. Shelf-Life Testing

Package integrity and simulated shipping testing was performed for the LvPS and OCS Liver Bile Salts Set to confirm that package integrity can be maintained during shipping. Real-time shelf-life testing demonstrates the safety and suitability of the LvPS for the labeled 12-month shelf life. In addition, real-time and accelerated shelf-life testing supports the safety and suitability of the OCS Liver Bile Salts Set for the labeled three-year shelf life.

## J. Animal Functional Testing

TransMedics performed functional animal studies to evaluate the safety, suitability, and effectiveness of the OCS Liver for the preservation of donor livers.

The animal studies used a porcine model to evaluate the performance of the OCS Liver. The anatomy and size of a pig liver closely resembles the human liver, making it a clinically suitable animal model that is feasible and practical to use in the laboratory setting.

The studies performed validated the ability of the OCS Liver to meet the performance specifications and that the configuration of the OCS Liver worked successfully during simulated surgical procedures. The animal studies performed are summarized in Table 5 below.

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Table 5: Summary of Animal Functional Studies

|  OCS Liver Preclinical Study | Number of Animals | Summary Results  |
| --- | --- | --- |
|  Phase 1: Up to 12-hour preservation on OCS Liver | OCS N=28 | Stable preservation with good liver hepatocellular, hepatobiliary, metabolic, and synthetic function.  |
|  Phase 2: 8-hour preservation followed by 4 hours of simulated transplantation | OCS N=5 | The OCS Liver met the prespecified acceptance criteria and demonstrated stable perfusion and metabolic parameters.  |
|  Phase 2 expanded: 8-hour preservation followed by 4 hours of simulated transplantation with control | OCS N=6 versus Control N=6 | OCS arm showed better recovery of function as compared to Cold Storage Control arm.
In addition, histology results showed better preserved hepatocellular and hepatobiliary structure as compared to Controls.  |
|  Phase 3: 12-hour preservation followed by 24 hours of simulated transplantation | OCS N=3 versus Control N=3 | OCS arm showed better recovery of function as compared to Cold Control arm.
In addition, histology results showed better preserved hepatocellular and hepatobility structure as compared to Controls.  |
|  Preclinical Validation Study to validate OCS Liver with Software Version 3.2.1-C | OCS N=2 | The OCS Liver met all the acceptance criteria for this validation.  |

X. SUMMARY OF PRIMARY CLINICAL STUDIES

The applicant performed a clinical study to establish a reasonable assurance of safety and effectiveness of liver transplant with the OCS Liver in the US under IDE #G140192. Data from this clinical study were the basis for the PMA approval decision. A summary of the clinical study is presented below.

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# A. Study Design

Patients were treated between January 24, 2016 and October 15, 2019. The database for this PMA reflected data collected through October 15, 2020 and included 429 consented recipients. There were 20 investigational sites.

The OCS Liver PROTECT trial was a prospective, multi-center, unblinded, randomized trial comparing the OCS Liver to Control (cold storage). The clinical objective of the trial was to compare the safety and the effectiveness of the OCS Liver versus cold storage (Control) to preserve and assess donor livers intended for transplantation that may benefit from warm oxygenated perfusion compared to cold static storage from one or more of the following donor characteristics:

- Donor age ≥ 40 years old; or
- Expected total cross clamp/cold ischemic time ≥ 6 hours; or
- Donor after Cardiac Death (DCD donor) with age ≤ 55 years old; or
- Steatotic liver &gt; 0% and ≤ 40% macrosteatosis at time of retrieval (based on retrieval biopsy readout (only If the donor liver was clinically suspected to be fatty by the retrieval surgeon at time of liver retrieval)).

A clinical events committee, comprised of three experienced experts in the field (two liver transplant surgeons and one liver transplant hepatologist), reviewed trial events. A Data Safety Monitoring Board, comprised of a liver transplant surgeon, liver transplant hepatologist, and an independent biostatistician, monitored the trial.

The control group was transplantation with the current standard of care, cold static storage.

1. Clinical Inclusion and Exclusion Criteria

Enrollment in the PROTECT study was limited to donor livers and recipients who met the following inclusion criteria.

Donor Liver Eligibility Criteria:

**Inclusion Criteria** - donors were required to meet at least one of the following:

- Donor age ≥ 40 years old; or
- Expected total cross clamp/cold ischemic time ≥ 6 hours; or
- Donor after Cardiac Death (DCD donor) with age ≤ 55 years old; or
- Steatotic liver &gt; 0% and ≤ 40% macrosteatosis at time of retrieval (based on retrieval biopsy readout (only if the donor liver was clinically suspected to be fatty by the retrieval surgeon at time of liver retrieval)).

Donor Livers were not permitted to enroll in the PROTECT study if they met any of the following exclusion criteria:

**Exclusion Criteria** - donor livers were excluded if they met any of the following

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criteria:
- Living donors
- Liver intended for split transplants
- Positive serology (HIV, Hepatitis B surface antigen and C)
- Presence of moderate or severe traumatic liver injury, or anatomical liver abnormalities that would compromise ex-vivo perfusion of the donor liver (i.e., accessory blood vessels or other abnormal anatomy that require surgical repair) and livers with active bleeding (e.g., hematomas)
- Donor livers with macrosteatosis of &gt;40% based on retrieval biopsy readout.

Recipient Eligibility Criteria:

## Inclusion Criteria
- Registered male or female primary liver transplant candidate
- ≥18 years old
- Signed, written informed consent document and authorization to use and disclose protected health information

Transplant recipient were not permitted to enroll in the PROTECT study if they met any of the following exclusion criteria:

## Exclusion Criteria:
Recipients were excluded if they meet any of the following criteria on the day of transplant
- Acute, fulminant liver failure
- Prior solid organ or bone marrow transplant
- Chronic use of hemodialysis or diagnosis of chronic renal failure, defined as chronic serum creatinine of &gt;3 mg/dl for &gt;2 weeks and/or requiring hemodialysis
- Multi-organ transplant
- Ventilator dependent
- Dependent on &gt;1 IV inotrope to maintain hemodynamics

2. Follow-up Schedule
All patients were scheduled to return for follow-up examinations at day 0, day 7, hospital discharge, day 30, 6 months, 12 months, and 24 months after transplant was received.

Pre- and post-implant assessments included medical history, Early Liver Allograft Dysfunction surveillance, mechanical ventilator support, liver graft-related adverse events, ICU or hospital stay, liver graft-related adverse events and serious adverse events, patient/graft survival and in some cases liver biopsy.

The detailed post-transplant assessment and follow-up schedules are shown in

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Table 6.
Table 6: Recipient Schedule of Assessments

|  Evaluations | Recipient Schedule of Assessments  |   |   |   |   |   |
| --- | --- | --- | --- | --- | --- | --- |
|   | Tx. Day -- Day 7 Post-Tx. | Discharge | Day 30 | Month 6 | Month 12 | Month 24  |
|  Eligibility & Informed Consent | X |  |  |  |  |   |
|  Randomization | X |  |  |  |  |   |
|  Demographic/Characteristics | X |  |  |  |  |   |
|  Medical & Risk Factors | X |  |  |  |  |   |
|  Transplant Details | X |  |  |  |  |   |
|  Early Liver Allograft Dysfunction Surveillance | X |  |  |  |  |   |
|  Mechanical Ventilator Support | X |  |  |  |  |   |
|  Patient Survival | X |  | X | X | X | X  |
|  Graft Survival | X |  | X | X | X | X  |
|  Immunosuppressive Meds & Induction (if applicable) | X | X |  |  |  |   |
|  Initial ICU & Hospital Stay | X | X |  |  |  |   |
|  Liver Graft-Related AE’s & SAE’s | X | X | X |  |  |   |
|  Liver Biopsy * | X |  |  |  | X | X  |

*only tests regularly scheduled per center SOC or performed due to a clinical cause will be collected.

3. Clinical Endpoints

The safety endpoint is the average number of liver graft-related serious adverse events (LGSAEs) in the first 30 days post liver transplantation, which are defined as:

1) primary non-function (defined as irreversible graft dysfunction, requiring emergency liver re-transplantation or death within the first 10 days, in the absence of immunologic or surgical causes);
2) ischemic biliary complications (ischemic biliary strictures, and non-anastomotic bile duct leaks);
3) vascular complications (liver graft-related coagulopathy, hepatic artery stenosis, hepatic artery thrombosis, and portal vein thrombosis); or
4) liver allograft infections (such as liver abscess, cholangitis, etc.).

The PROTECT trial included the following Effectiveness endpoints:

The Primary Effectiveness Endpoint was the incidence of Early Allograft Dysfunction (EAD), defined as the presence of one or more of the following criteria:

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1) AST level &gt; 2000 IU/L within the first 7 postoperative days;
2) bilirubin ≥ 10 mg/dL on postoperative day 7;
3) INR ≥ 1.6 on postoperative day 7; or
4) primary non-functioning graft within the first 7 days (defined as irreversible graft dysfunction requiring emergency liver re-transplantation or death, in the absence of immunologic or surgical causes).

The primary effectiveness endpoint of EAD is loosely based on the 2010 Olthoff³ publication, which attempted to validate this surrogate endpoint in liver transplant recipients. The Agency notes that the Olthoff definition includes the assessment of ALT in addition to AST, INR, and bilirubin. In the EAD definition used in the PROTECT Trial, ALT is left out and ALT levels within the first 7 days following transplantation are not included in the calculation of whether the recipients met the definition of EAD.

Secondary Effectiveness and OCS Donor Liver Assessment Endpoints include:

- OCS Donor Liver Assessment Endpoint, defined as successful measurement of donor liver perfusion parameters during preservation, including:
- Lactate levels
- Hepatic Artery and Portal Vein Pressure
- Average Bile Production Rate
- Patient survival at day 30 post-transplantation
- Patient survival at initial hospital discharge post liver transplantation.

Other Clinical Endpoints include:

- Length of initial post-transplant ICU stay
- Length of initial post-transplant hospital stay
- Evidence of ischemic biliary complications diagnosed at 6 and at 12 months
- Extent of reperfusion syndrome as assessed based on the rate of decrease of lactate
- Pathology sample score for liver tissue samples.

Regarding success/failure criteria, the primary hypothesis for this trial was that the OCS treatment is non-inferior to the Control with respect to EAD. The statistical null and alternative hypotheses for the primary effectiveness endpoint are:

$$
\mathrm{H}_{10}: \pi_{1,\mathrm{OCS}} \geq \pi_{1,\mathrm{Control}} + \delta,
$$

$$
\mathrm{H}_{11}: \pi_{1,\mathrm{OCS}} &lt; \pi_{1,\mathrm{Control}} + \delta,
$$

where π₁,OCS and π₁,Control are the true proportions of recipients with EAD within the first 7 postoperative days for the OCS and Control, respectively, and δ is the noninferiority margin 0.075. The hypothesis was planned to be evaluated using the Farrington and Manning score statistic with one-sided alpha of 0.05.

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If non-inferiority is demonstrated, the results were to be tested for superiority, using Fisher's exact test with a two-sided alpha of 0.05.

## B. Accountability of PMA Cohort

At the time of database lock, of 429 patients enrolled in the PMA study, 41% of patients were available for analysis at the completion of the study, the 24-month post-operative visit.

A total of 429 patients signed informed consent and 428 received one or more randomizations in the PROTECT trial. For the randomized patients, there were 476 matched donors that had an initial screening, and 300 were considered to be in the PROTECT trial (OCS 153 and Control 147). The enrollment consort diagram is presented in Figure 3 below.

The primary analysis population was pre-specified as the Per Protocol (PP) population which consists of all randomized patients who were transplanted and had no major protocol violations and for whom the donor liver received the complete preservation procedure as per the randomization assignment. In the PP analyses, patients were analyzed in the groups to which they were randomized. The primary analysis of the primary and secondary effectiveness endpoints, and of other endpoints are based on the PP population.

The Modified Intent-to-treat (mITT) population consists of all randomized patients who were transplanted in the trial. In the mITT population, patients were analyzed as randomized. The mITT analyses are the secondary analyses of effectiveness.

The As Treated (AT) population (also called the Safety Population (SP)) consists of all treated patients, i.e., all patients who were transplanted in the trial with a donor liver preserved with either OCS or Control. In analyses based on this population, patients were analyzed as treated. Analyses of safety endpoints are performed based on the AT population.

The Intent-to-Treat (ITT) population consists of the mITT population defined above plus an additional N=43 randomized subjects who were transplanted off-study using cold storage with a matched organ, plus two other randomized subjects for whom the preservation method was initiated but who did not receive a transplant due to death or donor liver turn down.

Figure 3: Enrollment Consort Diagram

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![img-1.jpeg](img-1.jpeg)

1 Patient withdrawn and transplanted (Tx) Off Study with a Non-Study- Liver Preserved Using Cold storage after Initial Donor Offer(s) were Declined for Tx at Retrieval and initial randomization(s) were broken (N=49):
- N=25 – Subsequent donor liver offer did not meet OCS Liver PROTECT trial inclusion criteria.
- N=21 – Site PI decided not to re-randomize patients at donor offer due to donor operating room (OR) logistical reasons or lack of trial trained retrieval staff at time of donor offer.
- N=3 – Patients no longer met trial eligibility criteria due to deteriorating health status or received split liver transplant.

2 Patient was Delisted for Tx (N=9: 6 OCS, 3 Control):
- N=3 (2 OCS, 1 Control) – Metastatic cancer discovered at recipient surgical exploration.
- N=4 (2 OCS, 2 Control) – Delisted for transplantation due to deteriorating health status.
- N=2 (2 OCS, 0 Control) – Deemed ineligible for trial by site PI and was withdrawn.

3 Patients Withdrew Consent for Trial (N=2: 1 OCS, 1 Control)

4 Patient withdrawn and transplanted Off Study with a Liver matched at randomization but Preserved Using Cold Storage (N=43: 28 OCS, 15 Control):
- N=39 (24 OCS, 15 Control) – Donor liver did not meet eligibility due to presence of accessory vessels, liver hematoma, or required surgical vascular repair.
- N=4 (4 OCS, 0 Control) – Logistical reasons, including:
- Donor family not consenting to research (requirement of organ procurement organizations).
- Unable to obtain pre-retrieval liver biopsy.
- OPO delaying OR time resulting in trained trial retrieval team being off call; and
- Recipient deterioration with renal insufficiency on day of transplant.

5 Rejected for Tx in Donor Body After Randomization (N=130: 57 OCS, 73 Control):
- N=42 (18 OCS, 24 Control) – DCD donor did not expire within 30 mins.
- N=31 (9 OCS, 22 Control) – Clinical judgement at retrieval.
- N=27 (13 OCS, 14 Control) – Steatosis.
- N=9 (3 OCS, 6 Control) – Cirrhosis or fibrosis of the donor liver.
- N=4 (2 OCS, 2 Control) – Vasculature abnormalities or diseased.
- N=3 (3OCS, 0 Control) – Donor-recipient organ size mismatch.
- N=2 (2 OCS, 0 Control) – Liver or Kidney malignancy discovered during retrieval.
- N=12 (7 OCS, 5 Control) – Other reasons: re-allocation, donor did not progress or logistical reasons.

6 DCD Donors Rejected for Transplant-by-Transplant Surgeon after clinical interpretation of Ex vivo Assessment Data obtained during OCS perfusion N=3
- N=2 – Rising lactate levels despite maximizing OCS Liver perfusion parameters.
- N=1 – Donor liver pre-retrieval biopsy revealed extensive bridging fibrosis.

7 Patient remained on waiting list at the end of study N=22 – includes 1 patient who had a donor liver turndown after OCS Liver Preservation and Assessment

8 One patient was transplanted on OCS with a Non-randomized liver. This patient is included in the AT population but not in the mITT or PP populations.

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# C. Study Population Demographics and Baseline Parameters

The demographics of the study population are typical for a liver transplant study performed in the US.

The donor demographics and baseline characteristics are shown in Table 7 and Table 8. Both donor groups were similar in risk factors of age  $\geq 40$  years, cross clamp time  $&gt;6$  hours and macrosteatosis; however, the OCS arm included more DCD donors (18% for OCS versus 9% for control).

Table 7: Donor Demographic and Baseline Characteristics (AT Population)

|  Parameter | OCS (N=152 (2)) | Control (N=146)  |
| --- | --- | --- |
|  Donor Age (years): mean ± SD | 45.84 ± 14.90 | 46.96 ± 15.22  |
|  Cause of death, n (%) |  |   |
|  • Cerebrovascular Hemorrhage | 44 (28.9%) | 50 (34.2%)  |
|  • Head trauma | 35 (23.0%) | 29 (19.9%)  |
|  • Cardiac | 13 (8.6%) | 10 (6.8%)  |
|  • Other (Anoxia, CSF infection, Suicide, Stroke) | 60 (39.5%) | 57 (39.0%)  |
|  Donor Characteristics(1), n(%) |  |   |
|  • ≥ 40 years old | 102 (67.1%) | 93 (63.7%)  |
|  • Total cross clamp ≥ 6 hours | 48 (31.6%) | 56 (38.4%)  |
|  • DCD ≤ 55 years old | 28 (18.4%) | 13 (8.9%)  |
|  • Steatotic liver > 0% and ≤ 40% macrosteatosis at time of retrieval | 95 (62.5%) | 86 (58.9%)  |
|  • Multiple Donor Characteristics | 95 (62.5%) | 85 (58.2%)  |
|  (1) Multiple donor characteristics (inclusion criteria) could be met (total 60.4% of all donors). (2) Does not include donor organ for Patient LV-01-999, as this patient was not randomized.  |   |   |

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Table 8: Additional Donor Characteristics for DBD and DCD Livers in PROTECT Trial (AT Population)

|  Parameter | DBD |   | DCD  |   |
| --- | --- | --- | --- | --- |
|   | OCS | Control | OCS | Control  |
|  Donor Age (years) |  |  |  |   |
|  Mean | 47.9 | 47.9 | 36.8 | 37.6  |
|  Median | 51.0 | 47.5 | 37.8 | 36.7  |
|  Min-Max | 10.9-83.7 | 13.0-80.6 | 15.2-54.0 | 23.3-51.5  |
|  Macrosteatosis (%) |  |  |  |   |
|  Mean | 4.5 | 3.1 | 0.9 | 6.8  |
|  Median | 0.0 | 0.0 | 0.0 | 0.0  |
|  Min-Max | 0.0-30.0 | 0.0-25.0 | 0.0-15.0 | 0.0-40.0  |
|  Cold Ischemic Time (min) |  |  |  |   |
|  Mean | 174.7 | 338.6 | 178.3 | 341.1  |
|  Median | 165.5 | 331.0 | 168.5 | 350.0  |
|  Min-Max | 115.0-420.0 | 154.0-660.0 | 115.0-273.0 | 175.0-479.0  |
|  Warm Ischemic Time (min) |  |  |  |   |
|  Mean |  |  | 21.0 | 21.7  |
|  Median |  |  | 22 | 21  |
|  Min-Max |  |  | 7-31 | 14-33  |
|  Weight (kg) |  |  |  |   |
|  Mean | 87.7 | 86.4 | 85.9 | 90.5  |
|  Median | 88.3 | 82.5 | 78.5 | 85.8  |
|  Min-Max | 48.0-153.2 | 46.5-183.0 | 56.0-134.0 | 67.3-139.6  |

The recipient demographics and baseline characteristics are shown in Table 9. The majority of the recipients were males (66-69%), with a mean age of 57-58 years and a mean MELD score of 28. Almost a third of the recipients had a history of diabetes and the most prevalent primary diagnosis was alcoholic cirrhosis. The two treatment groups were similar in all demographic and baseline characteristics with no significant differences noted.

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Table 9: Recipient Demographic and Baseline Characteristics (AT Population)

|  Parameter | OCS (N=153) | Control (N=146)  |
| --- | --- | --- |
|  Recipient Age (yrs): mean ± SD | 57.07 ± 10.33 | 58.59 ± 10.04  |
|  Gender, n (%) |  |   |
|  • Male | 102 (66.7%) | 100 (68.5%)  |
|  • Female | 51 (33.3%) | 46 (31.5%)  |
|  BMI (kg/m²): mean ± SD | 29.67 ± 5.38 | 29.51 ± 5.51  |
|  MELD Score: mean ± SD | 28.4 ± 6.90 | 28.0 ± 5.71  |
|  Median | 29.0 | 29.0  |
|  History of diabetes, n (%) | 44 (28.8%) | 44 (30.1%)  |
|  History of liver cancer, n (%) | 60 (39.2%) | 63 (43.2%)  |
|  Primary diagnosis, n (%) |  |   |
|  • Cholestatic Diseases | 9 (5.9%) | 8 (5.5%)  |
|  • Chronic Hepatitis | 27 (17.6%) | 36 (24.7%)  |
|  • Alcoholic Cirrhosis | 54 (35.3%) | 48 (32.9%)  |
|  • Metabolic Diseases | 6 (3.9%) | 6 (4.1%)  |
|  • Primary Hepatic Tumors | 14 (9.2%) | 15 (10.3%)  |
|  • NASH | 24 (15.7%) | 20 (13.7%)  |
|  • Other | 19 (12.4%) | 13 (8.9%)  |

D. Safety and Effectiveness Results

1. Safety Results

Safety Endpoint, LGRSAEs

There was a pre-specified safety endpoint based on the number of liver graft-related serious adverse events (LGRSAEs) in the cohort of 299 recipients available for the 30-day evaluation. LGRSAE results are presented in Figure 4 and Table 10 below.

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![img-2.jpeg](img-2.jpeg)
Figure 4: Safety Endpoint – Average number of LGRSAEs Per Transplanted Patient Within 30 Days Post-Transplant (AT Population)

The specific LGRSAEs are shown in Table 10. The OCS patients did not experience any ischemic biliary complications in the first 30 days post-transplant, while 2/146 (1%) of control patients had ischemic complications. Vascular complications occurred in 7/153 (5%) of OCS patients compared to 9/146 (6%) of control patients. There were no incidents of non-functioning graft or liver allograft infection for either OCS or control patients.

Table 10: LGRSAEs within 30 Days (AT Population)

|  LGRSAE within 30 Days Post-Transplant | OCS (n=153) |   | Control (n=146)  |   |
| --- | --- | --- | --- | --- |
|   |  Patients | Events | Patients | Events  |
|  Any LGRSAE | 7 (5%) | 8 | 11 (8%) | 13  |
|  • Non-functioning graft | 0 | 0 | 0 | 0  |
|  • Ischemic biliary complication | 0 | 0 | 2 (1%) | 2  |
|  • Vascular complication | 7 (5%) | 8 | 9 (6%) | 11  |
|  • Liver allograft infection | 0 | 0 | 0 | 0  |

# Patient Survival

Despite the lower rate of EAD for OCS compared to control, there was no difference in patient or graft survival for the OCS arm compared to the Control arm. Overall patient survival was high and comparable between the OCS and Control arms. The 30-day patient survival for both arms is 99.3%. The patient survival is 97.4% and 96.5% at 6 months and 94.0% and 93.7% at 12 months for OCS and Control, respectively in the PP population. These results are shown in Figure 5 below. Survival for the mITT population is similar, as are the results for the ITT population analysis (Figure 6 and Figure 7).

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![img-3.jpeg](img-3.jpeg)
Figure 5: Kaplan-Meier Overall Patient Survival through 24-Months (PP Population)

![img-4.jpeg](img-4.jpeg)
Figure 6: Kaplan-Meier Overall Patient Survival through 24-Months (mITT Population)

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![img-5.jpeg](img-5.jpeg)
Figure 7: Kaplan-Meier Overall Patient Survival through 24-Months (ITT Population)*

*Note that at 24 months, 3 deaths in OCS group occurred in subjects transplanted off-study using cold-storage

# Post-transplant ICU Stay and Initial Hospital Stay

The mean ICU stay was  $107 \pm 201.6$  hours for OCS compared to  $111 \pm 260.3$  hours for Control. The mean hospital stay was  $11.7 \pm 11.4$  days for OCS compared to  $11.4 \pm 12.7$  days for Control. The results are highly variable for both groups with wide confidence intervals.

The causes of death for PROTECT patients are shown in Figure 8 below.

![img-6.jpeg](img-6.jpeg)
Figure 8: Causes of Death in PROTECT patients through 12 months post-transplant

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# Serious Adverse Events

Serious Adverse Events were collected through 30 days post-transplant or initial hospital discharge. LGRSAEs were collected through 6 months post-transplant, and ischemic biliary complications were collected through 12 months post-transplant. A comprehensive summary of all these events is shown in Table 11 below. As previously discussed, ischemic biliary complications were lower in OCS compared to the Control group. Non-ischemic biliary anastomotic complications were higher in the OCS arm; however, bile leaks were higher in the Control arm. The remaining SAEs were typical of those experienced by liver transplant patients, and there were no differences between the two groups in the overall number of adverse events.

Table 11: CEC-adjudicated Treatment-Emergent SAEs by Preferred Term (As Treated Population) – Comprehensive listing includes all SAEs through 30 days/hospital discharge post-transplant and LGRSAEs through 6 months and ischemic biliary complications through 12 months post-transplant. SAEs that occurred in ≥2% of patients in either arm are shown.

|  Preferred Term | OCS (N=153) |   | Control (N=146)  |   |
| --- | --- | --- | --- | --- |
|   |  Subjects n (%) | Events n | Subjects n (%) | Events n  |
|  Any serious adverse event | 82 (53.6) | 150 | 72 (49.3) | 148  |
|  Biliary ischaemia | 4 (2.6) | 4 (2.7) | 14 (9.6) | 14 (9.5)  |
|  Biliary anastomosis complication | 13 (8.5) | 13 (8.7) | 6 (4.1) | 6 (4.1)  |
|  Post procedural bile leak | 4 (2.6) | 4 (2.7) | 11 (7.5) | 11 (7.4)  |
|  Renal failure acute | 11 (7.2) | 11 (7.3) | 7 (4.8) | 7 (4.7)  |
|  Transplant rejection | 5 (3.3) | 5 (3.3) | 7 (4.8) | 8 (5.4)  |
|  Post procedural haemorrhage | 5 (3.3) | 5 (3.3) | 7 (4.8) | 7 (4.7)  |
|  Convulsion | 2 (1.3) | 2 (1.3) | 5 (3.4) | 5 (3.4)  |
|  Drug toxicity | 5 (3.3) | 5 (3.3) | 2 (1.4) | 2 (1.4)  |
|  Atrial fibrillation | 3 (2.0) | 3 (2.0) | 4 (2.7) | 4 (2.7)  |
|  Pyrexia | 2 (1.3) | 2 (1.3) | 4 (2.7) | 4 (2.7)  |
|  Delirium | 1 (0.7) | 1 (0.7) | 4 (2.7) | 4 (2.7)  |
|  Hepatic artery stenosis | 2 (1.3) | 2 (1.3) | 4 (2.7) | 4 (2.7)  |
|  Pleural effusion | 1 (0.7) | 1 (0.7) | 4 (2.7) | 4 (2.7)  |
|  Respiratory failure | 3 (2.0) | 3 (2.0) | 3 (2.1) | 3 (2.0)  |
|  Ascites | 1 (0.7) | 1 (0.7) | 3 (2.1) | 3 (2.0)  |
|  Wound infection | 3 (2.0) | 3 (2.0) | 0 | 0  |
|  Anaemia | 3 (2.0) | 3 (2.0) | 1 (0.7) | 1 (0.7)  |

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# Device Malfunctions

In the OCS Liver PROTECT trial, there were three device malfunctions reported by trial centers (3/155, 1.9%). Two of three malfunctions were of small plastic parts that are not a critical part of the perfusion of the donor liver, or the overall function of the OCS Liver as further described below.

- One malfunction was reported in which a mounting tab for an IV infusion line plastic housing was broken, making it difficult to connect the Solution Delivery System (SDS) infusion cassette to the SDS driver at priming. This occurred prior to the donor liver instrumentation on the OCS Liver. The user obtained a spare cassette, and the preservation proceeded without any issues.
- One malfunction was reported for a portal vein (PV) flush port valve at the end of OCS perfusion and in preparation for cold flushing the donor liver in the recipient OR. The user flushed the portal vein directly through the PV cannula and bypassed the defective valve.
- One malfunction occurred during pre-retrieval OCS preparation, when the OCS liver perfusion module electrical connection could not be recognized by the OCS Liver Console. This occurred well before the liver was surgically retrieved. The retrieval and preservation proceeded using cold static storage without any issues.

Device malfunctions that were reported in the OCS Liver PROTECT trial did not subject the recipients to any harm given that two occurred well before retrieval. Importantly, all three donor livers were transplanted successfully to the recipients, and their results were analyzed in the PROTECT trial.

# Donor Liver Clinical Turndown After Assessment on OCS Liver

There were three DCD donor livers that were clinically turned down for transplantation. Two cases were due to rising lactate while being perfused on OCS Liver and one case was due to pre-retrieval pathology results. Figure 9 shows how the lactate levels, obtained during donor liver perfusion on the OCS Liver, in these three turndown livers compared to other livers in the OCS arm. No organs were turned down in the cold storage Control arm. The donor organ turndown impacted one recipient in the PROTECT trial who underwent unnecessary anesthesia prior to the donor organ turndown. No potential recipients underwent unnecessary incision.

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![img-7.jpeg](img-7.jpeg)
Figure 9: Mean OCS Liver Arterial Lactate Trend for Turned Down Donor Livers Compared to OCS Transplanted Donor Livers in PROTECT Trial

# 2. Effectiveness Results

# Primary Effectiveness Results

The primary endpoint for effectiveness was based on the 291 evaluable patients at the 7-day time point. The OCS Liver PROTECT trial met its primary effectiveness endpoint regarding Early Allograph Dysfunction (EAD) by demonstrating statistical non-inferiority (NI margin=7.5%, p&lt;0.001) and superiority of outcomes of the OCS arm compared to Control. The results demonstrated that use of OCS Liver was associated with a significant reduction of EAD compared to the Control in the primary analysis PP Population (OCS 18% (27/150) versus Control 31% (44/141) superiority p=0.009). See Figure 10 below.

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![img-8.jpeg](img-8.jpeg)
Figure 10: OCS Liver PROTECT Trial Primary Effectiveness Endpoint - Incidence of Post-Transplant Early Allograft Dysfunction (EAD) (PP Population)

Since the primary effectiveness endpoint EAD is a composite endpoint, each of the individual components of EAD (AST, bilirubin, and INR) were evaluated separately to see whether EAD incidence is driven by one component, and to ensure the similar trending across each component. Table 11 shows the number of recipients who met each of the seven possible combinations of the three EAD components.

In the PROTECT trial, most EAD events are driven by AST only, which is shown in row 3 (17 in OCS and 36 in Control) in Table 12 below.

Table 12: Frequency Table for 7 Different Combinations of Individual Components of the EAD Definition (296 Recipients: 151 OCS and 145 Control)

|  Row | Components of EAD |   |   | Number of Recipients  |   |
| --- | --- | --- | --- | --- | --- |
|   |  INR≥1.6 at Day 7 | Bilirubin≥10 at Day 7 | AST>2000 during Wk1  |   |   |
|   |  |  |  | OCS N | Control N  |
|  1 | INR≥1.6 | - | - | 3 | 2  |
|  2 | - | Bilirubin≥10 | - | 4 | 2  |
|  3 | - | - | AST>2000 | 17 | 36  |
|  4 | INR≥1.6 | Bilirubin≥10 | - | 0 | 0  |
|  5 | - | Bilirubin≥10 | AST>2000 | 0 | 3  |
|  6 | INR≥1.6 | Bilirubin≥10 | AST>2000 | 2 | 2  |
|  7 | INR≥1.6 | - | AST>2000 | 1 | 2  |
|  Total |  |  |  | 27 | 47  |

Generated by the FDA reviewer
Source: the sponsor's submitted dataset "ADSL" in the amendment

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A reduction in EAD was experienced in both the DBD and DCD donor cohorts in the PROTECT trial (Figure 11).

![img-9.jpeg](img-9.jpeg)
Figure 11: Incidence of Post-Transplant EAD in DBD and DCD Donor Cohorts in PROTECT Trial (PP Population)

# Secondary Effectiveness Endpoint, OCS Donor Liver Assessment During Perfusion

The OCS Liver allows for continuous monitoring of the donor liver during preservation. The rates of successful measurement of lactate levels, bile production, hepatic artery pressure, and portal vein pressure are shown in Table 13.

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Table 13: Secondary Endpoint – OCS Liver Assessment Parameters During Perfusion

|  OCS Liver Perfusion Parameters |   |
| --- | --- |
|  Percentage of livers for which OCS device monitoring allowed for ex vivo assessment prior to transplant | 93% (144/155)  |
|  Lactate Level | 94% (145/155)  |
|  Hepatic Artery Pressure | 100% (155/155)  |
|  Portal Vein Pressure | 100% (155/155)  |
|  Average Bile Production Rate | 99% (154/155)  |
|  * p-value from a one-sided exact binomial test, testing the null hypothesis that the true proportion is less than or equal to 0.85 versus the alternative hypothesis that it is greater than 0.85.  |   |

## Recipient Survival at Day 30 and at initial hospital discharge

The 30-day recipient survival and recipient survival to initial hospital discharge were high and similar in the OCS and Control arms (Figure 12).

Figure 12: Secondary Effectiveness Endpoints - Recipients’ Survival at Day 30 and at Initial Hospital Discharge (PP Population)
![img-10.jpeg](img-10.jpeg)
*Non-inferiority demonstrated with non-inferiority margin=7.5% and two-sided 90% CI

## Other Clinical Endpoints

Incidence of Ischemic Biliary Complications at 6 and 12 Months

In the PROTECT trial, ischemic biliary complications were site reported based on clinical findings. A lower incidence of ischemic biliary complications was observed in the OCS arm compared to the Control arm at 6 and 12 months follow-up (Figure 13).

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![img-11.jpeg](img-11.jpeg)
Figure 13: Incidence of Ischemic Biliary Complications Through 6 and 12 Months Post-Liver Transplant (PP Population)

At day 30 post-transplant, the rate of non-ischemic biliary complications was 8.5% for OCS compared to 4.1% for control, while the rate of post-transplant bile duct leak was 2.6% for OCS and 7.5% for control.

## Assessment of Recipient Lactate Levels

Recipient mean lactate levels post-reperfusion were reduced in the OCS group compared to in the Control group based on an ad hoc analysis (Table 14).

Table 14: Recipients' Mean Lactate Levels Post- Transplant (PP Population)

|  Timepoint | OCS Recipient Arterial Lactate (mmol/L) Mean ± SD N=152 | Control Recipient Arterial Lactate (mmol/L) Mean± SD N=146  |
| --- | --- | --- |
|  Anhepatic | 3.47 ± 1.706 | 3.55 ± 1.621  |
|  0-40 min after reperfusion | 4.05 ± 2.092 | 4.57 ± 2.532  |
|  90-120/150 min after reperfusion | 3.64 ± 2.220 | 4.33 ± 2.987  |

Donor livers were perfused on OCS and were maintained in a near physiologic condition based on OCS perfusion parameters, bile production, and blood gas results of the perfusate (Table 15). As seen in Figure 9, for most livers, the OCS Liver lactate trended down and then were stable during perfusion, indicating that the donor liver regained metabolic activity, although this did not result into a survival advantage for the OCS arm.

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Table 15: OCS Liver Perfusion Parameters and Perfusate Chemistry Levels

|  OCS Perfusion Parameters and Perfusate Chemistry | OCS (N=152)  |
| --- | --- |
|  OCS Liver Perfusion Time (mins) mean ± SD | 276.6 ± 117.4  |
|  Hepatic Artery Pressure (mmHg) - mean ± SD | 70.6 ± 16.2  |
|  Hepatic Artery Flow (L/min) - mean ± SD | 0.7 ± 0.2  |
|  Portal Vein Pressure (mmHg) - mean ± SD | 5.4 ± 2.3  |
|  Portal Vein Flow (L/min) - mean ± SD | 1.3 ± 0.1  |
|  Total Bile Production (ml) - mean ± SD | 28.3 ± 15.9  |
|  pH- mean ± SD | 7.43 ± 0.1  |
|  PaO₂ (mmHg) mean ± SD | 420.2 ± 80.7  |
|  PCO₂ (mmHg) mean ± SD | 41.5 ± 14.6  |
|  HCO₃ (mmHg) mean ± SD | 28.6 ± 10.3  |

## Ischemic Time

The use of the OCS Liver reduced the total cold ischemic time on the liver allografts by limiting the ischemic times to two time periods:

- Pre-OCS Ischemic Time: This is the time needed to surgically remove the donor liver from the body of the donor, perform the back table surgical preparation and instrument it on the OCS Liver. The OCS instrumentation takes ~10-15 minutes;
- Post-OCS Ischemic Time: this is the time needed to surgically reimplant the liver allograft into the recipient.

Otherwise, throughout the OCS perfusion, the conditions for the donor liver allograft were not ischemic given that it was perfused on OCS with warm, oxygenated blood perfusate until it was ready to be transplanted.

Control liver allografts were ischemic from the time they were procured from the donor body until they were implanted into the recipient.

Figure 14 shows the average durations of these time windows in the PROTECT trial.

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![img-12.jpeg](img-12.jpeg)
Figure 14: Average Out of Body Times in PROTECT Trial

The total ischemic time was reduced on the OCS Liver compared to Control, despite the OCS having longer total cross-clamp (out of body) time (Figure 15 below).

![img-13.jpeg](img-13.jpeg)
Figure 15: Total Ischemic and Cross-Clamp (Out of Body) Times in PROTECT Trial

# Transplantation of DCD Donor Livers

Figure 16 shows that among 55 DCD livers matched to randomized OCS patients, 28 (51%) were transplanted while among 51 DCD livers matched to randomized control patients, 13 (25%) were transplanted. The proportion of DBD livers matched to randomized OCS patients that were transplanted was 81%, and the proportion transplanted in the Control arm was 79%.

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![img-14.jpeg](img-14.jpeg)
Figure 16: Proportion of DBD and DCD Donor Livers Transplanted in PROTECT Trial

The OCS Liver provided additional opportunity for monitoring of hemodynamics and metabolic parameters of the DCD liver grafts, and a higher proportion of DCD livers transplanted was observed for OCS compared to the Control arm (51% versus 25%). The monitoring data provided by the OCS Liver during preservation allows the user to make an ex vivo assessment while the organ is being perfused.

## Pathology Assessment

To assess the impact of ischemia and reperfusion (IR) injury associated with each preservation method, the PROTECT trial pre-specified that three donor liver tissue samples be examined blindly by an independent core pathology laboratory with extensive experience in liver transplant pathology. These three samples were:

- Sample 1: taken to assess the baseline condition of the donor liver prior to initiation of any preservation method.
- Sample 2: taken after preservation and prior to transplantation into the recipient. This sample was taken only for hypothesis generation on the mechanism of potential pathological changes in the donor liver allograft. This is the first time when IR injury is expected to manifest with OCS, because this is the first biopsy after organ reperfusion.
- Sample 3: taken after transplantation and reperfusion of the donor liver in the recipient, which makes it the most clinically relevant for IR injury. This is particularly true in the PROTECT trial because the preservation methods for OCS and Control differed substantially. This is the timepoint

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where IR injury would first manifest in donor livers on cold storage, because this is the first biopsy after organ reperfusion in the control group, while in OCS, donor livers had already been reperfused, oxygenated, and were metabolically active throughout preservation.

All samples were examined for lobular inflammation, which is a marker for IR injury and for lobular necrosis, which is a sign of irreversible damage of the liver tissue.

# Lobular Inflammation

In this analysis, the pathological assessment demonstrated less lobular inflammation in post-transplant samples of the OCS preserved donor livers compared to Control arm (Figure 17).

![img-15.jpeg](img-15.jpeg)
Figure 17: Incidence of Lobular Inflammation in Donor Livers

The same finding of lower incidence of lobular inflammation was seen in both the DBD and DCD donor population post-transplant specimens in the PROTECT trial, see Figure 18 below.

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![img-16.jpeg](img-16.jpeg)
Figure 18: Incidence of Lobular Inflammation in Donor Livers Stratified by Donor Type DBD versus DCD

# Lobular Necrosis

In this analysis the post-transplant pathological assessment demonstrated that lobular necrosis was equivalent between the two trial arms (Figure 19). Although, decreased lobular inflammation was noted in the OCS arm, no difference in necrosis was observed in the post-transplant samples.

![img-17.jpeg](img-17.jpeg)
Figure 19: Incidence of Lobular Necrosis in Donor Livers

When the impact of donor type on this histological marker of irreversible liver damage was assessed, the DCD donor livers had a higher incidence of post-

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transplant lobular necrosis as compared to DBD, and the OCS arm was associated with lower incidence of lobular necrosis in the DCD arm as compared to Control (Figure 20).

![img-18.jpeg](img-18.jpeg)
Figure 20: Incidence of Lobular Necrosis in Donor Livers Stratified by Donor Type DBD versus DCD

## 3. Pediatric Extrapolation

In this premarket application, existing clinical data was not leveraged to support approval of a pediatric patient population.

## E. 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 pivotal clinical study included 112 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.

## XI. SUMMARY of SUPPLEMENTAL CLINICAL INFORMATION

### OCS PROTECT Continued Access Protocol

The OCS Liver PROTECT Continued Access Protocol (CAP) was approved by FDA for 74 subjects. The PROTECT CAP is a single-arm study, but otherwise the study design was the same as the OCS Liver PROTECT trial.

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A total of 74 subjects have been enrolled in OCS Liver PROTECT CAP. As of the April 8, 2021, all 74 subjects have reached 30 days post-transplant, 50 subjects have reached 6 months, and 19 subjects have reached 12 months. The study is on-going, and data are still being collected, monitored, verified, and adjudicated for all transplanted patients. A summary of the available data for these 74 subjects is provided in the sections that follow.

## Donor Characteristics and Demographics

Donor demographics and characteristics are shown in Table 16 below. There have been no donor liver turndowns after OCS perfusion in the PROTECT CAP. The donor characteristics are similar to the OCS Liver PROTECT trial, except that PROTECT CAP has a higher percentage of DCD donors (23% in CAP) compared to PROTECT (18%).

Table 16: Donor Demographic and Baseline Characteristics, OCS Liver PROTECT CAP

|  Parameter | OCS Patients (N=74)  |
| --- | --- |
|  Donor Age Mean ± SD | 47.12 ± 13.804  |
|  Cause of Death, n (%) |   |
|  • Anoxia | 37/74 (50.00%)  |
|  • Cerebrovascular/Stroke | 24/74 (32.43%)  |
|  • Head Trauma | 12/74 (16.22%)  |
|  • CNS Tumor | 0/74 (0.00%)  |
|  • Other (1) | 1/74 (1.35%)  |
|  Donor Inclusion Criteria, (2) n (%) |   |
|  • Donor age ≥ 40 years old | 50/74 (67.57%)  |
|  • Expected total cross clamp/cold ischemic time ≥ 6 hours | 33/74 (44.59%)  |
|  • Donor after circulatory death (DCD) with age ≤ 55 years old | 17/74 (22.97%)  |
|  • Steatotic liver greater than 0% macrosteatosis and less than or equal to 40% macrosteatosis at time of retrieval | 37/74 (50.00%)  |
|  Multiple Donor Characteristics | 43/74 (58.11%)  |
|  (1) Bacterial meningitis
(2) Multiple donor characteristics (inclusion criteria) could be met.  |   |

## Recipient Demographic and Baseline Characteristics

Recipient demographic and baseline characteristics are shown in Table 17 below and are similar to the OCS Liver PROTECT trial, except that PROTECT CAP has a higher percentage of primary hepatic tumor (17.6% in CAP) compared to PROTECT (9.2%).

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Table 17: Recipient Demographic and Baseline Characteristics, OCS Liver PROTECT CAP

|  Parameter | OCS Patients (N=74)  |
| --- | --- |
|  Age (years): Mean ± SD | 57.01 ± 11.572  |
|  Gender: |   |
|  • Male | 56/74 (75.68%)  |
|  • Female | 18/74 (24.32%)  |
|  BMI (kg/m²): Mean ± SD | 29.18 ± 6.258  |
|  MELD Score: Mean ± SD | 27.69 ± 6.034  |
|  Medical history, n (%) |   |
|  • History of diabetes | 22/74 (29.73%)  |
|  • History of liver cancer | 30/74 (40.54%)  |
|  Primary Diagnosis, n (%) |   |
|  • Alcoholic Cirrhosis | 30/74 (40.54%)  |
|  • Cholestatic Diseases | 5/74 (6.76%)  |
|  • Chronic Hepatitis | 12/74 (16.22%)  |
|  • Metabolic Diseases | 1/74 (1.35%)  |
|  • NAFLD/NASH | 10/74 (13.51%)  |
|  • Primary Hepatic Tumor | 13/74 (17.57%)  |
|  • Other | 3/74 (4.05%)  |
|  ○ Cholangiocarcinoma | 2/74 (2.70%)  |
|  ○ Primary Biliary Cholangitis | 1/74 (1.35%)  |

## Early Allograft Dysfunction (EAD)

EAD for all patients was adjudicated by the CEC and is shown in Table 18 below. The rate of EAD is slightly higher than that observed in the PROTECT trial. The difference in EAD between PROTECT and CAP is not statistically significant (p=0.2178, Fisher's Exact test).

Table 18: EAD Results, OCS Liver PROTECT CAP

|   | OCS Subjects (N=74)  |
| --- | --- |
|  EAD, n (%) | 19/74 (25.68%)  |
|  • AST level > 2000 IU/L within the first 7 postoperative days | 15/74 (20.27%)  |

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|   | OCS Subjects (N=74)  |
| --- | --- |
|  • Bilirubin ≥ 10 mg/dl on postoperative day 7 | 4/74 (5.41%)  |
|  • INR ≥ 1.6 on postoperative day 7 | 5/74 (6.76%)  |
|  • Primary non-functioning graft within the first 7 days | 0/74 (0.00%)  |

## Patient Survival/Graft Survival

By the date of database closure, all 74 patients met the 30-day post-transplant follow-up. The 30-day patient and graft survival were 98.7%. Long-term follow-up of the CAP patients is ongoing. To date, a total of five deaths have occurred among the 74 patients. None of the deaths was related to the liver graft. Summary of the causes of deaths reported were as follows:

- Patient 1: 73 y.o. recipient with MELD score of 28, BMI of 40 and severely compromised cardiac function was transplanted with a DBD donor organ. Prior to liver implantation, experience cardiac arrest several times intra-operatively and experienced disseminated intravascular coagulation (DIC) and pulmonary embolism requiring tissue plasminogen activator (TPA) administration during the transplant procedure. Liver function was negatively impacted due to severe hemodynamic compromise and DIC due to cardiac arrest. Patient was re-transplanted on day 9. Patient expired on day 111 from generalized sepsis.
- Patient 2: 47 y.o. recipient with MELD score of 40 and diagnosis with alcoholic liver cirrhosis, was transplanted with a DBD donor organ. The patient expired on day 30 due to sepsis secondary to perforated duodenal ulcer.
- Patient 3: 73 y.o. recipient with MELD score of 28, was transplanted with a DBD donor organ. Patient expired on day 59 due to sepsis of respiratory origin.
- Patient 4: 57 y.o. recipient with MELD score of 15, transplanted with a DBD donor organ. Patient expired on day 75 due to respiratory failure secondary to pre-existing hepatopulmonary syndrome.
- Patient 5: 61 y.o. recipient with MELD score of 32, was transplanted with a DBD donor organ. Patient expired on day 108 from respiratory sepsis secondary to mycobacterium lung abscess.

All the causes of death and liver graft relatedness have been CEC reviewed and adjudicated.

## Summary of PROTECT CAP Results

There has been a total of 74 subjects transplanted in the OCS Liver PROTECT CAP. The results for the OCS Liver PROTECT CAP to date are similar to those observed in the OCS arm of the OCS Liver PROTECT trial. Long-term follow-up is ongoing on all CAP patients.

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# XII. PANEL MEETING RECOMMENDATION AND FDA'S POST-PANEL ACTION

## A. Panel Meeting Recommendation

At an advisory meeting held on July 14, 2021, the Gastroenterology and Urology Device Panel Meeting TransMedics Organ Care System (OCS) Liver Panel voted 14/14 that there is reasonable assurance the device is safe, 14/14 that there is reasonable assurance that the device is effective, and 12/14 (1 No, 1 abstain) that the benefits of the device outweigh the risks in patients who meet the criteria specified in the proposed indication. https://www.fda.gov/advisory-committees/advisory-committee-calendar/july-14-2021-gastroenterology-and-urology-devices-panel-medical-devices-advisory-committee-meeting

## B. FDA's Post-Panel Action

FDA worked interactively with the applicant to formulate the indications for use, labeling, and post approval study protocols to address recommendations by the Panel and the FDA.

# XIII. CONCLUSIONS DRAWN FROM PRECLINICAL AND CLINICAL STUDIES

## A. Effectiveness Conclusions

The PROTECT trial demonstrated statistical superiority in reduction of EAD in the Per Protocol population compared to the Control arm. The OCS Liver PROTECT trial met the secondary effectiveness endpoint (OCS Donor Liver Assessment during Perfusion) and demonstrated that OCS Liver's capabilities for monitoring of lactate level, hepatic artery pressure, portal vein pressure and average bile production during preservation enabled monitoring of hemodynamics and metabolic function providing information that was used as part of surgeon decision-making to turn down livers for transplant. Despite the lower rate of EAD for the OCS arm compared to the Control arm, differences were not observed in clinically meaningful outcomes such as post-transplant ICU stay, initial hospital stay, and patient or graft survival.

## B. Safety Conclusions

The OCS Liver PROTECT trial met its safety endpoint by demonstrating that the average number of LGRSAEs per patient in the OCS arm was statistically non-inferior to the Control arm. Lower ischemic biliary complications were observed compared to Control at 6 months post-transplant (1.3% for OCS vs 8.5% for control) and at 12-months post-transplant (2.6% for OCS vs 9.9% for control). While non-ischemic biliary complications, measured at 30 days, were higher in the OCS (8.5%) compared to the control (4.1%) while the rate of post-transplant bile duct leak was 2.6% for OCS and 7.5% for control. The risks of the device are based on data collected in a clinical study conducted to support PMA approval as described above.

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The risks include device malfunction, although the rate reported in the PROTECT trial was low (3/155 1.9%) and no organs appeared injured or were deemed not transplantable due to any device malfunction. Three livers were also turned down in the OCS arm while no livers were turned down in the Control arm.

## C. Benefit-Risk Determination

The probable benefits of the device are also based on data collected in a clinical study conducted to support PMA approval as described above. The primary effectiveness endpoint in the PROTECT trial was an assessment of EAD. The OCS treatment arm resulted in an absolute 14.5% difference in EAD (OCS 17.9%, Control 32.4%), which was found to be both non-inferior (p&lt;0.0001) and superior (p=0.0044) according to the pre-specified analyses, compared to the Control. While this would appear to be a statistically and clinically significant benefit, there is uncertainty associated with this result. Although the primary endpoint of this study was the incidence of EAD, EAD is intended as a predictor of clinical outcomes¹, and it is less relevant as a proxy than the actual clinical outcomes of recipient and graft survival. In the study by Olthoff et al., EAD reliably predicted increased 6-month mortality and increased graft loss with an 8-10-fold difference between recipients with EAD versus the recipients without EAD. However, in the PROTECT Trial, despite a significant difference between the EAD rates at 7 days, no clinically or statistically significant differences between subsequent mortality or graft loss rates were observed. Given that host and graft survival are the most relevant measures of transplant success, the reduction in EAD in the OCS arm is of unclear significance. Despite the lower EAD rates in the OCS arm, there was not a correlation with other intermediate clinical outcomes (ICU stay, hospital stay) that might reflect a clinical benefit.

The assessment of EAD was based on, but was not exactly the same as, that described and validated by Olthoff et al.¹ A majority of recipients in the PROTECT trial (71.6%) were classified as having EAD by meeting the AST &gt;2000 criterion (note that ALT levels were not included as part of the PROTECT trial primary endpoint's definition of EAD, but a subsequent post hoc analysis revealed no difference in EAD rate if ALT were considered), while a majority of recipients in the Olthoff study were deemed to have EAD based on the elevated bilirubin (Total Bilirubin ≥10 mg/dL on post-operative day (POD) 7) criterion. The relative contribution of each criterion to the severity of EAD events and their relatedness to outcomes such as survival are unknown. Hence, it is challenging to evaluate the severity of EAD. Therefore, it is unknown if the predominance of elevated AST, but not bilirubin or INR, as the criterion for EAD is the reason there is no observed concomitant survival benefit. It is also likely that the study was underpowered to assess differences in clinically relevant outcomes such as patient and graft survival with respect to EAD. It does not appear that EAD serves as a proxy for survival in the PROTECT trial, thereby minimizing the purported benefit of decreased EAD in the OCS arm of the trial.

The PROTECT trial met the secondary effectiveness endpoint (OCS Donor Liver Assessment during Perfusion) and demonstrated that OCS Liver's capabilities for

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monitoring of lactate level, hepatic artery pressure, portal vein pressure and average bile production met the performance goal of 85% of donor livers preserved using OCS for the entire preservation period. Assessments were made for 144 out of 155 organs perfused on the OCS. However, there were no predefined transplantability criteria, and none of these parameters, including change in perfusion fluid lactate, liver enzymes, and bile output and concentration have been validated or shown to correlate with clinically relevant outcomes such as graft or recipient survival.

In the PROTECT trial, the sponsor reports an increase in the number of DCD donor livers transplanted in the OCS arm compared to the Control arm (OCS 50.9% (28/55), Control 25.5% (13/51)). However, there is uncertainty associated with this purported benefit due to limited data (only 41 out of 298 livers, 13.8% mITT population) and an imbalance between treatment arms, because more DCD organs were included in the OCS arm. The study design did not include stratification to ensure that an equal number of DCD organs were included in each arm. Furthermore, the PROTECT trial was open-label and the investigators had knowledge of the treatment assignment. Given the uncertainties in this limited subgroup analysis, no claims in increased DCD donor organ utilization can be made.

In the PROTECT trial, the sponsor also claims that the device resulted in a reduction of ischemic biliary complications, reperfusion syndrome, and lobular inflammation. However, even though these analyses were pre-specified as "Other Endpoints" in the Statistical Analysis Plan, they were not included in the multiplicity adjustment procedure and therefore, no statistical inference can be drawn for these "Other Endpoints."

The probable risks of the device are also based on data collected in a clinical study conducted to support PMA approval as described above. Use of the OCS device adds a risk of organ turndown when compared to the standard of care. In the PROTECT trial, the sponsor asserted that assessment of the organ while on the device resulted in clinical benefits such as identifying lower quality DCD livers that were unacceptable for transplant due to rising lactate and bridging fibrosis. However, it is unclear if these organs were damaged prior to being placed on the OCS-Liver, or if the damaged was caused after being placed on the OCS-Liver. Furthermore, criteria for suitability for transplant based on these parameters monitored by the OCS device are not established. The risk of donor organ turndown impacted one recipient in the PROTECT trial who underwent unnecessary anesthesia prior to the donor organ turndown. No potential recipients underwent unnecessary incision.

Use of the OCS device also adds a risk of device malfunction when compared to the standard of care. However, in the PROTECT trial, the rate of device malfunctions was low (3/155, 1.9%) and this risk is mitigated thought the conversion of the donor organ from the OCS Liver to cold storage.

Additional factors to be considered in determining probable risks and benefits for the Organ Care System (OCS™) Liver device included: donor organ and recipient

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disposition and trial design issues. Of the 476 donor livers uniquely matched to randomized recipients, 176 (37%) were considered as screening failures by the sponsor and were excluded from the PROTECT trial. Similarly, of the 429 consented (428 randomized) subjects, 129 (30%) were excluded from the PROTECT trial and did not have any primary and secondary endpoint data collected. Of those excluded subjects, 49 (11% of total) were transplanted outside of the trial and not followed, 43 were transplanted outside the trial with survival data. Due to the high proportion of post-randomization exclusion, these recipient and donor liver disposition issues increased the uncertainty associated with the trial results described above.

In conclusion, the device preserves donor DBD and DCD livers ≤55 years old and with ≤30 mins of warm ischemic time, macrosteatosis ≤15%, comparably to the cold, static, storage standard of care with similar graft and patient survival, with the additional probable benefit of decreased ischemic biliary complications and, importantly, the ability to monitor the organ during preservation which provides the transplant surgeon with additional information whereby to assess the organ prior to transplantation. The benefit of decreased EAD is unclear given the lack of correlation with patient or graft survival, but the PROTECT trial may have been underpowered to detect such differences. The additional risks of device malfunctions with their implications to the recipient in terms of donor organ transplantability and unnecessary procedures are considerable but no such outcomes were evidenced in the PROTECT trial. Serious consequences of device malfunction are mitigated by the opportunity to convert to cold storage which is explained in the device labeling. Further information will be gathered in the post-approval…

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