Draft Summary Of Safety And Effectiveness Data (ssed)


Download Draft Summary Of Safety And Effectiveness Data (ssed)


Preview text

DRAFT: Advisory Committee Briefing Materials: Available for Public Release.
DRAFT SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)

I. GENERAL INFORMATION
Device Generic Name:
Device Trade Name:

Ex Vivo Portable Organ Perfusion System for Donor Hearts
OCS™ Heart System

Applicant’s Name and Address:

TransMedics, Inc. 200 Minuteman Road, Suite 302 Andover, MA 01810

Premarket Approval Application (PMA) Number: Pxxxxxx

Date(s) of Panel Recommendation:

April 6, 2021

Date of Good Manufacturing Practice Inspection: N/A

Date of Notice of Approval to the Applicant:

TBD

II. INDICATIONS FOR USE
The TransMedics® Organ Care System (OCS™) Heart System is a portable extracorporeal heart perfusion and monitoring system indicated for the resuscitation, preservation, and assessment of donor hearts in a near-physiologic, normothermic and beating state intended for a potential transplant recipient. OCS Heart is indicated for donor hearts with one or more of the following characteristics:
• Expected cross-clamp or ischemic time ≥ 4 hours due to donor or recipient characteristics (e.g., donor-recipient geographical distance, expected recipient surgical time); or
• Expected cross-clamp or ischemic time ≥ 2 hours AND one or more of the following:
− Donor Age ≥ 55 years; or
− Donors with history of cardiac arrest and downtime ≥ 20 minutes; or
− Donor history of alcoholism; or
− Donor history of diabetes; or
− Donor Left Ventricular Ejection Fraction (LVEF) ≤ 50% but ≥ 40%; or

PMA: DRAFT Summary of Safety and Effectiveness Data

Page 1

− Donor history of Left Ventricular Hypertrophy (LVH) (septal or posterior wall thickness of > 12 ≤ 16 mm); or
− Donor angiogram with luminal irregularities but no significant coronary artery disease (CAD).

III. CONTRAINDICATIONS
Do not use the OCS Heart System if any of the following conditions exist. • Moderate to severe aortic valve incompetence in donor heart • Observed myocardial contusion on donor heart • Known unrepaired interatrial or interventricular defects including patent foramen ovale.

IV. WARNINGS AND PRECAUTIONS
Refer to the labeling for applicable warnings and precautions.

V. DEVICE DESCRIPTION

The OCS Heart System consists of:

• The OCS Heart Console (Heart Console)

• The OCS Heart Perfusion Set (HPS) – comprised of Heart Perfusion Module (HPM) and HPS Accessories

• The OCS Heart Solution Set – comprised of two heart preservation solutions, which are the OCS Priming Solution and the OCS Maintenance Solution.
These three major components are shown in Figure 1 below.

Figure 1:

Components of the OCS Heart System

OCSTM Heart Console

OCSTM Heart Perfusion Set

OCSTM Heart Solution

;:. l!!IE­
~:.::-:. S E M'TransMeoo

PMA: DRAFT Summary of Safety and Effectiveness Data

II
Page 2

A. Description of Major Components
Heart Console: The Heart Console is the reusable, non-sterile portable base unit for the OCS Heart System that includes the electronics, software, fluid pumping systems, monitoring systems, power supply, batteries, gas cylinder, mobile base, and Wireless Monitor. The Wireless Monitor displays perfusion and pressure parameters and allows the user to evaluate parameters and adjust specific system settings during transport of the donor heart. The Heart Console provides a rigid compartment to house and protect the HPM during transport.
HPS: The HPS consists of the HPM and the disposable HPS Accessories. The HPM provides a closed circulatory system to protect, maintain, and support the heart. It uses a physical conduit to connect to the heart, incorporates various sensors, and interfaces with the Heart Console to oxygenate, warm, and circulate the perfusate.
The accessories are intended to:
• Collect and filter the donor blood
• Prime and then infuse the OCS Heart Solution Set into the HPM
• Connect the heart to the HPM perfusion circuit
• Facilitate access through the aorta for examination of the heart
• Infuse cardioplegia to terminate the preservation.
OCS Heart Solution Set: The OCS Heart Solution Set consists of two proprietary heart preservation solutions - the OCS Priming Solution and the OCS Maintenance Solution. Additives are required at the time of use that are supplied and added by the user.
The OCS Heart Solution Set is not intended to be administered directly to the donor or the recipient.
B. Mode of Action
The OCS Heart System preserves the heart in a near-physiological, beating state by perfusing the heart with a warmed, donor-blood based solution that is supplemented with nutrients and oxygen in a controlled and protected environment, referred to as the circuit. The circuit is illustrated in Figure 2 below. The OCS Maintenance Solution is infused into this circuit. The heart consumes oxygen and nutrients as the blood travels from the aorta through the coronary arteries and returns blood to the circuit through its pulmonary artery. The OCS maintains the blood at a constant temperature, oxygenates the perfusate, and provides perfusate in a pulsatile flow.

PMA: DRAFT Summary of Safety and Effectiveness Data

Page 3

Figure 2:

Schematic of the OCS Fluid Flow

PA outflow cannula
CF and SvO2 probes

To adequately perfuse the heart, the OCS Heart System controls and monitors the preservation environment. The user can adjust blood flow rate, solution delivery rate, gas flow rate, and blood temperature within specified ranges, all of which contribute to the ability to adequately perfuse the donor heart. The OCS calculates and displays pertinent organ perfusion parameters, and provides alarms for parameters out of expected ranges, alarms for low gas and battery capacity, and alarms for sensor failures.

VI. ALTERNATIVE PRACTICES AND PROCEDURES
Conventional procedures used in the preservation of donor hearts are limited to cold, static storage of the donor heart in a hypothermic preservation solution prior to transplantation. Other options are not to receive a heart transplant, which would mean the patient would remain on the transplant waiting list, and may undergo circulatory/mechanical support, such as implantation of a ventricular assist device (VAD). In the U.S., 16% of the patients on the transplant waiting listing will either expire while waiting or become too ill to be transplanted.
There are no other legally marketed devices in the U.S. that provide portable ex-vivo perfusion and monitoring of donor hearts.

VII. MARKETING HISTORY
The OCS Heart System has been CE marked and approved for use in the EU since 2006. It is also approved for use in Australia, Saudi Arabia, United Arab Emirates, Israel, Taiwan, and Kazakhstan.

PMA: DRAFT Summary of Safety and Effectiveness Data

Page 4

VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH
Heart transplant patients, regardless of the method of donor organ preservation, may experience any of the following adverse events.

• Acute rejection • Airway anastomotic complications • Arrhythmia • Aspiration • Bleeding (major) • Death • Emphysema • Fever • Focal or systemic major infection • Gastro esophageal reflux disease • Graft failure • Hemodynamic instability • Hemothorax • Hepatic dysfunction • Hyperammonaemia • Malignancy (post-transplant
lymphoproliferative disorder (PTLD)

• Multiple organ failure • Myocardial infarction • Neurological dysfunction • Pancreatitis, peptic ulceration • Pleural bleeding • Pleural effusion • Pneumothorax • Primary Graft Dysfunction (PGD) • Pulmonary embolism (PE) • Pulmonary infarction • Renal dysfunction • Respiratory failure • Sepsis • Tracheobronchitis/pneumonitis/pneumonia • Venous thromboembolism (deep venous
thrombosis [DVT]) • Wound dehiscence.

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 Heart System: (A) engineering bench testing; (B) biocompatibility; (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 OCS Heart System, the Heart Console, and the HPS 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 specifications under evaluation.

PMA: DRAFT Summary of Safety and Effectiveness Data

Page 5

B. Biocompatibility

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

The HPS 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

Biocompatibility Test
Cytotoxicity Test (MEM Elution) Pyrogenicity (USP <151> Rabbit Pyrogen) Hemocompatibility (2 methods, direct and indirect contact) Sensitization (Guinea Pig Maximization, 2 extracts)
Intracutaneous Reactivity (2 extracts) Acute Systemic Toxicity (2 extracts) Genotoxicity (3 methods, 2 extracts each) • in vitro Bacterial Reverse Mutation • in vitro Mouse Lymphoma Assay • in vivo Mouse Peripheral Blood Micronucleus
Assay USP Physicochemical Tests: • Non-volatile residue • Residue on Ignition • Heavy Metals • Buffering Capacity

ISO Test Standard 10993-5 10993-11 10993-4
10993-10
10993-10 10993-11 10993-3
USP<661> Containers, Plastics

Results
Non-cytotoxic Non-pyrogenic Non-hemolytic
No delayed dermal contact sensitization No irritation No systemic toxicity observed Non-mutagenic
Meets USP limits; no significant extractables

All materials used to manufacture the OCS Heart Solution Set meet compendial requirements; thus, they are suitable and safe for their intended use. The results from analyses of the finished product included pH, osmolality, color, clarity, chemical analysis, particle size, sterility, and endotoxins. The tests performed on the finished product were all within specification. This Process Verification demonstrated that the OCS Heart Solution Set consistently fulfills the qualification requirements and meets specifications.

C. Software Verification and Validation
TransMedics performed system level software verification and validation testing to demonstrate the OCS Heart System performs as intended. The device passed all testing and met its requirements. Software documentation was provided in accordance with the FDA guidance

PMA: DRAFT Summary of Safety and Effectiveness Data

Page 6

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 does not contain the hardware or software required for many common network interfaces such as USB, Ethernet, or Wi-Fi. The OCS Heart System incorporates a Wireless Monitor dedicated to the Heart Console. The Wireless Monitor communications with the OCS Console using one of two redundant communication interfaces - hard-wired or Bluetooth. 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 Heart System 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 2 below.

Table 2:

Summary of Electrical, Thermal, and Mechanical Safety Testing

Test Description
General Requirements General Requirements for Testing ME Equipment Classification of ME Equipment and ME Systems ME Equipment, Identification Marking and Documents Protection Against Electrical Hazards from ME Equipment Protection Against Mechanical Hazards of ME Equipment and ME Systems Protection Against Unwanted and Excessive Radiation Hazards Protection Against Excessive Temperatures and Other Hazards

IEC/ANSI/AAMI 60601-1: 2005 +A1:2012 Clause 4 5 6 7 8 9
10 11

Result
Pass Pass Pass Pass Pass Pass
Pass Pass

PMA: DRAFT Summary of Safety and Effectiveness Data

Page 7

Test Description
Accuracy of Controls and Instruments and Protection Against Hazardous Outputs Hazardous Situations and Fault Conditions Programmable Electrical Medical Systems (PEMS) Construction of ME Equipment ME Systems

IEC/ANSI/AAMI 60601-1: 2005 +A1:2012 Clause
12

Result Pass

13

Pass

14

Pass

15

Pass

16

Pass

F. Electromagnetic Compatibility (EMC)

The OCS Heart System 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 (4th edition) – Group 1, Class A, non-life supporting equipment, CISPR 25, and RTCA DO-160G). The OCS Heart System met the requirements of the standards. The results are shown in Table 3 below.

Table 3:

Summary of Emission and Immunity Testing

Test Radiated Emissions AC Mains Conducted Emissions Harmonics Emissions Voltage Fluctuation/ Flicker Electrostatic Discharge Immunity Immunity to proximity fields from RF wireless communications equipment Radiated RF Immunity Electrical Fast Transients Immunity Surge Immunity Conducted RF Immunity Magnetic Field Immunity Voltage Dips/Interrupts Radiated Immunity Radiated Emissions Radiated Emissions Spurious Emissions

Standard EN55011/FCC Part 15 (CISPR 11) EN55011/FCC Part 15 (CISPR 11) IEC 61000-3-2 IEC 61000-3-3 IEC 61000-4-2 IEC 60601-1-2 Clause 8.10

Results Pass Pass Pass Pass Pass Pass

IEC 61000-4-3

Pass

IEC 61000-4-4

Pass

IEC 61000-4-5

Pass

IEC 61000-4-6

Pass

IEC 61000-4-8

Pass

IEC 61000-4-11

Pass

ISO 7137 and RTCA DO 160G

Pass

ISO 7137 and RTCA DO 160G

Pass

CISPR 25

Pass

FCC 47 CFR Part 15C

Pass

PMA: DRAFT Summary of Safety and Effectiveness Data

Page 8

G. Wireless Technology
The wireless connection between the OCS Console and Wireless Monitor is a peer-to-peer Bluetooth connection. 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 HPS 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. ETO and ethylene chlorohydrin (ECH) residuals were evaluated 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.
The OCS Heart Solution Set is steam sterilized. The sterilization cycle was validated to achieve a minimum SAL of 10-6 according to European Pharmacopoeia 5th edition 5.0 General Texts Chapter 5.1 page 445 – 450; General texts on Sterility and U.S. Pharmacopeia USP 28 NF 23 General Information Chapter <1211>; Sterilization and Sterility Assurance.

I. Shelf Life Testing
Package integrity and simulated shipping testing was performed for the HPS and OCS Heart Solution Set to confirm that package integrity can be maintained during shipping. Real-time and accelerated shelf life testing demonstrates the safety and suitability of the HPS for the labeled shelf life.
In addition, real-time and accelerated shelf life testing supports the safety and suitability of the OCS Heart Solution Set for the labeled shelf life.

J. Animal Functional Testing
TransMedics performed multiple functional animal studies to evaluate the safety, suitability, and effectiveness of the OCS Heart System for the preservation of donor hearts.
The animal studies used a porcine model to evaluate the performance of the OCS Heart System because it is a large animal model frequently used for thoracic work. The anatomy and size of the pig’s heart closely resembles the human heart, making it a clinically suitable animal model that is feasible and practical to use in the laboratory setting.
The testing demonstrated that the OCS Heart System adequately maintained and perfused the donor heart on the OCS when used in accordance with the current use model. The hearts were adequately maintained and perfused on the OCS Heart System according to the predefined protocol and perfusion parameters. The metabolic profile met the acceptance criteria of a stable trend throughout perfusion and a trend of neutral or absorbing venous-arterial differential. All acceptance criteria were met.
The data validated the ability of the OCS Heart System to meet the performance specifications and that the configuration of the OCS Heart System worked successfully during simulated surgical procedures.

PMA: DRAFT Summary of Safety and Effectiveness Data

Page 9

X. SUMMARY OF CLINICAL STUIDES
The primary clinical data set supporting this PMA application is the OCS Heart EXPAND trial and the OCS Heart EXPAND Continued Access Protocol (CAP). Additional data included in this PMA are the results of the PROCEED II trial and published long-term international studies of the OCS Heart System for standard criteria, extended criteria and DCD hearts.
A. OCS Heart EXPAND Trial
The primary clinical data sets supporting FDA approval of the OCS Heart System are the OCS Heart EXPAND trial and the OCS Heart EXPAND CAP. The following sections describe the OCS Heart EXPAND trial and results, followed by the pooled analysis of the OCS Heart EXPAND trial and the OCS Heart EXPAND CAP trials.
The purpose of the OCS Heart EXPAND trial was to evaluate the effectiveness of the OCS Heart System to resuscitate, preserve and assess donor hearts that may not meet current standard donor heart acceptance criteria for transplantation. In addition to assessing the impact of the OCS Heart System on expanding donor heart utilization from extended criteria donors, given that the OCS Heart EXPAND was the first of its kind trial, it also provided important short and long term clinical outcome data for these types of donor heart transplants in a prospective fashion.
1. Study Design
OCS Heart EXPAND trial was a prospective, single arm, multi-center trial of 75 transplanted subjects at 9 U.S. investigational sites.
a) Primary Effectiveness Endpoint
The primary effectiveness endpoint is a composite of patient survival at Day 30 post-transplant and freedom from severe ISHLT Primary Graft Dysfunction (PGD) at 24 hours post-transplant (as defined in Appendix 2 of the protocol according to ISHLT consensus manuscript (Kobashigawa, et al., 2014)). The primary hypothesis for the trial was that the true proportion of transplanted recipients with the composite of patient survival at Day 30 post-transplantation and freedom from severe PGD in the first 24 hours post-transplantation was greater than the performance goal value of 0.65 (65%). Given the lack of published literature on post-transplant clinical outcomes from these types of donor hearts at the time the OCS Heart EXPAND trial was being designed, the sponsor established this OPG based on published literature for standard criteria heart transplantation incidence of severe PGD of ~30% and on published OPTN/SRTR reports of 30-day patient mortality of ~5%.
b) Secondary Effectiveness Endpoints
• Patient survival at Day-30 post-transplantation.
• Incidence of severe ISHLT primary heart graft dysfunction (PGD) (left or right ventricle) in the first 24 hours post-transplantation (as defined in Appendix 2 of the protocol according to ISHLT consensus manuscript).
• Rate of donor heart utilization (i.e., the percentage of donor hearts successfully transplanted after preservation and assessment on the OCS Heart System).

PMA: DRAFT Summary of Safety and Effectiveness Data

Page 10

Preparing to load PDF file. please wait...

0 of 0
100%
Draft Summary Of Safety And Effectiveness Data (ssed)