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TransMedics' response to concerns raised by the FDA during the PROTECT trial of their OCS Liver System. The trial aimed to compare the safety and effectiveness of the OCS Liver System versus cold storage for preserving and assessing donor livers, focusing on various aspects such as assessment capabilities, missing data, statistical issues, randomization process, and device malfunctions. The document also highlights the clinical benefits of the OCS Liver System, including increased DCD donor liver utilization and improved post-transplant clinical outcomes.
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Advisory Committee Briefing Materials: Available for Public Release
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This document is intended to present to the Advisory Panel the following information:
▪ All clinical and scientific evidence supporting the approval of OCS Liver System PMA for the proposed indications below;
▪ TransMedics’ response to FDA’s key questions highlighted in the FDA Panel Executive Summary; and
▪ The scientific and clinical rationale behind TransMedics’ position, if different from the FDA’s.
Section 1 of this document is designed to provide the high-level summary of all the clinical
evidence and associated conclusions in support of the approval of this PMA for the OCS Liver
System. The primary data set supporting this PMA is the PROTECT trial, a randomized,
controlled, multicenter U.S. clinical trial comparing post-transplant outcomes for recipients of
donor livers preserved and assessed on the OCS Liver System to those of recipients of donor
livers preserved on standard of care ischemic cold storage. The primary and secondary
effectiveness endpoints were met, and the OCS Liver System demonstrated superiority to the
cold storage control in the reduction of Early Allograft Dysfunction (EAD). In addition, the use
of the OCS Liver System was associated with a clinically significant reduction of ischemic biliary
complications at 6 and 12 months. The safety endpoint was also met, and there were no safety
concerns identified for the OCS Liver System.
This Overview also outlines TransMedics’ position on the key areas of concerns raised by FDA in
their panel material, which focused on:
▪ The OCS Liver System’s assessment capabilities;
▪ Perceived missing data (from recipient screen failures) and appropriateness of an ITT analysis;
▪ Statistical issues including multiplicity adjustment;
▪ PROTECT trial randomization process and its potential impact on the trial results;
▪ The occurrence of 3 DCD liver allograft turndowns after OCS Liver assessment, and whether they pose a potential risk to the intended recipient;
▪ The definition of EAD and the clinical value of the significant reduction of EAD in the OCS arm that was demonstrated in the PROTECT Trial;
▪ The 3 device malfunctions that were reported and whether they pose a potential risk to the intended recipients;
▪ Clinical outcomes of the DCD liver subgroup in the PROTECT trial;
▪ Overall clinical benefit and value of the OCS Liver System
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In this PMA, TransMedics is seeking approval for the following indications for use for the OCS
Liver System:
The TransMedics® Organ Care System (OCS™) Liver is a portable extracorporeal liver perfusion and monitoring system indicated for the resuscitation, preservation, and assessment of liver allografts from donors after brain death (DBD) or liver allografts from donors after circulatory death (DCD) ≤55 years old in a near-physiologic, normothermic and functioning state intended for a potential transplant recipient.
Today, liver transplantation is universally accepted as the only curative treatment option for
end-stage liver disease secondary to acute fulminant hepatic failure, several forms of liver
cancers, and metabolic disorders. Today, there are several clinical challenges facing liver
transplant therapy:
▪ Shortage of donor liver allografts - The availability of donor liver allografts has not kept pace with the demand^1. The utilization of available DBD donor livers and the utilization of DCD donor livers are severely restricted by the limitations of cold ischemic storage of donor livers;
▪ High waiting list mortality of end-stage liver patients awaiting liver transplantation due to the shortage of supply of suitable donor livers for transplantation. The 2019 SRTR/OPTN Annual Report shows 35% mortality of the liver transplant waiting list in the US. (Figure 1 below).
Figure 1 : Three-year outcomes on Waiting List for Liver Transplantation
▪ High post-transplant complications in the form of Early Allograft Dysfunction (EAD) and Ischemic Biliary Complications (IBC) – Both are associated with short- and long- term graft failure and increased morbidity (Olthoff, et al., 2010; Hudcova, et al., 2017);
(^1) This background and summary are focused on organs from deceased donors, which make up the majority of liver transplants
today, and are appropriate for use of the OCS Liver System. The number of living donor transplants is relatively small: UNOS reported 8,415 deceased donor liver transplants for 2020, and 491 living donor liver transplants during this same year.
Transplanted ( 56 %) Waiting ( 9 %)
Died or Removed from Waiting List ( 35 %)
SRTR/OPTN Annual Report, 2019
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The OCS Liver System was developed to enable the following clinical advantages to liver transplantation:
The FDA raised a concern about OCS Liver’s assessment capabilities and whether the parameters are validated to assess donor liver function. First, TransMedics would like to clarify that the OCS perfusion chemistry levels are the same clinically validated tests used in everyday assessment of liver function both in the donor and in recipients post-transplant. Specifically, OCS livers were assessed using liver enzymes (AST and ALT) and lactate levels as well as bile production. Bile production is the hallmark of liver excretory function in humans. None of these tests are novel, nor were they used differently than their common use in clinical practice for several decades. Simply stated, the OCS Liver System provides the organ with a near- physiologic ex vivo environment that enables further assessment and monitoring of the organ by the same evaluations and assessment methods as clinicians currently use in the donor and recipient in vivo environments.
Second, we would like to point out that TransMedics provided the FDA with extensive animal testing results during the IDE review process that validated the relevance of these lab values, and we correlated them with liver histology. Figure 3 below shows the lactate and AST levels during OCS perfusion in animal experiments during 12 hours of perfusion on the OCS. The lactate levels were very consistent with AST levels and followed the same trend. In addition, we assessed these same parameters (AST and lactate) in simulated transplant studies in the swine model and the same trend was seen (see Figure 4 below). Both of these studies included extensive pathological assessment by a blinded liver transplant pathology core laboratory at
. These studies demonstrated that these biochemical markers correlated with normal well-preserved hepatocyte and biliary structure pathology compared to elevated levels seen in the Control arm, which was associated with severe histopathological injury to the swine livers’ hepatocytes and biliary tree. The preclinical animal studies are summarized in Appendix 2 of this document.
(b) (6)
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1.5.4. Safety Endpoint
The safety endpoint is the incidence of liver graft-related serious adverse events (LGRSAEs) in
the first 30 days post liver transplantation, which are defined as:
Safety events for all patients were adjudicated by the CEC.
1.5.5. Analysis Populations
Per Protocol (PP) population: This was pre-specified as the primary analysis population. It
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 As Treated (AT) population: It 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 Modified Intent-to-Treat (mITT) population: It 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.
Given the complexities of donor organ procurement for transplantation, and different logistical
and clinical reasons that a donor organ may not be accepted for transplantation or eligibility, a
traditional intent-to-treat analysis has never been used for designing any of TransMedics-
designed randomized controlled organ preservation studies for the reasons outlined in the box
below.
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and eligibility of the donor for the trial based solely on the preliminary clinical information provided. This screening was done without any randomization assignment.
− Donor liver found to be acceptable for transplant and meets trial eligibility criteria – these donor livers were procured, preserved using the randomized method and transplanted into a recipient in the PROTECT trial;
− Donor liver found to be acceptable for transplant, however, it did not meet the PROTECT eligibility criteria (e.g. presence of accessory vessels, etc.) or a logistical issue was encountered (e.g. donor family withdrew consent for research, etc.) - these livers were preserved using ischemic cold storage and were transplanted off-trial. The recipients of these donor livers were withdrawn from the PROTECT trial.
− Donor liver found to be not acceptable for transplantation (dry run) or the donor liver was turned down based on OCS Liver assessment parameters (turned down). The potential recipients for these donor livers in this category were returned back to the consented pool to be re-randomized if and when another donor liver was offered for them. This step was pre-specified in the PROTECT trial protocol to minimize any potential clinical bias of knowing the randomization assignment for a potential subsequent donor offer.
CONFIDENTIAL Page 19 of 121
of the OCS Liver System significantly reduced the total cold ischemic time on the liver allografts
by limiting the ischemic times to 2 obligatory time periods:
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.
On the other hand, Control liver allografts were ischemic from the time they were procured
from the donor body until they were implanted into the recipient. Figure 9 below
demonstrates these critical time windows.
Figure 9 : Overall Out of Body Times in PROTECT Trial
Based on the above unique characteristics of the OCS, the injurious total ischemic time was
significantly reduced on the OCS Liver System compared to Control, despite the OCS having
significantly longer total cross-clamp (out of body) time (Figure 10 below).
0 50 100 150 200 250 300 350 400 450 500
Control (n= 146 )
OCS (n= 152 ) 108 minutes Pre-OCS Ischemic Time (Procurement)
280 minutes OCS Oxygenated Blood Perfusion Time (Resuscitation, Preservation & Assessment)
339 minutes Total Ischemic and Cross-Clamp Time (Procurement, Preservation and Implantation)
67 minutes Post-OCS Ischemic Time (Implantation)
Time (minutes)
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Figure 10 : Total Ischemic and Cross-Clamp (Out of Body) Times in PROTECT Trial (mITT Population)
1.6.4.1. Donor Liver Clinical Turndown After Assessment on OCS Liver System
Given that the OCS Liver System enabled assessment of the donor livers ex-vivo, there were 3
DCD donor livers that were preserved and assessed on the OCS Liver System and were clinically
turned down for transplantation due to rising lactate while being perfused on OCS Liver System
in 2 cases and due to pre-retrieval pathology results in the third case. These 3 cases are
described below:
Hours [95% CI]
7. 6
5. 6
0
1
2
3
4
5
6
7
8
Cross-Clamp Time
2. 9
5. 6
0
1
2
3
4
5
6
7
8
Ischemic Time p < 0.
p < 0.
(b) (6)
(b) (6)
(b) (6)
