Upload
docong
View
220
Download
0
Embed Size (px)
Citation preview
1
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
UNITED STATES OF AMERICA
DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
+ + +
CENTER FOR DEVICES AND RADIOLOGICAL HEALTH
MEDICAL DEVICES ADVISORY COMMITTEE
+ + +
CIRCULATORY SYSTEM DEVICES PANEL
+ + +
February 18, 2016 8:00 a.m.
Hilton Washington DC North
620 Perry Parkway Gaithersburg, Maryland
PANEL MEMBERS: RICHARD L. PAGE, M.D. Panel Chair DAVID D. YUH, M.D. Voting Member RICHARD A. LANGE, M.D. Voting Member DAVID C. NAFTEL, Ph.D. Voting Member JOAQUIN E.G. CIGARROA, M.D. Voting Member DAVID E. KANDZARI, M.D. Voting Member JEFFREY A. BRINKER, M.D. Temporary Non-Voting Member DAVID J. SLOTWINER, M.D. Temporary Non-Voting Member PAMELA KARASIK, M.D. Temporary Non-Voting Member E. MAGNUS OHMAN, M.D. Temporary Non-Voting Member JEFFREY S. BORER, M.D. Temporary Non-Voting Member EMILY P. ZEITLER, M.D. Temporary Non-Voting Member NAVEEN THURAMALLA Industry Representative NAFTALI FRANKEL Consumer Representative DEBBIE DUNN Patient Representative CDR DIMITRUS CULBREATH Designated Federal Officer
2
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
FDA REPRESENTATIVES: BRAM D. ZUCKERMAN, M.D. Director, Division of Cardiovascular Devices Office of Device Evaluation MITCHELL SHEIN, M.S. Deputy Director, Division of Cardiovascular Devices Office of Device Evaluation JAMES SWINK Medical Devices Advisory Panel Coordinator Office of Device Evaluation DEBORAH KOTZ Press Contact FDA PRESENTERS: DANIELLE DORFMAN, B.S. Division of Cardiovascular Devices Office of Device Evaluation HETAL PATEL, M.S., B.S. Division of Cardiovascular Devices Office of Device Evaluation CAPT BRIAN LEWIS, M.D., USPHS Division of Cardiovascular Devices Office of Device Evaluation KIMBERLY SELZMAN, M.D., M.P.H. Division of Cardiovascular Devices Office of Device Evaluation INDUSTRY OPEN PUBLIC HEARING SPEAKERS (Boston Scientific): KENNETH STEIN, M.D. Chief Medical Officer, Rhythm Management Boston Scientific Corporation
3
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
INDUSTRY OPEN PUBLIC HEARING SPEAKERS/ADVISORS (Medtronic): DAVID STEINHAUS, M.D. Medical Director, Cardiac Rhythm Disease Management Vice President/General Manager, Heart Failure Medtronic, Inc. DWIGHT W. REYNOLDS, M.D. Chief, Cardiovascular Section, Department of Medicine Oklahoma Health Sciences Center University of Oklahoma ROBERT KOWAL, M.D. Co-Medical Director, Cardiac Electrophysiology Baylor Scott & White Health Care System KURT STROMBERG, B.S. Senior Principal Statistician Medtronic, Inc. JOHN HUMMEL, M.D. Professor of Medicine/Director of Electrophysiology Research Wexner Medical Center The Ohio State University INDUSTRY OPEN PUBLIC HEARING SPEAKERS/ADVISORS (St. Jude Medical): MARK D. CARLSON, M.D. Vice President, Global Clinical Affairs Chief Medical Officer St. Jude Medical VIVEK REDDY, M.D. Professor of Medicine and Cardiology Mount Sinai Hospital CHRIS HUBBARD, B.S., M.B.A. Vice President, Nanostim Technology St. Jude Medical JOSHUA COOPER, M.D. Director, Cardiac Electrophysiology Professor of Medicine Temple University
4
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
OPEN PUBLIC HEARING SPEAKERS: JAY G. RONQUILLO, M.D., M.P.H., M.M.Sc., M.Eng. National Center for Health Research BARRY LOVE, M.D. Director, Pediatric Electrophysiology and Congenital Cardiac Catheterization Program Mount Sinai Medical Center JAMES E. IP, M.D. Assistant Professor of Medicine Weill Cornell Medical College ANAND DHANDA, M.D. Patient
5
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
INDEX PAGE
CALL TO ORDER - Richard L. Page, M.D. 8 PANEL INTRODUCTIONS 8 CONFLICT OF INTEREST STATEMENT - CDR Dimitrus Culbreath 11 FDA INTRODUCTION - Mitchell Shein, M.S. 14 FDA PRESENTATION
Introduction, Panel Purpose, and General History - Danielle Dorfman, B.S. 17 Leadless Pacemaker Device Description and Comparison of Transvenous and Leadless Pacemakers - Hetal Patel, M.S., B.S. 19 Pre/Postmarket Balance Paradigm Development Strategy for Leadless Pacemakers - CAPT Brian Lewis, M.D. 22 Knowledge Gained and Remaining Knowledge Gaps for Leadless Pacemakers and Final Conclusions - Kimberly Selzman, M.D., M.P.H. 26 Q&A 35
INDUSTRY OPEN PUBLIC HEARING
Boston Scientific Corporation
Kenneth Stein, M.D. 51 Q&A 61
Medtronic, Inc.
David Steinhaus, M.D. 66 Dwight W. Reynolds, M.D. 68 David Steinhaus, M.D. 74 Q&A 78
6
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
INDEX PAGE
St. Jude Medical
Mark D. Carlson, M.D. 89 Vivek Reddy, M.D. 91 Mark D. Carlson, M.D. 97 Q&A 100
OPEN PUBLIC HEARING
Jay G. Ronquillo, M.D. 114 Barry Love, M.D. 117 James E. Ip, M.D. 123 Anand Dhanda, M.D. 127
PANEL DELIBERATIONS 129 FDA QUESTIONS
Question 1A through C 160 Question 2A(i) 183 Question 2A(ii) 186 Question 2B(i) 190 Question 2B(ii) through (v) 196 Question 2C(i) through (iv) 216 Question 2D 220 Question 3 222 Question 4 225
7
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
INDEX PAGE FINAL COMMENTS
Industry Representative - Naveen Thuramalla 228 Consumer Representative - Naftali Frankel 228 Patient Representative - Debbie Dunn 229
ADJOURNMENT 230
8
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
M E E T I N G
(8:00 a.m.)
DR. PAGE: Good morning. We've reached the hour of 8 o'clock, and I would like to
call this meeting of the Circulatory System Devices Panel to order.
I am Dr. Richard L. Page. I'm Chairperson of the Panel. I'm also a cardiac
electrophysiologist and Chair of the Department of Medicine at the University of Wisconsin
in Madison.
At this meeting, the Panel will discuss and make recommendations on clinical trial,
post-approval study design, and physician training requirements for leadless cardiac
pacemaker device technology. Specifically, this Committee will be asked to make
recommendations on the acceptability of adverse event rates in acute and chronic time
frames as well as indications for use of this device type (given availability of other
technologies with different adverse event profiles), required training and acceptability of
observed learning curves for the new device type, and necessary elements for post-
approval study collection. We will not be considering any individual PMA application today,
though the content of our discussions will be used by the Agency in their review of such
applications for leadless cardiac pacemakers.
Before we begin, I would like to ask our distinguished Panel members and FDA staff
seated at the table to introduce themselves. Please state your name, your area of
expertise, and your position, and affiliation.
Dr. Zuckerman, may we start with you?
DR. ZUCKERMAN: Good morning. Bram Zuckerman, Director, FDA Division of
9
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
Cardiovascular Devices.
DR. OHMAN: Good morning. Dr. Magnus Ohman from Duke. Specialty, clinical trials
and interventional cardiology.
DR. CIGARROA: Good morning. Joaquin Cigarroa, Clinical Chief for the Knight
Cardiovascular Institute at Oregon Health & Science University. Area of specialty,
interventional cardiology.
DR. SLOTWINER: Good morning. David Slotwiner, Director of Cardiac
Electrophysiology Laboratory at Weill Cornell Medical College, New York-
Presbyterian/Queens, and Associate Professor of Health Policy at Cornell.
DR. KANDZARI: Good morning, everyone. My name is David Kandzari. I'm the Chief
Scientific Officer and Director of Interventional Cardiology at the Piedmont Heart Institute
in Atlanta, Georgia.
DR. BORER: I'm Jeffrey Borer, cardiologist, State University of New York, Downstate
Medical Center.
DR. ZEITLER: Emily Zeitler, cardiology fellow at Duke University and research fellow
at the Duke Clinical Research Institute, with research expertise in implantable EP devices.
DR. YUH: Good morning. David Yuh, Chief of Cardiac Surgery at Yale University.
MR. SWINK: Good morning. James Swink, Advisory Committee Coordinator, FDA.
CDR CULBREATH: Good morning. Commander Dimitrus Culbreath, Designated
Federal Officer for the Circulatory System Devices Panel.
DR. LANGE: Good morning. Richard Lange, President of the Texas Tech University
Health Science Center in El Paso, and Dean of the Paul L. Foster School of Medicine, with
10
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
expertise in interventional cardiology.
DR. BRINKER: Jeff Brinker, Professor of Medicine at Johns Hopkins and
interventional cardiologist with a side job of lead extraction, which may become extinct
before I am.
DR. NAFTEL: I'm David Naftel. I am a biostatistician and a Professor of Surgery and
Professor of Biostatistics at the University of Alabama at Birmingham.
DR. KARASIK: Good morning. Pamela Karasik. I am a cardiac electrophysiologist at
the VA here in Washington, D.C.
MR. THURAMALLA: Good morning. This is Naveen Thuramalla. I'm the Vice
President of Engineering and Clinical Studies at Transonic Systems. I'll be serving as the
Industry Representative on this Panel. Thank you.
MR. FRANKEL: Good morning. My name is Naftali Frankel. I'm the Consumer
Representative.
MS. DUNN: Good morning. I'm Debbie Dunn. I am a heart patient. I had several
procedures. I live with a biventricular ICD device, it's number four for me, and I've had
many complications with lead extraction.
DR. PAGE: Thank you very much. As everyone can see, we have a very
distinguished, highly qualified Panel, and I very much look forward to doing our work today.
I will point out just for the panelists, please just push the button on your microphone
when you're called upon to speak, and don't forget to turn it off. It changes the acoustics
significantly otherwise. The other thing I will mention is that all of your comments,
concerns, questions are very important to the process. So I ask that we not have any side
11
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
conversations during these meetings. When the meeting is called to order, everything we
say should be in the minutes. I know what you have to say is important, so please wait to
be called upon and go ahead and speak into the microphone.
I will also mention, if anyone has not already done so, please sign the attendance
sheets that are at the tables by the door.
And now we'll ask Commander Culbreath, the Designated Federal Officer for the
Circulatory System Devices Panel, to make some introductory remarks.
CDR CULBREATH: Good morning. I will now read the Conflict of Interest Statement
dated February 18, 2016.
The Food and Drug Administration is convening today's meeting of the Circulatory
System Devices Panel of the Medical Devices Advisory Committee under the authority of
the Federal Advisory Committee Act of 1972. With the exception of the Industry
Representative, all members and consultants of the Panel are special Government
employees or regular Federal employees of other agencies and are subject to the Federal
conflict of interest laws and regulations.
The following information on the status of this Panel's compliance with Federal
ethics and conflict of interest laws covered by, but not limited to, those found at 18 U.S.C.
Section 208 are being provided to participants in today's meeting and the public.
FDA has determined that the members and consultants of this Panel are in
compliance with the Federal ethics and conflict of interest laws. Under 18 U.S.C. Section
208, Congress has authorized FDA to grant waivers to special Government employees and
regular Federal employees who have financial conflicts when it is determined that the
12
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
Agency's need for a particular individual's service outweighs his or her potential financial
conflict of interest.
Related to the discussions of today's meeting, members and consultants of this Panel
who are special Government employees or regular Federal employees have been screened
for potential financial conflicts of interest of their own as well as those imputed to them,
including those of their spouses or minor children and, for the purpose of 18 U.S.C. Section
208, their employers. These interests may include investments; consulting; expert witness
testimony; contracts/grants/CRADAs; teaching/speaking/writing; patents and royalties; and
primary employment.
For today's agenda, the Panel will discuss and make recommendations on clinical
trial, post-approval study design, and physician training requirements for leadless cardiac
pacemaker device technology. Specifically, the Panel will be asked to make
recommendations on the acceptability of adverse event rates in acute and chronic time
frames as well as indications for use of this device type (given availability of other
technologies for different adverse event profiles), requirements of training and
acceptability of observed learning curves for the new device type, and necessary elements
for post-approval study collections.
Based on the agenda for today's meeting and all financial interests reported by the
Panel members and consultants, no conflict of interest waivers have been issued in
accordance with 18 U.S.C. Section 208.
Mr. Naveen Thuramalla is serving as the Industry Representative, acting on behalf of
all related industry, and is employed by Transonic Systems, Inc.
13
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
We would like to remind members and consultants that if the discussions involve any
other products or firms not already on the agenda for which an FDA participant has a
personal or imputed financial interest, the participants need to exclude themselves from
such involvement and their exclusion will be noted for the record.
FDA encourages all participants to advise the Panel of any financial relationships that
they may have with any firms at issue.
A copy of this statement will be available for review at the registration table during
this meeting and will be included as a part of the official transcript. Thank you.
Before I turn the meeting back over to Dr. Page, I would like to make a few general
announcements.
The transcription of today's meeting will be available from Free State Court
Reporting, Inc., address 1378 Cape St. Claire Road, Annapolis, Maryland. Their phone
number is (410) 974-0947.
Information on purchasing videos of today's meeting can be found on the table
outside this meeting room.
The press contact for today's meeting is Deborah Kotz.
I would like to remind everyone that the members of the public and the press are
not permitted in the Panel area, which is behind the speaker's podium. I request that
reporters please wait to speak to FDA officials until after the Panel meeting has concluded.
If you are presenting in the Open Public Hearing section today and have not
previously provided an electronic copy of your slide presentation to FDA, please arrange to
do so with Mr. James Clark at the registration desk.
14
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
In order to help the transcriber identify who is speaking, please be sure to identify
yourself each and every time that you speak.
Finally, please silence your cell phones and other electronic devices at this time.
Thank you very much.
Back to you, Dr. Page.
DR. PAGE: Thank you, Commander Culbreath.
Before we get started on the very important work we have ahead of us, I would just
like to remind all the presenters that we have time limits. You've been told how much time
you have, and I ask you to stay within the time that you have been allotted.
We'll now hear a brief introduction from Mr. Mitchell Shein from the FDA, and then
the FDA presentation from the leadless pacemakers team, which consists of
Ms. Danielle Dorfman, Ms. Hetal Patel, Dr. Brian Lewis, and Dr. Kimberly Selzman. At the
conclusion of this presentation there will be time for brief questions from the Panel
members.
And now please go ahead, Mr. Shein.
MR. SHEIN: Good morning. I'm Mitchell Shein, and I'm a Deputy Director in the
Division of Cardiovascular Devices. On behalf of the Division, we thank you for your time in
being here today.
Before we get into the specific details of the issues we've convened you to address
today, we wanted to take a moment to establish the framework for those discussions.
Today we are asking you to discuss and provide us with your perspective on several issues
regarding a new class of implantable cardiac pacemakers, specifically, those that are self-
15
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
contained and are implanted entirely within the right ventricular chamber of the heart that
require no lead threaded through the vasculature to connect the pacemaker to the heart
and as a class are referred to as leadless pacemakers.
Today's general session Panel meeting is different from those you may have
participated in previously. While the devices we'll be discussing are not currently marketed
in the United States, we are asking you to provide input on issues related to adverse events,
indications, and postmarket surveillance. You will hear about specific devices during the
course of the day, including information about premarket clinical trials. However, there will
not, repeat not, be an informal or formal vote on any individual product. We are seeking
input that can be applied to all devices in this category.
FDA has decades of experience in regulating conventional transvenous cardiac
pacemakers, and there are well-established review standards and expectations for
nonclinical and clinical performance of these devices. However, the new leadless pacing
systems raise some new clinical questions, and we will be asking and seeking Panel input on
these issues today. Because these issues apply to the technology generally and are not
unique to any individual device, we have chosen the general issues Panel format as the
most efficient and appropriate way in which to discuss these issues and solicit the Panel's
input.
We will be asking you to provide your perspective on your performance expectations
for leadless pacemakers, regarding appropriate and acceptable complication rates,
appropriate indications for use, and what, if any, long-term questions should be addressed
in post-approval trials. This information will provide a template for our future reviews
16
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
against which to measure an individual device's performance.
As I mentioned, today, no leadless pacemaker has been approved for commercial
distribution in the United States. Yet we recognize the potential importance to patients of
innovative technologies that can reliably pace the heart and eliminate the transvenous
portion of a pacing system. Your deliberations in today's general session will help guide the
Agency in our future actions for devices of this type. Although FDA will only be discussing
publicly available information during today's meeting, and while you will not be discussing
specific content from any existing premarket or IDE application, we've invited each
company developing technology in this space for the United States market to present
information today, including available clinical data about their products that can inform
today's discussion.
So I'd like to offer the following as a framework for today's discussion and remind
you that we are seeking your general input on leadless pacemaker technology. We ask that
you resist the temptation to compare the individual performance of these devices to each
other. We will not be asking you to vote on the individual product's safety, effectiveness, or
the risk-benefit assessment. And we will look forward to what I'm sure is a very fruitful
Panel discussion on this interesting and innovative technology.
With that, I'd like to turn it over to the review team, Danielle Dorfman and Hetal
Patel.
DR. PAGE: And, Mr. Shein, my apologies for misstating your name earlier.
MR. SHEIN: That's quite all right.
DR. PAGE: Welcome, Ms. Dorfman.
17
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
MS. DORFMAN: Thanks. As we just said, my name is Danielle Dorfman, and I am a
biomedical engineer in the Implantable Electrophysiology Devices Branch in the Division of
Cardiovascular Devices in the Office of Device Evaluation. I will be presenting on behalf of
FDA along with Ms. Hetal Patel, Dr. Brian Lewis, and Dr. Kimberly Selzman. We would like
to acknowledge the following people for their support in preparing for this meeting.
FDA's presentation will consist of the sections shown on this slide. I will cover the
Panel purpose and general history of pacemaker technology. Ms. Patel will discuss leadless
pacemakers and compare them to transvenous pacemaker systems. Dr. Lewis will present
the pre/postmarket balance paradigm developed for leadless pacemakers. Finally,
Dr. Selzman will explain the knowledge base and knowledge gaps for leadless pacemakers
and conclude the presentation.
Per Mr. Shein's comments, I would now like to reiterate the purpose of today's
discussion. As mentioned, these are the topic areas that will be discussed today. Again, all
of the information presented by FDA originated from public sources. Manufacturers of
leadless pacemaker devices will have the opportunity to present more specific information
on their devices during the open industry hearing later today.
We will ask the Committee to make recommendations on generally acceptable acute
adverse event rates as well as indications for use for this device type. We will also ask for
recommendations on manufacturer-required training and necessary elements to be
included in post-approval study collection. The Panel's review and discussion of this
information will inform the Agency's premarket approval decisions on leadless pacemaker
devices.
18
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
It should be noted that although we are not seeking recommendations on the
approvability of one specific premarket submission, the Panel meeting is meant to inform
FDA of the clinical community's perspective on publicly available clinical data and
recommendations on indications, appropriate post-approval study design, and labeling for
this class of devices.
I will now discuss the general history of pacemaker technology.
On October 8th, 1958, the first pacemaker implantation was performed in Sweden.
The image on the slide shows the first implanted pacemaker. The first pacemaker implant
in the United States occurred in 1960. Nearly one million people are implanted with
pacemakers worldwide each year.
Transvenous pacemakers are implantable devices intended to provide electrical
pulses to stimulate the heart. Often referred to as pulse generators, they include a power
supply and electronics to deliver the pulses to correct cardiac rhythm disorders. The pulse
generator is implanted with leads or wires that interact directly with the heart to sense and
pace as needed. A pocket just beneath the collarbone is typically required for implantation
of a transvenous pacemaker. Pacemakers vary in system complexity and can have multiple
functions as a result of the ability to sense and/or stimulate both the atria and the
ventricles.
Pacemakers are life-sustaining/life-supporting devices. A PMA is required to be
submitted and reviewed by FDA to determine whether there is a reasonable assurance of
safety and effectiveness of these devices. Thus, a PMA would be required to be submitted
from a manufacturer introducing a pacemaker to the U.S. market for the first time or
19
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
implementing novel, innovative pacemaker technology. Furthermore, PMAs contain valid
scientific evidence, usually in the form of bench, animal, or clinical data, which is evaluated
by FDA to determine if the probable benefits of the device outweigh the risks. Device
labeling, manufacturing and quality system procedures, and post-approval study design all
need to be solidified before FDA approval of any PMA.
As mentioned by Mr. Shein, FDA has developed the ability to address pertinent
issues in determining the safety and effectiveness of transvenous pacemakers, and PMAs
for this device type are not usually taken before an Advisory Panel unless a particular
application presents an issue that can best be addressed through Panel review. In the case
of today's Panel meeting, FDA can leverage its experience with transvenous pacemakers to
the review of leadless pacemakers for many of the PMA elements listed on this slide.
However, there are new questions and issues pertaining specifically to the leadless
pacemaker. These include the published clinical data, considerations that should be made
for labeling, and what elements should be collected in the post-approval study. The Panel
members will be asked to address these today.
Ms. Patel will now discuss leadless pacemakers specifically.
MS. PATEL: As Ms. Dorfman mentioned, I'm Hetal Patel, a biomedical engineer in
the Division of Cardiovascular Devices. I will now discuss leadless pacemakers.
Current design of leadless pacemakers has the same inherent functionality as
transvenous, single-chamber pacemakers. However, the system does not have leads or a
pocket, which eliminates well-known complications such as pocket infections and lead
fractures. We will be discussing these differences in more detail later in the presentation.
20
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
Leadless pacemakers are currently being studied for VVIR pacing in humans. This
refers to a pacemaker that paces and senses the ventricle and is inhibited by a sensed
ventricular event and implements rate modulation in response to patient need. We will
discuss more of these clinical trials in a few minutes.
Leadless pacemakers are self-contained in a hermetically sealed capsule. The
capsule houses a battery and electronics to operate the system. Similar to most pacing
leads, the tip of the capsule includes a fixation mechanism and a monolithic controlled
release device, or MCRD. The MCRD is intended to elute a glucocorticosteroid to reduce
acute inflammation at the implantation site. Leadless pacemakers have rate responsive
functionality, and current device longevity estimates are based on bench data. Estimates
have shown that the device can last over 10 years depending on the programmed
parameters.
Medtronic has developed a leadless pacemaker called Micra, which is about 26 mm
in length and introduced through a 23 French catheter via the femoral vein to the right
ventricle, where it is attached to the myocardium via four nitinol tines. The device weighs
about 2 g and has an accelerometer-based rate response.
As presented at Heart Rhythm, Micra received CE mark in April 2015 based on results
from 60 patients over 3 months in the Medtronic Micra TPS Global Clinical Trial. The review
for CE mark approval included the following findings: 5.7% of patients experienced serious
adverse events, and all implant attempts were successful. Twenty-four hour ambulatory
surface ECGs and device electrograms indicated expected pacing and sensing performance
with no pauses due to inappropriate device performance. Additionally, all electrical
21
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
measurements were within expected ranges at 1 and 3 months.
St. Jude Medical has published results on a leadless pacemaker called Nanostim,
which is about 40 mm in length and introduced through an 18 French catheter to the right
ventricle, where it is attached to the cardiac wall by a helix. Nanostim is also about 2 g in
weight and uses a temperature-based rate response sensor.
As presented at Heart Rhythm, Nanostim received CE mark in August 2013 based on
results from 33 patients over 3 months in the LEADLESS study. In this study, serious adverse
events, device function, and electrical variables were collected and evaluated. The review
for CE mark approval included the following findings: There were no significant device-
related adverse events and one procedure-related event. Results demonstrated that pacing
and sensing thresholds were consistent and similar to those found in conventional
pacemakers.
Please note that there is development in this space across industry, but details are
not publicly available at this time.
We will now compare transvenous and leadless pacemakers. As previously
mentioned, the functionality of transvenous and leadless pacemakers is very similar.
However, there are many design differences which make leadless pacemakers a novel
technology. The leadless device does not require a transvenous lead and has a fixation
mechanism that is different from the familiar active fix helix or passive tines of leads. The
implantation technique is quite different and requires groin vascular access but no pocket.
Despite their significantly reduced size in comparison to a conventional pacemaker, the
leadless pacemaker has longer battery longevity projections. The device retrieval or
22
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
extraction procedures are also very different, as well as the replacement techniques.
This slide shows typical acute complications associated with transvenous and
leadless pacemaker devices. Since leadless pacemakers do not have a pocket or a lead,
these are not a source of complications. Femoral access complications are unique to the
leadless systems due to the implant technique.
Based on publicly available clinical data, the rates of cardiac injuries have been
reported to be higher. There are significant differences such as size of the device and
implant procedure, which may contribute to the trauma and related complications. The
publications have noted that cardiac injury complications such as cardiac perforation,
pericardial effusion, and tamponade with leadless pacemakers are more severe.
As expected for transvenous pacemakers, chronic performance from 5 to 10 years
includes a predictable decline in battery life and mechanical reliability of the lead.
However, a vast majority of pacemaker patients receive excellent pacing and sensing free of
operative or mechanical reliability failures. The chronic complication rates and chronic
performance of leadless pacemakers is currently unknown.
Dr. Lewis will now discuss the pre/postmarket balance paradigm development
strategy for leadless pacemakers.
DR. LEWIS: Thank you, Hetal.
My name is Dr. Brian Lewis. I am an arrhythmia cardiologist with FDA's Center for
Devices and Radiological Health, Division of Cardiovascular Devices. Today I'll provide an
overview of FDA's strategies to develop balanced pre- and postmarket data collection
capable of successfully supporting marketing applications for leadless pacemakers. We are
23
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
asking the Panel's input as we evolve these approaches.
FDA has a long history of reviewing transvenous pacemaker applications. The data
requirements are well established. I will review some ways that FDA's established practice
regulating transvenous pacemakers has helped formulate new FDA thinking on what data
should be required for leadless pacemakers. I will review FDA's evolving expectations for
leadless pacemaker pre- and postmarket data. As I have mentioned, we are seeking the
Panel's input and guidance to develop these expectations.
Just to review, transvenous VVIR pacemakers and really all conventional pacing
systems comprise mature technology with many years of market experience, with
significant similarities of device design across models. There is extensive bench testing
experience with transvenous systems and a good understanding of operative and early
post-implant safety and effectiveness. This understanding helps limit the need for clinical
data to answer questions of safety and effectiveness of transvenous pacemakers with
regard to implant, tip fixation, electrical measures, and rate response. These performance
issues are largely familiar to us and similar across systems.
However, when novel or innovative leads are proposed, concerns may be raised that
there could be new failure mechanisms, especially late mechanical failures of leads. FDA
therefore requires up to 5 years' experience, including approval studies with sufficient
enrollment to characterize single failures down to rates of approximately 0% to 1.5%.
On the next slide we will examine the time course of typical transvenous pacemaker
lead failures, which is one among several key factors FDA considered in its requirement for
5 years of lead follow-up in post-approval studies. The time course of typical transvenous
24
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
pacemaker lead failures is shown on this bathtub curve. Please note: Some implant and
early postoperative adverse events and device failures occur and taper at approximately 1
to 4 weeks, followed by a stable period relatively free of wear and tear-related failures
which require time to appear some years later.
As you can see, a study designed to capture all flex fatigue and mechanical failures
would require many years. Capturing this data before market approval is possible but
would delay approvals. Capturing this data in a balance of pre- and postmarket studies is
possible. FDA's paradigm for pacemaker lead data collection has been based on requiring
studies that are long enough to include some but not all late failures. The goal is that post-
approval data collection is adequate in size and duration to adequately inform users of
clinically meaningful failure modes as they choose among pacing lead options and make
informed decisions about whether to replace or depend on a chronically implanted lead at
pulse generator change.
As you look at this bathtub curve, note that FDA believes that lessons learned from
our transvenous experience translate well as we develop our regulatory paradigm for
leadless pacemakers with the Panel's guidance today. And there are some caveats, which
include:
• Based on clinical trials, the implanted population for leadless pacemakers
includes older and more frail patients at uniquely greater risk for adverse
events that are under discussion today.
• Leadless pacemakers differ in some important design and function ways from
transvenous pacemakers.
25
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
So it is these differences in target population and device design and function raising
different device effectiveness and safety concerns that are on FDA's mind today as we
consider whether our transvenous lead data collection paradigm fits or needs modifications
when we review future leadless pacemaker applications.
Let me briefly review several general situations that could be relevant when FDA
regulations tell us a post-approval study is needed:
• When real world experience and more generalizable data are needed that
could differ compared to IDE data from tertiary sites or centers of excellence;
• When important outstanding questions are raised about safety and
effectiveness for key subgroups;
• And most importantly, to characterize late or long-term performance that are
not practical to obtain before PMA approval.
Our CDRH strategic priorities task us with striking the right balance between
premarket and postmarket data collection and shifting, when appropriate, some premarket
data needs to the postmarket setting. As you know, premarket data must demonstrate a
reasonable assurance of safety and effectiveness, not an absolute assurance.
As I have presented, FDA hopes that with the Panel's input, future post-approval
studies for leadless pacemakers will be designed to include sufficient experience about
wear and tear failures to inform users of clinically meaningful failure modes as they choose
among pacing options and make informed decisions about how to handle device end of life.
We need to draw a line on the bathtub curve that makes sense.
For pacing leads, 5 years of post-approval study helps inform users of performance
26
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
as they change the pulse generator and decide if they can depend on or must replace the
lead. For leadless pacemakers, differences in device design such as battery life raise
questions, including whether to remove or leave expired devices in the heart. These new
questions challenge us to come up with the right balance of pre- and postmarket data
collection to address these questions.
FDA thanks you for your attention to these key performance questions. We want to
get the size and duration of data collection right with your help.
The next speaker is Dr. Kim Selzman.
DR. SELZMAN: Good Morning. I'm Kim Selzman. I am a cardiac electrophysiologist
working with FDA's Division of Cardiovascular Devices. I'm also the associate chief of
cardiology at the Salt Lake City VA Hospital.
I'll be speaking today on the knowledge base that we have, to date, on leadless
pacemakers, including published animal data, published clinical data, and our extensive
historical and current knowledge of transvenous pacemakers, some of which we believe we
can extrapolate to inform us in our understanding of leadless pacemakers. But more
importantly, we'd like to share with the Panel where we believe our knowledge gaps remain
with this technology. We will be asking the Panel later on today how to best address these
remaining gaps in knowledge.
We have extensive experience and a long regulatory history with transvenous
pacemakers, and this knowledge can be leveraged to inform our understanding of leadless
pacemakers. This table on the similarities and differences between leadless and
transvenous pacemakers was previously presented. I show it again here because when we
27
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
talk about what we can and cannot leverage from our transvenous pacemaker experience,
we're more readily able to use data and our knowledge base on the items that are similar
and not so much on the aspects that are quite different.
Since basic device function is similar, we believe we can leverage aspects of
transvenous pacemakers, such as pacing capture threshold, sensing, and the utility of
having steroid elution at the distal electrode. However, we feel we're less able to leverage
other aspects such as dislodgement from inadequate fixation, other procedural
complications, and certain device-related adverse events given the differences in physical
characteristics between the devices and the different implant techniques.
Through published animal studies and the two published prospective clinical studies,
we have gained some experience with the acute safety and effectiveness profiles as well as
safety and effectiveness in the short- and midterm ranges, meaning 30 days and 6 to 12
months. I'll be reviewing in the subsequent slides some of the specifics of our leadless
pacemaker experience to date.
One important difference between a leadless pacemaker and a transvenous
pacemaker is the implant procedure. Access is through the femoral vein rather than the
subclavian or another superior vein, and the sheath used to deliver the catheter is 18 to 23
French compared to 7 French for a typical transvenous pacemaker lead or 8 French for an
ablation catheter. The delivery catheter is over 100 cm long and has to be manipulated
from the femoral vein in the groin to the right ventricle. The device also has to be
disconnected, or untethered, from the catheter after it has been fixated to the RV
endocardium. Therefore, the potential challenges and complications of the implant
28
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
procedure are quite different from transvenous pacemakers.
Regarding safety, we have implant- and device-related adverse event rates from the
two published prospective studies referenced here. The percentages shown here on the
right-hand column represent combined data from the two studies and includes data from
over 1,200 subjects with about half them, or 600, completing at least 6 months of follow-
up. We know that the acute procedural success rate is high, it's over 95%, and that the
incidence of any serious adverse device effect or procedural complication was roughly 5%.
To review the most important procedural complications, acute perforations were
around 1.5%. Some of these perforations did result in tamponade and emergency surgery.
Any cardiac injury, which is mostly comprised of perforations but also includes other
injuries to the myocardium or tricuspid valve, was about 1.7%. Any surgical repair that was
needed was about 0.3%.
Embolizations, where the device acutely migrates from the right ventricle during
implant, and dislodgements which occur post-implant were collectively about up to 1%.
Serious groin complications such as AV fistulas and pseudoaneurysms were 0.6% to 0.7%.
And serious bleeding, such as those necessitating transfusion or surgical repair, occurred in
0.4%. And this doesn't include the less serious groin complications such as groin
hematomas, which occurred about 1% to 2% of the time. Of note, for the two studies
combined, there were three deaths reported as procedure related.
To put these adverse events into context when compared to transvenous pacemaker
adverse event rates, which is shown in blue on the left, the overall major device-related
complication rates are not that different (4% to 6.5% versus 4% to 5.8%). But the types of
29
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
events as well as the frequency and severity of certain events are different. The most
important or concerning difference appears to be the rates of cardiac perforation and
cardiac injury. This occurs about 0.5% in the literature for transvenous pacemakers and was
reported to be about 1.5% in the leadless pacemaker studies. Again, most of these required
some intervention, including pericardiocentesis and emergency cardiac surgery. One of the
risks for RV perforation may be frequent repositioning of the device, which did occur 15% to
30% of the time. Also a trend was seen with lower BMI and female sex as possible risk
factors for perforation.
For the other adverse events, only leadless devices can embolize; however, the
dislodgement rate for leadless devices is lower. Also the reoperation rate is lower. And due
to the differences between the two devices, there is a tradeoff where the leadless
pacemakers have groin vascular complications such as AV fistulas and slightly more vascular
bleeding, but adverse events such as pneumothorax don't exist.
In terms of the procedural death rate, it is unclear why it is higher than that for
transvenous pacemakers, but it may be related to the delivery catheter, the device itself,
patient selection, or just the fact that it is a new technology.
Given that the implant procedure is quite different than that of a transvenous
pacemaker and that repositioning during the implant, which is sometimes necessary, is also
very different from repositioning a transvenous lead, the question of a learning curve was
raised. A learning curve is often seen with new devices and new technology. In general, as
implanters gain experience and learn best practices over time, implantation success
increases and procedure-related complications decrease. St. Jude did conduct a learning
30
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
curve analysis and reported that after 10 implants, the device-related serious adverse
events were almost reduced by half. And so it does appear that, similar to other new
technologies, there might be a learning curve with the implant procedure for leadless
pacemakers. This raises the issue that training may be beneficial and valuable to implanters
who are new to this technology.
When looking at safety and device- or procedure-related adverse events, I think it's
worth briefly mentioning who was receiving these devices and if they seem representative
of patients who might receive the device when marketed. The enrolled patients in these
two trials were older with a mean age of 76 years, and they had a fairly high frequency of
comorbidities such as coronary disease and diabetes. These demographics do seem
consistent with who is receiving transvenous single-chamber pacemakers currently, as well
as who is likely to receive VVI leadless pacemakers when market approved.
When looking at safety beyond the implant procedure over the midterm time frame
of 6 to 12 months, event-free survival is fairly stable after the initial 2 weeks. Almost all of
the significant adverse device effects occurred early on, within 14 days of implant. But loss
of device function did occur 0.1% of the time. System revision was needed in about 0.4% or
1 for every 250 implants over 6 months. And device repositioning for sensing or pacing
capture threshold issues was about 1% over the initial 30 days.
However, there have been essentially no device-related infections seen with the
leadless pacemaker, at least up to 6 to 12 months, which is a major long-term concern for
transvenous pacemakers. And, of course, there were no lead or pocket complications,
which are also long-term concerns for transvenous devices. So although some of the acute
31
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
procedural complications with leadless pacemakers are more frequent, such as
perforations, the most common longer-term concerns with transvenous devices, including
infection, lead issues, and pocket complications, are not relevant to the leadless pacemaker.
It therefore appears that there are fewer overall midterm events, at least based on the 6- to
12-month data which have been reported in the literature.
Shifting gears from safety to effectiveness. When we look over a window of 6 to 12
months post-implant, the interrogation data, meaning sensing and threshold data, remain
quite stable from implant. The sensed R wave at 6 months was greater than 5 mV in the
overwhelming majority of subjects. The pacing capture threshold was less than 2 V at 6
months, again in the overwhelming majority of patients. Based on this data and also our
transvenous pacemaker experience, our belief is that the device's ability to pace and sense
will remain stable for the long term.
Now that we've reviewed the leadless pacemaker experience gained so far, I will be
reviewing in the subsequent slides where we believe the remaining knowledge gaps are.
The Panel will be asked today to comment on how best to approach these remaining
questions.
When looking at what knowledge gaps remain, although we have collected
procedure-related adverse events and short-term safety and effectiveness data, it could be
different in a real-world setting. There is no clinical long-term data available on reliability,
functionality, or safety since the two studies followed patients for 6 months. Battery
estimates are only from bench testing and short-term clinical battery assessments also only
out 6 to 12 months. This is particularly relevant for these devices because it ties into the
32
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
fact that we don't yet have a great understanding of how best to treat patients whose
leadless pacemaker has reached end of life. There are no data, either animal or clinical, on
retrievals or extractions several years post-implant, let alone 10 years out, which is the
projected time to battery end of life.
In terms of what to do when a device reaches end of life, it's unclear whether the
device should be removed or left in place and turned off. And lastly, there is essentially no
data on device-device interactions, which may occur when there is a leadless pacemaker
alongside another leadless pacemaker or when a leadless pacemaker and transvenous
device are both present.
To focus on device retrievals for a moment, there were only eight retrievals in study
subjects for both trials combined. Although these were all successful, none were greater
than 15 months post-implant. There have been two case reports in the literature where
patients with a leadless pacemaker died of unrelated causes at 12 and 19 months post-
implant, respectively. Autopsies showed that in both instances there was encapsulation
present around the device. In one case, which is shown in the bottom left figure,
encapsulation was mostly seen in the distal half of the device. In the other case, shown in
the figure to the right of the screen, it was almost fully encapsulated and adherent to the
papillary muscle as well.
If only the distal end of the device is encapsulated, the device can likely be retrieved,
but if the device is fully encapsulated, it likely cannot be extracted percutaneously because
the retrieval mechanism at the proximal end of the device needs to be fully accessible to
the retrieval catheters which snare the proximal end of the device.
33
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
There is also some available animal data looking at device removal in sheep, with
retrievals varying from 3 to 28 months post-implant. All but one showed only distal
encapsulation and were successfully retrieved. However, one device was completely
encapsulated, and this was 28 months post-implant, and therefore the docking interface on
the proximal end could not be accessed and the device could not be retrieved. Again, these
retrieval data are all less than 2.5 years post-implant and not long term or close to the
projected battery life expectancy.
Given that device retrieval at 10 years is unknown and that the projected battery
longevity is approximately 10 years, it's unclear what the best practice for device
replacement is. There are different options for device replacement when the original
device reaches end of life. The first and second options are to remove the leadless
pacemaker and place a new leadless pacemaker, or to remove the leadless device and
implant a transvenous pacemaker. The third and fourth options are to turn the leadless
pacemaker off -- these devices can be programmed completely off -- and place either a new
leadless or a transvenous pacemaker.
There are minimal data on any of these four options. In the two clinical studies,
there were only occasional instances of device retrieval and placement of a second leadless
device, but the numbers are small and the retrievals occurred no greater than 15 months
post-implant. Also, in terms of leaving the original leadless pacemaker in place and turning
it off, the possibility of device-device interactions is raised. However, this has also not been
extensively studied. There have not been patients implanted with side-by-side leadless
pacemakers to date. The publication on the Micra device did report that there were two
34
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
subjects who had the leadless device turned off and then received a transvenous
pacemaker, and there was no mention of device-device interaction at least in those two
patients. Conversely, patients with an indwelling transvenous pacemaker lead were
excluded from enrolling in the Micra and Nanostim trials. So adding a leadless pacemaker
in patients with a previously implanted transvenous device has not been studied.
With no clinical data on leadless-to-leadless co-implantations and only two subjects
with a co-implanted leadless and transvenous pacemaker, there do remain electrical and
mechanical concerns. There may be electrical device-device interactions with a second
leadless pacemaker, even if the original device is off. We think if the devices are not
touching and the original device is off, there shouldn't be any interaction, but this has not
been fully studied or demonstrated.
There may also be mechanical or physiologic concerns. One issue is that it's
unknown how many leadless pacemakers in the right ventricle is acceptable. As a
theoretical but plausible example, someone undergoing an initial leadless pacemaker
placement at the age of 50 could undergo three implants in his or her lifetime. Also
unknown is whether multiple leadless pacemakers fixated to the apex or low septal wall can
affect right ventricular function. And yet another question is whether the risk of
thromboembolic phenomena increases when there are multiple leadless pacemakers in
place.
And so, in conclusion, we have published data on the early experience of leadless
pacemakers, but given our priority to strike the right balance between premarket clinical
data and postmarket data collection, some questions currently remain unanswered. We
35
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
have published data on the implant procedural success and implant procedural risks, and
we have an understanding of device effectiveness at least out 6 to 12 months, which we do
believe to be representative of longer-term performance.
However, there are many questions that remain unanswered that will need to be
addressed. The most salient ones are:
• The procedural adverse event rate in the real world and the implant
procedure learning curve;
• The long-term safety, reliability, and incidence of late device failures;
• The long-term (meaning 5- to 10-year) effectiveness;
• Battery longevity;
• The feasibility of device retrieval several years post-implant, and along a
similar line, how best to manage leadless pacemaker devices that have
reached end of life, whether it's best to extract or to leave in place; and
• Finally, for devices that are left in place, the concern and need to better
understand if device-device interactions occur.
We look forward to the Panel's discussion and recommendations on these
knowledge gaps this afternoon. This concludes FDA's presentation.
DR. PAGE: Thank you very much for a very clear and concise presentation. I might
have you stay at the lectern for one moment because I have one question. And after that
we'll be -- I'll be asking the Panel to ask any brief clarifying questions of the FDA. I will
remind the Panel that we will all have time for questions of the FDA and the sponsors
during the Panel deliberations in the afternoon.
36
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
Just in terms of nomenclature, you clarified something, at least in FDA's perspective,
that wasn't clear to me in terms of the wording. Specifically, you used the term
"embolization" for when a device -- and this would be a leadless device -- moves at the time
of implant, as opposed to dislodgement being applicable to either a lead tip or the leadless
pacemaker moving at some time after the acute procedure. Is that the nomenclature that
FDA is using?
DR. SELZMAN: Yes. Yes, it is.
DR. PAGE: Okay.
DR. SELZMAN: So embolization during the acute procedure where it can possibly
lead to the right ventricle. Obviously, transvenous leads can't do that. So we use the term
"dislodgement" for post-implant leadless devices that have basically come un-fixated from
the RV endocardium and may or may not have left the right ventricle.
DR. PAGE: Okay. So you're not calling those embolized devices if they actually --
DR. SELZMAN: Correct, if they're post-implant.
DR. PAGE: -- post-acute dislodge and embolize?
DR. SELZMAN: Correct.
DR. PAGE: Okay.
DR. SELZMAN: We're referring embolized for the acute procedure just to -- the
difference from a patient perspective would be that it's happening at the time of the
procedure, and so you could retrieve the leadless pacemaker and reimplant it, as opposed
to a second procedure which would be needed post-implant.
DR. PAGE: I think I understand, but we'll just need to be careful as we discuss the
37
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
particular potential complications.
I'd now like to open up to the Panel. Again, brief clarifying questions. And I see
Dr. Slotwiner and Dr. Borer first.
Dr. Slotwiner.
DR. SLOTWINER: Thank you.
Dr. Selzman, I just have one question on your Slide --
DR. PAGE: Please speak up.
DR. SLOTWINER: Oh, sorry. One question on your Slide 37, comparing the
complications between the leadless and the transvenous pacemakers. Were the
transvenous -- did that include dual-chamber pacemakers, or is that just single-chamber
pacemaker data?
DR. SELZMAN: You're asking specifically about the complication rates?
DR. SLOTWINER: Yes.
DR. SELZMAN: So we tried our best to get single-chamber data, but some of that
data is a mix because it's just hard. Sometimes the literature doesn't distinguish always
between single and dual. So there are some numbers that might be a little higher than
what you would expect for a single chamber.
DR. PAGE: Dr. Borer and then Dr. Yuh.
DR. BORER: Thank you. And thank you for a superb presentation. I have several
questions, but I'm only going to ask one right now because I think you will have the data.
As I looked through the Panel packet, it was clear that among the patients who received a
leadless pacemaker, a substantial proportion had underlying atrial fibrillation, which means
38
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
they were anticoagulated, and the issue to me here then is do we know anything about the
compatibility of the leadless pacemakers with NOACs? Because, of course, very
unfortunate interaction was found with valve replacement, heart valves. Do we know
anything about that? Can people use NOACs when leadless pacemakers are inserted, or can
they not?
DR. SELZMAN: My recollection of data that has been presented to us is that a lot of
times the NOACs were held. And we can get more from -- maybe more information from
St. Jude and Medtronic later today. But my understanding is that a lot of times it was held.
And so the implant procedure was not done while fully anticoagulated with a NOAC.
DR. BORER: I wasn't concerned about the implantation. I was concerned about
chronic use. The atrial fibrillation is going to continue whether the leadless pacemaker is in
place or not.
DR. ZUCKERMAN: Okay. So, Dr. Borer, that is an excellent question, and it helps us
envision where the technology is going. But as Dr. Selzman indicated, the actual company
information is proprietary today, unless the company in their presentations wants to
disclose an answer to your key question. So we would advise you to ask the companies.
DR. PAGE: Thank you.
Dr. Yuh and then Dr. Brinker.
DR. YUH: Thank you very much for a great presentation. I'm seeking some degree of
guidance. So one way that this Committee can be helpful to you is where to draw that line
in the bathtub, correct, in terms of perceived complication risk and not to focus necessarily
on the inherent differences in the device designs between, for example, the two devices
39
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
that have been presented. So if the devices, though, have inherent different differences,
for example, passive versus active fixation mechanisms with presumably associated
different rates of complications for those different mechanisms, as an example, can you
give us some guidance of how we are to lump all of these devices as a class to draw one line
in that bathtub?
MR. SHEIN: So I'll take it. You know, I think to start, we're looking for the Panel, as a
surrogate for the clinical community at large, to give us an idea what tolerance for adverse
events are. We've seen a description of adverse events in the published literature, and
you'll shortly have an opportunity to hear from some of industry, I'm sure, who may be able
to discuss the details better there. The extent to which you can give us insight on what that
tolerance level may be, we will then be charged with turning around and applying it to
individual applications. With part of that, we are obviously going to have to consider the
individual device characteristics that may differentiate them, as you're suggesting with the
fixation mechanism.
So to the extent that you can provide us some guidance on that, it would be helpful.
As far as drawing a line in the sand, again, everything in science, there's a subjective part to
it, and you have to take lots of things into consideration. And I think that's one of those
elements that when you look at the composite of a device, you have to take all its
characteristics in place, and that may require some interpretation at that point.
DR. YUH: Thank you.
DR. ZUCKERMAN: So, Dr. Yuh, I think you've brought up a great point. Mr. Shein has
begun an introductory explanation. But, you know, this is one of the things that the Panel
40
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
will grapple with, the general principles. For example, Dr. Lewis, in introducing the bathtub
slide, you know, indicated that our usual post-approval study follow-up is 5 years.
Significant general complications that we might expect for this technology might be longer
out. It's that sort of general discussion we're looking for.
DR. PAGE: Dr. Brinker.
DR. BRINKER: What is FDA's expectation with regard to MR compatibility, especially
in view of safety concerns?
MR. SHEIN: So MR compatibility is an issue that we, to date, are expecting
demonstration from an individual firm based on their device, based on computer modeling
of heating potential, with respect to other problems that might be associated with that.
Certainly, this Panel has reviewed a couple devices at this point in time regarding those
issues. We don't have an expectation that a device must be labeled MR conditional.
However, if a manufacturer approached us and wanted to have their device labeled as such,
they would need to present the data to support that.
DR. BRINKER: I suppose that you do have some expectation that appropriate testing
for every device would need to be done to look at heat and to look at the possibility of
dislodgement by the MR field and maybe the maximum amount of MR energy that could be
applied to the patient.
MR. SHEIN: Absolutely.
DR. PAGE: Thank you, Dr. Brinker.
Dr. Kandzari.
DR. KANDZARI: Good morning. Perhaps this is a more directed question for you,
41
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
Dr. Selzman, as an electrophysiologist. But you had shared the baseline demographics
pooled from the experience of the leadless pacemaker, and in the provisional documents
from one of the sponsors we saw, the other, I didn't, and in the primary manuscript are the
indications for pacing, and I wanted to get your perspective on the indications and if they
were representative of the experience with transvenous pacemakers. And specifically, as I
recall, in one of the sponsors' experience or in the clinical trial experience, 60% -- 55% to
60% of the individuals received it for atrial fibrillation with bradycardia. There's about a
third of the individuals who received it for bradycardia with unexplained syncope or it said
perceived electrophysiologic findings.
So while the age, the sex differentiation, the COPD, etc., might be similar to other
prior predicate historical controls, are the indications representative in your experience as
well?
DR. SELZMAN: It's a great question. In fact, later today when we ask the Panel
questions, we do have a question along those exact lines because we want to get the
Panel's input on who they believe is most appropriate to receive these devices, and if any
subgroup should be included, excluded, if there are any differences in terms of who should
receive them versus transvenous pacemakers. So we do want the Panel's input on that.
DR. KANDZARI: So in your experience, though, as a practitioner, would you say that
distribution is representative of clinical practice in terms of people who get a VVIR pacer?
DR. SELZMAN: Or who was enrolled in the trial, the trials --
DR. KANDZARI: Is that fractionation remolded in the clinical trial representative of
patients today who receive a transvenous pacer?
42
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
DR. SELZMAN: I believe so. Yes, I do believe that the patients enrolled in the trial, as
I mentioned, you know, they tend to be older, frailer. I think that does match the
demographic of who is receiving single-chamber pacemakers currently. They tend to have,
again, the older, that have atrial fibrillation, other comorbidities. Does that answer your
question?
DR. KANDZARI: And then I guess I would assume as well that about -- in these
patients, about two-thirds are going to receive it for atrial fibrillation with chronotropic
issues, a third for bradycardia and unexplained syncope.
DR. SELZMAN: Probably. But, again, that's what we want the Panel's input on.
Yeah.
DR. PAGE: Thank you, Dr. Kandzari.
And I would reiterate that we have some practicing and experienced
electrophysiologists on the Panel as well, and that will, I think, lead to a robust discussion of
the representation of the population of patients that have been studied.
Dr. Naftel.
DR. NAFTEL: So I'm making a list. I have to make a list. So there's a great list of the
implant adverse events on Slide 37, and then on Slide 40 there's midterm safety. So I'm
thinking about the bathtub curve, which I'm sure we're going to be discussing again and
again. So what are the events that we're looking for late? So I think it's everything you've
listed in the midterm safety, and then it's through other places, battery life, device retrieval,
infection, dislodgement, thrombosis. So we're going to make a list sometime today, right?
And then we're going to talk about each one and where we think it falls from a bathtub
43
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
curve. So I'm just making my list, and I'll be listening real closely to the manufacturers and
see what their list is, too.
DR. SELZMAN: Yes, I think that's correct. I think, as we tried to show in our
presentation, there are a lot of adverse events that can be caught early on that are
procedural or peri-implant. And then there are some potential concerns that we have,
particularly when the battery reaches end of life. And that's going to be far to the right of
the bathtub curve. So we feel like there's going to be kind of a calm period in the middle,
but how to capture the early as well as the late events that we want to capture.
DR. LEWIS: One other thing. So I hear in your question, you're asking what kinds of
wear and tear failures might we expect? And I think that what you're hearing is that there's
a difference in the general experience, FDA's understanding of what kinds of adverse events
might occur early, mid, and late. Late, largely unknown. So the question that's posed is
based essentially on your experience at large with medical devices in the absence of specific
kinds of adverse event types identified for long-term wear and tear.
MR. SHEIN: So I would echo the clinical perspective from FDA. I think that, as Kim
mentioned earlier in her presentation, we can draw largely on the transvenous pacemakers
to inform us of the kinds of things we would see at end of life. The actual rates of those
occurrences and the sequelae that might be associated with them are what's unknown and
we would hope to capture in longer-term monitoring of these devices.
DR. PAGE: Yes, Mr. Frankel.
MR. FRANKEL: I just want to ask regarding the device infections, that in the longer-
term data, whether it's midterm or longer-term data, if there is any type of information
44
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
that --
DR. PAGE: Could you speak a little bit louder, please?
MR. FRANKEL: If there's any type of information that would indicate the potential
for infections that might come longer term, because I know that leads are not an issue here
but the device itself. Because obviously with pacemakers, transvenous, there's the short-
term, and then there's the longer-term infections that are of a different concern, a different
nature. Do we have any data that would indicate that might be a longer-term problem?
MR. SHEIN: So, again, we're limited to being able to comment today on the
information that's in the peer-reviewed literature and publicly available. I think that you've
heard the comments of what we've seen in that. I think that that's a question that might be
better asked of the industry that will be speaking over the course of today.
DR. PAGE: Thank you.
Dr. Lange.
DR. LANGE: This is directed to Dr. Selzman, and it regards Slide 38 and the last
statement, that St. Jude conducted analysis of operating experience. And I think I wrote
verbatim what you said. I just wanted to know, Dr. Selzman, because the comment you had
made was, after 10 procedures, the complication rate was decreased by 50%, and I just
want to understand that. Was that operators that did 10 or more had 50% less
complications, or after the operator did more than 10, the complication rate went down by
50%? What is your understanding of that?
DR. SELZMAN: So this is in Dr. Reddy's published paper on Nanostim. So we can get
his take on it. But the way I interpreted it is that if you look at the complications that occur,
45
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
if you look at their prior experience, that's where you get the 50% reduction.
DR. PAGE: And, Dr. Lange, I'll ask you to bring that up later because that's a very
insightful question, basically the concept being -- just giving a heads-up for FDA and
industry -- it's a site that did a lot of cases, good from the get-go because it's a site that
does a lot of cases, as opposed to what Dr. Lange was specifically asking. Per individual, in
your first 10, you have twice the chance of complication as your next whatever. And, again,
you don't have that information. We'll see if the sponsors have that information, but it's
worthy of discussion.
Dr. Ohman.
DR. OHMAN: Thank you. And good morning. I'm struggling a little bit with the
concept of embolization. Did I get this right, that it's beyond 24 hours? So when the device
leaves the ventricle? And I'm sort of wondering about this because it really gets to the
knowledge gap a lot. You know, what is -- when the device leaves the ventricle by its own
accord, I presume that it's embolization and not dislodgement. Am I right or wrong?
DR. SELZMAN: The way that we have used it is embolization is during the implant
procedure, and dislodgement is after the procedure. Even though you're right, you could
call -- technically, that would be embolization, but we're calling them -- we're lumping them
all as dislodgements.
DR. OHMAN: Okay. I guess I'm then worrying about the unmet or the knowledge
gap in dislodgements, because if the device travels or leaves the ventricle, what's the
consequences? And I haven't seen this, and maybe it isn't available just yet, but I haven't
seen any of the numbers of what's the outcome. And in this regard, there's just two sort of
46
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
very simple things that happen to patients. They get instrumentation of the right ventricle.
And so that's a large knowledge gap. We don't really know what happens when we put
other devices in the ventricle. And then the other one is cardiopulmonary resuscitation,
because if you have cardiac resuscitation, you predominantly actually compress the right
ventricle. And so this is an area where I don't see any comment in either this one or even
the later ones that I read. So this is an area that is fairly large to me. It would be fairly
disastrous if you had a device that you did CPR and then the patient couldn't be paced
because the device was no longer in the ventricle. So that, to me, is maybe the number one
issue as just a simple doctor thinking about these patients.
DR. PAGE: Thank you, Dr. Ohman. I think you brought up two very important points.
In terms of the CPR, that is not something that we've had in our materials. It's something
that we will need to discuss. The second issue that you brought up kind of follows on my
earlier comment. In terms of semantics, I understand what the FDA was saying in terms of
embolization being what happened acutely during the procedure, and dislodgement being
either micro-dislodgement or macro-dislodgement, which a leadless pacemaker would
include potentially embolization. I suggest that we, as a committee, use the terminology for
the post-acute dislodgement too. If it embolizes, call that dislodgement with embolization,
and use the other term that's been put forward for the embolization alone to be -- or we
could put in front of that, acute embolization or intraprocedural embolization, which is
what you're discussing. But, in fact, dislodgement is a very different thing potentially when
you have a lead or when you have a leadless device.
Looking around the Panel, are we in agreement that we'll be more precise about that
47
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
and not necessarily, with all due respect, to accept your definition of embolization being
only what happens during the acute procedure? Looking around, are we in agreement?
Okay.
Did I see any other -- Dr. Borer has a question.
DR. BORER: Yeah. I don't expect that you're going to have an answer to this, but I
want to raise it so it doesn't get lost somewhere, and that's a follow-on to the earlier
question about infection. This is a foreign body that's larger than a pacemaker lead that's
sitting in the heart, and I'm wondering what kind of recommendations are made and what
basis we have for such recommendations for endocarditis prophylaxis. One the few
remaining indications for endocarditis prophylaxis for dental or urological procedures, and
maybe colonic procedures, is the presence of a replacement valve, a cardiac valve
replacement in the heart. And here we have devices that are -- they're a little smaller than
cardiac replacement valves, but they're sitting there in the heart.
Do we have to worry about the potential for endocarditis and the need for
endocarditis prophylaxis for non-cardiac procedures? I don't know if you have any
information that speaks to that yet, but it's something that I don't think we should forget
about.
MR. SHEIN: It's a good concern, and I don't think we have the data to present on
that.
DR. PAGE: Thank you, Dr. Borer.
Dr. Brinker.
DR. BRINKER: Thank you. With regard to infection, I assume that there is no plastic
48
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
covering of the device itself. Number one. So that would make it much more resistant to
an infection that would be protected by biofilm. Number two is that there are no guidelines
now suggesting that permanent pacemakers receive endocarditis prophylaxis. So that
would also make it another consideration. I don't think that these necessarily would. And if
they're basically metallic, I think the risk of an infection and a prolonged infection would be
very low. That being said, the fibrous tissue encasing a device could become infected by a
process of endocarditis, and that, I think, would be an infrequent thing but something that
needs some care and thinking about.
So a lot of people -- I assume a lot of implanters might feel that a leadless device
offers certain protection against endocarditis, and patients that are at high risk for infection
on a CID, a cardiovascular implantable device, electronic implantable device, might want to
use these. Now, I'm using -- particularly people receiving catheter dialysis, extremely high
risk for infection and a real problem for us who take out chronic leads. So this would be an
important issue because I can see this being a potential indication for such a device.
DR. PAGE: Thank you, Dr. Brinker. You did comment, and if FDA is able to address
this, having looked at all the technical aspects of the two devices that are in the public
domain, the actual tissue interface, as to metallic versus other covering, what is in contact
with the endocardium in terms of the actual materials in the two devices? I'm sure this can
be handled by our sponsors. If you'd like, we can hold that until later. Thank you very
much.
DR. LEWIS: One further comment, and that is, is that the device may or may not be
extractable in the event of endocarditis down the road.
49
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
DR. PAGE: Thank you.
Dr. Cigarroa.
DR. CIGARROA: Just a couple of points for discussion as we go throughout the day as
it relates to knowledge gap. So certainly the demographic of our patient population that
received VVI pacemakers over the course of the last 15 years has changed, with an average
age of about 80. As we take a look at the method of implantation, that is, large vascular
access, and the two different modalities of securement of the device into the RV, just a
couple of points to consider.
First of all, approximately 5% of all patients undergoing hemodialysis, not just
chronic kidney disease, receive pacemakers. So to your point, the issue -- and I would raise
three issues there. Number one, vascular complications, number two, risk of infection, and
number three, perforation and effusions, which in uremic states may occur at higher
frequencies. So there is a knowledge gap.
The second is, in this age group, the presence of concomitant coronary artery
disease and patients on either dual antiplatelet therapy or triple therapy; again, knowledge
gaps as to the risk of vast complications and again potential risk of perforation, effusion,
and possibly tamponade.
So as we begin to go throughout the day, it would be of interest to me, as the
sponsors go through this, as to whether or not there's any data that may be shared with us.
DR. PAGE: Thank you, Dr. Cigarroa.
Dr. Zeitler.
DR. ZEITLER: I have a clarification question. One of the knowledge gaps that we're
50
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
tasked with addressing is the issue of device-device interaction, for which, based on the
materials, there really aren't many data to go on. But I'm curious to know if there are any
data or if perhaps this is not part of our task to address the issues of device-device
interaction with devices that are completely off with other devices or devices that may both
be functioning. For example, a patient who might be appropriate for a leadless pacemaker
might be the exact same patient who's appropriate for a subcutaneous ICD. And I'm
wondering if there are any data related to those types of interactions or if that's outside of
our scope.
DR. SELZMAN: Currently FDA is not aware of any known data with leadless
pacemaker and either transvenous defibrillators or subcutaneous defibrillators. We'll hear
more from the sponsors later, but we're not aware of any currently available data on that.
DR. PAGE: Dr. Zuckerman, it appears we're ready to close this part of the meeting.
I'm going to suggest that we take a 20-minute break and reconvene at 9:40. Does that work
for FDA?
DR. ZUCKERMAN: In a moment. I'd like to make two clarifying comments.
DR. PAGE: Yes, please.
DR. ZUCKERMAN: Number one, I want to thank the Panel for posing a great set of
clinically important scenarios. Certainly, if the sponsors who are speaking in the next
section want to just chat with me during the break, I'd be happy to, if they want to perhaps
revise their comments a bit. But I think that many of the comments made by the panelists
refer to the concept of what is reasonable to study premarket approval versus post-
approval? There will be many important datasets and clinical scenarios for this device
51
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
technology. And so as the panelists go through these scenarios, I think they can help the
sponsors and FDA by really indicating if these are rate-limiting premarket issues versus
interesting questions for the postmarket that can add to an important knowledge base.
Thank you.
DR. PAGE: Thank you very much.
Before we break, I do want to remind the Panel members that we will not discuss
the meeting topic during the break among ourselves or with any other member of the
audience. We will resume at 9:40. Thank you.
(Off the record at 9:23 a.m.)
(On the record at 9:40 a.m.)
DR. PAGE: I'm happy to reconvene this Panel. We're now going to begin the
Industry Open Public Hearing. We have three companies who have requested time to
speak: Boston Scientific, Medtronic, and St. Jude. The first company will be Boston
Scientific. At the conclusion of each presentation, there will be time for Panel member
questions. The three companies have offered to provide mockup devices, and what we've
decided to do and I'll ask you to do is at the lunch break, to put them on the table there so
if the panelists wish to examine the devices, we will have that opportunity over the lunch
break. And feel free to hold it up during your presentation, if you like, but we will not be
distributing them to the Panel, but we will have the opportunity to examine during the
break.
I'll now welcome Boston Scientific for a 20-minute presentation. Welcome.
DR. STEIN: Thank you. Good morning. You would think, after all these panels, that
52
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
I'd remember that. Dr. Page, members of the Committee, and members of FDA, my name's
Ken Stein. I am the Chief Medical Officer for Rhythm Management at Boston Scientific, and
I'd like to thank you for inviting us to give our perspectives on the promise of leadless
pacemaker systems. Today I'd like to cover four areas as I discuss the leadless pacing
system that Boston Scientific currently has in preclinical evaluation.
First, I'll give you our perspective on the unmet medical need for a leadless
pacemaker. There are some patients who require VVIR pacing for whom traditional
transvenous pacing systems are not adequate and who would benefit from having a
leadless alternative. I'll also introduce a completely separate area of need, and that is --
and it came up earlier this morning -- the need for a leadless pacing system that can
coordinate with a subcutaneous ICD and that could provide anti-bradycardia or anti-
tachycardia pacing therapy when needed.
I'll then briefly describe the leadless pacing system that Boston Scientific currently
has in development.
And following that, I'll discuss some of the safety considerations that are guiding the
development of our leadless pacing system, including performance criteria, thoughts
around encapsulation and device replacement considerations, and the appropriate level of
implanter training.
Finally, I'll close by addressing the important benefit-risk considerations as we
consider which patients would most benefit from having this novel therapy available.
I'll begin by addressing the unmet clinical need for leadless pacing as bradycardia
therapy. Since the first cardiac pacemaker was implanted in a human by Ake Senning in
53
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
1958, almost 60 years ago, the field has progressed substantially with the introduction of
long-lasting batteries, device programmability, rate of active pacing, enhanced diagnostics,
and great progress in pacemaker lead reliability and lead durability. Transvenous
pacemakers are well recognized as a highly safe, a highly effective, a life-saving and a life-
improving technology. Nevertheless, there are intrinsic risks associated with a transvenous
pacing system: risks of infection, risks of venous occlusion, risks of tricuspid regurgitation,
and as you've heard already, remedial actions may require lead extraction, a procedure
with significant risk, both of morbidity and of mortality.
Although determining the magnitude of benefit will require long-term trial data, in
theory at least, avoiding the need for a lead directly connecting the subcutaneous pocket
with the endovasculature may help to mitigate these risks, and thus, leadless pacing might
be preferred for selected patients at high risk of these complications.
We feel that a much more significant unmet need can only be addressed if we
broaden our thinking of what a leadless pacing system can do. I'm referring to the
development of a leadless pacing system that's capable of communicating with and
coordinating with the subcutaneous ICD to deliver anti-bradycardia or anti-tachycardia
therapy. As you know, the S-ICD was approved by the FDA in September 2012 as the only
alternative to conventional transvenous defibrillators in order to entirely avoid the acute
and the chronic complications that are associated with placing a lead in the right ventricle,
including the risks of lead extraction.
Although the vast majority of patients with an S-ICD are well served with the device,
a minority of S-ICD patients will, over time, either develop a need for anti-bradycardia
54
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
pacing support or anti-tachycardia pacing to terminate recurrent monomorphic VT.
Conversion to a transvenous pacing system has been quite rare in patients who are
currently being selected for the S-ICD. In our pooled EFFORTLESS IDE cohort, 0.06% of
patients per year required conversion for pacing support. However, in the broader
population of patients evaluated in our MADIT II study, the pacemaker rate in the control
group was 2.4% per year. Similar results were seen in the SCD-HeFT trial, which also
showed an annualized pacemaker rate of 2.4% per year in the control group. With respect
to anti-tachycardia pacing, recurrent monomorphic VT was observed in 0.4% of patients per
year in our pooled EFFORTLESS IDE cohort versus 1.8% per year in SCD-HeFT.
Now, today, patients who require anti-tachycardia pacing or bradycardia pacing
support only have transvenous options and so for the most part are not eligible for the
S-ICD. Existing S-ICD patients who require anti-tachy pacing have to go to implantation of a
second transvenous system and explantation or deactivation of the S-ICD. Therefore, a
leadless pacing system that can coordinate with an S-ICD offers an alternative to a
transvenous system and expands the pool of patients who can be considered for the S-ICD
while continuing to avoid the known risks of transvenous ICD leads, thus fulfilling an
important need.
Now, let me briefly describe Boston Scientific's leadless pacing system that's
currently in preclinical evaluation. Our leadless pacer is designed as a VVIR pacing system
with a targeted longevity of more than 10 years in typical use conditions. The most
important design consideration reflects our dual goals of achieving robust fixation while
also minimizing the risk of life-threatening cardiac perforation. Specifically, after initial
55
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
testing, we elected to use a nitinol talon design or tine design rather than a screw-in design,
as we found that it provides strong fixation to minimize embolization while also minimizing
the risk of perforation. Additionally, our delivery catheter system has been designed to
improve usability and prevent adverse events such as perforation. We did this by designing
a catheter with active tip deflection and active extension as well as an atraumatic tip.
Throughout the implant procedure, the implanter will maintain control of the leadless
pacemaker via a tether and will also have the ability to flush the delivery lumen and to
inject contrast throughout the implant procedure.
The accessories of the leadless system include a 21 French introducer for both
delivery and retrieval catheters, as well as snares. And the snare recapture feature on the
distal end of the device is designed to facilitate retrieval, if necessary. An external
programmer will allow for device interrogation and programming.
Let me also show you how our leadless pacing system was designed from the ground
up to work in concert with the S-ICD. In a patient with a coordinated system, the leadless
pacemaker and the S-ICD will be able to interact one with the other via a wireless
communication link. Here's how the two systems will work together. The Boston Scientific
leadless pacemaker will sense and treat bradycardia independently of the S-ICD. The S-ICD
will continue to sense tachycardia and will command the anti-tachycardia pacing, if
necessary, from the leadless pacemaker. We believe it's important for the S-ICD to
maintain control of discrimination and decision making in order to ensure the safest and
most effective integration and coordination of therapy for the patient. While anti-tachy
pacing schemes are built into the leadless pacer, they can only be activated by the S-ICD or,
56
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
if necessary, by an external programmer. Each ATP attempt and the decision as to whether
or not to divert to a shock will always be controlled by the S-ICD.
I'm pleased to confirm for the Panel that the group from the Academic Medical
Center in Amsterdam will be presenting the results of our initial preclinical studies showing
the ability of the S-ICD to successfully trigger ATP via our leadless pacemaker in an animal
study, at the upcoming ACC Scientific Session in Chicago.
As we think about the coordinated system, I'd like to point out three potential use
cases. Figure A shows the case in which a patient receives an S-ICD first, followed by a
leadless pacemaker at a later date. For example, this could be an S-ICD patient who
subsequently developed recurrent monomorphic VT, who might choose to be implanted
with a leadless pacemaker in order to provide anti-tachycardia therapy while still avoiding a
lead in the heart.
Figure B depicts a leadless pacemaker patient who then subsequently develops an
ICD indication, and the patient is implanted with the S-ICD in order to provide defibrillation
therapy while still continuing to avoid transvenous leads.
Figure C depicts the case of a de novo patient with unusual anatomy or difficult
vascular access who might require that both devices be implanted at the same time during
the initial implant procedure.
Let me now turn to the specific considerations necessary to prove the safety of
leadless pacing. For the most part, these considerations apply irrespective of whether the
system is to be used as a simple VVIR pacemaker or as a sophisticated component of a
system in combination with the S-ICD.
57
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
In contrasting the leadless pacemaker with conventional transvenous pacing
systems, it's important to begin by recognizing that the nature, but also the severity, of
complications will be different across the two technologies. For example, device
embolization, whether acute or chronic, is unique to the leadless pacer. While perforation
and pericardial effusions are shared by both, the severity of a perforation is far greater with
the current large diameter of leadless pacing systems.
Based on what we've learned from other manufacturers' published experience and
the experience that we've gained with our own product during development, Boston
Scientific intends to tailor our physician and patient information to ensure appropriate risk
awareness and avoidance. As a fundamental principle, the risk of adverse events with the
leadless pacer should be, at worst, comparable to the risk with the current generation
transvenous system implant, excepting that there will be a small group of patients in which
one or the other technology can only be used for reasons of comorbid conditions, anatomy,
or extraordinary patient circumstance.
Traditionally, we evaluate the safety of a transvenous pacemaker system in two
steps. First, a safety endpoint evaluation is performed in which an aggregated rate of all
device-related complications, including events such as perforation, pericardial effusion, and
dislodgement, is compared against a predefined performance goal. But, second, the
components of this aggregated rate are evaluated separately, ensuring that each individual
one is within the bounds of acceptability. And Boston Scientific believes that applying a
similar approach is appropriate in evaluating the safety of a leadless pacemaker system,
with particular attention to the occurrence of life-threatening complications such as cardiac
58
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
perforation.
In this context, FDA asked the Panel to consider the rate of occurrence of adverse
events at implant with leadless pacing devices as compared to traditional pacemakers. In
order to do that, it's essential that the Panel have access to data on adverse event rates
from a large sample of contemporary transvenous pacemaker systems.
The data on this slide reflect the as yet unpublished but most contemporary data we
have available. These are the pooled 24-month results of two ongoing transvenous
pacemaker IDE studies, INGEVITY and SAMURAI, currently under evaluation by the FDA and
reflecting the combined experience of 1,300 patients. Major system complications were
classified using the same definition used in Medtronic's Micra trial.
To approximate the leadless pacemaker population, two groups were evaluated for
purposes of this presentation, single-chamber pacemaker patients and dual-chamber
pacemaker patients with right atrial lead complication data excluded. The data show that
the results from the single- and dual-chamber populations are quite similar with respect to
perforation, pericardial effusion, and dislodgement, and therefore that these rates may be
used together as a basis of comparison for the leadless pacemaker. Overall, event rates
with contemporary transvenous leads are quite low, with rates of perforation less than
0.5% and combined rates of perforation and pericardial effusion less than 0.7%.
In addition to acute complications, as we've already heard, the chronic issues from
leadless pacers will also differ from those that we're familiar with from transvenous pacing
systems. We certainly need to consider the degree to which these devices will become
encapsulated over time and the effect encapsulation will have on extraction and retrieval,
59
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
should that be necessary.
In our preclinical testing, we've seen great variability in 90-day encapsulation within
the canine model, as seen in the top panel. And we also see considerably less
encapsulation in ovine versus canine models, as seen in the lower panels.
Although we are thus uncertain about the time course of encapsulation of these
devices in humans, we believe that it is highly likely that the device will be fully
encapsulated by the end of its typical battery life, and therefore Boston Scientific feels
strongly that physicians will need to consider a plan as to how they will manage device
replacement at the time of a patient's initial device implant.
Shared decision making between patient and physician is mandatory. Simply put,
the implications of a lifetime of leadless pacemaker replacements in a young patient with
few comorbidities are very different when contrasted with an elderly patient with complex
underlying medical conditions and a limited life expectancy.
As leadless delivery tools and techniques will differ significantly across
manufacturers, a device-specific training strategy preparing implanting physicians and allied
health professionals to safely and effectively manage patients throughout the implant and
follow-up of these systems is needed. Boston Scientific has a long history of successfully
training physicians on the use of novel technologies, including the first endocardial ICD
leads, cardiac resynchronization therapy, the S-ICD, and most recently WATCHMAN.
And we anticipate that our training strategy, similar to these, will include a blended
approach using online study followed by a face-to-face professional training event,
including case observation, simulator training, and hands-on training in preclinical models.
60
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
In Phase III, physicians will perform their initial cases with mentoring by qualified
independent physician operators. Finally, in Phase IV, the transition to independence,
physicians implant independently with support from trained Boston Scientific field
personnel.
Let me close by addressing the benefit-risk considerations unique to leadless pacing
systems. Now, these considerations will differ according to the clinical use. For VVI pacing,
a well-established therapy already exists with excellent short-term and long-term safety.
However, as we've discussed, there are intrinsic risks associated with endovascular leads
connected to a subcutaneous pocket, and therefore we believe that for appropriately
selected patients at high risk of complications from endovascular leads, leadless pacing will
offer a positive benefit-risk as long as the rate of life-threatening complications can be
proven to be acceptably low.
In contrast, for patients with an S-ICD who manifest a need for anti-tachycardia or
brady pacing, the benefit versus risk of a leadless pacemaker, in coordination with an S-ICD,
needs to be evaluated against the alternative of device explant with implantation of a new
transvenous ICD. We need to consider not only the acute risks of the procedure but also
the known risks of chronic ICD leads.
In closing, I'd like to thank the Panel for your attention and to emphasize that
whether the leadless pacemaker is used as a separate, run-of-the-mill VVIR pacemaker or as
part of a coordinated system with an S-ICD, a patient-centered, individualized approach to
benefit-risk assessment will be of paramount importance.
Thank you.
61
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
DR. PAGE: Thank you, Dr. Stein, for that very clear and concise presentation.
We now have exactly 10 minutes for the Panel to ask any brief clarifying questions of
the sponsor. Please remember that we will have time to ask the sponsor questions during
the Panel deliberations in the afternoon. I am going to keep it to 10 minutes just because
we have two more presentations to go through before lunch. So I'll now open -- Dr. Borer
first.
DR. BORER: Thank you, Ken. That was terrific. I have one clarifying question here.
I'm very focused on the perforation/effusion complication, and your data here, which are
from a prospective study that you generated, looked very nice compared with the other
data that we saw in our Panel packet and particularly from the EU data, where the
perforation rate was 2.2%. Obviously, you know, different datasets, whatever. There's all
kinds of variability. But can you give me some insight into the comparatively good results
that you've observed through 24 months compared with what we've been faced with from
the Panel packet?
DR. STEIN: Thank you, Dr. Borer. We've looked at our data. I would love to be able
to tell you that our data with our new leads are that much better than anything that's ever
been demonstrated before. I wish I could say that, but I can't. And so what I'm showing
here are also the rates that have been seen and what we've been able to glean from the
literature from eight other prospective premarket pacemaker lead approval trials. And,
again, you know, when we look at those trials, which frankly are a mixture of all the various
manufacturers that are represented here, the rates are relatively similar. Again, the mean
perforation rate is 0.3%. The mean pericardial effusion rate is 0.4%. And so, again, I think
62
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
that the numbers I showed today, I like just because they're the most contemporary data
that we have. But we think they're quite similar to what's previously been reported.
DR. PAGE: If I may just clarify. Dr. Borer, they were showing data that were not
from their device. Were you clear on that? The perforation data was from --
DR. BORER: Absolutely.
DR. PAGE: -- preexisting transvenous devices.
DR. BORER: Right.
DR. PAGE: Okay.
DR. BORER: Sure. That is the comparator, though, and we were given a great deal of
comparative information, and these look better.
DR. PAGE: Thank you.
I've got Dr. Yuh and Dr. Lange and Dr. Brinker and Dr. Naftel.
Dr. Yuh.
DR. YUH: Yes. Is there any potential risk of interference with the wireless coupling
between your LP and S-ICD devices, with either enabling other devices or other wireless
sources?
DR. STEIN: So, as of yet, we've only done preclinical testing. Our preclinical testing
is focused precisely on that issue, ensuring that we will have robust communication
between the leadless pacemaker and the S-ICD. We're confident at this point that we will
have it. We will be presenting some of that data at ACC coming up in Chicago. I'm anxious
not to violate any embargoes this time around and -- but clearly that is also going to be
critical for us to demonstrate beyond the preclinical model once we get into human testing.
63
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
DR. PAGE: Thank you. Dr. Lange.
(Off microphone response.)
DR. PAGE: Thank you.
Dr. Brinker.
DR. BRINKER: I might have misinterpreted some of what you said in your
presentation with regard to your wanting to avoid active fixation and develop these, what
would be called tines. Are they, in fact, tines? They're already in their exposed state when
the device goes in, and there is no extrusion of any active fixation element.
DR. STEIN: Yes, that's right. They become exposed once the device leaves the
delivery sheath. They're obviously compressed within a sheath until the device is -- until
the sheath is withdrawn. And we're referring them to talons. Again, I'm glad you'll have a
chance to see them. I just want to emphasize that they're not sort of -- I'm trying to find
the right word, and the engineers are going to hate me for saying this, but they're not the
kind of short stubby tines that we're used to with passive fixation transvenously. These are
longer, and that's just why we picked a different term.
DR. BRINKER: Right. So I just want to expand on that a little bit. We've all lived
through areas of wear. Certain tine leads don't do as well in certain situations, like a right
ventricle that's not well trabeculated. Do you think this would be a problem with your
device?
DR. STEIN: We're actually confident that this is going to give us the best balance
between assuring robust fixation in a vast majority of cases, but also avoiding what really
concerns us most, which is the risk of acute perforation during implant.
64
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
DR. BRINKER: Thank you.
DR. PAGE: Thank you.
Dr. Naftel.
DR. NAFTEL: So thank you for the clear presentation. On Slide 16, where you talk
about benefit-risk considerations -- so the last bullet just so jumps out at me. So you say,
for appropriately selected patients at high risk of complications from endovascular leads,
and then you say these are the patients to focus on. So I'm just fascinated. And exactly
who are these patients? And you go on. And we also have to show that the rate of life-
threatening complications can be proven to be acceptably low. So it's a great statement.
Can you be precise?
DR. STEIN: I don't know that I can be precise as yet about patient selection. We
haven't started our own human clinical testing of these devices. Let me begin, though,
about the rate of life-threatening complications. It does seem to us that what the bar ought
to be is comparability to existing transvenous devices. Again, I think we need to accept that
there will be unique patient circumstances because of vascular access issues or unusual
congenital malformations of cardiac anatomy. Patients may only be able to use a device
like this, right? And so for some patients, epicardial pacing may be the only other
alternative. But for patients who are candidates for a transvenous pacemaker, again it
seems to us, as a fundamental principle, that the risk of a life-threatening complication has
to be, at worst, comparable to the risk with a transvenous lead implant. Now, who are
appropriately selected patients? I think I might -- Rick, am I running over? I'm sorry.
DR. PAGE: If you can wrap up in just a few moments, that would be great.
65
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
DR. STEIN: I'll wrap up quick. So in terms of appropriate complications -- in terms of
appropriately selected patients, right, I think we've started thinking around that because
the issue is going to be, you know, if you have a 20-year-old patient who needs a
pacemaker, who's going to need a lifetime of these replacements and we don't know, you
know, exactly what the experience is going to be at retrieval and we don't know how many
of these devices they're going to end up having in their right ventricle, they're probably not
the right folks to start with, whereas if you have an elderly patient, a patient who is at high
risk of complications from a transvenous lead -- and we've heard some of the things around
that, potentially a high risk of infection, etc., potentially multiple comorbidities -- you know,
those may be the best patients to start with.
DR. PAGE: Thank you.
Dr. Slotwiner had a brief clarifying question and then to be responded to with a brief
response, please.
DR. SLOTWINER: Thank you. It may not be brief, so feel free to answer later. Sorry.
But I'm interested to hear, as this novel technology comes forth -- and I'm thinking of that
bathtub curve of -- you know, the right end of the curve, how Boston Scientific feels or
believes what data should be available pre-approval and what mechanisms should be
available post-approval and how to bridge that. And that's obviously not a small question.
So if you want to save that for later.
DR. STEIN: Well, I think I can be quick on that. Pre-approval, we think the standard
should be similar to what's needed pre-approval for a transvenous lead. Post-approval, this
is the poster child case for a total product life cycle approach, and I would anticipate that
66
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
this will be the sort of novel technology that would be well served by having a rigorous,
comprehensive registry.
DR. SLOTWINER: Thank you.
DR. PAGE: Great. I want to thank the sponsor very much.
And we will now move on to the next presentation. This is going to be from
Medtronic. At the conclusion of the presentation, there will be time for Panel members.
And I believe you're anticipating 25 minutes; is that correct?
DR. STEINHAUS: Correct.
DR. PAGE: Thank you.
DR. STEINHAUS: Very good. Could I have the script up, please? I think we've got the
wrong presentation here because it says -- do you want me to do yours?
UNIDENTIFIED SPEAKER: Yeah.
(Laughter.)
DR. STEINHAUS: I could do that. So good morning. My name is David Steinhaus. I
am the Medical Director and Vice President for our Cardiac Rhythm and Heart Failure
division at Medtronic. I'm actually delighted to be here to introduce you to the Micra
transcatheter pacing system, which in our view represents a significant transformation in
pacemaker therapy.
Micra is the result of more than a decade of work by Medtronic engineers and
scientists, and the FDA has asked us to provide our clinical experience as well as answer
questions about the follow-up of this new technology.
I would like to introduce our clinical experts who will be participating in the
67
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
discussion on behalf of Medtronic. Dr. Dwight Reynolds is a regents' professor and Chief of
the Cardiovascular Section at the University of Oklahoma. He served as the principal
investigator for the Micra Global Clinical Trial. We also have other participants from the
clinical trial who can respond to your questions. Dr. John Hummel is a Professor of
Medicine and Director of Electrophysiology Research at The Ohio State University Wexner
Medical Center in Columbus. And Dr. Robert Kowal is the Co-Medical Director of Cardiac
Electrophysiology at Baylor Scott & White Health Care System in Dallas. Presenters today
have been compensated for their time and expenses.
So we've organized our presentation to give you a brief introduction to the Micra
technology, provide an overview of the clinical study results, and to address FDA's
questions.
Starting with the first battery powered pacemaker, which Medtronic's founder, Earl
Bakken, developed nearly 60 years ago, there have been continuous technologic advances
in cardiac pacing. Pacemakers have gotten smaller, batteries have lasted longer, and leads
have gotten more reliable. Yet, as good as these systems have become, one in eight
patients will experience a complication from this therapy. Most of these are related either
to the leads, the pocket, or the implantation technique.
Now, as a result of miniaturization, we have for the first time the ability to implant a
tiny pacemaker non-surgically directly into the heart without the need for a subcutaneous
pocket or lead. This device, which is smaller than one cubic centimeter, has the potential to
significantly decrease the complication burden. This advance in technology is evident in
every component of the device.
68
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
At the top of this slide we see Medtronic's components, which include ultra low
power circuitry design, a dramatically miniaturized battery, and flexible nitinol tines for
fixation. The tines are Micra's most unique and crucial design element. Our engineers
developed these tines to hold strong enough that if you just engaged two of them, two of
the four, you'll have 15 times the holding force required for fixation. Yet they're flexible
enough that you can reposition the device without tearing the myocardial tissue or the
valve. Since the device will become encapsulated over time, it became important to have a
programmable device off mode. This would eliminate the possibility of inappropriate
therapy being delivered in competition with subsequent devices. Additionally, Micra is
compatible with MR imaging, provides accelerometer-based rate responsive pacing, capture
management to optimize battery consumption, and remote monitoring capability.
With that as the background, I would ask Dr. Reynolds to provide an overview of the
Micra's clinical data trial.
DR. REYNOLDS: Thank you, Dr. Steinhaus.
It's been my pleasure to be here today to discuss what has been one of the most
exciting times in my three and a half decades of implanting and using electronic devices. As
the PI of the Micra study, I had the privilege of seeing how this technology works and what
it can offer to our patients.
Let me start by showing you the key findings from the global clinical trial that were
just published in the New England Journal of Medicine. The Micra transcatheter ventricular
pacemaker was successfully implanted in 99.2% of patients. The study met its primary
efficacy and safety objectives with wide margins; 98 percent of patients had a low and
69
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
stable pacing threshold at 6 months, and 96% of patients were free from device- or
procedure-related major complications at 6 months. Micra patients had 51% fewer major
complications compared to traditional pacemakers, and remarkably, there were no
dislodgements and no infections. These are impressive results, especially when you
consider that this was a first-in-human trial.
The implant procedure for Micra is actually straightforward and relatively easy. The
delivery catheter is advanced from a femoral vein into the right atrium, then maneuvered
into the right ventricle. The device is deployed by pulling back on the delivery catheter.
Electrical parameters are measured, and fixation is verified by ensuring that at least two
tines are engaged in the myocardium with a tug-and-hold test. Then the tether is cut, and
the delivery catheter is removed.
The Micra clinical development program was robust and global with a clinically
diverse patient population and wide range of implanter expertise. There were 725 patients
with implant attempts performed by 94 different implanters in 56 different centers in 19
countries on five different continents. We didn't implant in South America or Antarctica.
There were no enrollment restrictions by comorbidity.
To put Micra's performance in context, we established a predefined historical
control group that were comprised of six recent pacemaker studies published from 2000 to
2012. Four of these studies had the rigorous data collection required for FDA approval.
The Micra patient population was older and sicker than those in the historical
control. As you can see from this slide, they had significantly more hypertension, atrial
fibrillation, valvular disease, diabetes, and chronic lung disease. Also, of importance, there
70
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
was a balanced representation by sex, with 41% of Micra patients being female.
As I mentioned, 96% of Micra patients were free from device- or procedure-related
major complications at 6 months. The remaining 4% or 25 patients experienced 28 major
complications. Major complications were defined as events resulting in death, loss of
device function, hospitalization, prolonged hospitalization by 48 hours, and/or system
revision. There were no deaths related to the device, but there was one death that was
adjudicated as procedure related. It was due to metabolic acidosis in a patient with end-
stage renal disease who underwent a concomitant ablation procedure. Major complications
were driven by cardiac perforations and effusions, which I will discuss in more detail
shortly. Of note, despite the larger introducer sheath, there were only five groin-related
complications such as AV fistulas and pseudoaneurysms, and there were only three events
that resulted in system revisions.
When comparing all major complications with the historical control group, Micra had
51% fewer major complications than traditional pacemakers. Even when adjusting for
differences in patient populations, propensity matching confirmed this reduction.
Going beyond Medtronic's historical control, we can also benchmark Micra's
performance against two other more recently published studies from 2012 and 2014. Now,
while the definitions of complications vary to some degree with the studies, Micra's
complication rates appear to compare favorably to the Danish registry and to the Dutch
FOLLOWPACE study.
Now, let's turn our attention to the FDA's first question surrounding the clinical
importance of the adverse events. The FDA has asked for a discussion of the clinical
71
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
significance of the specific events listed here, as compared to traditional pacemakers.
Again, Micra had no cases of dislodgement, device embolization, and there were no major
complications associated with arrhythmias or stroke.
In terms of cardiac perforation or effusions, the Micra rate is not significantly higher
than historical control, even though we didn't adjust for the fact that Micra patients were
older and had more comorbidities. And for context, the published perforation rate with
atrial fibrillation ablation procedure is around 2%. So let's go into more detail on these
particular events.
The first finding is that Micra patients who experienced perforations and effusions,
regardless of their severity, all had one or more risk factors that were specific to these
events. Of note, these are the same reported risk factors for perforations and effusions
with traditional pacing systems. Importantly, in looking at the occurrence of these
complications, they do not appear to be related to implanter training or experience. This
leads us to believe that these events are more related to the patient population than to a
specific technology or procedural technique.
This is further supported as we compare Micra's rates to the six individual
pacemaker studies in the historical control and to a large study from the Mayo Clinic.
Again, Micra's perforation and effusion rate is well within the range of currently available
systems.
By the way, these results are mirrored by the clinical experience in Europe since
Micra was released there last spring. In that 700-patient experience, to date, Micra has a
perforation rate of 0.7%.
72
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
While the small number of perforations and effusions make it difficult to draw
conclusions, Micra patients who had these events were more likely to undergo surgical
repair or pericardiocentesis when compared to the historical control group. However,
these rates appear to be comparable to independent single-center reports, one of which
shown on the right side was published in 2013.
In short, the perforation and effusion rate is in line with the latest reports of
traditional pacemaker procedures, and the overall safety profile shows that Micra patients,
although older and sicker, fared favorably with a significant reduction in complications.
Next, FDA has asked to identify any patient subgroups that may have increased risk
of adverse events with leadless pacemakers. To address this important question, we looked
at all major complications against multiple subgroups by age, gender, and comorbidities. As
you can see in this forest plot, no matter what group we analyzed, patients with Micra fared
at least as well as those with traditional pacemakers. No subgroups experienced increased
risk of complication, and most subgroups appear to have done better with Micra.
Regarding FDA's question on physician training, Medtronic's training program, at
launch, is designed to ensure that physicians will be competent to safely perform the
procedure. Physicians will also be informed about potential adverse events and appropriate
device and patient selection. This will be done through Medtronic's program, which
includes both a structured online program as well as in-person training identical to the one
conducted in the clinical trial.
For the procedural learning, Medtronic will utilize one of two methods, one in the
training lab and one in the implanter's hospital. In the lab, implanters will train on animals,
73
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
cadavers, or both. And, in addition, they'll also train on simulators. In the hospital,
implanters will have hands-on training with a simulator as well as being proctored by an
experienced implanter.
Specifically, as was the case during the trial, first implanters at each institution will
be trained in the training lab, and following, implanters will be trained in their hospital. We
know this training approach works because it led to the outstanding results we saw in the
clinical trial. And as you can see in the graph, there were low and similar complication rates
with both training groups.
We also observed no learning curve for implanting physicians with regard to
complications. To illustrate this point, we saw that the acute risk of major complications
was low for the implanter's first 10 procedures and remained low after the first 10
procedures. And as mentioned, these results occurred in a diverse group of 94 implanters
in a first-in-human application of this technology, with an overall 99.2% implant success
rate. These data convey confidence that the proposed training program will ensure
physicians are appropriately trained to safely implant Micra beginning with their first case.
I'd like to conclude my portion of this presentation by taking a step back and asking a
simple but very important question. Has this new technology accomplished what it was
designed to do? As good as transvenous pacing has been, complications clearly exist. Micra
was specifically designed to eliminate the major ones, lead- and pocket-based complications
such as infections and vascular occlusions.
As you can see in this table from the trial, Micra has decreased or eliminated the
short-term complications. But even in the long term we anticipate reductions in infections
74
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
and venous obstruction, and we've certainly eliminated Twiddler's syndrome and lead
fractures and lead insulation breaches. We also expect that tricuspid valve injuries will be
substantially less likely. Finally, as I've shown, Micra met its primary efficacy and safety
objectives with wide margins.
In my 36 years of cardiac electronic device experience, there have been few
technological advances that I would characterize as transformational for patient care.
Based on its design and the strong clinical trial results, I believe Micra represents that
transformation.
Thank you all for your time.
DR. STEINHAUS: Well, thank you, Dr. Reynolds.
I'd like to continue with the FDA's second question, which focuses on post-approval
requirements for the assessment of acute and long-term performance of this technology.
Given the FDA's guidance to estimate precisely acute or long-term individual complications
occurring at rates as low as 1%, the required sample size would be 1,895 patients enrolled.
Given the estimated attrition rates of this population, this sample size would allow at least
1,000 patients to be followed for a minimum of 5 years, and 500 to 800 patients followed
for 8 years. We've proposed broad inclusion criteria to mimic real-world clinical experience.
The second part of FDA's question on post-approval requirements is focused on what
happens when a device is depleted or deactivated if a patient needs an upgrade. If we want
to characterize these rarer events, we have to look beyond a traditional postmarketing trial.
We will leverage, in addition, our entire database of U.S. implants. Every patient who
receives a Medtronic pacemaker or defibrillator in the United States is entered into a
75
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
registration system.
If a subsequent device has been placed and Medtronic has been contacted, the
implanting -- I'm sorry. If a subsequent device has been placed and the Micra has been
deactivated or explanted, Medtronic would then contact the implanting center and request
the patient's clinical data surrounding the revision. We would then be able to summarize
the type of system revision, including how extraction is attempted, the success rate, and
report any associated complications. We estimate that with this approach, we can
characterize 250 events within 5 years.
Now, turning to FDA's question on device end-of-life or end-of-service options, the
FDA has asked us to comment on what should be addressed in labeling regarding
extractions, replacements, and best practices. To answer that question, we need to
highlight a few important points for context.
First, one Micra will be sufficient for the majority of patients. Second, for those who
need to have their devices replaced, Medtronic recommends leaving Micra in place, turning
it off, and implanting a new device. After all, Micra is less than one cubic centimeter, is
expected to be completely encapsulated, and similar to other devices such as coronary
stents, it can be left in situ. Regarding the rare need for an extraction, this should be done
only when necessary, before complete encapsulation, and should be performed by
someone skilled in traditional lead extraction.
I would like to explain why Medtronic's primary recommendation is to leave the
Micra in place. Micra takes up only 0.5% of the volume of the right ventricle. As you can
see in this picture of a cadaver heart, multiple Micra devices can easily be left in place.
76
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
Again, complete encapsulation is expected, which actually may protect against infection.
Once Micra is turned off, other devices can be safely implanted. In our clinical experience,
five patients had devices successfully placed alongside Micra.
Regarding extractions, Micra was designed with a retrieval feature at the proximal
end. This enables removal by a standard percutaneous snare. Our current experience
shows that there have been a total of nine attempts to remove Micra, all percutaneously.
All seven that occurred within the first 6 months were successful, and a new device was
placed after removal. The two attempted retrievals that occurred after 6 months were
unsuccessful. In both cases, the physician decided to turn Micra off, leave it in place, and
add a new device. There were no adverse events associated with these retrieval attempts.
Turning now to FDA's questions on indications for use. Here, the FDA has asked a
number of questions about appropriate use of this device. You've seen them in the Panel
packet. We would like to propose a relatively straightforward approach. Since Micra VVIR
pacing therapy is the same as any traditional single-chamber ventricular pacemaker,
Medtronic believes the indication should simply be the same as is indicated on this slide.
Our experience in the clinical study showed that physicians were consistent with
guideline recommendations. Most patients had bradycardia associated with permanent or
persistent atrial tachycardia or fibrillation. This is a Class I guideline recommendation for
VVIR pacing. For patients who could be considered for dual-chamber devices, investigators
had guideline-recommended reasons for receiving VVI pacing, such as advanced age or the
infrequent need for pacing.
To specifically address the FDA's question on pacemaker syndrome, we observed
77
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
that only one patient in the Micra trial experienced a major complication associated with
this condition.
I would now like to sum up for some final takeaways. Years of extensive engineering
and research work and a robust clinical program have resulted in Micra meeting its efficacy
and safety objectives by wide margins. Even with older and sicker patients, Micra was able
to reduce or eliminate the common complications of traditional pacemakers. We are
confident, through our comprehensive training program, which was proven successful in the
clinical trials, that physicians will be sufficiently trained from their first implant. And we are
committed to partnering with the FDA in providing essential and precise real-world
performance data in the most timely manner possible.
In closing, Medtronic was founded on the principle of collaboration between
physicians and engineers in the service of patients. This is our mission. We understand
what Micra can mean for patients, and we as a team are proud to be part of this continuing
history of innovation.
As with all our therapies, we also understand and are committed to the need for
careful follow-up. The picture on the right is our very first Micra patient, and I'm happy to
report that 2½ years later, he's doing very well. And by the way, I should note that it's
interesting. Our first U.S. patient was implanted literally 2 years ago today, which is really
quite a compliment to the FDA for getting this done so quickly. We'd like to extend our
thanks to our patients and the engineers and doctors involved in this project, as well as the
FDA for their leadership and partnership.
Last, I want to do one other thing, which is acknowledge our vice president and
78
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
general manager for pacing at Medtronic, Brian Urke, who unfortunately cannot be here
today because he's fighting recurrent leukemia. Our thoughts are with him.
So thank you for your attention and time. We look forward to your questions.
DR. PAGE: Thank you very much.
I'd like to now to ask if the Panel has any brief clarifying questions. We have 15
minutes for this section.
Dr. Kandzari.
DR. KANDZARI: Thank you for your presentation. Actually, the previous speaker
highlighted one of or introduced a question that I had about the experience that you've had
to date with this technology outside the United States. I realize it's been an abbreviated
time, less than 1 year since CE mark approval, but it sounded as if there's a continued
surveillance or registry with data regarding that. And we heard, I think, very briefly an issue
about a very low perforation rate. But in your clinical trials experience, you demonstrated
no evidence of dislodgement or embolization, and I wondered if that still holds true to date
because, I think, in real-world practice we should anticipate something like that.
DR. STEINHAUS: What we know about in our total experience from Europe and the
United States is that there have been no dislodgements, you know, or embolizations. There
has been one infection, and that was in Malaysia. It was removed, the device was removed
at 45 days without trouble.
By the way, Dr. Page, if you'd like, I wrote down some of the questions the Panel had
asked before. If you'd like me to go through those quickly, I can do that, or we can wait
until later.
79
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
DR. PAGE: For now let's save those, and let's see if there are specific clarifying
questions from the Panel now, just during this period of time.
DR. STEINHAUS: Okay.
DR. PAGE: I see Dr. Borer, Dr. Brinker, and Dr. Lange.
Dr. Borer.
DR. BORER: Thank you. Thank you, that was a really nice presentation. I want to
focus on the perforation issue. And I hope that Dr. Naftel will listen closely to puncture my
balloon because there may be a statistical error here. But as I looked through the data, I
did a calculation a few days ago. I don't think it's quite reasonable to say there's no
statistically significant difference between this rate and that rate when the number of
events is relatively small and therefore, gee, there's no difference here. There is a
difference, and in a superiority analysis, no significant difference really isn't what we're
interested in.
So I looked at all the studies that you noted in your presentation where transvenous
-- conventional transvenous systems were used. There were 7,255 patients. And I won't go
through the kind of calculation I did, but I found that risk of a perforation was 0.02% per
patient. When I went through the same calculation with the admittedly far fewer data with
Micra -- so there's a lot more variability -- I found a rate of 0.22% likelihood of perforation
per patient. That's a 10% difference. Tenfold. I'm sorry, a tenfold difference, which seems
to me to be, you know, a little bit of a concern.
I agree with what Ken Stein said earlier. For this extraordinary technology to be
applied as widely as I think it can be and probably should be, the bar is the safety. It's got
80
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
to be at least as safe as conventional methodology. And the biggest concern, then, that I
have is perforation. So, you know, maybe you can respond to this, and of course, it's hard
for you to do that because you don't have my calculation method in front of you.
DR. PAGE: Dr. Borer, I might ask that we not ask them to respond to that
specifically. We have another presentation to go, and I think we need to look at the
frequency of perforation in total. So I think it's a very important point. Let's put that on
hold for now. I'm not going to call on Dr. Naftel because when we do close for lunch, I
might ask for an analysis that can kind of help fold this all together. Is that okay with you,
Dr. Borer?
(Off microphone response.)
DR. PAGE: Thank you.
Dr. Brinker.
DR. BRINKER: Two short questions. In the indications, do you particularly screen for
people who might develop a ventricular dyssynchrony, and knowing that right ventricular
pacing would be -- can be a cause of that, where it wasn't present before?
And, number two, which is more to the point, in that one case of infection, was the
retrieved device actually infected?
DR. STEINHAUS: As best we know, it was infected.
So, Dr. Kowal, do you want to answer that question about selection of patients?
DR. KOWAL: Rob Kowal from the Baylor Health Care System, Baylor Scott & White
Health Care.
I can best answer by how we handled this at our clinical center, and that is, as you
81
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
alluded to, we have ideas as to which patients fare better or worse with right ventricular
pacing. We chose a subset of patients who we would choose for typical VVI and not need
CRT in general. So if we had a suspicion that they would need CRT instead of typical VVI
pacing, we did not enroll them in the study.
DR. BRINKER: But you would accept the fact that you don't really know whether
they develop a problem until they become 100% VVI pacing?
DR. KOWAL: That is true.
DR. BRINKER: Did you ever have to upgrade?
DR. KOWAL: We did not. And, in fact, there was only one patient in the entire study
that needed an upgrade specifically because of a pacemaker syndrome.
DR. BRINKER: Thank you.
DR. KOWAL: Or similar situations.
DR. PAGE: Dr. Lange.
DR. LANGE: Two questions. The issue of implanter training and number of
procedures will be an issue we discuss later, and I couldn't tell either from your slides or
from the background material that you all presented -- by the way, your presentation was
very good, but I couldn't tell how many of the physicians, implanting physicians, had done
10 or more procedures, and I'm wondering if sometime during the break, if we could do
that.
And my other question relates to the complication risk with both training
methodologies. And it's hard for me to tell which slide is page 15 of our presentation, but
there was no difference between the training lab and a hospital. There were 483 patients in
82
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
those studies, but there are 725 reported in the study. So I'm not sure if we can update
that to show all 725 patients and whether they were done within the training lab or the
hospital. I don't know if that's available or not.
DR. STEINHAUS: I will certainly look into that and see if I can find it.
DR. LANGE: I appreciate it.
DR. PAGE: Thank you.
Dr. Zeitler.
DR. ZEITLER: Yes, I have two questions. The first is related to the risk factors
associated with the effusion and perforation. I see that both sex and BMI were examined,
and I wonder if there was any assessment of interaction between the two or if those were
independent. And the second question is related to remote monitoring. I didn't see any
mention of that in the presentation or in the background materials, and now that we have
authoritative recommendations about how to use remote monitoring, I'm wondering how
that played into the study that has been conducted and how that could be leveraged as part
of a post-approval examination of the technology.
DR. STEINHAUS: Would you like to answer the question about -- the statistical
question, Kurt? So I'd like to bring our statistician up to tell you about that.
MR. STROMBERG: Hi. Good morning. Kurt Stromberg. I'm the senior principal
statistician at Medtronic.
And in terms of the multivariate analysis, with only 13 events, it was actually quite
hard to do a multivariate analysis. One of the things we did find is body habitus is quite
confounded with sex. So it was really hard to tease those two things apart.
83
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
DR. PAGE: Thank you.
I see Dr. Cigarroa has a question. I just want one other -- to ask one clarifying
question myself.
Dr. Steinhaus, you mentioned that there have been five cases where the leadless
pacemaker was implanted in the setting of another leadless pacemaker left in place, and
that's news to us. Is that correct?
DR. STEINHAUS: No, that's incorrect. We've had five patients who had leadless
pacemakers where another lead was implanted.
DR. PAGE: It's where another lead was implanted.
DR. STEINHAUS: We don't have any patients who have more than one leadless
pacemaker.
DR. PAGE: Okay, so I misheard you. In the two cases where the device could not be
extracted and was attempted, in those two cases a standard transvenous lead was placed?
DR. STEINHAUS: That's correct.
DR. PAGE: Okay, thank you.
Dr. Cigarroa.
DR. CIGARROA: Thank you. Do you have any data about how dual antiplatelet
therapy was managed in these individuals and whether there was any difference in patients
who developed effusions and/or tamponades?
And then, secondarily, how was guidance provided regarding antithrombotic
therapy, percentage that may have been bridged or not bridged, and whether any of these
cases were done on warfarin or not?
84
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
DR. STEINHAUS: I don't right now have any data on the dual antiplatelet question. I
do have data on the number of patients who were anticoagulated, and I think if it serves me
right, I think 28% were on anticoagulation at the time of the procedure. That could either
be Coumadin or NOACs, or in some cases, some physicians elected to use heparin at the
time of the procedure.
DR. PAGE: Dr. Kandzari.
DR. KANDZARI: I just have a quick question for my own clarification. As I prepared
for this meeting, it's puzzled me that, in theory, if you had two of these devices -- and I
think this is relevant for all of the presentations -- do you have enough fidelity to turn one
off then, and then turn the other one on and manage them separately?
DR. STEINHAUS: Yes.
DR. KANDZARI: Okay, thanks.
DR. PAGE: Maybe you can expand on that for the audience and the Panel.
(Laughter.)
DR. STEINHAUS: The telemetry will know which device is which one, and we'll be
able to program one off and then one on. I think that's what you were getting at.
DR. KANDZARI: Yes, thank you.
DR. STEINHAUS: Okay.
DR. PAGE: Thank you very much.
DR. STEINHAUS: Is that sufficient?
DR. PAGE: Yes, that's perfect. Thank you very much.
Dr. Karasik.
85
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
DR. KARASIK: Thank you. I have a couple of short questions. First, could you tell us
why the two devices were removed late? What was the indication --
DR. PAGE: I'm sorry, I can't hear you.
DR. KARASIK: Could you expand on what the indications were for removing those
two devices late in the --
DR. STEINHAUS: I think Dr. Hummel's kind of pretty aware of those two patients, so
I'm going to ask him to do that.
DR. KARASIK: Okay.
DR. HUMMEL: John Hummel, Ohio State University.
The two patients that underwent late retrieval were anticipated to undergo
transvenous placement, and the operators felt that they wanted to remove the device.
Now, we would recommend leaving the device in place. So I can't speak exactly as to what
their motivation was to remove it. The first one was snared at 220 days post-implant, but
the physician was uncomfortable with applying too much tension, elected to turn it off and
abandon it and leave it in place. A transvenous system was subsequently implanted. And
then the second retrieval attempt, again, the Micra was able to be snared, but the
fluoroscopy system failed. And so they elected, for obvious reasons, not to go any further
and a bi-V pacemaker, a CRT pacemaker, was implanted.
DR. PAGE: Dr. Hummel, if you could expand just for a moment. The indication for
those two replacements of the device was what again?
DR. HUMMEL: The first one, I believe, was high thresholds. I'm not absolutely
certain on that, but I believe it was. And the second was pacemaker syndrome and RV
86
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
pacing cardiomyopathy, so a CRT pacer was implanted.
DR. PAGE: I see. Thank you very much.
I saw Mr. Frankel and then Dr. Brinker and Dr. Karasik.
MR. FRANKEL: First of all, I just want to know, regarding the training for extraction
method, I saw that regarding implantation. But in the scenario where there is extraction
that's necessary, what's going to be the training protocol for that?
And another thing is knowing that there has been an incidence of infection and
there's been failure in terms of extraction after 6 months, what's the outlook in terms of
patients that find themselves where there's infection after 6 months?
DR. STEINHAUS: Those are both very good questions. The first question about
training is that we do have a training module and a modular system to be able to show
them how to use the snares and how to use the end product. Most of these are standard
snares that people have used before for the same sort of purposes, but they'll be trained on
that.
The second question about infection is actually interesting. We think once the thing
becomes totally endothelialized, it's going to be less susceptible to infection. I can't tell you
that for certain because I don't have any good data on that and no one does, but that
certainly is a possibility as stents are and other devices that are left in the body are. In
terms of this particular procedure, this was about 45 days after, so it would be sort of more
in the acute phase before you'd expect to see full encapsulation and endothelialization. So
that's kind of where we are. I think that is an open question. I think it's possible that there
will be infections and that certainly there will be late infections, and they'll have to be dealt
87
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
with. Either we'll have to try to extract them if we can, or if we can't extract them, it will
have be done surgically or managed with chronic antibiotics.
DR. PAGE: Thank you.
Dr. Karasik, a very brief clarifying question, please.
DR. KARASIK: Very brief. Did any patients in the clinical trial require cardioversion
over the course of their follow-up?
DR. STEINHAUS: Yes, I think there have been three cardioversions. How many?
(Off microphone comment.)
DR. STEINHAUS: Six. There have been six cardioversions, and they've all been no
problem.
DR. PAGE: Thank you.
And the last clarifying question from Dr. Brinker.
DR. BRINKER: Yes. My understanding is your device has a sort of active fixation
mechanism, that is, it extrudes and goes under the endocardium. When you say you snare
them, is pulling on the snare a method of retraction of the tines, or you just pull it out?
DR. STEINHAUS: You just pull it out. That's why I said the most interesting design
feature, I think, of the device is actually the fixation, because you wanted enough power to
hold the thing even if you only engage two of the four tines. Yet, on the other hand, if you
want to be able to pull it back and reposition it, you want it to pull out. So it's more like a
spring and pulls out and then it would be --
DR. BRINKER: Pulls out straight?
DR. STEINHAUS: Yes.
88
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
DR. PAGE: Now the last brief clarifying question from Dr. Lange.
DR. LANGE: In your supplemental data, background data on page 34, you have a
detailed listing of cardiac effusions and perforations. You list where the final Micra location
is. On four of those it shows NA, traditional. If over the break, you could clarify where
these were placed and what that means.
DR. STEINHAUS: The ones where it says NA, Table 8. Okay.
DR. LANGE: Thank you.
DR. STEINHAUS: We'll look at that.
DR. PAGE: So we're going to close this part of the discussion. I thank Medtronic very
much for a very clear presentation. During this discussion a number of questions were
starting to be generated, and I'll try to summarize these just to give a heads-up in terms of
the next presentation, and more likely, after lunch, if you wouldn't mind working on this.
There's been the question that Dr. Lange just had about location of the device placement;
and there's been the issue of anticoagulation and how that was handled; an issue of
training, specifically in your training algorithm -- Medtronic now -- the differences between
possibly a hospital and the non-hospital training; the issue of perforation and statistics that
was brought up by Dr. Borer.
And I'm going to look for -- perhaps you're making your question clear, along with
Dr. Naftel and with the representatives from St. Jude, when we -- after we've heard their
talk, so we can really pin this down. And finally the issue of, again, Dr. Lange's question
about procedures. We saw the data from Medtronic. The issue of the learning curve, I
think, still needs to be explored, and that's something we'll at least want to talk more about
89
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
and have a better understanding of that. And I think Dr. Lange specifically asked about
those individuals who had done -- why don't you restate it for me, please, Dr. Lange.
DR. LANGE: One is to include data on all 725 patients, and the other is how many
physicians had done 10 or more procedures. Thank you.
DR. PAGE: Great. Thank you. And I'll now turn this meeting over to the next
presentation. This is going to be the presentation by St. Jude. I will remind that at the
conclusion of the presentation, Panel members will have an opportunity to ask questions.
And I believe you're anticipating an expectation of 25 minutes, Dr. Carlson.
Welcome.
DR. CARLSON: Mr. Chairman and distinguished members of the Panel, good
morning. My name is Mark Carlson, and I am the Chief Medical Officer and Vice President
of Global Clinical Affairs at St. Jude Medical. On behalf of St. Jude, I would like to thank the
FDA and the Panel for your time and effort in convening this meeting to discuss the
breakthrough technology of leadless pacemakers. And I'd like to go off script for a moment
and thank the FDA for what I thought was an excellent presentation this morning.
The Nanostim leadless pacemaker was designed to address issues associated with
conventional pacemakers, including discomfort, cosmetic concerns, hematomas, and
infections. In addition, pacemaker leads are at risk for fractures and abrasions, and they
can become infected, requiring extraction, which is associated with risks, including death.
Finally, mobility is restricted, particularly in the weeks after implant.
Now, how often do these complications really occur? These are data from the
FOLLOWPACE study, which you've heard about earlier today, published in 2012, which
90
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
included more than 1,500 patients receiving single-chamber and dual-chamber pacemakers.
The Kaplan-Meier curve shows that just 2 months after implant, the complication rate was
12.4%, and in subsequent years, an additional 10% of patients experienced chronic
complications. These types of problems inspired the development of the leadless
pacemaker.
The design of the Nanostim leadless pacemaker accounted for each of these issues.
Before I describe the device, you will notice a box highlighting one of FDA's specific
questions. You will see this throughout the presentation.
The Nanostim device is approximately 42 mm long, 6 mm wide, and can be delivered
through an 18 French introducer in the femoral vein. The device is fully self-contained. The
battery, the electronics, and the pacing element are all within the device. It provides
traditional single-chamber pacing therapy in patients clinically indicated for VVI or VVIR
pacemaker therapy. Yet, the device has many of the features that are available in
conventional pacemakers. It has a single-turn helix and stabilizing nylon tines for secure
fixation. It includes a steroid-eluting electrode, as is standard with conventional
pacemakers. It could be programmed to be rate responsive. It has a substantial battery
life. And as you can see in the picture, the back of the device has a docking button that
allows for percutaneous delivery, acute repositioning, and retrieval if needed. The
Nanostim leadless pacemaker also has magnet mode to assess battery longevity, and the
device is MRI compatible.
The steerable catheter is advanced through the tricuspid valve into the right
ventricle. The right ventricle is opacified to identify the desired implant location. The
91
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
protective sleeve is retracted, and the device is advanced to the endocardium. The desired
device position is confirmed in the right and left anterior oblique views. The device is then
affixed to the endocardium with one full rotation. A deflection test is performed to ensure
the integrity of fixation. After assessment of electrical measurements, the pacemaker is
released from the delivery catheter.
For today's presentation, Dr. Vivek Reddy will present results from the Nanostim
leadless pacemaker pivotal trial, called the LEADLESS -- pardon me, the LEADLESS II study.
Dr. Reddy is a Professor of Medicine and Cardiology at Mount Sinai Hospital in New York
and was the principal investigator of the study. Following Dr. Reddy's presentation, I will
return to discuss learnings from the European Union postmarket study, the proposed post-
approval study, and the training program. In addition, we have invited subject matter
experts to answer any questions you may have. These include Dr. Paul Friedman, who is
Director of Implantable Devices, Professor of Medicine, Mayo Clinic, Minnesota; and
Dr. Joshua Cooper, Director, Cardiac Electrophysiology and Professor of Medicine at Temple
University, Pennsylvania; as well as two of my colleagues from St. Jude Medical. All of the
experts invited today have been compensated for their time in preparing for this meeting.
Thank you. Dr. Reddy will now present key data from the trial.
DR. REDDY: Thank you, Dr. Carlson. Good morning.
The LEADLESS II clinical trial is a prospective, multicenter, non-randomized trial of
patients indicated for single-chamber right ventricular pacing. This ongoing study is being
conducted at 56 centers in the United States, Canada, and Australia, including a total of 100
operators. I should note that only one of these 100 operators had prior experience with
92
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
leadless pacing before participating in this study.
Six hundred and sixty-seven represents our total sample size. Most of the data we'll
present today are based on a pre-specified analysis of the first 300 patients followed for 6
months and additional data published in the New England Journal of Medicine in September
of 2015.
In discussing the data, I'll refer to two cohorts, the primary analysis cohort and the
total cohort. The primary analysis cohort includes the first 300 consecutively enrolled
patients with 6 months of follow-up. The device was implanted and followed in 289 or 96%
of these 300 patients. At the time of the database cutoff for the manuscript, we also had
data on an additional 226 patients with less than 6 months of follow-up in which the device
was successfully implanted in 95%. Combining these 226 patients with the primary cohort
of 300 patients yields the total cohort of 526 patients.
These are the key patient demographics. The primary cohort is in the middle
column, and the total cohort is on the right. The mean age was approximately 76 years, and
approximately 40% of these patients enrolled were women. The patients had a range of
comorbidities; 40% had coronary disease, 80% had hypertension, and 27% had diabetes. I
want to highlight that about 60% of the patients were taking oral anticoagulants, and 47%
were on antiplatelet therapy. So, overall, this is an elderly population with significant
comorbidities, not surprising for a cohort indicated for single-chamber ventricular pacing.
These are the key procedural characteristics. The Nanostim leadless pacemaker was
successfully implanted in 96% of the patients. The majority of the patients, 70%, were
successfully implanted at the first endocardial site attempted, that is, without the need to
93
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
reposition the device. In the remaining 30%, the device was repositioned at least once,
which is similar to the experience with traditional pacemaker leads. The device was placed
in the septum in the majority of the patients. Now, based on early experience, St. Jude
Medical recommended septum implantation when possible. Accordingly, we can see that
the proportion of patients or the proportion of devices implanted in the septum, relative to
the apex, shifted over the course the study.
The primary effectiveness endpoint was defined as a combination of acceptable pace
capture threshold and acceptable sensing amplitude at 6 months. The primary safety
endpoint was defined as freedom from serious adverse events through 6 months. Both of
these endpoints were achieved, as demonstrated by the p-values displayed here.
In this slide we present the adverse event rates for the primary cohort as well as the
total cohort. You can see that the event rates are similar (6.7% and 6.5%). So let's focus on
the total cohort as we review these adverse events.
Cardiac perforation occurred at a rate of 1.5%. Vascular complications and device
dislodgement each occurred at a rate of 1.1%. And elevated pacing threshold elevation
occurred at a rate of 0.8%. Other events occurred in 2.5% of patients. These occurred at
lower frequency and are listed below.
Now, let's take a closer look at these first four categories. Of the eight patients
adjudicated as having cardiac perforation, three required surgical intervention while two
were drained percutaneously. The remaining three patients did not require
pericardiocentesis. One of these patients ultimately received a traditional pacemaker. The
vascular complication rate is in line with other similar percutaneous procedures.
94
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
When it occurred, device dislodgement was identified in the early postoperative
period. In each case the device was retrieved percutaneously and either a new leadless
pacemaker or a traditional pacemaker was placed. There were four cases where pacing
threshold elevation was noted and device replacement was indicated. In all of these cases,
the Nanostim was retrieved percutaneously and replaced with a new Nanostim device.
Here's the Kaplan-Meier analysis of freedom from serious adverse device effects for
the total cohort. As you can see, all SADEs occurred within the first 2 weeks of the
procedure. There were no late SADEs, at least up to the 360 days of follow-up.
Sorry, my clicker is unhappy. Let's put these device adverse effects in context with
traditional pacemaker rates. In the bar graph, in blue, you see the 6-month follow-up data
for the Nanostim total cohort. For comparison, in red, you see the 2-month follow-up data
for the FOLLOWPACE study discussed by Dr. Carlson in his introductory remarks. Vascular
access events occurred approximately five times as often as with traditional pacemakers.
The dislodgement rates, device or lead, were similar, as were electrical issues related to
pacing or sensing. The cardiac perforation rate was higher with the Nanostim device. While
this difference is certainly important, there are two key mitigating factors. First, while the
perforation rate for the standard pacemakers in the FOLLOWPACE study was only 0.3%,
remember that many other studies have reported higher perforation rates, ranging as high
1% to 1.5%. And, second, the other major traumatic complication of pacemaker
implantation, pneumothorax, occurred 10 times more frequently with the traditional
pacemaker.
Furthermore, there were three additional groups of adverse events that only
95
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
occurred with traditional pacemakers, at least in the first 2 months reported in the
FOLLOWPACE study: pocket-related complications like hematomas, lead-related
complications such as diaphragmatic or pocket stimulation, and infections, whether related
to the pocket or the lead.
Together, these data indicate that the Nanostim leadless pacemaker does have an
acceptable safety profile.
This slide focuses on deaths that occurred during the study. Overall, 28 patients
expired over the course of the study. None of these occurred during the procedure.
Twenty-five were related to the procedure or the device. The remaining three -- I'm sorry.
Twenty-five were not related to the procedure or the device. The remaining three deaths
were adjudicated as procedure related. I'm going to go through these in detail.
One patient with cancer sustained a respiratory arrest due to airway constriction
during the implant attempt. Pacemaker implantation was abandoned. The patient required
tracheotomy and mechanical ventilation, was ultimately made DNR, and expired 14 days
later.
The second patient had a successful implant but sustained a large right groin
hematoma with a three-point drop in hemoglobin. The patient was discharged to home
without transfusion and 2 weeks later was found unresponsive and expired.
The third patient's right atrium was perforated during the implant attempt, and he
developed atrial fibrillation. Two days after the attempt, he experienced a large right
middle cerebral arterial stroke and ultimately expired.
Together, these three deaths constitute a procedure-related mortality rate of less
96
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
than 1%.
For the composite safety endpoint, an analysis was performed to determine if any
factors might predict serious adverse effects. Statistical modeling was conducted for these
explanatory variables. As shown in this forest plot, the 95% confidence intervals do include
1 for all of these factors, indicating that none of these factors were statistically significant
predictors.
Another important feature of the device relates to retrievability. In this animation
you see the custom Nanostim snare aligned with the docking button. The operator closes
and locks the snare around the docking button, mates the retrieval catheter with the
pacemaker, brings the protective sleeve halfway over the pacemaker, and with the
fluoroscopic guidance unscrews the pacemaker. Once the pacemaker is fully unscrewed,
the protective sleeve is advanced to fully cover the helix, and the entire system is removed.
Retrieval is important over the lifetime of the device for the following reasons: end of
service, device upgrade, infection, elevated thresholds, and patient preference.
Seven patients underwent device retrieval, on average 160 days post-implant and
ranging between 1 and 413 days. The reasons for retrieval are shown here: four because of
elevated pacing thresholds, two for CRT upgrade, and one elective explant. All retrievals
were successfully accomplished without serious adverse device effects.
To summarize, the device was successfully implanted in 96% of the patients, and the
pre-specified safety and effectiveness endpoints were achieved. Complication rates were
similar to those observed with traditional pacemakers without many of the risks that are
inherent with conventional pacemakers with leads. Again, recall that 99 of the 100
97
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
operators in this study had never implanted a leadless pacemaker prior to participation in
this study. Also, early experience demonstrated that the device is safely retrievable
percutaneously.
Thank you. I'd now like to invite Dr. Carlson back to the lectern.
DR. CARLSON: Thank you, Dr. Reddy.
I will now discuss learnings from the ongoing European Union postmarket study in
which we continue to enroll and monitor patients and their devices, the proposed U.S. post-
approval study, and the training program for physicians who wish to implant the Nanostim
leadless pacemaker.
This slide summarizes learnings from the European Union postmarket study that
started enrolling patients in December 2013. Based on review of data from the first 147
implants, we enhanced the patient selection criteria, required high-resolution fluoroscopy,
recommended septal rather than apical implants whenever possible, and enhanced the
training program.
This slide shows serious adverse device effects in the European Union postmarket
study before and after enhancements were implemented. You can see that after
implementing the enhancements, the rates of cardiac perforation and device dislodgement
decreased considerably.
Now I would like to describe our proposed U.S. post-approval study. The post-
approval study will be a prospective, non-randomized, multicenter study designed to
evaluate the long-term safety of the Nanostim leadless pacemaker and end-of-service
management. Data collected will help to characterize acute and long-term safety as well as
98
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
patient management at the time of device replacement or deactivation. The primary
endpoint of the study is freedom from complications.
The post-approval study will collect data at implant, pre-discharge, 2 weeks post-
implant, and every 6 months thereafter, up to 7 years post-implant. As stated previously,
data will be collected at the time of device retrieval or deactivation. The sample size of
1,700 patients is driven by the intent to adequately characterize adverse events. This
design allows for early and late adverse events to be estimated within a 90% confidence
interval width of 1%. The study will include patients currently participating in the LEADLESS
II study as well as newly enrolled patients.
In addition to our post-approval study, we will have -- we have developed a
Nanostim physician education and training program. The training program will be
mandatory and is similar to the LEADLESS II IDE study training programs with revisions
based on key learnings from that study and the global experience.
To participate in the training program, physicians must demonstrate qualifications
for implanting pacemakers and have an established practice affiliation with an institution
that has resources to support leadless pacemaker implantation. Centers must also have
high-resolution fluoroscopic equipment and proper emergency facilities to manage
potential complications.
There are seven modules that must be completed. Didactic training will cover the
system components, handle operations, procedural overview, patient selection, specific tips
for optimizing outcomes, a review of the clinical study data, and a discussion of best
implant and retrieval practices. Hands-on training will include an implant demonstration,
99
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
animal lab training and/or virtual reality training, which I will describe in more detail on the
next slide.
In addition, physician trainees will view a video compendium that reflects worldwide
learnings using fluoro images and cines to demonstrate correct and incorrect implant and
retrieval techniques. The Nanostim virtual reality system allows physicians to experience
the catheter handle functions and appropriate use, the correct implant procedural
sequence, and correct and incorrect use of the system, with special emphasis on how to
avoid complications. Physicians use tools identical to those used in the actual procedure.
The system provides visual feedback that is representative of a human case, including
warning messages when the operator does not employ correct technique.
The final training step is site training, on-boarding, and live or recorded case
observation, followed by Nanostim human implants with in-case support provided by
personnel certified by St. Jude Medical. Upon successful completion of all required training
steps, the physician will receive certification from St. Jude Medical for Nanostim leadless
pacemaker system management.
In summary, the benefits of the Nanostim leadless pacemaker are apparent, and the
rates of certain acute complications are in line with those of traditional pacemakers. In
addition, there were no serious adverse device effects after 2 weeks, and there was an
absence of certain complications that occur with traditional pacemakers. A robust training
program will support safe use of the Nanostim leadless pacemaker upon commercialization,
and event rates will continue to be monitored in post-approval studies to ensure this
balance remains favorable.
100
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
Thank you for your time and attention. I'm happy to address any questions you may
have.
DR. PAGE: Thank you for that very clear and concise presentation.
I'd now offer the opportunity for the Panel to pose any brief clarifying questions.
We have 15 minutes. I see Dr. Cigarroa and Dr. Brinker, Dr. Zeitler, and Dr. Yuh.
DR. CIGARROA: Can you clarify, on the four patients that had an elevation of pacing
threshold, what was the timing for each of those in terms of the change of thresholds?
DR. CARLSON: You know, I've got the timing for all the patients, and we may be able
to pull that up. I can't, off the top of my head, tell you about those.
DR. CIGARROA: This afternoon would be fine.
DR. CARLSON: Great. The range was between 1 and 413 days for all of the
retrievals.
DR. CIGARROA: The question would be as to the proposed mechanism, and that is
potential movement acutely without embolization and/or dislodgement --
DR. CARLSON: Sure.
DR. CIGARROA: -- versus the development of scarring and other mechanisms.
DR. CARLSON: I can tell you that none of them had dislodged or had appeared to
have dislodged. So we'll come back this afternoon. Thanks so much.
DR. PAGE: Dr. Brinker.
DR. BRINKER: Just a couple more general questions, and that is, are these devices
programmed by the usual programmer, and is there a special place to apply or a header to
use to interrogate these devices?
101
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
DR. CARLSON: Standard programming, and unless I'm mistaken, there's a standard
wand that's placed over the chest.
DR. BRINKER: So the next question is, is the software capable of doing this going to
be imported or downloaded or inserted into programmers across the country once the
device is approved, assuming it will be?
DR. CARLSON: We certainly intend to include this in programmers.
DR. BRINKER: Regardless of whether -- right, regardless of whether they were
implanting?
DR. CARLSON: Yes, it will be included in our standard programmers.
DR. BRINKER: Finally, is there technology built into the device that will accept
evolutionary changes in software, including perhaps interaction with other devices?
DR. CARLSON: A very good question, and I'm going to ask Mr. Hubbard if he can
address that. We certainly have the intent to develop, and we're working on a dual-
chamber device.
MR. HUBBARD: Thank you, Mark.
Could you repeat the question, please?
DR. BRINKER: So are the devices, as they exist, capable of evolutionary change via
software to allow --
UNIDENTIFIED SPEAKER: Software upgrades.
MR. HUBBARD: Yes. Yes, absolutely.
DR. BRINKER: -- it to interact with other --
DR. PAGE: Mr. or Dr. Hubbard, please state your full name.
102
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
MR. HUBBARD: Oh, I'm sorry.
DR. PAGE: Thank you.
MR. HUBBARD: Chris Hubbard. I'm the Vice President of Nanostim Technology for
St. Jude Medical.
So I'm sorry, I misunderstood your question. So no. In terms of being able to
upgrade present devices so that they could communicate with another device, I cannot with
surety at this point say that that's the case. As Dr. Carlson mentioned, we are, however,
working on devices in the future that will be able to communicate with other multiple
Nanostim devices placed in other chambers.
DR. BRINKER: Thank you.
DR. PAGE: Thank you.
Dr. Zeitler.
DR. ZEITLER: This question actually builds off of what Dr. Brinker just asked, and I
think it got overlooked in the last session. But I am curious about the role that remote
monitoring will play in monitoring the Nanostim and really other devices in this class and
how that would play into a post-approval study.
And a second question, which I think just needs a brief answer. Given that the
recommendation was made to place the Nanostim in the septum, has there been any
experience with a patient undergoing an endomyocardial biopsy in the setting of a
Nanostim device, given that we do that in the septum typically?
DR. CARLSON: Thanks. Both good questions. I'll answer them in reverse order. I'm
not aware of anybody with a Nanostim device who has undergone a biopsy. Having said
103
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
that, we, as you know, often attempt to implant leads in the septum, and there's an
experience there. Your first question again?
DR. ZEITLER: Nobody wants to answer a lot of my questions.
(Laughter.)
DR. CARLSON: Oh, I'll answer it, I'll answer it. The current Nanostim device does not
have remote monitoring capability. It's something that we're working on in future devices.
Yes, it's interrogated, as standard pacemakers have been for years, in person with a
programmer.
DR. PAGE: Thank you.
Dr. Yuh.
DR. YUH: You know, one thing that struck me, I mean, looking at all of the factors
that are predisposed to serious adverse events, is the lack of assessing right ventricular wall
thickness, particularly with the Nanostim device, which has an active fixation screw-in
mechanism. Has there been any thought or is there any data with respect to right
ventricular wall thickness in the regions where the device is being implanted, and if that
correlates in any way with the incidences of perforation that you have had where the wall is
particularly thin? I was just curious that that could conceivably be looked at with TTE pre-
procedurally. It's just something that, as a non-implanter, I was just curious about.
DR. CARLSON: So I don't have any systematically gathered data from -- in the entire
cohort. We are aware of instances in which patients who received the Nanostim device and
would have been excluded in the IDE study had very thin right ventricular walls.
DR. PAGE: Thank you.
104
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
Dr. Lange.
DR. LANGE: And thanks for presenting the postmarket study and what you all have
done to decrease the perforation rate, because it looks like in the larger study it was about
1.5% and it went up to 4%, and now after these procedures, down to 2%.
I have a specific question about the enhanced patient safety or selection criteria. In
light of the fact that we weren't able to identify any patient criteria or any patient
characteristics that were associated with the increased adverse events, what enhanced
selection of criteria are you all recommending?
DR. CARLSON: I'm hoping to pull up a slide here on that. And I have it here. It's a bit
of an eye chart, but these are some of the changes that we made after analyzing the first
147 patients. Many of these are related to implant technique, but some were associated
with patient selection as well. There was a tendency in Europe, there were some
individuals who were using the device as a device of last resort in patients who were
extremely ill, had had radiation for lymphoma 50 years before, and had undergone -- that
particular individual had undergone three cardiovascular procedures in the days before the
implant. So at the time, we believed that at the time of the study and the time of the IDE
study, that this should not be viewed as a therapy of last resort. As we gain additional
experience, it may certainly become that.
DR. PAGE: Dr. Carlson, can you clarify? COI is referring to what on this slide?
DR. CARLSON: Current of injury.
DR. PAGE: Okay. So your recommendation is to wait 20 minutes if you see current
of injury or in all --
105
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
DR. CARLSON: See, the point here is to decrease repositioning. And early on,
physicians, when they saw a high threshold or sometimes wanted to quickly move to
another site, were recommending that if the thresholds were somewhat elevated in the
initial site, first were recommending that mapping be performed. Secondly, if the threshold
is elevated in that initial site, wait and oftentimes it comes down into a normal range and
repositioning is no longer necessary. We've seen that in the European Union study.
DR. PAGE: Great. And while we're on that topic of the implant technique, in your
video, which was very clear, you show a puff of contrast. Is that standard procedure? Is it
necessary? And are there any issues in terms of the amount of contrast potentially and
renal dysfunction?
DR. CARLSON: It's a very small amount of contrast media. We haven't seen any
renal complications. And it's something that we recommend, but I wouldn't say it's
required.
DR. PAGE: Okay, fair enough. And the last technical issue I just had a question on is
you showed a video of the sleeve going down, and actually what the video clarified is your
extraction is not undertaken until the sleeve is actually gone halfway down the device; is
that correct?
DR. CARLSON: That's correct.
DR. PAGE: And this is obviously not a laser extraction type sheath.
DR. CARLSON: No.
DR. PAGE: Is it robust like the old extraction non-laser sheaths are, or is it a thin
sheath? My question is getting to the issue of if there is significant fibrosis there, to what
106
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
degree that plays a role in your extraction.
DR. CARLSON: Sure. It's a relatively robust sheath. Let me ask Dr. Reddy to
comment on extractions since he has some experience.
DR. REDDY: Thank you. In this first generation extraction catheter, the sheath is
basically the same type of sheath as with the implantation catheter. So its preface was
mainly to protect the helix. Now, certainly you can imagine, as you may be suggesting, the
future generation for a retrievable catheter may involve something that's more cutting, that
may take away fibrous tissue if it's there's, etc. But at least with this current sheath, in our
experience, as we presented, we were able to extract all of the devices.
DR. PAGE: Great, thank you. I have Dr. Karasik, Dr. Naftel, and Dr. Kandzari.
Dr. Karasik.
(Off microphone response.)
DR. PAGE: Okay, Dr. Naftel.
DR. NAFTEL: So I really appreciate this meeting where we're all thinking together,
but I need a little help thinking. If you go to your Slide 17 -- and I know this isn't a PMA
meeting, but you opened the door, so thank you.
DR. CARLSON: Whose idea was that?
(Laughter.)
DR. NAFTEL: Primary effectiveness and safety endpoints achieved, and you give us
some nice p-values. But as we're trying to figure out what the rates should be and all of
that, could you tell us what the target endpoints were and what --
DR. CARLSON: Sure.
107
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
DR. NAFTEL: -- your endpoints were? Can you give me more than the p-values?
DR. CARLSON: We'll pull up some slides to do exactly that, if you can give our people
on the back --
DR. PAGE: So FDA is keeping track of the questions. Can you restate that for us
again, Dr. Naftel? This is homework over lunch?
DR. NAFTEL: Yeah. If I can just see the rates that the p-values are based on, but the
target and the observed.
DR. CARLSON: And I have two slides that will address that, and one is here. So here
are the forest plots for the primary effectiveness endpoint in the intention-to-treat and the
successful implant group.
DR. PAGE: Dr. Naftel, does that satisfy you?
(Simultaneous speech.)
DR. PAGE: So you can have a little bit of time for lunch, perhaps. We'll now move on
to Dr. Kandzari.
DR. KANDZARI: Thank you. Dr. Carlson, I wanted to revisit Slide 30, which
represents the European postmarket surveillance experience, and characterize this a little
bit further. It's been raised about, I think we would uniformly agree, a high perforation rate
of 4% in this early experience, and you mentioned these esoteric -- and of one case of
complex patients. But tell us a little bit more about this high occurrence of perforation.
Were these centers that performed the initial trial? So were they experienced
operators and still had this 4% perforation rate? You know, how does this experience of a
reasonable number, 150 patients relative to your initial cohort of 289 in the United States,
108
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
how does this differ with regard to the procedure and the technique and the operators and
the patients to have a more than twofold higher incidence?
DR. CARLSON: Lots of questions there, and I'll try to address them.
DR. KANDZARI: Really one. Explain the 4% rate.
DR. CARLSON: Yeah. New implanters, almost all of whom had not participated in
the initial study, and a variety of reasons for the events. I can name a few. One, a portable
C-arm with very low fidelity X-ray guidance that resulted in not being able to see the
anatomy appropriately; one that I mentioned. Another case where the patient actually had
a temporary wire in before the procedure was performed, and in retrospect, it was evident
that the temporary wire had already perforated the right ventricle. So one of our
recommendations is not to implant the Nanostim device in a patient who already has a
perforation.
Dr. Reddy, you probably remember some more of these as you were involved in both
trials. Do you want to comment?
DR. PAGE: I'll tell you what, I'm going to defer for Dr. Reddy right now. We're
starting to run out of time. This will be an item for significant discussion.
DR. CARLSON: But suffice it to say, some very straightforward things that can be
avoided with simple measures.
DR. PAGE: We're running out of time, but brief clarifying questions from --
Dr. Ohman and Dr. Slotwiner had their hands raised.
DR. OHMAN: So I was curious about the 28 deaths, and you presented the etiology
of three. It's unusual to have a 5% mortality rate after a standard pacemaker insertion at 6
109
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
months, so the rate is surprisingly high. Now, you shared with us some of the issues with
some individual patients, but I think it would be helpful to clarify what these other 25
deaths were due to. I realize that you can't do it on the spot, but that's a higher number
than I had expected.
DR. CARLSON: It's an elderly and complex population with a number of
comorbidities, and I'm not sure that for a single-chamber pacemaker cohort with this many
comorbidities, that it actually is out of line. Having said that, we had -- and I won't ask him
to come up now, but Josh Cooper -- Dr. Cooper was the head of our clinical events
committee, and each of these was reviewed with painstaking care to identify the degree to
which it was related or not to the device and the procedure.
DR. PAGE: So let's suggest that both sponsors provide slides. There aren't so many
deaths that I can't imagine that you can generate -- you can't generate specifics for us to at
least get a feel for that.
Dr. Zuckerman, you've got your microphone lit.
DR. ZUCKERMAN: Yeah. Again, thank you for that wise counsel. And it looks like
there will be a lot of lunchtime work. But I think the general principles enumerated in the
two last talks are that we need a large number of patients to look at very low frequency
event rates that can be very serious, and it's important to do this efficiently because, as
Dr. Carlson's fine presentation has pointed out, there's potentially a lot of learning that can
take place.
So my question for Dr. Carlson and Medtronic, after lunch, is how can we do this
most efficiently so that we can optimize patient enrollment, get consecutive patients at
110
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
sites, etc., so this won't take 100 hundred years but will be done very quickly?
DR. CARLSON: Thank you, Dr. Zuckerman.
DR. PAGE: Thank you.
Dr. Slotwiner, you have a brief clarifying question that we need to do, take care of
now?
DR. SLOTWINER: Yes, a question --
DR. PAGE: Please go ahead.
DR. SLOTWINER: -- maybe for both companies. I'm curious if you know what
percentage of patients required an upgrade to either a dual-chamber or biventricular device
and if you have information.
DR. CARLSON: Sure. We had two patients who were upgraded to a biventricular
device. There were no upgrades to dual-chamber devices of which I'm aware. There
weren't any.
DR. PAGE: And, Mr. Thuramalla, did you have your hand raised? Yes, please go
ahead.
MR. THURAMALLA: This is Naveen Thuramalla.
A quick clarifying question. Can the Nanostim device be turned off? And if yes, then
you'd still recommend retrieval or turning it off? Thank you.
DR. CARLSON: The device can be turned off. At this point it's physician judgment
regarding retrieval versus having it remain in place. But the physicians who have
encountered this, to date, have chosen to attempt to retrieve it and have been successful in
every case.
111
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
DR. PAGE: Dr. Naftel.
DR. NAFTEL: This is just clarifying for all companies. Have any of these patients had
ventricular assist devices, temporary, permanent, left or right?
DR. CARLSON: None of the St. Jude patients have had that. And David Steinhaus is
not -- is agreeing that none of theirs have either, just for the record, if I may speak for you,
David.
DR. PAGE: Mr. Frankel, did you have your hand raised?
MR. FRANKEL: Yeah, just a quick clarification question. Regarding the seven
retrievals, which has been impressive, 100% success --
DR. PAGE: Please speak up.
MR. FRANKEL: -- the range is quite broad. I was just wondering how many of those
seven were -- exactly where were they on the spectrum in terms of length of implantation?
Just to get an idea. So, you know, were they mostly very shortly thereafter or were they --
DR. CARLSON: It's a range all the way through. I don't have a slide showing that
right now, but there are some in the 200 range. I'm sorry, I do have a slide. There were
two at 1 day, there was one at 100 days, one at 13, one at 208, one at 413 days, and one at
382 days.
MR. FRANKEL: Thank you.
DR. CARLSON: And in the EU it ranged between 9 and 560, I believe -- 506 days.
DR. PAGE: Dr. Lange.
DR. LANGE: Both industry sponsors mentioned that their devices were MRI
compatible, and after lunch, if you could tell us what that means.
112
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
DR. PAGE: Okay, everybody get that? And we have heard comments from our
Industry and our Consumer Representative.
Ms. Dunn, do you have any questions or comments now that you want to provide?
Or certainly we'll ask for your input after the break.
MS. DUNN: Just quickly. I was just curious about the age. The average age is about
75 years old.
DR. CARLSON: Yes.
MS. DUNN: Were younger patients -- obviously it was posed to them to enroll in the
study?
DR. CARLSON: The youngest patient enrolled in our study was 19 years of age. So
they were allowed, yes.
MS. DUNN: Okay, thank you.
DR. PAGE: Okay, we are actually ahead of schedule. I'm going to suggest we break
for lunch. Panel members, please do not discuss the meeting topic during lunch among
yourselves or with any member of the audience. We were scheduled for a 50-minute lunch,
so shall we make it 12:25? Will that work for FDA and for our open public comment to be
starting that early, Dr. Zuckerman?
(Off microphone response.)
DR. PAGE: Okay. So we'll reconvene at 12:25. Thank you very much.
(Whereupon, at 11:37 a.m., a lunch recess was taken.)
113
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
A F T E R N O O N S E S S I O N
(12:27 p.m.)
DR. PAGE: The time is 12:27. I'd like to call this Panel meeting back to order. We
will now proceed with the Open Public Hearing portion of the meeting. Public attendees
are given an opportunity to address the Panel, to present data, information, or views
relevant to the meeting agenda.
Commander Culbreath will now read the Open Public Hearing disclosure process
statement.
CDR CULBREATH: Good afternoon. Both the FDA and Drug Administration and the
public believe in a transparent process for information gathering and discussion making. To
ensure such transparency at the public hearing section of the Advisory Committee meeting,
FDA believes that it is important to understand the context of an individual's presentation.
For this reason, FDA encourages you, the Open Public Hearing speaker, at the
beginning of your written or oral statement, to advise the Committee of any financial
relationship that you may have with any company or groups that may be affected by the
topic of this meeting. For example, this financial information may include a company or
group payment of your travel, your lodging, or of expenses in connection with your
attendance at this meeting. Likewise, FDA encourages you, at the beginning of your
statement, to advise the Committee if you do not have any such financial relationships. If
you choose not to address this issue of financial relationships at the beginning of your
statement, it will not preclude you from speaking.
FDA has received four requests to speak prior to the final date published in the
114
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
federal registration. Each speaker will be given 10 minutes to speak.
Back to you, Dr. Page.
DR. PAGE: Thank you very much.
As Commander Culbreath stated, you have 10 minutes, and we will cut you off at 10
minutes. So if you have an 11-minute talk and you really want to give that conclusion in the
last minute, you won't have time. So please go ahead and present. Keep it under 10
minutes. We have a lot of work to do, and we look forward to this very important part of
our meeting.
Our first speaker is Dr. Jay Ronquillo. He's from the National Center for Health
Research.
Dr. Ronquillo.
DR. RONQUILLO: Thank you very much for the opportunity to speak today. My
name is Dr. Jay Ronquillo, and I am speaking on behalf of the National Center for Health
Research. I am a physician who trained at Massachusetts General Hospital. I have two
electrical engineering degrees from Cornell, a master of public health from Harvard, and a
master's in biomedical informatics from Harvard Medical School. These are the
perspectives I bring with me today.
Our research center analyzes scientific and medical data and provides objective
health information to patients, providers, and policymakers. We do not accept funding
from the drug or medical device industry, and I have no conflicts of interest.
Implantable cardiac pacemakers have played an important role in the clinical care of
patients for decades. Leadless cardiac pacemakers represent a related but new technology
115
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
with the potential to improve the lives of patients. However, it will be important to make
sure that a high standard and evidence-based approach is used to ensure that the right
balance exists between the risks and benefits of this new technology.
Leadless pacemakers demonstrate a different distribution in the rate and type of
adverse events compared to traditional pacemakers. There seems to be lower rates for
some complications such as pneumothorax, or even the absence of other complications like
pocket-related hematomas, bleeding and infection, or lead-related fracture or
dislodgement. However, there are potentially higher rates of certain complications such as
right ventricular perforation with tamponade and even the introduction of entirely new
complications such as the more vascular access issues.
In sum, there is a complex tradeoff of adverse events for these devices, and these
tradeoffs need to be assessed in the context of how they impact patients relative to the
traditional products currently on the market.
While the acute performance of leadless cardiac pacemakers is important, the
intermediate and long-term performance of these devices requires significantly more data.
We need to know more about novel complications, clinical outcomes, and adverse events,
but also how they overlap and compare with traditional pacemakers. For example, better
data are needed for direct and indirect complications caused by encapsulation of the
leadless pacemaker and how that possibly compares with lead encapsulation of traditional
pacemakers. What are the potential differences involved with extraction and replacement
or co-implantation of both types of devices at the end of their mechanical reliability and
battery life? These are the key questions regarding safety and effectiveness.
116
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
Post-approval study design and surveillance will likely play an important role in the
long-term success of leadless pacemakers. While the complete understanding or
assessment of long-term performance may not be possible at the time of approval, any
post-approval study paradigm must be capable of filling those knowledge gaps in a timely
manner. It is essential to clearly identify the important factors from the physician and
patient perspectives and anticipate adverse outcomes before they significantly harm a
patient's life and quality of life.
In summary, leadless pacemakers have the potential to improve the care of patients
with various cardiac rhythm disorders. However, this will require an understanding of how
acute adverse events compare and contrast with those of traditional pacemakers. I
encourage you to urge the FDA to require comprehensive data regarding the intermediate
and long-term safety and effectiveness of leadless pacemakers. Post-approval studies
should clearly assess these adverse factors. They should provide context regarding the
entire spectrum of safety and effectiveness in a way that enables physicians to make sound
decisions, and it allows patients to fully and clearly understand the risks and benefits of this
new technology.
Thank you again for the opportunity to speak today and for consideration of our
views.
DR. PAGE: Thank you very much, Dr. Ronquillo.
Our next speaker is Dr. Barry Love from the Congenital Cardiac Catheterization
Laboratory at Mount Sinai Medical Center, New York, New York.
Dr. Love.
117
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
DR. LOVE: Thank you. Thank you for this opportunity to speak and address the
Panel today. My name is Dr. Barry Love. I am the Director of Pediatric Electrophysiology
and also the Congenital Cardiac Catheterization Program at Mount Sinai Medical Center,
and as well, I am board certified in adult congenital heart disease. So I see a lot of patients
from childhood through adults with varying problems with congenital heart disease, and
many of them require pacemakers.
I want to bring up this 800-pound gorilla in the room, which is really the 8-pound
gorilla in the room, the baby and the children with pacemakers. I believe Patient
Representative Dunn has already brought up and was questioning a little bit about, you
know, the younger size. A lot of times we're talking about the median age of patients that
were getting these devices in the trials, and we're talking about 70-year-olds. I think that
there's significant applicability to pediatrics. And I'll refer you to the Medtronic
presentation, to Slide 50, where they show Dr. Lillehei in 1958 with a child who had
received one of the first pacemakers; again, pioneering technology, but used in children.
I just want to point out that I have a disclosure. I am a consultant and proctor for
St. Jude Medical on the structural heart side and not the CRM side. I've not received any
honoraria or expenses for this presentation.
So background: Pacemakers are important and prevalent in children and adults with
congenital heart disease. Current pacemaker technology, transvenous and epicardial, has
significant drawbacks in congenital heart disease, and leadless pacemaker systems have the
potential to overcome many of these drawbacks, but there are many unknowns of leadless
pacemaker technology in this patient population.
118
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
No studies have been done in children or adults with congenital heart disease using
leadless pacemakers. And once these pacemakers are approved, they will be used in
children and adults with congenital heart disease, and we don't yet know how this
technology should best be used.
So just to back up, what children and adults with congenital heart disease need
pacemakers? So the prevalence of serious congenital heart disease needing intervention is
about 1 in 1,000, and over a lifetime, about 5% of those patients with surgically repaired
congenital heart disease may require a pacemaker. Other indications for pacing in children
include congenital complete heart block and some congenital long QT syndromes that
require pacing and other various indications, but the majority are for surgically induced
complete heart block.
And as you can see from the slide here from a study that we did not long ago, again,
about half the indications for pacing in children are due to surgical complete heart block,
and that's due to the closeness of the conduction system to the ventricular and septal
defects. Typically, they comprise a large proportion of many of the parts of complex
congenital heart disease. Surgical sinus node dysfunction, congenital heart block, long QT
syndrome, progressive AV block are all other indications for pacing in children.
So some of the challenges in congenital heart disease and device therapy are patient
size and growth; anticipated patient longevity means multiple generator changes; a greater
risk of lead failure due to time implanted and patient activity; and congenital anatomic
issues that make device placement problematic in some patients. I'm going to show you
some examples of that.
119
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
So the age at first implantation in children and adults with congenital heart disease
again spans the spectrum from infants through adulthood.
The types of devices implanted: Many are dual chamber, but a good proportion are
single chamber, and many of them could get by even with just single-chamber devices.
And, again, a large proportion are epicardial at this point. Again, a lot of the comparisons
that have been done right now between the leadless pacemaker and current pacemaker
technology has been to be -- has been transvenous pacemakers. But, again, I would stress
that many of our patients require epicardial pacemakers. And so, again, the calculus may
change a little bit.
I'm just going to focus on some of the disadvantages with the different types of
pacemaker systems that are currently available. Again, epicardial disadvantages. You need
to open the chest. There may be higher thresholds. Lower lead impedances drain the
battery faster. It may be difficult to achieve satisfactory lead position, especially in patients
who have had multiple cardiac surgeries. And abdominal pocket is often less optimal for
rate response, and it's often less comfortable.
Some of the big disadvantages of transvenous approach is that leads may cause
thrombosis and scarring of the vein and inability to approach in the future. There may be
difficulty in accommodating a dual-chamber system. It's difficult to achieve enough slack to
provide for growth in children. And many patients are not candidates for transvenous
pacemakers because we can't get to where we need to from the transvenous approach.
I want to point this out, the high failure rates of pacemaker leads in children. Again,
this is really pretty impressive. So looking at the blue, that's the rate of transvenous
120
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
pacemaker lead failure, and as you can see, out to about 15 years we have about only 65%
of the leads are still working. And you can see the dramatic difference, dramatically worse
for patients who received epicardial lead -- epicardial pacing systems, from the standpoint
of the leads. Clearly, we could do better.
I want to show you a couple case examples. This is a 1-month-old who was born
with transposition of the great arteries, had an arterial switch, was complicated by
ventricular failure and needing ECMO. He had mediastinitis and had heart block and
needed a pacemaker. We didn't want to put one in epicardially in this patient because of
the mediastinitis, and one was put in transvenously, and this was achieved in a small infant
using a 4 French transvenous lead and a small pacemaker.
But at age 6 years, there were high lead thresholds, and the patient still had
complete heart block and needed to undergo laser lead extraction. So this is what the
pacemaker looked like at that point. Again, just because of size and growth, the lead has
pulled back, and you can see that it's really pulled quite taut in the right ventricle, high
pacing thresholds, and there was complete occlusion of the vein. And so we needed to use
laser lead extraction, which again is somewhat hazardous in a small child especially. We
remove the old lead, maintain venous access, and were able to reimplant a new lead. So I
would just ask you to ask yourself, we have lead failure in both the transvenous and
epicardial leads that are both common in children, but a leadless pacemaker for an implant
at age six may be desirable in this patient to avoid lead problems over her lifetime.
I'll show you a second case example. This is a female born with congenital complete
heart block, had an epicardial single-chamber pacemaker placed in the newborn period. At
121
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
age 4, had lead failure and had a new dual-chamber epicardial system placed. At age 5
years, had ventricular lead failure, and a new lead was placed from an epicardial approach
but transatrially because they weren't able to achieve a good pacing site on the ventricle.
At age 7 years, had atrial lead failure and was set VVIR at age 10; had high ventricular lead
impedance, battery depletion, and had a new transvenous dual-chamber pacemaker system
and the old abdominal generator replaced.
So, again, this is this patient's chest X-ray, and that's a lot of leads already in this
patient at age 10. So this patient has continued risk for lead failure over time, and again a
leadless pacemaker may have a role to reduce lead burden in this patient.
I'm going to go through this quickly because I'm running out of time. I'll just make
the point that this is an adult patient who has the type of ventricular repair called the one-
and-a-half ventricle repair. You can't get there transvenously because you can't go through
the system. His SVC is connected directly to his pulmonary arteries. He has a series of --
he's had a series of epicardial leads placed and has poor ventricular pacing thresholds. This
patient, if we needed to, would be a good candidate for a leadless pacemaker. And, again,
this is a patient with complex congenital heart disease that potentially could benefit.
I'd just like to point out that patients with transvenous pacemakers are more likely
to have stroke if they have intracardiac shunt. This is a paper that was written by Paul
Khairy and others in Circulation (2006). And, again, it just shows the incidence of stroke in
patients who don't have on the top and patients who do have intracardiac shunt -- excuse
me -- epicardial leads and transvenous leads in terms of the risk of stroke in patients who
have intracardiac shunt. And so, potentially, transvenous leads in patients who have
122
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
potential for right-to-left shunt, where you can have thrombosis on the leads and such, may
be at increased risk for thrombosis and again may be important for that consideration.
So I'm just going to say the size of the delivery system, what patient is appropriate to
consider? I'll just say our experience from the interventional side, that we use 22 French
delivery systems, which are approved for Medtronic Melody valve placement for children
more than 30 kg. But there are large studies in the literature -- not large, but studies in the
literature that include children down to a median weight of 21 and as low as 13.8 kg even
using that 22 French delivery system.
So what are some potential issues with leadless pacemakers? The size of the heart.
Will the volume of the leadless pacemaker lead to problems in any group? I don't think so.
Again, these are 1 cc devices. The average size of the right ventricle is about 70 mL/m2. So
that should be sufficient even with multiple devices. Is any anatomy problematic for
implantation? We don't know.
Device longevity and pacemaker removal and implantation, that we've heard about
and discussed again, is obviously something that we're going to want to know about.
So I think that this leadless pacemaker technology has an important role to play in
children and adults with congenital heart disease, and the need for these devices may be
even greatest in this patient population.
These devices will be used in children and adults with congenital heart disease. And
this is my takeaway message. I think that the FDA should encourage the device
manufacturers to establish a registry for children and adults with congenital heart disease
so the risks of these devices can be bared out over time. And, again, we've heard some
123
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
studies that were going to consider 7 years. I mean, I think long term, 10 or 15 years would
be more an appropriate horizon to be thinking about including a registry for all of these
patients.
I thank you for your attention.
DR. PAGE: Thank you very much, Dr. Love.
Our next speaker is Dr. James Ip, Assistant Professor of Medicine, Weill Cornell
Medical Center, also from New York.
DR. IP: Hi. Good afternoon. Thank you for the opportunity to share with you my
own experience with these devices as well as my own perspective. My name is James Ip. I
am a cardiac electrophysiologist and Assistant Professor of Medicine at Weill Cornell
Medical College in New York City. Through a series of cases, I'd like to convince you that
having leadless pacemakers available is important for physicians as well as their patients.
I have no conflicts of interest to disclose, other than the fact that St. Jude Medical
provided for my transportation for this meeting today.
I was one of the investigators in the LEADLESS II trial that was published in the New
England Journal of Medicine a few months ago, as Dr. Reddy shared this morning. And just
in case anyone is wondering, I have no relationship to the other Dr. Ip that was also
involved in this study.
As the site principal investigator for Cornell, it was quite difficult to enroll for this
trial. After all, many New Yorkers are hesitant to proceed with any investigational devices
and are very skeptical about their medical care. Fortunately I was able to inform them that
the device had already received CE marking in Europe in 2013.
124
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
So in August of 2014 I met my first patient who, in my mind, was a perfect candidate
for the device. She was an 85-year-old woman who had syncope as a result of bradycardia,
and because of her fall, she had to have corrective surgery of her spine. Given her
longstanding persistent atrial fibrillation, all she needed was a single-chamber device, and I
thought the leadless pacemaker would be perfect for her because of her limited mobility
and her need for extensive physical rehabilitation, and this would've been difficult with a
traditional transvenous device.
As you can see on this fluoroscopy, the device was able to be implanted without
much difficulty, other than trying to visualize the device around her Harrington rods. There
were no complications from this procedure.
My second patient was referred to me by my colleague. And I apologize for showing
this picture to you soon after lunch, but this was a 75-year-old woman who had a
pacemaker implanted two months prior to this picture. Somehow she ignored the signs
that she was developing a pocket erosion and did not seek medical attention until her
pacemaker literally fell out of her chest while she was in the shower. Because of her
obvious wound-healing issues and her thin skin, a leadless pacemaker was a clear
alternative to having another device to avoid recurrence of this potential complication.
And as I mentioned, it was difficult to recruit for this trial, not only because of the
countless questions I received from patients, family members, and the referring
cardiologists, but they would inevitably ask me the question, Dr. Ip, how many of these
devices have you implanted? Here is an example of one such patient who my colleague
referred to me for the device but politely declined. Unfortunately, while my colleague was
125
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
implanting a traditional transvenous pacemaker, he had difficulty with venous access. And
as you can see, this venogram shows that he had a total occlusion of his brachiocephalic
vein. As a result, he ended up with a right-sided single-chamber pacemaker as well as a
left-sided pneumothorax. In retrospect, had he elected to have the leadless pacemaker, he
could've potentially avoided this known complication and he would've avoided the bilateral
incisions in his chest.
In addition to pocket erosion, pneumothorax, and venous obstruction, transvenous
leads can lead to other potential complications such as tricuspid regurgitation. The leads
themselves, by passing through the tricuspid valve, can prevent coaptation of the leads and
cause tricuspid regurgitation.
Although this was not the patient I implanted for this indication, this is another
example of a patient who developed tricuspid regurgitation from transvenous leads. As you
can see, this patient developed acute tricuspid regurgitation shortly after having a
transvenous lead implanted, and the 3D echocardiogram shows that the lead was impinging
on the septal leaflet of the tricuspid valve and causing tricuspid regurgitation.
Some of the most compelling cases for the support of this new technology involve
patients that have limited options besides a leadless pacemaker. This was a 68-year-old
man who was referred to me by one of my colleagues because of recurrent complications
from his pacemaker. He had a pacemaker implanted originally 5 years ago, and over the
years he developed a venous obstruction and superior vena cava syndrome. After his
device was implanted, he had stents placed, and unfortunately his new transvenous
pacemaker ended up failing shortly after it was placed because of the interaction between
126
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
the leads and the stents. Therefore, his only options were to either have an open
thoracotomy and have an epicardial lead placed or to have a leadless pacemaker implanted.
As part of the continuing access program, I was able to offer him the leadless device, and to
him the choice was clear. I was able to implant the leadless device without any
complication and without any concern that it would interact with his SVC stent.
And finally some patients prefer to have a leadless pacemaker. I met Mrs. P. a
couple weeks ago, and she recently celebrated her 101st birthday, as you can see in this
photo that she provided for me. She was admitted to the hospital with syncope and
bradycardia. She was a sharp and independent 101-year-old, and when I gave her the
choice between a transvenous lead or a leadless pacemaker, she chose the latter because
she figured it was more -- it was less invasive and her recovery would be quicker.
My initial experience with leadless pacemaker implants has been favorable. In 25
patients who I have implanted with an average age of 85, I was able to implant all of them
except for one. All met efficacy criteria with good pacing and sensing parameters, and
there were no complications as a result of the procedure.
In conclusion, having access to leadless pacemakers is essential for physicians and
patients. And although there are some limitations to the technology and it's not for every
patient, it is my hope that we can continue to provide this leadless pacemaker as part of our
armamentarium of cardiac rhythm devices to better treat our patients, such as this
delightful 101-year-old.
Thank you very much.
DR. PAGE: Thank you, Dr. Ip.
127
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
Our next speaker is Anand Dhanda, Dr. Anand Dhanda from Annapolis. No other
affiliation reported.
Welcome, Dr. Dhanda.
DR. DHANDA: Hello. Good afternoon. My name is Dr. Anand Dhanda. I am a
practicing urologist in Maryland, in Annapolis, and I'm a recipient of a leadless pacemaker.
My history goes almost about 4 or 5 years ago when I started getting syncopal
attacks, and my cardiologist investigated me by putting the 24-hour monitors and then
1-month monitors, when finally they found that I have bradycardia, which is causing
syncopal attacks. And this news leaked out to my chief of surgery, and he said there's no
way you're going to operate if you have a pacemaker done because you may fall in the
operating room and the patient may have a problem with you.
So I had to look for a pacemaker. I had an opinion from my cardiologist to go to
Johns Hopkins. So I went there, and they said that yes, we can offer you, but it was a
traditional pacemaker. And I kept inquiring from them whether they can offer me
something else. So they didn't have anything.
My wife is a physician too. We came home. We went on the Internet and looked
around at the companies who make pacemakers. We went on their websites to find out
whether they have anything new coming up which I can go for it. The reasons for that was
I'm a swimmer, I swim almost every other day, and I'm a golfer. I didn't want to carry a box
on my chest, and I read about that there are a lot of complications of the traditional
pacemaker, the pocket infections, breaking of the leads, and then go back to the operating
room for several times.
128
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
So our research indicated that there is a leadless pacemaker available, and Dr. Vivek
Reddy's name came up. So I went on the Internet and listened to his talks he had given to
cardiologist societies and all of that, and we came to the conclusion that that's what I want.
So I live in Baltimore. We called Dr. Reddy over the weekend. He was kind of
enough to answer this phone call. We had a long discussion about this leadless pacemaker
and the complications. We spent a lot of time on the phone, and I was already scheduled
for a pacemaker at Johns Hopkins 3 days from that day. I decided to cancel that and made a
trip to New York with the idea that if I don't like it, then he can always put on a traditional
pacemaker.
So that morning I did not eat or drink. I was NPO. So I went to New York with my
family, and we had a long conversation with Dr. Reddy, and he convinced me, and I was
convinced that this is for me. And so we went ahead, and this is December 2014, and I had
a leadless pacemaker implanted. I spent all night at New York and came back the next day,
and the research follow-ups were done like 2 weeks, 4 weeks, and then 3 months, and 6
months. Now I am almost a year and a half from the leadless pacemaker, and I'm very
happy with it. I can continue my activities, and I haven't had any more problems, though I
developed hypertension, but I'm not sure it's because of that or not. My cardiologist
doesn't think about it. So I'm on medication for that. Otherwise I don't take any
medications.
Thank you.
DR. PAGE: Thank you, Dr. Dhanda.
Does anybody from the Panel have -- first of all, is there anybody else in the
129
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
audience who wishes to address the Panel during this open public comment?
Does anybody on the Panel have any questions for the people who have spoken
during this segment of our meeting?
Seeing none, I will pronounce the Open Public Hearing to be officially closed, and
we'll proceed with today's agenda.
We're now going to begin Panel deliberations. Although this portion is open to
public observers, public attendees may not participate except at the specific request of the
Panel Chair.
Additionally, we request that all persons who are asked speak identify themselves
each time they come to the lectern. This helps the transcriptionist identify the speakers.
During this period of time, we will open up the floor to questions for both the sponsor and
the FDA.
Now, we had a number of questions, and what I'm looking to do here is address --
give an opportunity for each of the three sponsors who spoke to address questions or give
any further brief comments that they care to provide, to provide the Panel to ask them
specific questions during that time. And then we will move, in order to structure our
discussion, more into the questions relatively sooner than later. The agenda only called for
an hour and a half or so to address the questions. They have many sub-questions, and I
think to get our arms around the very many issues involved here, it's better to do that with
some structure.
But to start things off, I'd like to go in the order that we had the presentations this
morning and first offer representatives from Boston Scientific to ask if they have any other
130
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
comments for the Committee, and ask the Committee if they have any other questions for
you. And please state your name for the record.
DR. STEIN: Yes, thanks. Ken Stein from Boston Scientific.
I don't think we had any specific homework requests over lunch. Two comments,
though, on the questions that came up earlier in the day. There was a question, I think,
from Dr. Ohman regarding CPR. While we're only in preclinical models, we haven't gone
into human work, we have done some work where we've looked at the effect of doing CPR
in canines and have not had any issues in terms of lead dislodgement or embolization.
And then in response to questions about remote monitoring, we fully appreciate the
question and appreciate the importance of remote monitoring and do envision that a
capability for doing remote monitoring will be an important facet of a leadless pacing
system.
DR. PAGE: Any other comments or questions from the Panel for Dr. Stein?
Thank you very much.
Next I'd like to call the representatives from Medtronic. I think we gave you a little
bit of homework over lunch. And please state your name and present the responses that
you have for the questions we had, and then we'll see if we have any further questions for
you.
DR. STEINHAUS: My name's David Steinhaus from Medtronic.
I have one comment to make first, and then I'll go right to your questions, and the
comment really is about how to assess this. And it's been kind of a question about whether
or not you have to have the same level of performance in terms of complications as a
131
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
traditional system or which complications are more important. And my concern would be,
like everything else, this has to have a risk-benefit equation. You have to balance the risks
that we know about against the potential benefits, both acute and long-term, for example,
not having leads in long term and not having to take out leads in long term and all of those
things. And I think it's really a balance.
So there's no one number you can come up with that's going to say this is the risk we
are prepared to accept, because we don't really fully understand entirely what the long-
term benefits are and if they are going to be better or not. We believe, for example,
infection rates will be lower with this device, particularly over the longer term. There's no
pocket. At least half of the infections are pocket infections. So I just wanted to throw that
out there first.
Second of all, I wanted to address one of the first questions of Dr. Zeitler. Yes,
remote monitoring, we have remote monitoring. I'm sorry I didn't answer it before. Maybe
I got lost in the other question, but in fact, we will have remote monitoring available. The
device is fully capable. What we've done is we've just developed the software related to
being able to follow it on our CareLink system. That is going to be submitted very shortly to
the FDA. We expect that to happen at some point after launch, to be able to have full and
clear remote monitoring as other devices have, so just as our other devices.
The second question: MRI compatibility was raised, and what do you mean by MRI
compatible? MRI conditional is kind of the official term, and it's because no CIE device can
be said to be completely MRI safe. There's always some level of residual risk, and so what
they call it is MR conditional. Those are devices which are approved for use with MRI
132
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
devices. And, in fact, there are sort of three ways we look at that. One is to think about,
well, does this do anything in terms of dislodgement? The question was raised about
dislodgement in the magnetic field. That has been looked at carefully, and that will not
happen.
We also looked at other things like lead tip heating in the past. This falls under a lot
of modeling that we do in terms of testing for internal effects and all. And basically, to
summarize that, it's just like our other MRI-compatible devices. It will have a SureScan
mode just like our other devices. Lead tip heating was at 0.4 degrees at the maximum,
which isn't enough to cause any type of injury. And it will also be compatible for not only
1.5 T devices, as our current devices are, but also for 3 T devices. So that's what we're
asking for, and we've given the data to the FDA to support that.
The third thing was the question of upgrades. Could I have Slide AA-9, please, up?
The question was raised, how many upgrades were there to either dual-chamber systems or
to ICDs? Could I have that slide up, please? I guess I have to put the slide up here. So in
the study there were four patients. Two went on to biventricular systems, and two went on
to traditional transvenous systems. You can see here the continued access protocol. One
had traditional transvenous elevated thresholds, and one went on to biventricular. So
basically the reason was either elevated thresholds or biventricular. You will, of course,
also remember the one patient who had pacemaker syndrome in the trial. Okay. Does that
answer your questions sufficiently there?
DR. PAGE: I believe so.
DR. STEINHAUS: The fourth one I think, Bram, you asked, in terms of how can we
133
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
speed up these postmarket studies so we get data in a quick time? We're also very
cognizant and want to do that. I think one thing is to have broad inclusion criteria. That's
our plan, is to have a very broad inclusion criteria. Second is we hope to have 200 centers
enrolling. We already have 170 centers in what we call the post-approval network that
Medtronic has, and the advantage to that, of course, is that we can alleviate all of the legal
work and all the kind of the stuff that has to go on with each center so that we can just go
directly to the IRBs. A lot of this stuff has already been pre-approved, and we hope to get
that going.
And then also we expect to have -- we're going to re-consent the patients so we can
have a leading-edge follow-up done better, so we can put those patients and dump them
into the post-approval trial, as well. That's the plan.
You asked a question about page 34, the table. I think the question was asked, what
does the NA mean? Can we flash that up, please? I think that's Slide PT-8. Okay. Can we
put that up, please? Okay. So this is the table I think you were referring to, and this is the
detail on the cardiac effusions and perforations. You said, okay, look, some of them came
from the apex or the septum, and we know where the final location was, and therefore they
were marked NA. Those four were not implanted, so we don't know where they were put
in. We only recorded at the time, after the implant was successful, that they were put in, in
that position in the apical. So we don't know, for example, if they were tried in the septum
and then went to the apex and then vice versa. So I don't have that information down. I
can tell you that the number of repositionings does relate to the chance of perforations that
we've seen before. So that's that question.
134
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
And could I have CL-16, please? Slide CL-16. Okay. You also asked a question about,
what about site placement? I think similar to the previous study, 66 were put in the apex,
and 33% were put in the septum. Does that answer your question reasonably, hopefully?
DR. PAGE: I believe so. I just want to see if we're tracking on the numbers. So you
had a 99.2% success with six attempts and not success. And if you go back to the previous
slide, were almost all of those represented on that previous slide? Because I counted the
NAs.
DR. STEINHAUS: The previous slide was the four NAs, right.
DR. PAGE: Four of those six were perforations that terminated the procedure?
DR. STEINHAUS: I believe that's correct, but let me ask our clinical team. The
answer to that is yes.
DR. PAGE: Okay.
DR. STEINHAUS: Okay, everybody's cool with that?
DR. PAGE: Thank you.
DR. STEINHAUS: All right. And the next question would be you wanted to know
about total deaths. The question was raised, are they too high, and what are they all
about? We have two slides to address that. The first is interesting. We actually compared
-- could I have that slide up, please? It is Slide AA-10. This is interesting. We actually
compared the actual survival rate for patients in the Micra study to the actual survival rate
that we get from our CareLink analysis in other patients. So this would be the same survival
rate you'd expect to see in a VVIR population. But you can see that actually the survival
rate is better than that. So, in fact, if you look at the numbers, it really is about 5% to 10%
135
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
per year falloff in this type of population is what we would expect. So we certainly didn't
see any higher rate of death in this population overall.
Could I have the next slide, please, which is Slide CL-28? This shows all of the
deaths, and you can kind of see here, there were 29 deaths in our study. I think that's
about 4% or something like that, the total over this course of the time period of the study.
You can see what they were. Seven were cardiac. Most were from heart failure. And then,
of course, there's a whole potpourri of other reasons why people died, which is not
unexpected in this population of patients.
DR. PAGE: And just for the record, what we're seeing is, of those 29 deaths, you're
showing us seven were adjudicated as cardiac.
DR. STEINHAUS: That's correct.
DR. PAGE: And the other 22 were adjudicated as non-cardiac.
DR. STEINHAUS: That's correct. All of this is --
DR. PAGE: And unrelated to the procedure.
DR. STEINHAUS: That's correct. All of this is adjudicated data. If you remember,
there was only one procedural-related death that was not related to the device.
DR. PAGE: Thank you.
DR. STEINHAUS: The next one is -- the question was asked, I believe, by Dr. Lange,
how many patients had done -- how many physicians had done more than 10 patients? And
I think the answer to that is, that of the 96 total implanters, 25 or 27%. So 25 implanters,
27% of the implanters, had done more than 10 devices. So a fair number there.
And, in fact, the question was raised also, I think by Dr. Lange, what about the issue
136
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
of complications between the first 10 and the last 10? Was there anything different about
that? Could I have Slide AA-4 up, please? And you wanted to have the entire cohort of 700-
and-X patients. And you can see here, this is the training for those patients, and you can
see the ones trained in the lab versus the ones trained at the hospital are virtually the
same, and that accounts for the entire number. Also I think I can tell you that, of this
number, it was unrelated to perforations, for example, which people were concerned
about, were unrelated to training, and they were also unrelated to the number of devices
you had done. So that's the answer to that question, I think.
DR. PAGE: And just so I'm clear, you stated that 25 or 26% of the implanters had
done over 10. So three-quarters of the implanters did 10 or less?
DR. STEINHAUS: That's correct.
DR. PAGE: Thanks.
DR. STEINHAUS: That's correct. Could I have Slide AA-6 up, please? This is really
going to the question of perforations. Again, you can see the risk of perforation as the risk
of total overall complications is about the same, depending on whether you were trained in
a lab or trained locally at the hospital. So, again, I think it confirms that either method of
training is equivalent in that regard.
Okay. The question was raised about anticoagulation. What about anticoagulation,
and how does that relate to the complication rates? Could I have Slide AA-5 up, please?
And what you see here is you see we didn't systematically look at the antiplatelet drugs,
which you had asked about. We made no systematic changes in that during the trial. We
didn't say stop or start them. They were left entirely to physician discretion. You can see
137
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
here, in blue, we have none; in orange we have the IV heparin plus the oral anticoagulants;
and then the oral anticoagulants only during the procedure. You can see that, all of the
different complications.
Interestingly enough, if you look at effusion, effusion was actually more likely --
again, small numbers, but more likely to happen if you had no anticoagulation, in fact, than
if you were anticoagulated with heparin or with oral anticoagulation agents, which is an
interesting finding. I hope that answers your question regarding that.
DR. PAGE: I believe so. Thank you.
DR. STEINHAUS: Great. The next question you asked was about CPR testing and
whether the lead could possibly dislodge with CPR. Actually, we were more interested in it
from the standpoint of automobile crashes or things like that. So if you get in an
automobile crash, would this thing dislodge? And that's more likely, I think, than CPR. And
actually we tested -- we know the amount of acceleration and deceleration, and we actually
tested for that. And actually, in order to dislodge this, you have to have more than what is
a fatal deceleration. So the deceleration would kill you before the device would dislodge. I
think that probably answers the CPR question reasonably well, as well.
In terms of infection, the whole question -- a lot of questions were raised about
infection. There was a question raised about dialysis. I think you asked that question.
Twenty-six of the patients who were in the trial were on dialysis, and there were no
infections in that group, to date.
Another issue was the volume of this device. Somehow this is larger than a lead and
therefore might be more prone to having a sepsis and all. And it actually turns out that the
138
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
volume of Micra in the right ventricle is about the same as the volume of a standard
defibrillation lead in the right ventricle. So they aren't that different in terms of the amount
of prosthetic material which resides in the right ventricle. And surely if you consider the
entire vasculature, it's even more than that. So we think that's that issue.
Interestingly enough, during the study there were 14 cases of sepsis or sepsis-
related -- that actually cleared. So there were no infections of the device during the trial,
although there were 14 episodes of documented sepsis or bacteremia, which again were
adjudicated by the committee. So interesting. I don't know what that exactly means, but
hopefully it means that there's some resistance to getting these things infected.
The other thing about it is, remember that when we do lead extraction, we can
actually cure most patients even if we leave the tip of the lead in place. That's been well
documented by older studies. So the idea would be that maybe this is again possible. Even
if they get infected, you might be able to cure the infection without removing the device.
And then, finally, remember also that most of the vegetations which occur when you
have infections are actually on the tricuspid valve, and that may be related to roughing of
the tricuspid valve in some way or other, making it a more likely spot for vegetations. And
remember, this is below the tricuspid valve and should not interfere with that, in our view.
So that's the sort of infection questions that I think were asked. Does that answer them
well enough?
DR. PAGE: I believe so. Thank you.
DR. STEINHAUS: Okay. And then, finally, there are two other questions. Finally, one
is we talked about the antiplatelet agents not being systematically looked at.
139
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
And then the final one is the question was asked about what material this is. Is this
just metal? And this is metal, it's titanium, but it is covered in Parylene. So there is an
anode and there is the tip, which are not covered, but of course the rest of it is covered in
Parylene. So the anode would actually be an anode.
DR. BRINKER: What is Parylene, exactly?
DR. STEINHAUS: It's a polymer compound. He's shaking his head yes.
DR. BRINKER: Okay. So by my way of thinking, that would be a site for infection to
take hold if they went sepsis. That's just a point. Obviously, you haven't experienced that,
but I don't think -- and primarily because the access -- the cause of infection is reduced
dramatically in those patients. But I think that that would make me more concerned than if
the device was completely metallic.
DR. STEINHAUS: Yeah, okay. That's all I have for the homework I think you gave me.
Did you think you gave me any more?
DR. PAGE: I'm looking at the Panel. And Dr. Borer?
DR. BORER: I have two questions.
DR. PAGE: Well, actually, I was asking whether there are any questions that we had
asked that they haven't responded to.
DR. BORER: Yeah, yeah.
DR. PAGE: Great. Go ahead, please.
DR. BORER: Yeah. One was specifically with regard to interaction with NOACs. I
heard NOACs come through in one answer, but I don't know what experience you have with
NOACs and whether there is concern about the interaction of the product with a NOAC.
140
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
DR. STEINHAUS: We don't have specific -- I don't have that available now. That is
obviously obtainable. We did look for that and the issue about it, but I couldn't separate
out the NOACs from the other oral anticoagulants in the data that I was able to gather in
that hour.
DR. BORER: Okay.
DR. STEINHAUS: So maybe we only get an A-minus on it.
DR. BORER: Also I believe that Dr. Lange asked a question about this. I didn't, but it
was of interest to me. You had one-third of your implants on the septum and two-thirds at
the apex, and the apex was more commonly associated with perforation. Pacemaker
syndrome, as I understand it, currently does not involve an assessment of interventricular
dyssynchrony, only atrial ventricular dyssynchrony. But it would be of interest to know
about interventricular dyssynchrony, and I'd like to know -- and, again, I think that Dr. Lange
asked a question along these lines. Do you have information about the effect, the
hemodynamic effect of putting the lead on the septum versus apex?
DR. STEINHAUS: We do not have that data. When we talked about septum, I think
mostly you have to realize that given the cant of the way the lead is set, it is likely to go to
the apical portion of the septum. It is not likely to go high up into the septum where people
would traditionally put septal pacemakers.
DR. PAGE: Thank you.
Dr. Cigarroa.
DR. CIGARROA: Certainly with transvenous leads there, in a large analysis
retrospective of several -- I think over 10,000 patients, apical RV lead placement was
141
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
associated with (a) greater occurrence of tricuspid regurgitation, (b) greater occurrence of
mitral regurgitation, and (c) a slightly lower ejection fraction, independent of impingement
on the tricuspid leaflet.
DR. PAGE: The data you're quoting is related to placement elsewhere in transvenous
leads?
DR. CIGARROA: So with transvenous lead placement at the apex versus the septum.
DR. PAGE: Thank you.
DR. STEINHAUS: Yes. Remember, when most people talk about septal placing, there
is a whole literature of that that we're aware of. They talk about more higher on the
septum than we would be able to get with this device at the current time without impinging
on the valve.
DR. PAGE: Dr. Steinhaus, as a former implanter, my general experience with any
active fixation lead was to try to be at the apical septum as opposed to the apex itself or
apical free wall. Are you implying that what you're calling septal placement here -- and I'll
be interested to hear what St. Jude says about this. When you're talking about septal
placement, is that what you're referring to, going down, sounding the apex of the RV --
DR. STEINHAUS: Yeah.
DR. PAGE: -- and then just pivoting just septal from that and maybe up the septum
slightly?
DR. STEINHAUS: I think that's basically true, and I am getting nods from the
implanters on the answer to this.
DR. PAGE: Okay, thank you. Dr. Brinker and then Dr. Lange.
142
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
DR. BRINKER: Just one quick question to emphasize my lack of knowledge about the
specific way the device makes its pulse known. So the cathode is at the tip?
DR. STEINHAUS: That's correct.
DR. BRINKER: And where is the anode?
DR. STEINHAUS: It's a ring, which is several millimeters from the end of the device.
You can actually see --
DR. BRINKER: It's still a short space?
DR. STEINHAUS: Yes, it's about the same spacing as a normal bipolar lead would be.
DR. BRINKER: Okay.
DR. STEINHAUS: What's the spacing? Eighteen millimeters.
DR. BRINKER: Okay. Is it possible to reverse polarity?
DR. STEINHAUS: I don't know the answer to that question. No.
DR. BRINKER: Okay, thank you.
DR. PAGE: Dr. Lange.
DR. LANGE: We're all going to be struggling with how to reduce the rate of
perforations and trying to identify what those risk factors are and the location maybe of
one of them. Your data are a little interesting because what you presented suggests an
inverse relationship. Of the 24 physicians that had implanted more than 10, 6 of those had
a complication or 25% had a perforation as a complication. Of the remaining 70, only 7
caused a perforation, which is 10%. What it suggests is the more procedures you do, it
doesn't become safer. Actually, your data suggests that it becomes a little bit more
dangerous.
143
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
DR. STEINHAUS: I don't know if we gave you per patient. Remember, we got to take
-- it's the number per patient, right? So if I only implanted 1 and I didn't get one and I
implanted 10 and got one, I may be a better implanter than the 1, right?
DR. LANGE: Correct. Thank you for clarifying that. I appreciate the comment.
DR. PAGE: Again, we're just looking for specific questions in follow-up to Medtronic.
But I just want to ask briefly, because this came up in the subsequent presentation, do you
have recommendations, or is it common practice to use a puff of contrast during your
implant? And do you have any statement or potential requirement for any specific sort of
high-fidelity or high-definition fluoroscopy?
DR. STEINHAUS: Let me answer the first -- the second question first because I'll
answer that, and I'll ask Dr. Kowal to answer the question about implantation. No, we don't
have any specific requirement for high-fidelity X-ray equipment.
DR. KOWAL: Robert Kowal, Baylor Health Care System.
So we had a series of recommendations involved in the education process to ensure
good visualization of location and leveraging the ability of fluoroscopy to go to various
views, RAO, AP, and LAO. Catheter manipulation techniques were also taught vis-à-vis how
the sheath interacted with the catheter itself to ensure that that was done safely. And then
there was some guidance relating to repositioning attempts. And if I can have that. So
there was no proscription about using contrast. But what the recommendation of the
steering committee was, was that if there was a need for more than two redeployments, to
take a few steps to make sure that the process was going smoothly. One was to ensure you
had adequate tip pressure and there were some cues based on fluoroscopy to make sure
144
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
that was going on; secondly, to remove the device and make sure there was no clot at the
interface; and thirdly, to use a puff of contrast to see -- to make sure where you were
relative to trabeculation. And then there was shifting position and then, lastly, considering
what the patient requirements were and whether or not, based on comorbid conditions,
you could accept perhaps a little bit higher threshold than you were otherwise trying to
target. And the target at the time -- the target of the trial was under 1 V with an R wave of
greater than five.
DR. PAGE: Great, thank you. Dr. Ohman.
DR. OHMAN: I have one follow-up question, and I may have misheard you. You said
that for your postmarketing study, you're going to target 200 sites. Put that in perspective
for me. Would it be fair to say we have about 1,500 hospitals putting in pacemakers in our
country? Do you see where I'm getting at here? It might actually -- and you have a learning
curve to some extent. So I'm trying to sort of balance out is that 200 going to be sort of
reflective on the total experience? And this is a wonderful disruptive technology. So we
should all learn as, you know, in medicine we sometimes learn from our mistakes the best,
and if I'm to follow up on that, most mistakes tend to happen in the low volume, at least in
interventional cardiology. I should be careful to state that.
DR. STEINHAUS: I think we can anticipate that as well. I think you're correct in
saying that we would typically go to the higher volume centers so that we can get
enrollment and one of the -- that is the problem. It's just a classic curve where, you know,
200 centers do most of the bulk of the devices. So I'm not sure exactly what that number
would be, but I would guess 80% in the first 200, and then it falls off rather dramatically. So
145
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
one of the criteria we usually use when we select sites is a site that has a fair number of
pacemaker procedures so that we can enroll. It doesn't help us if you're doing 10
pacemakers a year and you're going to enroll 1 out of 10. So we get one enrollment a year.
That would kind of slow us down. So that's the tradeoff of that.
DR. OHMAN: Yeah. So if I can challenge you just a little bit, then --
DR. STEINHAUS: Sure.
DR. OHMAN: -- because if the majority of the challenges are going to be in the other
20%, we're going to be at a loss. We're going to know what the best people can do but not
really what the worst people can do. And I hate to use those sort of terms. And today, with
electronic medical records, it shouldn't really be hard to capture everybody because we
really have facilities now that will be able to have all the data, if we really reached out and
did it.
DR. STEINHAUS: Yeah. Let me kind of answer you in two ways. First of all, this slide
might be helpful. This is from our study. This is the diversity of the implanted population
that we actually had. So this is the number of -- now we don't -- I can't tell you total
implants because I can only tell you the number of Medtronic implants, right? But if you
look here, you could see the difference between patients [sic] who did more than -- less
than 20 and more than 100. You can kind of see the numbers. There's obviously a curve
that isn't too surprising, I think, to see. So that's the first one.
And your next question was a challenge about -- give me the second.
DR. OHMAN: The second is that if complications are more likely to happen in the
low-volume centers and where we could learn from that as a physician entity group, we
146
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
should really learn about that, I think --
DR. STEINHAUS: Yeah.
DR. OHMAN: -- because that's where the sort of challenges might occur.
DR. STEINHAUS: And I think you alluded to the fact. As for electronic medical
records, which everybody has, we ought to be able to get to every patient. We do get to
every patient. I have every patient in a registration system. So whenever we do a patient,
that patient is in the system, and that's how we propose to look at this problem of what
people do at the end of service of this device, because that will follow a lot more patients,
all the implants we'll be able to look at in that situation. It's not perfect because you can't
-- you know, if somebody gets implanted with our device and then gets another device or
falls off the map or whatever, you don't find it. But it will actually find a whole lot more
than just the postmarket study will find. So that is, in fact, our plan.
The other problem is, of course, when you starting thinking about how would you
register, you got to have follow-up. It's not just the acute data. We're pretty good on the
acute data, right? What we're most interested in is finding out what happens 2 years,
5 years, 8 years later. And that, you have to have kind of almost documented prospective
follow-up. It's kind of hard to do that with a registry or something like that.
DR. PAGE: Thank you.
Dr. Kandzari.
DR. KANDZARI: You amplified or you hinted toward this in the latter comments here,
but if you could just amplify further this concept of the postmarket surveillance study. And
the real question is capturing what happens to these people at end of service. In a
147
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
traditional postmarket surveillance study, as you know well, it's 3 to 5 years, and we're
really interested in what happens beyond this. And so how do you logistically see capturing
the end of service or end of life events for these patients, or whether it's left in, whether it's
taken out, or when people transition to another device? If you could just provide more
clarity for us, that would be terrific.
DR. STEINHAUS: Sure. Well, this is a challenge. I mean, I'll admit that that's a
challenge. We do a pretty good job of chronic follow-up of our devices already. I think
you've seen -- most of the people in the room have probably seen our product performance
reviews. Every manufacturer has them. I think every manufacturer does a pretty good job
of that. You can tell how long the batteries last, whether there's a subset of batteries that
don't last as well. All of that is pretty well documented. We do that from a number of
different ways. Returned product analysis for one. A lot of them come back. We also have
CareLink follow-up. We have a Social Security database follow-up to see if people have
died. So there are ways we can get at this data.
I think the more interesting question, I think, which you raised, is how you get to this
problem the FDA wants to know about, which is what -- are people going to take these out?
And if they take them out, are they going to hurt people by taking them out? Or are they
going to leave them in? What's going to be that experience? If we just look at our 1,895-
patient sample size and we look at that, which would be large for a postmarket study, but a
reasonable sized study, then I think it's like you get 25 events in 5 years. Somebody
calculated that. It was somewhere in that ballpark. We'd like to get a whole lot more
events than that because you want to have some precision about what the data means, and
148
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
we want to get at least 250. I think by using this registration system, we've calculated that
we probably can get 250 in that period of time. Otherwise you're going to have to wait
until -- you know, the average life expectancy of our device now, through our trial and the
700 actual patients, is 12.5 years. So if you wait for that, I mean, you know -- and then, of
course, you're going to have attrition because some of the patients are going to die. This is
an elderly population. We need 1,895 patients to get 1,000 patients followed for 5 years,
and that's mostly because of mortality, right? So that's the problem, how you do this.
And I think the FDA has appropriately asked this question. We're going to have to
think about it as well, because I think also we are used to getting returned products back
when they're traditional devices, right? If there's a problem, we usually get them. Now,
what's interesting -- and we know that because we can compare the CareLink to what we
actually get back. But with this device, we really expect it won't be taken out. It will
probably just be left in place. So the ability, then, to look at that is going to be less. So
we're going to have to think hard about that, with the FDA, about how we can actually
follow these patients and get good data.
DR. PAGE: Thank you.
Dr. Slotwiner and then Dr. Yuh.
DR. SLOTWINER: To follow up on both of my colleagues' comments and looking at
the mandate we've been given by the FDA today, which is to look at this disruptive new
technology at the very beginning of its career, it seems like we're at a unique time to look
for long-range problems. And I'm wondering if Medtronic would consider an observational
registry that would include all patients, those such as children who would not probably be
149
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
studied otherwise, that would include other manufacturers and that could perhaps capture
the inevitable progress of these devices as they move to dual chamber and interact with
other devices.
DR. PAGE: Dr. Slotwiner, I'm going to put that very important question on hold until
we've -- rather than put Medtronic on the spot, because that's going to be something for --
rather than us asking what they think, I think we need to come up with what we think and
then see what we can arrange. And, again, I want to keep our discussion of the more global
issues to the global response to the questions. So right now I'm looking for just specific
questions for Medtronic regarding questions you had or their specific system and then
we're going to go on to the next presentation. And then, as a group, we will take all of
these issues one at a time.
Dr. Yuh.
DR. YUH: I was just curious. For your enrollment sites, do you require a cardiac
surgical backup on site? Given that this device is relatively easy to reposition and the
chances of perforation are higher with more frequent repositioning, do you have that as a
requirement or no? Do you envision that going down the line here?
DR. STEINHAUS: Sorry, we have not and we believe this is just -- I mean, when you
look at the complication rates of this device versus the regular pacemakers, which can also
do this, in every category, if you look at every patient, all the high-risk patients, they
actually do better with this type of therapy than with the other therapy. So we don't really
want to restrict this to only centers that have surgical backup, is our feeling about it.
DR. PAGE: And one more question or comment from Dr. Cigarroa.
150
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
DR. CIGARROA: Just a point of clarification. You had stated that you would envision
200 sites, implanting sites that would participate in new data in the real world. There are
170 at present, so 30 additional.
DR. STEINHAUS: We have 200 sites total. We do have the ability to get very quick
access or quicker access, I would say, to 170 centers because they belong to this network
that we already have. And that means that we've negotiated the contracts with the
hospitals, that means we've negotiated with the IRB that we can just put, you know,
something in and that's how that works.
DR. CIGARROA: So 200 existing with the opportunity to bring --
DR. STEINHAUS: Others. Oh, yes.
DR. CIGARROA: Okay.
DR. PAGE: Thank you, Dr. Steinhaus.
I'm going to suggest we move on to ask the representatives from St. Jude to address
specifically the questions that we put forth before the lunch break.
Welcome, Dr. Carlson.
DR. CARLSON: Thank you, Dr. Page.
Let's start with the MRI question. We've submitted data as part of our PMA
demonstrating that the Nanostim device is MRI compatible with 1.5 T devices and a full
body scan. We're in the process of developing data to address 3.0 T as well. We've
received reports of patients in the trial who have undergone MRI without incident. We
have not received any reports of adverse events related to MRI.
So let me call up this next slide here. So there was a question about the number of
151
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
cases, greater than or equal to 10 cases versus less than 10 cases. And this was an analysis
that was performed and reported in the New England Journal of Medicine, and you can see
the rate of adverse events, serious adverse events in the first 10 cases of a particular
physician/implanter was 6.9%, and thereafter it was 3.1%.
Now, having said this, this is not statistically significant, and you can see the p-value
there, and it's also based on a very small number of adverse events. In particular, I think,
on the right side, greater than 10 cases is two adverse events. And it's also based on a
relatively small number of physicians who had more than 10 cases: 13 at the time out of
100.
DR. PAGE: That's helpful, Dr. Carlson. Specifically in terms of these data, were they
collected before you had modified the recommended procedure in terms of the implant?
DR. CARLSON: Some of the cases on the left side were before, but I don't know
exactly how many. All of the cases on the right side were after.
DR. PAGE: Thank you.
Dr. Naftel.
DR. NAFTEL: Can you go back to that slide?
DR. CARLSON: I hope so. There it is.
DR. NAFTEL: Yeah. So as we have the discussions this afternoon, we really need to
pay attention to the numbers. So 3.1%. Everybody looks at that, including me, and says
wow, it's 3.1 and it's not 3.11 or 3.2. But if you put in parentheses how many cases that is,
how many events, it's two.
DR. CARLSON: Right.
152
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
DR. NAFTEL: It's two. That's all it is.
DR. CARLSON: That's why I bring it up today.
DR. NAFTEL: Yeah. So I'm going to say we're going to have to do this all afternoon,
because it sounds -- what is it, 6.9 versus 3.1.
DR. CARLSON: Yeah, 50% decrease.
DR. NAFTEL: Two events. So one event would be 1.5; three is what, 4.6. So you just
got to keep that in mind because it's going to be the whole thing about that bathtub curve.
DR. CARLSON: Yeah. We wanted you to know that as you're thinking about this.
DR. NAFTEL: Yeah. And I personally, on every slide like this, I'd put 3.1 (2 events).
DR. CARLSON: Two.
DR. NAFTEL: That's what I would do.
DR. PAGE: But similarly the number for the 6.9% is 20-something. So my question --
DR. CARLSON: Yeah, it would be 20, I think.
DR. PAGE: My question, Dr. Naftel, is just regarding two out of -- the confidence
interval is around 2 out of 64. It would be very broad. The confidence intervals of high 20s
out 462 --
DR. CARLSON: Good point.
DR. PAGE: -- would be sharper, wouldn't they? Okay, thank you.
DR. CARLSON: Good point. Okay, there was a question about threshold elevations,
and I think the question was when were those threshold elevations noted? Am I
remembering that correctly? I hope.
DR. PAGE: Yes.
153
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
DR. CARLSON: Okay.
DR. PAGE: And I thought you answered that.
DR. CARLSON: Well, I'm not sure I did.
DR. PAGE: Okay.
DR. CARLSON: But it's a quick answer. They were noted at implant or within 72
hours of implant. You may ask, well, why did they leave the device in at implant? And for
whatever reasons, they were thinking that they would decrease. They did not.
DR. PAGE: I thought you showed us that there were a number that were removed
because of threshold elevations --
DR. CARLSON: These were the four patients. These were four patients whose
devices were removed, were retrieved because of elevated thresholds. And I think the
question was when were those thresholds noticed to be high?
DR. PAGE: Great, thank you.
DR. CARLSON: Thank you, Dr. Page.
Okay, the next question we'll address has to do with the deaths, and I'd like to ask
Dr. Cooper to come to the podium. Dr. Cooper was the head of our clinical events
committee.
DR. COOPER: Thank you. Josh Cooper, Director of EP at Temple University Hospital
in Philadelphia.
We had sort of a very -- a philosophy of guilty until proven innocent in our CEC, and
that if there was any possibility that the device or the procedure could be implicated in a
complication, particularly a death, then we said let's implicate the device. In terms of the
154
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
deaths we saw, it basically is reflective of the patient population in whom these devices
were implanted. And when you see the deaths here -- I'm sorry for the small type there --
most of these deaths were not at all cardiac related and not related to the procedure.
DR. CARLSON: This is in the Panel pack.
DR. COOPER: Oh, okay. So you have it in the Panel pack. The bottom line is, is that
this reflects the old and sick population, and these patients died of other things such as
renal failure, liver failure, respiratory failure, and we had very good documentation of
follow-up of the device performance leading up to that death. So pacing thresholds were
good. Pacing was seen. Most of these patients were not pacemaker dependent, and the
circumstances of death, in general, were actually very well described. Even patients who
had cancer and were in hospice programs, the details of the death were very carefully
detailed. And if they were not, then we solicited additional information to try to tease out
what exactly happened. And the bottom line is, is that this reflects the population rather
than the device or the procedure.
DR. PAGE: And just for the record, if I'm reading it correctly, there were 28 deaths,
and you felt firm in your adjudication that 4 of the 28 were cardiac.
DR. COOPER: Were cardiac in nature, correct.
DR. PAGE: Thank you.
Dr. Lange.
DR. CARLSON: Thank you, Dr. Cooper.
DR. LANGE: Wait. Expand on that just a bit because -- and so there are some that
are clearly cardiac. Some of the unknowns I was having difficulty with.
155
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
DR. COOPER: Yeah.
DR. LANGE: There's a sudden --
DR. COOPER: Right.
DR. LANGE: -- without worsening heart failure. There's some that have worsening
heart failure but weren't adjudicated as cardiac.
DR. COOPER: Sure. So we abided by the definitions that were provided to us as the
CEC, and the definition of sudden was basically within 24 hours. If the patient had been
sort of seen, was alive and well and then was dead within a 24-hour period with no
antecedent illness, that was thought to be related to the cause of death. So there were
patients who -- just let me go back. Unknown deaths does not necessarily mean that it was
unknown whether it was related to the device or the procedure or not, but we couldn't
specifically characterize the death as renal failure versus liver failure versus respiratory
failure. And so we tried to pinpoint an organ system implicated in the cause of death. And
if we could not, even with solicited documentation, then we listed it as unknown. And,
again, it's unknown in terms of organ system of death.
In terms of patients who had heart failure leading up to death, if the medical
records, outpatient records, inpatient hospital stay, nursing notes from hospice care listed
heart failure as a potential -- as a diagnosis that was ongoing, then we adjudicated the
events are per our directive, that heart failure was present prior to death. In terms of heart
failure being the cause of death, if the patient, in general -- and there was only really one
patient who was adjudicated as dying of heart failure. It was very well documented that
that patient had progressive heart failure, and it was not thought to be caused by the
156
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
device. But this patient had a cardiomyopathy and congestive heart failure as presumably
the mode of death.
DR. LANGE: I guess there are two issues -- one is if the cause of death was cardiac or
not.
DR. COOPER: Right.
DR. LANGE: The second issue is whether it's related to the device or not. And it just
appears that several of the deaths -- you have a sudden death or if you have -- and there
are three or four patients there. And if you have non-sudden with worsening heart failure,
to me those appear to be cardiac caused. Now, whether they're device related or not is a
different issue.
DR. COOPER: Right. And, again, these definitions perhaps could be tweaked in
retrospect. But there were patients who had, for example, a pneumonia death but had
heart failure in the weeks leading up to that death. So that was adjudicated as a non-
cardiac cause of death being pulmonary or pneumonia in nature, but they did have
documented heart failure leading up to it. Why it was felt in our directives to include
antecedent to death heart failure as a present condition as opposed to a cause of death,
that was part of, you know, the rules that were outlined for us.
DR. PAGE: Thank you, Dr. Cooper.
Why don't you go ahead and proceed, Dr. Carlson.
DR. CARLSON: Thank you, Dr. Page.
There was a question about enrollment by operator, and I addressed this already,
but I'll show you a slide that's very similar to what you saw from Medtronic, which shows
157
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
the number of patients and the operators on the x-axis. And you can see again that there
were -- this is in 526 patients, I believe. Yes. And there were, I think, 13 patients -- 13
physicians who implanted more than 10 leads.
Okay, a question about anticoagulation. And my answer will be very similar to
Dr. Steinhaus' in that we do not have information about NOACs versus warfarin at the time
of implant and patients who were taken off them for a few days or at the time of the
implant. So I'm not able to address your question, Dr. Borer.
A question about the volume of the puff of the opacification agent, and that's 4 to
5 cc.
And then to address a question that Medtronic addressed as well, in terms of rate of
enrollment and how quickly we're modeling to enroll in this study, we believe that we can
enroll the requisite number of patients within 2 years. If somebody could pull up -- well, I
don't even know that we need to pull up the slide. But we're modeling, when we activate
all of the centers, to enroll up to 90 patients per month. Now, it will take some time to get
the patients -- pardon me, all the sites up, but once we do that, we anticipate that we'll be
able to enroll at a rate that's similar to the IDE study.
The IDE study met its timeline, which I think everybody in here would recognize as
unusual. There's a lot of excitement about this technology, and we anticipate that we'll be
able to do so. We also anticipate that we'll have 475 active patients at the end of 9 years,
and that by that point we will have 203 devices that are at end of service and for which we
will have information that the FDA is interested in about whether they're retrieved,
whether they remained, whether they're there in combination with another device. This is
158
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
a very conservative estimate. You can see that we're modeling the end-of-service rate to be
flat across that time, which is extremely unlikely. It's likely that for reasons of change-outs
for upgrades and things like that, that that rate will actually increase as time goes on.
That completes the questions that we had to answer.
DR. PAGE: Thank you very much.
Are there any questions or comments specifically for St. Jude from the Panel?
Yes, Dr. Naftel.
DR. NAFTEL: The end of service, does that include dead people?
DR. CARLSON: It does not. These are devices where we'll have information about
how the device is managed after end of service, and we're choosing end of service because
end of life with regards to a device implies battery depletion, of which we expect to see
very few and have not yet. And end of life on the patient side has other meanings.
DR. PAGE: Dr. Zeitler.
DR. ZEITLER: One question. I don't believe that we discussed the issue of
dislodgement with embolization of the six -- there were six devices with dislodgement and
embolization. And I'm just curious, were those events discovered based on symptomatic
presentation, or was there some sort of screening X-ray or other imaging to detect them?
Or what were those presentations like?
DR. CARLSON: They were all reported within the first 14 days. All of them were
retrieved without issue. There was pacing. I know that in some cases patients had fatigue.
I don't know of any cases where it was picked up on X-ray, although that may have been the
case.
159
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
DR. PAGE: Thank you.
Dr. Cigarroa.
DR. CIGARROA: Just a clarification on MRI conditional. Are patients who are pacer
dependent, would they be able to undergo an MRI? I know that we have an investigational
process --
DR. CARLSON: Yeah.
DR. CIGARROA: -- where we perform MRIs on patients with pacemakers, but there's
exclusion criteria of pacemaker dependency.
DR. CARLSON: I don't know that we would exclude pacemaker-dependent patients.
I think that's a question for conversation with the FDA and our engineers. The idea would
be either to program the device off or in the OO mode at the time of the scan.
DR. CIGARROA: Thank you.
DR. CARLSON: The definition of pacemaker dependence is another rabbit hole I
don't want to go down.
DR. PAGE: If there are no further questions for St. Jude, thank you very much,
Dr. Carlson.
DR. CARLSON: Thank you.
DR. PAGE: I want to ask the FDA, are there any further comments or statements for
the Panel at this time?
DR. ZUCKERMAN: No, I think we're good to go into the next section, Dr. Page.
DR. PAGE: Great. It's now quarter of 2:00. What I'm thinking is we could take a
10-minute break, if that would work, and then we will address the questions and work on
160
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
those until the close of the meeting, however long that might take. Does that work? Okay,
we will be adjourned until 2:00 even, let's say. Thank you.
(Off the record at 1:46 p.m.)
(On the record at 2:01 p.m.)
DR. PAGE: Okay, I'm going to bring the Panel back to order. We will now address
the FDA questions to the Panel. Panel members, you can find a copy of the FDA questions
in your panel folder. I'm going to ask representatives from the FDA to read the questions
for us, and then I'll stop you along the way because each question has several sub-
questions, and I want to address one at a time. Ms. Patel will read the first question;
Dr. Lewis, the second; Ms. Dorfman, the third; and Dr. Selzman, the fourth question.
So, Ms. Patel, would you like to go ahead and read Question No. 1 for us?
MS. PATEL: Sure.
Question 1A reads: Please discuss the clinical significance and any concerns you
might have for the rate of occurrence of each of the following adverse events observed to
occur at implant with leadless pacemaker devices as compared to traditional pacemakers.
This would include cardiac perforation, pericardial effusion, dislodgement, embolization
(i.e., acute migration during implant necessitating retrieval), or serious groin complications
necessitating repair or transfusions.
DR. PAGE: And I'll stop you there just in terms of the Panel or -- is there anything we
should add to this list?
Seeing no additions, if we come up with anything more, we can do so.
Ms. Patel, please go ahead, and I'd like to kind of combine the discussion with the
161
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
second and third parts of Question 1, so go ahead and read B and C.
MS. PATEL: Question 1B reads: There were certain subgroups that were reported in
the published studies as having a possible increased risk of a cardiac perforation during the
implant procedure, i.e., female patients and patients with a low BMI. Based on the adverse
event rates associated with leadless pacemaker devices, is there any subgroup you would
exclude from receiving this device or that you would specify in the labeling?
Question 1C reads: Please discuss what measures you would recommend to ensure
that implanting physicians are adequately trained and informed regarding adverse events
and appropriate device and patient selection.
DR. PAGE: Okay, I'm going to first draw our attention to parts A and B, and I'm
looking for any comments from the Panel with regard to these two questions.
Dr. Kandzari.
DR. KANDZARI: Actually, as Chair, can I ask a clarification, a provocative question
now, and that is that we're under the assumption we're considering these technologies as a
class effect; is that right? Can you clarify that?
DR. PAGE: Yes, we are. We're not in a position to compare devices. We've learned
of one device on the horizon and two that have significant experience, but we, as a group,
are here to discuss what are the class risks, what are the class-risk patients at greatest risk,
and eventually how we can mitigate against those.
Is that meeting your satisfaction, Dr. Zuckerman?
DR. ZUCKERMAN: That's very well stated. Thank you for responding.
DR. PAGE: Dr. Yuh.
162
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
DR. YUH: I remember that one exclusionary criteria for enrollment was a dilated
right ventricular chamber. Should that be included in terms of risk for perforation?
DR. PAGE: Comments about that?
And just to confirm, that was a contraindication to the -- both studies?
DR. YUH: No, I think there was one study group, I forget which one, where it was an
exclusionary -- it was excluded from the study group, that category of patients. I don't
recall which device.
DR. PAGE: I'm looking for representatives from Medtronic and St. Jude just to
comment briefly as to whether -- I don't recall an exclusion for dilated cardiomyopathy.
Dr. Reynolds, please address the lectern and give your name.
DR. REYNOLDS: Dwight Reynolds, University of Oklahoma.
In the Micra trial, there were no exclusions for pulmonary hypertension, COPD, or
size of right ventricle.
DR. PAGE: Thank you.
Does St. Jude want to comment?
DR. REDDY: Sure. Vivek Reddy for St. Jude Medical.
In the Nanostim trial, there was no exclusion for right ventricle chamber size. There
was an exclusion for pulmonary hypertension set at 40.
DR. PAGE: Thank you for that clarification.
Yes, Ms. Dunn.
MS. DUNN: I, too, have a question. Can you hear me?
I do have a question about why female patients and patients with low BMI suffered
163
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
more cardiac perforations. Is that because of their size? And if so, I guess my question is
two-part; how would that affect younger patients, more fit patients, and the pediatric
population?
DR. PAGE: That's an important question, and I believe we have the expertise on the
Panel now in terms of implanting electrophysiologists who might comment as to the finding
of women, and especially elderly women, having higher risk for endocardial leads of either
leadless or standard pacemakers.
Does any one of the electrophysiologists want to comment on this, or shall I?
Dr. Slotwiner.
DR. SLOTWINER: Sure. So, in general, patients with smaller BMI have thinner right
ventricular free walls, are more prone to free wall damage, rupture, pericardial fusion,
vascular complications, as well. So it's not surprising or unexpected that we would see that
same trend here with this device. It's, I think, just a natural result of the physiology of that
group.
MS. DUNN: Is that also for pediatric patients, then?
DR. SLOTWINER: You know, it hasn't been studied in pediatric patients, as we heard,
and I'm not a pediatric electrophysiologist. I would imagine that similar risks are associated
in that group, but I can't speak with certainty about it.
MS. DUNN: Thank you.
DR. PAGE: Dr. Cigarroa.
DR. CIGARROA: I would simply add that within the pediatric population, they often
have associated other abnormalities which may, in fact, be associated with abnormalities of
164
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
the right ventricle, including right ventricular hypertrophy, so I think it just, it depends on
the actual patient and what their associated comorbidities are.
MS. DUNN: So just another portion. So was this a deliberate exclusion of pediatric
patients from the study because of this risk?
DR. PAGE: I believe the answer is yes, in terms of the enrollment criteria. Was there
an age, a low age cutoff for the two trials? I thought they were 18, is that correct, or --
UNIDENTIFIED SPEAKER: Correct, yes.
DR. PAGE: So, indeed, that was the exclusion criteria for these clinical trials that
we've heard about today.
I'm going to open up the discussion a little bit. Cardiac perforation is -- are you --
we're specifically asked are you concerned about cardiac perforation, Dr. Slotwiner --
DR. SLOTWINER: Yes.
DR. PAGE: -- in this group? And tell us why.
DR. SLOTWINER: Yes. So to answer Question 1, part A.
DR. PAGE: Please speak up.
DR. SLOTWINER: I'm sorry.
To answer Question 1, part A, I am concerned about cardiac perforation. Clearly,
that is a potentially lethal complication, and it is occurring more frequently with these
leadless devices than with transvenous. I don't think it's insurmountable, but compared to
the transvenous device that we have, which is acceptable and a well-established technology
and applicable for most patients, I think we need to expect that this class of device have a
similar complication rate. So yes, I'm concerned.
165
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
DR. PAGE: That's very helpful. I'm going to take your comment in two parts.
First of all, I want to look around at the Panel and just see if it is other people's
impression that there -- this is a signal and there is concern that there is increased
perforation and effusion and potentially tamponade. And I'm seeing a yes from the Panel
there, as a class.
The other thing you bring up is something I think the Panel should address sooner
rather than later, and that is the following: we've seen a number of complications that may
or may not be higher with one device or lower with the other device. And as a panel, do we
feel that individual complications, specifically perforation and tamponade, should be
similar, or whether we as a panel should be looking at follow-up with regard to overall
complications? For example, pneumothorax. Clearly, there's a lower instance of
pneumothorax with the leadless pacemaker, and there is at least a consensus that I'm
seeing that there is likely a higher instance of perforation. But do we, as a panel,
recommend to the FDA that they look at each individual complication or look at the overall
important complications as a group?
Is that a fair question for me to pose to the Panel, Dr. Zuckerman?
DR. ZUCKERMAN: Yes. You are posing a question that we often see at panel
meetings as to how we look at both the totality of the data and individual endpoints and at
the end of the day come up with an appropriate benefit-risk assessment.
DR. PAGE: Thank you.
Dr. Cigarroa and then Dr. Borer.
DR. CIGARROA: So it certainly relates to the issue of cardiac perforation. I, too,
166
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
agree that it is a concern, but it's not insurmountable.
Two comments: When one has a different delivery system and associated rigidity,
different pressure points with which one has to engage due to the mechanism of fixation,
one would imagine that the rates would be potentially different, and therefore, I think one
needs to look at it in a device-specific way because there's so many different interactions.
And so I would say, yes, it should be looked at in a device-specific way.
And then secondarily, as I mentioned earlier, I think that it becomes important -- we
know that in transvenous lead systems, that especially in elderly people who are on dual
antiplatelet therapy, that rates of effusions are greater, and so I would also state an
understanding of the impact of dual antiplatelet therapy or antiplatelet therapy coupled
with antithrombotic therapy is also an important clinical issue, especially in this
demographic.
DR. PAGE: Thank you, Dr. Cigarroa.
Dr. Borer.
DR. BORER: Yeah, I agree with Dr. Cigarroa, but I think the impact of this question is
not specifically with regard to individual devices but with regard to individual complications,
and I certainly do think that the FDA needs to look at the individual complications rather
than the totality of complications. Down at the bottom of the list is serious groin
complications. I'm not terribly worried about that. You know, there are thousands and
thousands of catheterizations done from the groin every year with a variety of techniques.
The reason, I would guess, most likely reason for serious groin complications with this
methodology right now is the size the catheters that are being used, and that's likely to
167
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
come down with time. So I think those are relatively easily dealt with.
Embolization didn't occur very often. It's a concern, but cardiac perforation is a big
deal to me because it's potentially lethal, and if not lethal, it is also relatively likely to lead
to an additional procedure and perhaps open-chest surgery. I mean, this is a big deal, and
as I look at the data, although clearly we don't have enough numbers to be able to say this
with any precision, it looks as if there are about 50% more perforations with the leadless
pacemaker currently than with the conventional approach. And that is a concern to me,
and I think the FDA should be looking at that specifically, and at effusions.
Dislodgements and embolization were relatively uncommon, and dislodgement can
occur with either, so I'm not nearly as worried about these other complications as I am
about perforation and effusion, and I think that therefore the FDA really should be looking
at the complications individually, not in total.
DR. PAGE: I was not suggesting that they not look at them, but likewise the issue of
setting the bar as being equivalent for each individual one is one that I think we will need to
have to have a discussion about, perhaps.
Dr. Brinker.
DR. BRINKER: Thank you.
Well, I think Dr. Cigarroa made a very important comment, and that is that these
things, when you look at them, you -- I'm amazed that they aren't associated with higher
complication rates because they're rigid by nature of their construct. And we know, even
from the traditional leads, that when you use a stiff stylette, you have a higher incidence of
perforation. Secondly, the patient population here isn't the same as the patient population
168
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
in most of these other studies mentioned. They are older and they are more frail, and they
were picked, I think, purposely for getting the better part of the benefit that these devices
might offer them. So while I think it is a concern that there is this perforation rate, I think,
number one, that proper training and care is probably one of the reasons why the rates
seem to have gone down a bit or at least not increased as less experienced people get into
the game. But other modifications of the device over time will also probably be important.
That being said, I think that the benefits -- I think at the end of the game, the net benefit
and the -- over other alternative devices for this particular group of patients needs to be the
determinator and not a specific endpoint like the perforation data.
DR. PAGE: Thank you.
Dr. Ohman.
DR. OHMAN: Yes. So I see this a little bit like Dr. Borer. We have, what I would call
life threatening, where the closeness to the ultimate poor outcome mortality is very
significant, such as cardiac perforation. Even though dislodgement wasn't really --
dislodgement, not being the fact that the device leaves the ventricle, hasn't been something
that we've seen. It doesn't actually mean that we might not see it in the future. And so
that, I presume, would be a very bad outcome. Embolization being just in the first 24 hours
and serious groin are much less related to mortality than some of the others.
And there's two that are not on here that I'm sort of thinking a little bit about, and
one, shouldn't we really just understand what the correct mortality is? I mean, after all, we
know it's going to be low, but we certainly would want to understand it because in a new
technology disruptive like this, it would be very important to include that. And the final one
169
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
that is not on the list would be infection, because if these devices become infected, I don't
know exactly what we would do. I mean, you would obviously try to retrieve it, but we
don't know the consequences of doing that, as I see it right now. So you have some very
serious ones that I think are very appropriate. I think we're missing maybe one or two. But
I think they should be grouped in a sort of very serious/moderately serious, if they were to
be grouped together.
DR. PAGE: Dr. Yuh.
DR. YUH: I think I hate to harp on it with all the concern about perforation, and yes,
it is one of the ultimate complications. I think there should be further serious consideration
in terms of answering part B specifically in terms of subgroups that should be -- where there
should be caution. Is structural considerations -- I mean, why do they perforate, why do
these devices perforate? If it's not the technical expertise of the operator, is it a structural
consideration in terms of dimensions or the conformation of the right ventricle or the
placement of the lead or -- you know, the locale selection. I think more serious
consideration should be made towards that to mitigate -- you can't obviously eliminate the
risk, but to mitigate the risk in the setting of what appears to be a higher risk as opposed to
the conventional pacemakers with leads.
DR. PAGE: Let me ask you to clarify that, Dr. Yuh, because you bring up a very good
point. But as a prior implanter with standard pacemaker technology, if I was going to get a
perforation, it was going to happen with a standard system in an elderly, frail woman. So
are you suggesting that this population just be followed, or are you suggesting that it ought
to be avoided with the caveat that there -- I think the -- at least the electrophysiologists in
170
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
the room and the data would suggest that those patients are at high risk with either device.
DR. YUH: No, I think that's a very good point. And, again, as a non-implanter, I
probably don't have the same perspective and insight -- I know I don't -- as you do. But it
seems to me that there are certain things that you, as an experienced implanter, would
know would place a patient, a frail patient, at higher risk for perforation. And given that
this device has a class -- appears to have a higher rate of perforation anyway, isn't there
something else that we can do or look into more within reason to mitigate that risk?
DR. PAGE: Fair enough, thank you.
Dr. Karasik. I got it.
DR. KARASIK: Thank you.
So to follow up on that point, one of the things that sort of surprised me about all
this is we haven't really heard anything about imaging studies. Nobody's presented data on
what this looks like. You know, using echo at the time of implant, 6 months, a year out. We
don't really know how this device lays in the ventricle. You've shown us one picture where
it becomes completely encapsulated. But it might be interesting to be able to look at the
ventricle. I mean, we have multiple ways of imaging the heart, and maybe in frail, small
women we should somehow image the ventricle before we put it in so we know where to
go. We have all kinds of ways to map the ventricle and look at it, and I don't know if that
was ever used in -- you know, in any way in any of the clinical trials, but I really saw very
little mention of that in the supplemental information.
DR. PAGE: Any other comments about how imaging might help us in identifying
those at higher risk?
171
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
It's an interesting thought.
Dr. Cigarroa.
DR. CIGARROA: You know, certainly, I think that it is -- you know, even surface
echocardiography with 3D reconstruction helps, at least me, when I am doing difficult RV
biopsies in terms of location before we take tissue and I think that in certain subgroups
could, could be helpful. Now, again, as you begin to think about the interactions about how
many attempts, it might also place us in a false sense of security.
DR. PAGE: Thank you.
In terms of subgroups, there were a couple of groups that we've mentioned have not
been included. The pulmonary hypertension was not included in one of the studies;
pediatrics and patients with preexisting leads, we have no data for. Per Question 1B, are
there comments as to whether patients would be excluded or at least culled out in the
labeling in terms of these populations in addition to, perhaps, the groups we've already
discussed: patients on anticoagulation; certainly low BMI; elderly women? Comments
about pediatrics and specifically pulmonary hypertension?
Dr. Borer.
DR. BORER: With regard to -- I don't know about pediatrics. I mean, we have very
few data, and we need data to be able to draw some inferences, but with regard to
pulmonary hypertension or preexisting leads or whatever, I don't think that I've heard
anything that suggests that there's such a risk associated with this or likely to be, that these
patients need to be excluded from consideration. I think the point has to be made in
labeling or however else that you've got to be careful, that we don't have much
172
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
information.
But I'd like to go back for a moment and ask for a clarification. I'm assuming, in all
this, that what the FDA ultimately is focusing on is developing a set of OPCs for these
devices, objective performance criteria for approvability, because there certainly aren't
going to be randomized controlled trials of conventional pacemakers versus these new ones
for leadless pacemakers. And with that in mind, I would go back to what I said earlier. I do
think that data need to be available with regard to the individual potential adverse events
because that's what the OPCs would be based on. Is that what the FDA is thinking about
ultimately, developing OPCs for leadless pacemakers?
DR. ZUCKERMAN: Again, Dr. Borer, I'd like to focus the discussion more in a general
context of what you've seen from the FDA presentation as well as the sponsor
presentations this morning, is that several Panel members, including yourself, have stated
we've tried to cull out the major endpoints. We've given a certain weight to some of the
individual endpoints. We will be carefully looking at those point estimates, the so-called
OPC method, in addition to looking at the data in aggregate, and I think you've -- and other
Panel members -- have provided the FDA with, you know, a solution to 1A, if everyone is in
agreement with Dr. Ohman's recent point, that certainly infection should be on this list as
well as some assessment of cardiovascular mortality. I mean, it's a difficult multivariate
problem, and as Dr. Brinker pointed out, the patient populations are never the same, but
the clinical reality is that we need to utilize all these aspects to come up with a decision.
DR. PAGE: Thank you, Dr. Zuckerman. You did my job for me in summarizing 1A.
And I do want to move on to 1B, specifically subgroups that either should be culled
173
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
out or would not be. And even potentially not even included.
Dr. Cigarroa, Dr. Lange.
DR. CIGARROA: So, in short, I don't think that, of the inclusion patients in the data
that we reviewed today, I do not believe that any particular subgroup should be excluded.
As per your prior comments, same risk factors associated with transvenous placement in
terms of perforation. So I would not cull out any particular group to be excluded. I would
cull in, for whatever information we will be gathering in the future, that patients with
chronic kidney disease be included. As we know, complication rates in them with
traditional pacemaker leads are increased for both infection and bleeding and perforations.
DR. PAGE: Thank you.
Before I go to the other people who have raised their hands, is there consensus that
there's not any specific group excluded? I would mention that I personally would think that
the FDA should consider at least stating groups in which there might be higher risk, such as
frail, low BMI, and women. I think it should be mentioned that there is no experience with
preexisting leads, no experience with congenital heart disease in pediatrics.
And I think that's pretty well addressing part B, Dr. Zuckerman? Is that getting at the
question to the satisfaction of --
DR. ZUCKERMAN: Yes. I think you've given a good summary, Dr. Page. If I've heard
you correctly, though, even in the subgroups where there's no prior experience, this would
be noted in labeling, but those populations would not be contraindicated. In fact, I think
Dr. Love gave an excellent presentation today about the potential need for pediatric
investigation. We heard from Dr. Steinhaus that it needs to be done carefully. But, you
174
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
know, this is the sort of follow-up that FDA would like to hear about from the industry, how
can we get reasonable data in these other subgroups in a post-approval setting.
DR. PAGE: Great. And we'll be talking about the post-approval study in a bit. I
would like to just, since we have the expertise here, there was a mention of crosstalk, and
for those who don't understand, if you have two leads that bump together, there is
potential for crosstalk and actually sensing. And the issue of putting a leadless pacemaker
where there's a remnant lead, presumably endocardial pacing lead, is there any guidance
that we might give FDA that could eventually lead to maybe recommendations as to
placement of these devices? I'm looking for especially electrophysiologists to comment.
Dr. Slotwiner.
DR. SLOTWINER: I think we would need the manufacturers to give us that data and
explain exactly what the sensing antenna is and if there's any experience from animal data.
I don't feel like I would have enough --
DR. PAGE: Well, Dr. Slotwiner, you put in a lot of leads, haven't you, in patients who
already have a lead?
DR. SLOTWINER: Yes.
DR. PAGE: How do you place the second lead? The point I'm getting at, don't you
try to keep it so it's not knocking into the previous lead?
DR. SLOTWINER: Absolutely.
DR. PAGE: Okay.
DR. SLOTWINER: Yes. But there's --
DR. PAGE: I'm looking to the electrophysiologists first here just in terms of we're in
175
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
uncharted territory here, but as soon as this product is approved, if it were to be approved,
people would be putting it in patients, potentially, who already have a lead, and I just want
to at least, in anticipation of a leadless pacemaker going into another leadless pacemaker in
the future, that's something we ought to be thinking about. But right now, they might go in
next to another lead, and your recommendation would be put a little bit of territory
between the two leads?
DR. SLOTWINER: Yeah.
DR. PAGE: For the electrophysiologists in the Panel, are we comfortable with that
general recommendation given the fact that we don't have any other information?
I'm looking for concurrence. Okay.
Dr. Brinker.
DR. BRINKER: I'm not a card-carrying electrophysiologist, but I have done a few, and
I take out a lot of leads, but the history of crosstalk is one of physical contact between the
electrodes, not necessarily anywhere else in the body, of a lead. And I think it's practical
appreciation by anybody who's going to put in any pacemaker that the electrodes should be
near each other, near enough to touch each other. The more interesting issue that may be
applied, is there something -- since it's not clear to me that anything but the tip of this lead
is actually tethered, I wonder if interference with hitting the body of the lead with another
lead or a catheter or anything might have any provocation of electrical --
DR. PAGE: I don't think we know the answer to that, but I'm seeing Dr. Carlson, who
might be able to address it. And just briefly, we'd be happy to have both companies with
experience comment, the issue being given the fact that unlike all other endocardial leads,
176
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
this is tethered only at one end, has there been any experience where there was potential
for mechanical crosstalk or other mechanical issues?
DR. CARLSON: Yeah, we've done an animal study of 11 animals in which two devices
were placed adjacent to each other and touching each other along the length. We've got a
picture of it, if you want to look at it later. It was a 30-day study, and there were no issues
regarding pacing, sensing, or any mechanical issues whatsoever. And I think Dr. Brinker is
raising an important point. It would be very difficult to implant one of these in a way that
the electrodes would touch one another.
DR. PAGE: Fair enough, thank you.
Does Medtronic have any -- if it's a no, you can just shake your head. Good, thank
you.
(Laughter.)
DR. PAGE: That was a shaked head by Dr. Steinhaus, for the record.
So I'd like to move on to C. And, again, we're not talking about one device or
another; we're talking about a class. We've read C already, but specifically it's discussing
the measures that you'd recommend to ensure that implanting physicians are adequately
trained and informed regarding adverse events and appropriate device and patient
selection. I'm looking to -- for comments.
Dr. Kandzari.
DR. KANDZARI: So this also translates from the certain subgroups that might be at
increased risk for perforation. But as I recall, the forest plot, that although statistical
significance aside, the greater predictor, greatest predictor was the number of attempts,
177
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
and when you exceeded what was a 10 or more, it seems like the complication rate really
increased. And so I think that with regard to physician training and coinciding with
predicting subgroups, that that needs to be an important lesson learned. The other that's
not mentioned, but the sponsors referenced this from their clinical trials, is that if you have
patients with a left bundle branch block, for instance, we know this from right heart
catheterization, that we can induce asystole in these individuals, so consideration of
transvenous or backup pacing is essential, as well.
DR. PAGE: Dr. Cigarroa.
DR. CIGARROA: I agree with both points, and it's interesting with regards to the first
point that you mentioned. Sometimes the more comfortable we become with hardware,
the more willing we are to try multiple different positions, and paradoxically, we could be
placing, even if one were experienced, placing that patient at an increased risk of
perforation. So I think that should be included in training. I think the inflection point, at
least, one of the slides, may have even been with fewer than 10 in which the event rate
went up.
DR. PAGE: Thank you.
So we saw two different styles of training. One, for one, there was the hospital or
the non-hospital for the first one and then hospital for subsequent at that institution. Does
this give us enough guidance and the FDA enough guidance in terms of assuring that
physicians are adequately trained?
Dr. Lange.
DR. LANGE: It seems like there were two approaches. One is where you train a
178
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
person at your site and then send him off to train everybody else at the hospital as opposed
to the more rigid, where there's several modules that everybody goes through. I feel more
comfortable with the latter than the first. You can imagine where the quality of the
individuals who go to the training and are able to train other individuals in their experience
would be varied, and so I don't think that's very adequate.
The other thing I want to highlight is you mentioned, in terms of adverse events and
appropriate device and patient selection, not only appropriate device but appropriate
placement; that is, we need to know whether it's apical or whether it's septal or not when
we look at complication rates going forward. We need to have that information.
DR. PAGE: So you would advocate that the location of the device in post-approval
data would be recorded?
DR. LANGE: It would be recorded so we can determine whether there's a difference
in terms of perforation.
DR. PAGE: Thank you.
Dr. Cigarroa and then Dr. Slotwiner.
DR. CIGARROA: So I'd like to focus a moment on vascular complications. You know,
when we look at the demographic of age 80 and we look at the percentage of female
gender being included, even though we do these procedures day in and day out, most
operators are not used to using systems that are larger than 6 French or 7 French unless
you are implanting structural heart devices or aortic endovascular devices. And in some of
the documentation I read with regards to training, the vascular access training was left to
the individual sites, and I would state although there are comments that ultrasound should
179
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
be used, that going from implanting systems through 6 and 7 French is vastly different than
18 to 24 French systems. And I would emphasize in the training that that should be part of
it. I know that in the trial it wasn't, but if you take a look at, you know, the classic trial
representation, you're also looking at operators who are used to operating in a structural
space.
DR. PAGE: Very good point.
Other comments?
Dr. Kandzari.
DR. KANDZARI: One of the other considerations for us is not so much instruction
with regard to the implantation technique, but also to make some statement to operators
with regard to what to do about removal. I mean, right now removal is buyer beware or do
it at your own risk, right? I mean, we've heard even from the sponsors variability or
inconsistencies about recommendations for removal are not -- and to be fair to everyone
here, we don't -- we're just not going to capture that data for some time. And so I think
that there needs to be some general statement, however, with regard to consideration of
removal, that it needs to be very individualized, and time may be an important factor, the
time of implant may be an important factor.
DR. PAGE: You raise a very important point. I see that as more -- that we'll cover
that more in Question 3, if that's okay with you, Dr. Zuckerman. But we do need to have a
robust discussion about that and whatever recommendations we can provide. But I'm going
to hold the question of what to do, extract or leave in, to Question 3.
Dr. Slotwiner.
180
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
Well, actually, before we go on, Dr. Slotwiner -- Mr. Frankel, you had your hand
raised earlier. I'm sorry I didn't call on you.
MR. FRANKEL: I just want to ask for clarification regarding the age because on the
one hand, the data shows that we're talking about around 75-80 or a little bit older than
that. On the other hand, we're talking about potential for multiple implantations in the
data also, and then we're at the same time talking -- I saw one slide saying that it's primarily
going to be patients where it's a one-time implantation. So I just wanted to just get a better
clarity in that sense, how we're viewing this in terms of the use presently, how it's going to
be labeled in the age, because I know that it was addressed a couple of times; I just wanted
a little bit more clarity in that sense.
DR. PAGE: Thank you for bringing that up. It's a very important issue, and it gets to
the issue of being patient centered and making recommendations around the age and what
is the likelihood of outliving your device. We do this with cardiac valves.
Any comments from the Panel in terms -- we've talked about the -- we're not
excluding older age, and we're not actually recommending not to implant in younger age
based on our discussion, but -- and we should always have comments about being patient
and family centered and making, giving the opportunities. But in what way might you couch
that discussion or decision as to someone who might live through two or three devices?
Dr. Cigarroa raised his hand.
DR. CIGARROA: So I think it goes to the heart of shared decision making, and I think
that when there are different sets of complications and different implications -- and, you
know, I would state that, you know, avoidance in a young individual of transvenous leads
181
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
that result in tricuspid regurgitation in a third of patients is not to be underestimated, and I
think it simply goes to shared decision making going through; it's like a chess game. I mean,
you know, there will be a series of moves, and one should at the outset have those
discussions. And I think that as a person who sees lots of general cardiology patients, we
have an under-appreciation of the impact, especially in young people, of the risk of
significant tricuspid regurgitation over the many years and the impact that has on RV
function. So I would not let age dissuade me here, but there's simply a series of discussions
and points regarding acute complications and chronic implications as we look at things 10
years, 15 years, 20 years down the road.
DR. PAGE: Thank you, Dr. Cigarroa.
I do want to keep us moving, but Dr. Lange has a comment.
MR. FRANKEL: I was going to follow up directly to --
DR. PAGE: Yes, sir.
MR. FRANKEL: I'm sorry.
How do you view, in terms of the concern of infection, the unknown question?
Sometimes you have to weigh the known variables versus the unknown variables as far as
risk is concerned. So to the point of what you were just making with the younger patient,
the unknown risk of it, you know, a ticking time bomb, so to speak, if extraction is not
possible for certain devices and there might be a risk of infection, how would you weigh
that overall?
DR. PAGE: I think you're bringing up a good question. I'd like to open it to others
beyond Dr. Cigarroa, and that is the issue of infection as a risk. We've learned something
182
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
from the data already. Do we think that this device is more likely to become infected or
less likely to become infected?
Now, Dr. Cigarroa.
DR. CIGARROA: So given the absence of the issue of pocket hematomas and
infections and the fact that we believe that it will become encapsulated, I personally believe
that the overall risk of infection -- now I'm extrapolating as I look at the multiple
components of a transvenous lead system versus this individual device and where it's
located and what it's not doing to the tricuspid valve. I would say it is an unknown issue,
but I personally believe that the overall infection rate will probably be lower, but that if it
does happen to be delayed and it is encapsulated, that could pose a serious issue, including
the need for an operation.
DR. PAGE: I'm going to go out on a limb here and state that I believe the consensus
would be it is no more of risk of infection based on what we've heard and perhaps less? If
anybody has a contrary perspective, speak now. And we did hear of 15 devices, of patients
in one of the series who were documented bacteremia or septic who cleared their infection
with this device in place without an explant, which provides small numbers but some
comfort.
Dr. Lange, did you have a quick question?
DR. LANGE: I'd just say, in the shared decision-making process, my urge to the
companies and the FDA is we have to provide material that the patient can understand that
tells what we do know and what we don't know so they can be a part of that decision-
making process.
183
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
DR. PAGE: Very well stated.
So, Dr. Zuckerman, if I may summarize for Question 1C, I think there's consensus that
there needs to be a robust training mechanism for physicians who are going to implant.
This would include understanding that the more times you're repositioning, possibly the
greater risk, the various higher risk groups, the fact that left bundle branch block patients
may develop acute complete heart block as you're manipulating that large sheet. The issue
of vascular access is a big deal. A lot of electrophysiologists are used to working up here
and not necessarily with a sheet of that size. And at the heart of this, and everything is
shared decision making and being patient centered in terms of recommendations and
providing information for patients and their families to make an important decision. Does
that answer Question 1C to your satisfaction?
DR. ZUCKERMAN: Okay, I think those comments have been very helpful to underline
the importance of a good training program so that the right patients in the end are selected
with hopefully a minimum of complications. Thank you.
DR. PAGE: Thank you very much.
I'll now ask Dr. Lewis to read Question No. 2.
DR. LEWIS: This question will ask the Panel's opinion on the structure, size, and
content of the post-approval study. I will break the question down into four sections to
address acute 30-day performance, long-term performance, device issues at end-of-life, and
the device issues when placed next to an abandoned transvenous pacemaker lead.
Let's start with acute: Acute performance can be defined as 30 days from implant,
which includes both the pre-discharge or 24 hours post-implant data and the post-discharge
184
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
to 30 days data. Based on current publicly available data, the adverse events most likely to
occur within 24 hours include groin complications, hematoma, vascular issues, and
perforations. The events most likely to occur between 24 hours and 30 days include
dislodgements and threshold increases.
Please indicate which acute performance issues you believe should be captured
through collection of post-approval data. If there are other issues you believe should be
captured through the collection of postmarket data, please discuss those as well.
DR. PAGE: I'm going to put us on hold right there, and I'd like comments from the
Panel. We've talked about some of these acute issues already, but I'd just like to hear from
you as to if you want to refer to Question 1 or what other specific events you want to
capture in the acute period.
(Pause.)
DR. PAGE: I'm asking the Panel.
Dr. Slotwiner.
DR. SLOTWINER: I don't know. It didn't seem too much of an answer, but I guess if
patients required upgrade to a different system, if patients develop pacemaker syndrome or
heart failure --
DR. PAGE: Speak up a little bit, please.
DR. SLOTWINER: Oh, sorry. If patients required an upgrade to a different system, if
they developed heart failure or pacemaker syndrome acutely.
DR. PAGE: So you'd want to keep track of whether there's a requirement for an
upgrade. Again, right now we're looking at 30 day.
185
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
DR. SLOTWINER: Yeah, it's probably a short time period, so --
DR. PAGE: But potentially pacemaker syndrome. And just to help things out, we've
listed five in Question 1A. Those seem to be excellent candidates to me. We've added
infection as well as mortality. Are we capturing everything there in terms of the events?
Dr. Kandzari and then Dr. Zeitler.
DR. KANDZARI: One additional in looking at the reasons for revision have been
incomplete capture or unacceptable thresholds, and that seems to occur early, at least in a
reasonable number of patients, so I think that should be added.
DR. PAGE: Thank you. Failure to capture. Would you add failure to sense, as well?
Why not?
DR. PAGE: Dr. Zeitler.
DR. ZEITLER: That was largely my comment, just acute electrical performance seems
to be absent from the list.
DR. PAGE: Well stated. Acute electrical performance.
Other additional events we should be capturing?
So in response to Question 2A(i), we're providing a number of events that have
already been listed. We added mortality, infection, and acute failure to sense/failure to
capture. Does that meet your satisfaction, Dr. Zuckerman?
DR. ZUCKERMAN: That's very helpful.
DR. PAGE: Great.
Now, Dr. Naftel, I hope you're ready to be put on the spot as we consider issues of
sample size for the post-approval study.
186
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
Dr. Lewis, would you please read 2A(ii)?
DR. LEWIS: 2A(ii). Again, acute. The post-approval study sample size dictated by the
desired precisions and confidence interval range. For example, assuming a complication
rate of 1% and a confidence interval of plus or minus 0.5%, a sample size of 1,741 patients
would be needed. To put this into context, if a 5-year adverse event rate of 10% is assumed
for a cohort of 1,000 patients, the confidence interval width would be 0.038.
Please indicate which sample size is appropriate based on the table shown. Keep in
mind the high occurrence of acute adverse event rates for leadless pacemakers.
DR. PAGE: Thank you.
Dr. Lange.
DR. LANGE: May I just ask for a clarification? This must assume some duration of
the study, and the sample size you pick will obviously determine, be determined by how
long. So does the FDA have a recommendation? In other words, this 1,741, is that based
upon a 5-year study, a year study, 10-year study?
DR. LEWIS: It's coming up in a question.
DR. ZUCKERMAN: Okay. So excellent question, Dr. Lange. I think where Dr. Lewis is
going with this question is this is just the sample size needed to accurately assess acute
events. What you're pointing out is because we also have to look at chronic long-term
effects, I think both sponsors have shown us today that there's probably more than an
adequate sample size for the acute events, basically 1,700 patients, if I heard correctly,
because there's going to be such a large attrition once we get out to, you know, the chronic
time point. Does that make sense?
187
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
DR. LANGE: Not really.
DR. ZUCKERMAN: Okay.
DR. LANGE: Because I asked -- because you were talking about sample size for the
acute events, but this is looking at a 5-year event rate.
DR. ZUCKERMAN: That's the next part of the question.
DR. PAGE: If it's not clear, let me clarify. What we're being asked to look at right
here is over the 30-day acute period, how many patients would we need to enroll to
identify the complications at the rates we've seen with confidence intervals around the
target confidence intervals that you see there.
DR. LANGE: Thanks for the clarification. It helps.
DR. PAGE: And my impression is that -- yes, Dr. Borer.
DR. BORER: Yeah. I want to ask a question, I guess, that will get an answer. The
upper bound of the confidence interval here is 1.6% and -- great, thank you. And I'm a little
concerned about that. As I looked at the data, it seemed to me that what we were talking
about was probably something like a half a percent difference in incidence of events when
we look at the historical data from transvenous systems and the data from the leadless
pacemaker. That's a 50% difference. And given the large number of pacemakers that are
going to be put in, the potential for -- and I'm talking about with regard to perforations
specifically. With a large number of pacemakers that are put in each year, if a substantial
proportion of them were leadless, that could mean a fairly large number of individuals who
have a terrible event who wouldn't have had one. And I'd like to know with some
reasonable certainty that that is true or not true, and I don't think 1.6 will do it. I think we
188
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
have to have the upper bound of the confidence interval being lower than that.
I would want to know about a half a percent difference between the OPC that we set
up and a leadless pacemaker, so I think that the minimum sample size needed there, on
line 1, is sort of okay, but I would be happier if the sample size were larger so that we can
be more precise about the difference between what we're seeing and what we're looking
for.
DR. PAGE: Noted.
Other comments as to whether you analysts believe this is in the right ballpark? Or
Dr. Naftel, do you want to provide a comment? And keep in mind this is a post-approval
study. It's looking at a target complication rate as opposed to -- it's not comparing to any
specific population.
DR. BORER: No, it is comparing actually. It is. There is a presumed acceptable
maximum that we know historically from transvenous pacemaker systems, and that's what
it's being compared against, and that's what's determining what we want to see. So no,
there's no direct comparison, but there is an OPC.
DR. PAGE: Right. The issue is the OPC and what we think is the appropriate number
that we're willing to accept, but no prospective comparator.
Dr. Naftel, do you want to provide some clarity as to the numbers here?
DR. NAFTEL: I'd like to. So a couple things. I got confused reading this also. I
thought it was going long-term. So just a couple of technical details. A complication rate of
1%, remember rate is always per unit time, but presumably this is 1% in the first 30 days.
So it's real important about that. And then I need to talk to the FDA statisticians, because if
189
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
you look at the bottom line, 1% bottom row plus or minus 1.5%, so if you make a
confidence interval, you go into negative territory, which you can't do. Doesn't make sense.
And so what that tells you is we're in the wrong scale; we should be on the hazard scale
where you can have an asymmetric confidence limit. So I can talk to the statisticians later,
but when I look at the upper limit, the 95% confidence limit, I'm thinking maybe those are
asymmetric, like they're supposed to be. So I don't know where the top statisticians are.
DR. ZUCKERMAN: Okay. Dr. Naftel, actually it was an FDA epidemiologist who
worked this out. The bottom line is that you do have an asymmetric distribution. You need
to calculate an exact confidence interval. It's not symmetric. We can confirm that the
upper limit is about 1.6% if we assume a point estimate of 1% to, you know, respond to
Dr. Borer's comment. Certainly, if we increase sample size, which we haven't done, it's a
little bit unclear as to whether we get a big bang for the buck. For example, just doing a
sample size now of 2,000 patients, upper confidence interval is about 1.5%. So there's this
uncertainty that we're dealing with weighed against the fact that this is going to be a
difficult trial perhaps to enroll 2,000 patients.
DR. NAFTEL: What he said.
(Laughter.)
DR. PAGE: Fair enough.
To paraphrase Dr. Borer, the 1,741 is the best of the three but wishes there were
more. Is the rest of the Panel potentially satisfied with 1,741 or that ballpark? I'm seeing
heads nod.
So, Dr. Zuckerman, the Panel generally believes that the numbers put forward,
190
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
specifically 1,741, is reasonable assuming that it's calculated within the asymmetric target
interval to allow for 30-day complication rates. We'd always like more data, but we
understand the limitations. There is some concern that we would know more if we enrolled
more patients. Is that adequate?
DR. ZUCKERMAN: Yes. And off line we can look at increased sample size to see if it's
reasonable.
DR. PAGE: Great. Thank you very much.
Let's move ahead with Question 2, part B.
DR. LEWIS: 2B(i). FDA acknowledges that the long-term performance of leadless
pacemakers is not well understood at this time. The estimated longevity for these devices
is predicted to be anywhere from 6 to 12 years.
Please comment on the types of late device failures you would expect to be
important to capture, given the design of leadless pacemakers.
DR. PAGE: I'm going to stop us at (i) and just have us discuss and make sure we're
adequately capturing the long-term complications or problems that might be encountered,
and then after that, I think we're going to be able to take (ii) through (v). So let me have
panelists comment on the late device failures or complications that we should be
considering.
Dr. Slotwiner and then Dr. Zeitler.
DR. SLOTWINER: You know, I think the battery chemistry is new, and we always had
the opportunity to be surprised by battery chemistry down the road. And so I think we
need to be particularly cognizant of the fact that despite the engineers' best efforts, there's
191
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
no substitute for time in real life, so I think we have to be prepared for that.
DR. PAGE: Great, battery.
Dr. Zeitler.
DR. ZEITLER: I think that over the long term is the perfect opportunity to evaluate
device-device interaction, so not just other cardiac rhythm devices but even circulatory --
LVADs or other devices. That would be a real missed opportunity to not capture device-
device interaction over the long term.
DR. PAGE: Thank you.
Dr. Lange.
DR. LANGE: In addition, device failure or device malfunction either because of
exposure to MRI or to cardioversion.
DR. PAGE: Or even spontaneous device failure?
DR. LANGE: Even spontaneous, yeah. Electrical failure.
DR. PAGE: We've also discussed dislodgement, and again, the other possibility of
late dislodgement and embolization. So shall we include that among the potential
complications?
How about electrical sensing and pacing thresholds?
DR. KANDZARI: And infection.
DR. PAGE: Infection.
MS. DUNN: I do have a question. If a patient was to --
DR. PAGE: I'm sorry.
MS. DUNN: I'm sorry. I have a question. If a patient was --
192
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
DR. PAGE: And, again, for the record, this is Ms. Dunn.
MS. DUNN: Oh, thank you. Sorry.
If a patient was to contract a staph infection in another part of their body, would this
device need to be removed as a foreign object?
DR. PAGE: I'll hazard an answer to you, and I don't know that we know the answer.
It may relate to how long the device is put in place. There was the comment, the
presentation of 15 patients who had sepsis or bacteremia. They did not mention what
bacterium was involved that did clear, and there was one device infection that was
extracted by the St. Jude and -- one.
Dr. Carlson.
DR. CARLSON: Thank you. We had four infections, all of which cleared. Two of
them were staph; one was MRSA.
DR. PAGE: Thank you very much. That's helpful.
Other long-term. Dr. Naftel.
DR. NAFTEL: So we all like having an explicit list of potential adverse events, and I
think we always should, but this is one case, given that there's no long-term experience, I
think the unanticipated adverse events -- and I hate a text box like that, but I think that's
really important because it could be the battery. I hear batteries explode and things
happen. So I think this is one case where "unanticipated" needs to really be --
DR. PAGE: Good point. And one way we might capture those is devices going out of
service.
Mr. Frankel, you had a comment or question?
193
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
MR. FRANKEL: I think it was mentioned earlier about prophylaxis as to whether or
not what the recommendations would be for that in the short term versus long term
because -- is it going to be treated like a valve replacement in terms of whether in the long
term it will not be necessary, or will it be necessary in the long term as well as in the short
term?
DR. PAGE: The question of antibiotic prophylaxis, does anybody who has taken care
of these -- general pacemakers prophylax? HA no longer recommends that. I don't know
that we have any data for this device. I personally don't know that I would expect a
difference in prophylaxis for this device than a transvenous standard pacemaker, but I'm
looking to the Panel to see if anybody feels differently.
I'm not seeing any. So I think we would be mute on this, but there's not a specific
indication for that.
And there was another hand up. Actually Dr. Karasik and then Dr. Brinker.
DR. KARASIK: I was just wondering if we should look at things like thrombus
formation.
DR. PAGE: Say that again?
DR. KARASIK: If we should look at thrombus formation. There's been no discussion
about the thrombogenicity of the device. And although most patients will seem to have
atrial fibrillation and may be anti-coagulated, it might be interesting to know whether it
could be a nidus for clot formation. And then also this question about patients who are on
NOACs. I think there should be some way to capture information about pulmonary emboli
and things like that.
194
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
DR. PAGE: Okay.
Dr. Brinker.
DR. BRINKER: So just to get back to the question about prophylaxis. I agree totally
that there's no need for that except for the -- what we -- most all of us commonly do now is
procedural antibiotics. Now, I don't know whether you would even give procedural
antibiotic coverage for this being that it's a percutaneous event, but I wonder whether the
manufacturers have thought about that or mandated it.
DR. PAGE: Interesting question. Was antibiotic, prophylactic antibiotic coverage
provided for these clinical trials?
DR. REYNOLDS: Dwight Reynolds from the University of Oklahoma.
In the Micra trial, we left it to discretion of the individuals and recommended
generally that they follow their own, what they did with regular pacemakers.
DR. PAGE: And do you have data as to whether they provided antibiotics?
DR. REYNOLDS: We do have the data, but we don't have it off the top of our heads.
DR. PAGE: Okay. If you can give it to us in the next few minutes, that would be
great.
Dr. Carlson, were you going to comment?
DR. CARLSON: Dr. Page, same answer.
DR. PAGE: Thank you very much.
In terms of the implanting physicians, may I see a show of hands of who gives
routine antibiotic prophylaxis for pacemaker implantation?
(Show of hands.)
195
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
DR. PAGE: Let me see hands of anybody who doesn't.
(Show of hands.)
DR. PAGE: And does anybody think this would be handled differently from what
we're doing in a standard way?
So what we're seeing, Dr. Zuckerman, just getting ahead of ourselves, is that
generally antibiotic prophylaxis is provided. In terms of the longer-term complications, we
already went through those in terms of the acute complications, battery life, spontaneous
failure of the device, dislodgement with or without embolization, electrical failure, either
sensing or pacing, what happens with LVADs or other intracardiac devices. There is a
concern about potential thrombus.
And Dr. Kandzari may have another thought.
DR. KANDZARI: I think you can categorize it under dislodgement, but erosion would
be another important one.
DR. PAGE: Say that again?
DR. KANDZARI: Erosion.
DR. PAGE: Erosion.
DR. KANDZARI: So we --
DR. PAGE: Expand on that.
DR. KANDZARI: Well, we've seen many, many of the device implants, whether it's
valves, occluded devices erode into the myocardial wall and create VSDs, for instance, or
ASDs. So I don't think it's going to cause an ASD given its location, but that's the analogy.
DR. PAGE: Sure. And that might also fall into Dr. Naftel's "unanticipated," and one
196
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
way of capturing these would be devices that are taken out of service in terms of the
longer-term follow-up.
Dr. Zuckerman, does that adequately address this question?
DR. ZUCKERMAN: Yes. That's a very complete and helpful list.
DR. PAGE: Thank you.
We'll now go on with part B. And why don't we go through 2(i) to (v)?
DR. LEWIS: Question 2B(ii), regarding long-term outcomes.
Based on the current paradigm for post-approval studies for leads, a complication-
free rate is used as the endpoint for long-term performance. This rate usually includes
adverse device effects, serious adverse device effects, and complications (which require
invasive intervention or lead to death). Please comment on the appropriateness of using a
complication-free rate endpoint for leadless pacemakers or suggest an alternative endpoint
to evaluate the long-term performance of these devices.
DR. PAGE: And let's have you go through --
DR. LEWIS: Good.
DR. PAGE: -- the others, and we'll talk about how this trial would look.
DR. LEWIS: 2B(iii): Please provide recommendations for ways to ensure the
completion of a long-term post-approval study considering:
a. the difficulty in implementing such a study;
b. patients lost to follow-up over the course of a long study;
c. the ability to characterize end of life device failures; and
d. the ability to accurately collect device disposition when a new device is placed.
197
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
Question 2B(iv): Please comment on the ideal duration of follow-up time to assess
long-term performance of leadless pacemakers.
And, finally, when considering long-term performance and potential complications
that may occur, does this change the appropriate sample size that was determined from
Part A?
DR. PAGE: Thank you very much.
So, to summarize, these questions include the idea that a complication-free rate is
the endpoint for the long-term trial. As I read that, my only concern is there are different
complications, and a minor complication versus an embolization or sudden cardiac arrest or
failure to pace or whatever is different, but I'm interested in comments about that and
likewise the challenges of developing this study. And we'll hold off on the size of the trial
for now.
Comments from the Panel? Dr. Ohman and then Dr. Slotwiner.
DR. OHMAN: Yes. So this is an interesting dynamic, and we're all going to learn
together. I mean, quite frankly, we don't really know what this is going to look like 10 years
from now, and in that scenario, when we're going to learn together, the best approach that
we can take as a society, I believe, is to capture everyone. So everyone who gets one of
these devices should be in the registry, no matter where they're done and how they're done
because that's the quickest way for us to get answers to the unknown, at least as I see it.
DR. PAGE: So I guess I'm looking for clarity perhaps from FDA on this. These are
post-approval that are going to be involving consent; is that correct? You're envisioning
consent for the post -- the 1,700 patient post-approval study. Is that right, Dr. Zuckerman?
198
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
DR. ZUCKERMAN: Yes.
DR. PAGE: And on the other hand, what Dr. Ohman is mentioning is perhaps
mandatory registries or the fact that the device companies keep track of their devices
pretty darn well anyway, independent of that, and you're advocating in addition to this
post-approval study, because that's what we're talking about right now, some other way of
capturing failure of these devices in any number of ways, including battery, circuitry,
sensing, pacing, the same way leads are currently followed by the device companies; is that
right?
DR. OHMAN: Yeah. Well, to clarify my thinking here a little bit is that if you are
going to have a registry and you're going to have, let's say, 2,000 patients, and you are
going to try to get this information to all of us as quickly as possible, you might as well do
that in every site that actually does this procedure. We have had a very good experience
with TAVR, for example, where registration and the use of this approach, we had no real
knowledge how this would look 5 years down the line. Now we know quite a bit. And I see
this as a relatively infrequent use of a pacemaker technology in a very high-risk population
overall, and therefore, let's garnish all the information as we can.
DR. PAGE: Thank you.
Comments from the Panel.
Dr. Slotwiner.
DR. SLOTWINER: Yeah, I agree with Dr. Ohman 100%. I think this is a very disruptive
technology, and it's at the beginning of a career that none of us can predict. I think the
unpredictable complications are perhaps the ones that we need to be watching out the
199
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
most for, and we're up against a very established technology, single-chamber pacemaker,
so a very low or complication-free rate, I think, is what we should accept. I think that the
post-approval studies similar to TAVR and similar to the left atrial appendage device could
be perhaps nested into a registry, but I think we should capture every patient and capture
this technology as it evolves.
DR. PAGE: Well, let me just ask for clarification. The TAVR, for example, involved a
very limited number of centers that were doing that, and in that post-approval study or in
that registry, were those patients part of a study in which there was informed consent?
Because I see this as somewhat different. We're acknowledging there will be leadless
pacemaker, VVI pacemakers, placed in a number -- many, many hospitals, I would
anticipate, once it's -- if this were to be approved and if that is the case, or maybe I'm
thinking wrong, I'm looking to FDA for guidance on this, but the -- I can't imagine getting an
IRB approved in every little hospital that might be using this technology as opposed to the
registry for -- to keep track of these devices outside of the specific post-approval trial that
we're talking about here, about 2,000 patients, informed consent.
Dr. Zuckerman, can you give us guidance in terms of FDA's perspective on this?
DR. ZUCKERMAN: Number one, the informed consent is a difficult issue, as you're
pointing out. In the TAVR example, a central IRB was used, and there is a waiver of
informed consent. But I don't think, going forward, for a variety of reasons, that that's
going to be the model that may continue. So I think, Dr. Page, you're appropriately asking
the Panel to consider alternatives to what Dr. Ohman has presented. Certainly, that might
be the ideal, but I think the general issues that FDA would look for, given the disruptive
200
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
nature of this technology and the importance to get the data sooner rather than later, are a
controlled, responsible release from the sponsor, the ability to meet certain enrollment
endpoints at certain dates, training that includes training the investigators at sites for the
need for actually enrolling these patients in a post-approval study. Other, you know, key
things like this that if Panel members could mention would be helpful for all concerned.
DR. PAGE: So I'm looking at the Panel for further recommendations to the FDA.
Dr. Naftel.
DR. NAFTEL: So my comments have nothing to do with any companies that are
represented here today. We've worked in INTERMACS, the registry for ventricular assist
devices, we've worked with every single company that makes VADs, and every single
company early on said we know about our patients, we know what happens, we know
everything, and it's just simply not even close to true. I know Medtronic is a different
company, you make such an effort to follow your patients, but the fact is, depending on
data that the companies think they've collected, it just doesn't work. So in TAVR, I'm very
familiar with that, you know, a real live study with real endpoints and all that. That's
worked well. INTERMACS has worked extremely well. So I'm saying there's an opportunity
to learn a lot from the companies, but I'm leaning towards Bram, as I always do, that this
would need to be a real live study with inclusion/exclusion criteria. It would just have to be
a real study with real definitions, real everything. And that's --
DR. PAGE: And, Dr. Naftel, I think that's what we're being asked to consider, but are
you saying those would be the only patients who are receiving this device, or if that's a
subset of the patients that are receiving the device and being followed through alternate
201
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
means?
DR. NAFTEL: Subset of what?
DR. PAGE: Subset of a patient population receiving the device.
DR. NAFTEL: Yes.
DR. PAGE: So, again, the device release would not be limited to those in this post-
approval study, but the post-approval study would be conducted in a way that really
collects data in a way that we can trust is complete?
DR. NAFTEL: Yes. Now, on the other hand, FDA is always telling us that you consider
the totality of evidence, so if something does pop up at 10 years, the MDR system will --
that's another place to look. Certainly, working with the companies and all the information
that they do collect, that would be another place. And then finally this post-approval study.
So I'm advocating look at everything that we have at our use, just like FDA always does, but
have a study with inclusion/exclusion, informed consent, on and on.
DR. PAGE: And while we're putting you on the spot, if I may ask, did you comment
on the complication-free rate as an endpoint of this post-approval study?
DR. NAFTEL: Yes. Does it include death as a complication-free survival?
Okay, so if it does, then you have to remember these patients are 75, 80 years old,
so you'd have to be careful that you -- whenever you look at that event-free survival, you
need to have the U.S. life table or something right beside it so you don't get jaded because
survival of a 66-year-old is in question.
DR. PAGE: So if I may, looking at just a complication-free rate, including death, it
doesn't seem to be that useful. We need to look at the specific complications as they might
202
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
occur, including the unanticipated.
Dr. Lange.
DR. LANGE: Death has to be a part of it, because if someone adjudicates, well, they
died but it wasn't related to the device or not, that's very subjective. So I agree, it needs to
be compared, age adjusted, and what the norm is.
Let me come back to the study. It appears that we have about 170 sites that have
already -- are already approved to put these in, have been through the IRB approval rate.
And yet I don't understand all the intricacies, but again, I'll come back to what Magnus said.
The TAVR data were collected very quickly, so in a very short period of time, and the
patients were not cherry picked; they were pretty much consecutive patients that rolled
over a short number of years that allowed us to collect a huge amount of data. And to the
extent that we can do that with this technology, this disruptive technology, we'll ensure
that it's more accurate, it's quickly obtained, and it's done in a uniform manner.
DR. NAFTEL: Just one question.
DR. PAGE: Yes, Dr. Naftel.
DR. NAFTEL: And I don't know the answer to this, but TAVR is a joint project
between FDA and societies and all. I think the amount of money was huge.
DR. ZUCKERMAN: Okay, but I think the Panel has discussed several options. The
TAVR model, in its applicability to this particular case, could be stated perhaps as the
following: The industry was able to work together with the professional societies and FDA
to try to define an optimal infrastructure in terms of definitions, data collection, case report
form, etc., so that everyone wasn't reinventing the wheel, (a).
203
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
(b) There is potentially strength in numbers by combining data from a class. So
certainly the Agency would be willing to consider such a model if the industry might be
willing to propose it. I think there's also a role for the professional societies to strongly
underline the need for post-approval study data collection, and certainly, HRS and ACC
representative are here, and if the word can get out, I think that will be quite helpful.
DR. PAGE: Thank you.
So I think we should address (iii). Any comments specifically related to ensuring
completion and specifically addressing these issues? Basically, they're laying out issues
we've talked about, a fair amount.
Dr. Naftel.
DR. NAFTEL: Well, these issues are key, but it comes down to are you talking about a
prospective, professionally run study or not? All these things that's a professionally run
study with monitors and phone calls, are you enrolling and all that, so all these are totally
manageable with the right personnel and the right structure.
DR. PAGE: Fair enough.
Now, if we had this study generated and funded, would -- I'm looking for comments
as to the duration of follow-up. We've seen some estimates from industry. I don't
remember the numbers specifically off hand.
Dr. Lange.
DR. LANGE: Numbers from our -- 8 years in one study and 9 years on another, so
somewhere in the 8- to 10-year period.
DR. PAGE: And as I recall, that would allow for an estimate of 200 devices coming
204
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
out of service. Are we satisfied with that, in general? I'm looking around at nodding heads.
UNIDENTIFIED SPEAKER: Yeah.
DR. LANGE: And, Rick, we -- and we all know that follow-up is different. The first 30
days, the event rates you're looking at, what you're looking at is very different than what
you're looking at, your 1 to 10, so it's not nearly as expensive to do that study.
DR. PAGE: Right. And now for part (i) [sic], looking again at the table, which is
similar or identical to the last one, would we be satisfied with this number?
DR. LANGE: I was thinking 1,742, but it's just a thought.
(Laughter.)
DR. ZUCKERMAN: So let's take -- pause a moment, Dr. Page, because these are
critical questions. I think, for 3(i) [sic], we've indicated, as Dr. Naftel has stated, that a
study, whether it's run by a sponsor or an independent professional organization, has to be
extremely well constructed and take into account all these points listed, which are
challenging points.
The next question dealt with the fact that traditional lead studies run out to 5 years,
and I think one sponsor, Medtronic, offered that. St. Jude was a little bit further out for
their main study to 7 years. And I think I heard from the Advisory Panel that a study that
went out even farther to really understand end-of-life issues would be most beneficial here.
If we could just clarify that, I think it will be helpful.
DR. PAGE: Thank you.
Dr. Lange.
DR. LANGE: The clarification is for many individuals that we're going to present this,
205
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
this will be the only device they need and that was this device will outlive them. So I need
to think of how long the device lives, and that's hence the reason to go further than 5 years.
DR. PAGE: And also the issue of battery life. I think we need to follow these devices
one way or another, whether it's specifically in the post-approval study or in some other
way, because we're going to learn an awful lot between years 8 and 12 when these devices
run out of power and then need to be addressed and in large numbers will be addressed
one way or another, which we'll be talking about when we get to part C.
Dr. Cigarroa and then Dr. Ohman.
DR. CIGARROA: So, Dr. Page, I agree with you. I think that it is the different sample
sizes and duration of follow-up that were presented, I think that the year 9 with 475 active
patients, 203 end of service of the device will provide us that information. I think that going
5 years will not. And understanding how these devices are managed and what happens to
the patients becomes critical.
DR. PAGE: Thank you.
Dr. Ohman.
DR. OHMAN: So the benefit, if there is anything we would have suggested earlier,
was that if you take everybody, you will enroll everybody in the first 2 years. And so you
would actually really frontload your information, and then if you go with the calculation
that the mortality rate is 5% every 6 months, if I recall that correctly, by 5 years, half the
patients are dead. So in a way -- and that's not related to the device; it's just natural
history. So in a way, I think I'm advocating frontload, longer follow-up.
DR. PAGE: And frontload and very large study; is that right?
206
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
DR. OHMAN: Well, the sample size doesn't change.
DR. PAGE: And what is -- well, let's move on to the last part and the sample size, and
again, this is the post-approval study. This is not the overall population, I hope, one way or
another we're going to be tracking.
Comments regarding the numbers here with the target confidence interval with --
Dr. Brinker.
DR. BRINKER: Can I just have a clarification? The 1,700-and-odd patients will not
include people already being followed? Or what --
DR. LEWIS: It can.
DR. BRINKER: And so I'm not certain that -- I would bet that industry would like to
use those patients since they already will have almost all this period of time, 3 to 5 years
time in the bin and so we're not going to be starting.
DR. PAGE: It's the same population, right? For this. So we were okay with the
number before. Are we still okay with the number? I'm seeing -- help us out here.
DR. KARASIK: Okay, so then I need a clarification. There are approximately 1,000
patients who already have this device in, right? So if we're saying 1,741, we're only adding
700 new data points.
DR. PAGE: No, I was interpreting this as 1,741 new patients --
DR. KARASIK: Well, that's --
DR. PAGE: -- in a post-approval study --
DR. KARASIK: No, that's not what he just asked.
DR. PAGE: -- being registered. Okay. Thank you for bringing up that. I was
207
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
assuming the post-approval study was new real-world collection, but I'm looking to the
Panel as to what you thought we were talking about. And maybe we should ask FDA what
you were talking about.
DR. ZUCKERMAN: Okay. I think if we could pause a moment and ask each sponsor
what they were thinking about when they noted the number 1,700. The way I interpreted it
was that it's the number at time T equals zero, and that's why Dr. Cigarroa's comment is
very important. But given the high attrition rate of a study like this, by the time that you
get out to 10 years, he was suggesting that a sample size of roughly 500 patients might be
very realistic. Can Dr. Steinhaus and Dr. Carlson give us some further information? Then
we can continue.
DR. STEINHAUS: This is Dr. Steinhaus.
I think that that's exactly what we had in mind. We had in mind the 1,895 was going
to be the full component of the enrollment. We could frontload with some re-consenting of
the patients who have already been in so we could get the longer-term follow-up, but with
attrition, at 5 years we would expect to have 1,000 patients, and at 10 years or whatever
that number is. I think we said 8 years, we thought we'd have between 500 and 800
patients.
DR. PAGE: I'm sorry, Dr. Steinhaus, I'm not clear. So are you saying those -- from the
point where the device might be approved, are those 18- or 1700 patients enrolled from
that point forward, or are you talking about making use of the patients who have already
been enrolled in the trial thus far?
DR. STEINHAUS: So let me call for help here and ask my colleagues. What were you
208
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
having in mind, Kurt?
(Off microphone response.)
DR. STEINHAUS: So that would be part of the 1,800. Yes, I think that was the idea,
was the idea. Any patients we could enroll from this previous trial would be part of the
1,895 or whatever that was.
DR. PAGE: And likewise for the acute evaluation that we were talking about earlier
in terms of a 30-day post-approval --
DR. STEINHAUS: They already had their data, right? We already had that data.
DR. PAGE: Okay. Was that the -- thank you.
Was that likewise St. Jude's perspective? And then I want to hear from FDA because
that was not how I interpreted the presentations.
DR. CARLSON: Now I know why this button is always off. David keeps on turning it
off on me.
We intend to enroll patients who are in the IDE study. Now, we may not be able to
enroll all of them, but all of their data would count toward the endpoint. And there will be
a substantial number of new patients who are enrolled. We don't anticipate that we're
going to be able to enroll all of the patients from the IDE study.
DR. PAGE: Okay. So the patients who have already -- the acute data that we have
are already known to us to a certain degree, about half of them.
DR. CARLSON: It would count, and frankly, that turns out to be pretty conservative
because you've got very early information when there are people who have an implanted
device for.
209
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
DR. PAGE: And FDA, was that what you were anticipating, or were you anticipating a
post-approval study actually being conducted post-approval?
DR. LEWIS: It's very common to include the IDE patients in a post-approval study. I
think a good way for us to ask for clarification from the Panel would be to ask how many
additional or total, whichever you would like to address, patients would you want to see
entering and exiting the study?
DR. PAGE: Entering and exiting the study post-approval?
DR. LEWIS: At the end of the duration of the post-approval study, how many
patients would you like to see at the finish line? Total at the beginning --
DR. PAGE: Let's --
DR. LEWIS: -- carried through early.
DR. ZUCKERMAN: Okay --
(Simultaneous speech.)
DR. ZUCKERMAN: Dr. Page, let's rephrase it this way because I think you've put the
problem into a proper perspective. For the acute complication part of the study, the study
that looks at what happens from 0 to 30 days, what is the recommendation of the Advisory
Panel? Can we employ prior IDE patients? My personal inclination would be no, but I'd like
to hear from the Advisory Panel. And then for the longer-term 10-year study, can we, if
possible, re-consent some of the patients to have them part of this longer-term cohort
study?
DR. PAGE: Right. And I appreciate you putting it exactly like that. And I want to --
so right now, let's talk about the acute. This was an earlier question, but we may not have
210
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
all been talking about the same number of patients. I was personally anticipating that the
post-approval study being conducted post-approval, and as such, 30-day acute
complications being collected from a new cohort of patients after approval of the device.
Do other panelists -- was that how you were interpreting it? Or, otherwise, what
number do you think need to be collected post-approval in terms of acute data?
Dr. Cigarroa, Dr. Lange, and then Dr. Borer.
DR. CIGARROA: Well, that came back to a point of clarification earlier during the
sponsor presentations where I asked, you know, the 200 existing sites and how many
additional sites would be brought online, because the issue of acute complications is heavily
influenced by the preexistent experience of working with hardware like this, albeit
different. And that gets back to my point of operators who are used to working in
structural space. And so I think that it would be okay to have a component included, but I
don't think that it should predominate for the acute complications. I have no issue with
regards to inclusion for the long term.
DR. PAGE: And Dr. Lange?
DR. LANGE: I take a slightly different approach. There's a premarket study, and
that's what we have, and then a postmarket study. And, again, the EU postmarket study,
the strong hint is that the complication rate is higher or substantially higher than it was in
the premarket study, so I think the postmarket study for the acute complications has to be a
completely separate study.
DR. PAGE: And I'm seeing Dr. Borer nodding. Do you have further amplification,
Dr. Borer?
211
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
DR. BORER: No. I think the key point is that what we want is an interpretable
dataset, and if we start with patients who have come from different studies with different
criteria, different protocols, it's going to be hard to interpret the study. It may be the best
we can get, but it's going to be hard to do it. I think a new study ought to begin post-
approval.
DR. PAGE: Thank you, Dr. Borer.
So, Dr. Zuckerman, I'm going to go back to Question 2A(ii), when we were giving
numbers, just for clarification, that we did not make it clear, but our recommendation --
and this is for you and industry to navigate, was that those would be new patients.
Now I'm going to move on to the question that we're on, actually, and that is in
terms of this patient population, are we satisfied with that number, and would we be
satisfied with enrolling patients who are already part of the premarket evaluation?
Dr. Naftel.
DR. NAFTEL: So a couple of things. We used to distinguish between post-approval
studies and postmarket surveillance of IDE patients, so I have to admit I'd be more than a
little surprised if the two current studies, Medtronic and St. Jude, in the informed consent, I
bet in the informed consent you specifically said, you know, please be part of this study and
you'll be followed until death or something like that, like -- now you're shaking your head.
So I'm surprised you didn't have in the informed consent the ability to continue to follow
the patients. So let's say you didn't and let's say you made that -- and I'm going to label it a
mistake. Let's say you made that mistake.
I'm very much opposed to enrolling these patients after the fact in a post-approval
212
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
study because you'd have to go consent them again. You will have missed everybody that's
mad, everybody who's dead, everybody who's moved away, and it's going to be really hard
to have a whole timeline from time zero forward if you have these less-censored patients
joining at 2 years or 3 years post-implant, so I would -- I wish the informed consent had
been done correctly for a postmarket surveillance, but if it hadn't been done that way, I
would vote to exclude the patients from the post-approval study, the IDE patients.
DR. PAGE: Dr. Borer.
DR. BORER: Yeah, I agree completely. I mean, this is rife with unintentional
selection bias or intentional selection bias and a skewing of the interpretation of the
results. I don't think it would be a good idea. I agree exactly with what you just said.
DR. PAGE: My impression is there will be consensus around this.
Dr. Ohman, do you have a contrary perspective?
DR. OHMAN: I do because I think we have an opportunity now that all of these
patients are still being followed, and so that while some patients may actually find that they
don't want to have anything more to do with it, then we'll have to respect patient
empowerment, particularly in a randomized clinical trial, but it's actually not very different
from a patient who decides that he's going to withdraw his consent and signs a consent to
that effect, which also happens in clinical trials. So to me, if it's acted upon in an
appropriate time, I actually do not think that the bias that I think Dr. Naftel is sort of
reaching out to wouldn't be substantial. It's always there, but I would rather have much
more longer-term data, and remember, the sooner we get to the 10-year point or whatever
number the FDA decides on, we'll have the most data, and see if we can leverage patients
213
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
that had at least 2 or 3 years of follow-up, we would actually all be much better off.
DR. PAGE: So, Dr. Ohman, if I may, we were on (v), and we're talking about a
number, and based on our previous discussion, the number of 1,741 seemed appropriate,
and would you still want to enroll that number, or would you be satisfied with some of that
1,741 coming from patients in the premarket studies that subsequently need to be
consented?
DR. OHMAN: The latter.
DR. PAGE: So you would be --
DR. OHMAN: Okay with actually having --
DR. PAGE: You're okay with that.
DR. OHMAN: -- a mixture of people for that 1,741.
DR. PAGE: But you like the 1,741 number?
DR. OHMAN: Yes.
DR. PAGE: Dr. Cigarroa and then Dr. Kandzari.
DR. CIGARROA: It's the same position I had advocated for, and I agree.
DR. PAGE: Dr. Kandzari.
DR. KANDZARI: Well, one of the solutions for everybody, then, is to add on above
1,741, right? Add on the patients who are included in the IDE study and still stay with 1,741
and get as many as you can for longitudinal follow-up from the IDE study. I might propose a
compromise, then. If we could look at the numbers perhaps off line at a later date, if you
had, for -- you know, realistically, you've got 289 patients or 500-plus patients in one clinical
trial, for instance. How many of those realistically can you contact and will consent to
214
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
longitudinal follow-up? Over, let's say, 50% at best, optimistically. That's 250 patients.
So your confidence intervals with a sample size of 1,500, I think 1,500 patients still
would be very representative of real-world clinical practice for the acute performance
across a broad selection of -- un-selection of patients. And then having, as others have
mentioned, having longitudinal follow-up from the IDE study. Let's say 250 patients
combined with 1,500 is going to give you an adequate sample size to solve our dilemma for
late-term follow-up.
DR. PAGE: Fair enough. So you put forward a straw man that I think will be
negotiated off line.
Dr. Zuckerman, you want me to summarize (ii) through (v) in terms of the discussion,
or is anything unclear? I think, from my standpoint, what we have made clear is that the
previous numbers included newly enrolled patients. There is some concern among the
Panel about bringing in the already enrolled patients from the premarket evaluation. There
is, I think, a general wish that we always would like to have as much information as
possible, but that would need to be balanced certainly with some new enrollment possibly
up to this sample size or some other negotiated number. Do you have any further
comments or concerns with going through the remainder of part B as we have?
DR. ZUCKERMAN: No, I think that well summarizes it. And just to put this issue to
rest, the expected sample size at, say, 8 to 10 years would be in the 500 patient range,
Dr. Cigarroa. Does the rest of the Panel agree with that?
DR. PAGE: You're saying that based on estimates from the number of 1,741 or the
desire from the Panel to have that many patients still with the pacemaker and alive at that
215
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
point in time?
DR. ZUCKERMAN: With the pacemaker and alive given the realistic high attrition rate
due to mortality that we expect in this elderly population.
DR. PAGE: I guess my question is does that -- we need to look at the graph. Will
1,741 get us to 500 at 9 years?
DR. CIGARROA: So the numbers I have are approximately, if one wrote 1,800 at that
period of 9 years, and that came off of a recent slide from earlier, we'd have 475 patients
alive, of which 203 would be at end of life for the --
DR. PAGE: Good, good. And I think generally there's comfort within the Panel with
those numbers.
I'd like to move on to question part C, Dr. Lewis.
DR. LEWIS: FDA is considering collecting data on what clinicians decide to do with
devices after they reach end of life. FDA expects that physicians may prefer one or two
approaches over the others. It should be noted that it is suspected that the leadless
pacemaker may be fully encapsulated after several years, which differs from traditional
pacemaker/lead systems. FDA expects data collection on the end of life device
management as part of the post-approval study to be observational (that is, not hypothesis
driven). FDA sees the following likely scenarios for device end of life:
• Explant the leadless pacemaker and implant another leadless pacemaker or
transvenous pacemaker or ICD.
• Turn off the leadless pacemaker and implant an adjacent leadless pacemaker,
adjacent transvenous pacemaker, or adjacent ICD.
216
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
DR. PAGE: And why don't you proceed with parts (i), single (i) through (iv)?
DR. LEWIS: Good.
i. Please discuss the value of collecting data on how clinicians manage leadless
pacemaker devices when they reach end of life. Is collecting this end-of-life data
necessary? If so, please address the questions on the following slide:
ii. Given the observational nature of the Post Approval Study, what criteria should
be used to determine the sample size, for example, acceptable rates of
occurrence or precision of rates?
iii. Regarding the scenarios outlined, what is an appropriate follow-up time to assess
for new device interactions with the previously implanted device?
iv. Please recommend an approach to evaluate device removal/extraction; for
example, how often it is attempted, success rates, and complications associated
with removal or extraction?
DR. PAGE: Okay. So I'm going to hazard that in response to (i), we think it is
important to collect this, so we can go on to (ii) through (iv). Any comments in terms of
these specific questions?
Dr. Naftel.
DR. NAFTEL: So in the last 5 or 10 years, FDA has so stepped up the game when it
comes to post-approval studies, and it's very appropriate. In the opening paragraph where
it says this will be observational, not hypothesis driven, I'm fine with that, but only if there's
a promise that whatever is found in the end-of-life part of this is specifically addressed and,
if appropriate, put in the labeling at that time, you know, 10 years down the road. I mean,
217
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
this can't be just an open-ended "let's see what happens." It may not be hypothesis driven,
but it needs to have a purpose, and that purpose would be the labeling, in my opinion.
DR. ZUCKERMAN: Great point, Dr. Naftel. Point number one is both the industry
and FDA have stepped up to the bar within the last 5 years regarding the quality of post-
approval studies, and we would expect the same thing here, and a major reason for post-
approval studies is to update the labeling as appropriate. You know, as Dr. Lewis
introduced in his talk this morning, we were looking for the appropriate pre/postmarket
balance to study these devices throughout their developmental cycle. The other alternative
is just to wait 10 years on this cohort, which I don't think is the objective of anyone in the
room, so that certainly in the post-approval period, we're looking to obtain high quality
data and to use those data to improve our knowledge base.
DR. PAGE: Dr. Borer.
DR. BORER: Yeah, I agree. I don't have any objection to an observational database
being collected and being put into a label, but in order for that to be done -- and what I'm
going to suggest now is probably beyond the scope of what we can talk about here, but I
mention it so that it can be considered by the FDA and industry as these things move
forward. In order to be able to interpret an observational database, it's going to be
necessary to have characterized the population at the outset, and therefore it needs to be
decided what characteristics are going to be documented. And we haven't done that. We
haven't done that here today; we haven't tried to. But that's going to have to be done. If it
is, then the data can be put into the label in a way that might be meaningful to the ultimate
user. But I think it's crucial that that needs to be done, the characterization of the
218
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
population somehow so that they will be interpretable.
DR. PAGE: Other comments, especially for those, the (ii) and (iii)?
Dr. Ohman.
DR. OHMAN: Well, I find myself very hard or very challenged, actually, to come up
with any number because we don't know anything yet. Unless maybe Medtronic and St.
Jude actually has some experience as to what we should expect, but this is largely an
unknown. And one of the reasons for getting the data for utilizing the early enrolled
patients is because the sooner we can get to some of these things, I would say maybe if the
Panel is still doing well in 10 years' time, we'll come back and sit down and discuss exactly
what that would look like. Now, on the other hand, I was very interested to hear that this
might be the device for golfers, and so this may actually take off in a completely different
way than we anticipate, so I'm just very challenged that -- to come up with numbers to
which we have no basis, or at least not me, as a single --
DR. PAGE: I think we might all share that challenge, and the numbers that we're
talking about so far in the post-approval study, do you think we're getting at the right
ballpark?
DR. OHMAN: Well, I think the way I see it is that we're leveraging the patients
already enrolled, we're going to get some new patients coming in, and I would sort of, not
to address D that you will come to eventually, but the more open this registry can be for
capturing every new possible inclination for using this device, that would be the best way
we can go, given the limitations.
DR. PAGE: And triple (iii) asks how long we would follow after placement of one
219
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
device or another, and I don't know that we have a number for that, but I'd continue them
in follow-up of the trial.
Dr. Thuramalla, or Mr. Thuramalla and then Mr. Frankel.
MR. THURAMALLA: So on item number (iii), the new device interactions, I think we
need to clarify what does new device mean? Is it any device, like Dr. Zeitler was saying, any
device that can be in the cardiac rhythm area, or just a leadless pacemaker we're talking
about?
DR. PAGE: Well, previous to that, it goes through four but actually it's six different
scenarios, just before, in terms of your leaving, explanting the device and putting in a new
leadless or a new lead pacemaker, defibrillator, or just turning off the LP and putting in
those leads.
MR. THURAMALLA: Thank you for the clarification. So the new device is anything
that's available and known today, not something that's going to be invented and coming
into the market as we go through this post-approval study?
DR. PAGE: All we have is what's anticipated here.
Mr. Frankel.
MR. FRANKEL: In terms of duration follow-up, the battery life is, to this point, still
unknown. We have an estimate of 6 to 12 years. Because of the unknown factor of how
long they're actually going to go for, is there a possibility of just linking the length to battery
life? Is that an approach that we're taking, or is it, instead of setting an actual number in
terms of years, just linking it to the actual, what we see in the future in terms of actual
battery life?
220
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
DR. PAGE: I'll try to answer that, but I -- the -- in terms of post-approval study, we
need to come up with a number. I think we're anticipating that long-term there would be
some sort of registry, either industry or otherwise, that would be keeping track of these. Is
that what the Panel would be anticipating? Dr. Zuckerman's nodding his head.
We're asked to recommend an approach to evaluate device removal/extraction, how
often is it attempted, success rates, and complications. Again, the next question we
comment on what we recommend, but this is what do we capture in terms of complications
of the procedure.
Yes.
DR. BRINKER: I think they're -- pretty much any complication that can be correlated
with the extraction procedure. We know a whole bunch of the big ones, but we would like
to know what unanticipated complications are. Embolization, tamponade, arrhythmia
resulting in the need for cardioversion, death. It goes the gamut of what we see now.
Pieces left, if that's possible, to break off the tip or whatever.
DR. PAGE: So, Dr. Zuckerman, my impression is that there's already literature in
terms of expected complications of extraction procedures, and a number of them have
been mentioned here. Do you need further guidance from us on that specific question?
DR. ZUCKERMAN: No, I think your comments and those of Dr. Brinker are very
helpful.
DR. PAGE: So let's go on to question part D.
DR. LEWIS: A physician may choose to implant a leadless pacemaker to replace a
transvenous VVIR pacemaker system when a patient has a faulty or non-functional lead.
221
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
Currently, the FDA is not aware of published literature on mechanical or electrical
interactions between a leadless pacemaker and a prior transvenous pacemaker lead system.
Please discuss if the post-approval study design should incorporate data collection for
patients who receive a leadless pacemaker as a replacement for a transvenous system and
what type of data should be collected.
DR. PAGE: Comments from the Panel or -- first of all, what are we looking for if
we're placing a leadless pacemaker near an already preexisting, mature endocardial lead,
and then the issue of do we want to collect these, and how should we do so?
Dr. Brinker.
DR. BRINKER: So I want to make sure that this is not a question asking for the
inclusion of such patients selectively as opposed to, you know, go out and hunt for such
patients to add to the database rather than taking these from the numbers that are already
been -- already been approved. So my suspicion is that any electrical interference would be
made obvious. I don't think there's much that -- we visited the interactive aspects of two
devices or more already, and I don't think there's any -- I don't think that there's going to be
a whole lot of these patients. I don't think we need to go out and look for them, but we
should take advantage of their occurrence and find out if there are any reported cases of
interaction.
DR. PAGE: Fair enough. I'm looking around at the Panel and I'm seeing concurrence,
and I would agree, rather than having a set number, certainly collecting these. I think
common sense will prevail. We'll see a lot more of leadless pacemakers put in next to leads
than we will leadless pacemakers put in next to leadless pacemaker over the next 5 years
222
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
because I'm anticipating these devices will not need a subsequent device very often. So we
will gather information, I think, fairly quickly on this.
Dr. Zuckerman, does that adequately respond to part D?
DR. ZUCKERMAN: Yes, it does.
DR. PAGE: Let's now invite Ms. Dorfman to read Question 3.
MS. DORFMAN: Thanks.
In the absence of data on long-term performance and end-of-life options for leadless
pacemakers, please comment on content and points to address for appropriate labeling
regarding extractions, replacements, and best practices at this time.
DR. PAGE: Thank you.
Before we specifically address this question, I'd like comments from the Panel as to
what you think we've learned about what we would anticipate in these leads. When they
reach end of life, do you think they're going to be encapsulated or free and clear in the
heart and ready to be extracted?
Dr. Lange.
DR. LANGE: This may be one of those circumstances where this device is specific,
there's the longer devices, and how they're adhered may be shorter devices that are
different, so this may be more device specific than general class.
DR. PAGE: Dr. Borer.
DR. BORER: I don't think we can provide guidance on best practices or how to label
except to say, hey, we don't have much in the way of information here. What we have is
very little and this is what it is, there a few case reports right now, but nothing's being
223
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
approved right now. By the time FDA is ready to approve, there will be more data. I think I
would say it's necessary to revisit this particular question at the time when approval is
being considered, and the totality of data available then can guide what kind of information
can be put in the label. We can't guess at what's going to happen.
DR. PAGE: Dr. Kandzari and then Dr. Brinker.
DR. KANDZARI: This reminds me at the end of so many manuscripts that we write
where we say more studies are needed, and I think we have to say something, though, and
so my suggestion would be that the comment is there are very limited data regarding
extraction, and limited data exists showing success of extraction, failure of extraction, and
complications associated with failure. And the timing of extraction from implant may have
an important role in predicting that outcome. And right now, then, we therefore have to
leave it to an individual as discretion between the patient -- discussion between a patient
and the physician.
DR. PAGE: Thank you.
Dr. Brinker.
DR. BRINKER: So I'd make two comments. One is that the elderly population in
which this is mainly aimed at as of now is less likely to fibrose than a younger population, if
there is any correlation between lead pacemakers, because the response to the foreign
body is less. Having said that, I would say that everything that Dr. Kandzari said about the
limited knowledge and the options available, but would add that if extraction is
contemplated, someone with experience with the extraction, if possible, should be
involved.
224
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
DR. PAGE: Certainly.
Dr. Cigarroa.
DR. CIGARROA: So at least one of the presenting sponsors, I believe it was
Medtronic, in essence, had a general recommendation that the device not be removed, i.e.,
in the chronic phase. And I think that, you know, we -- I agree with the other panelists that
there is limited data, but I'd like to, in essence, challenge us, in the absence of an infection
in a device that has anchors and will have at least some degree of associated fibrosis and
encapsulation, in the absence of an infection, why would one want to remove it and the
associated risk of perforation in an elderly group with multiple comorbidities?
DR. PAGE: Why, indeed?
Other potential -- electrophysiologists, if you had a patient hypothetically, and
Medtronic put forward, indeed, that they thought generally it would be prudent to put in a
new device with a chronic end-of-battery life device, I wouldn't even consider personally
trying to extract what I would see is likely fibrosed in place and would put one a little
distance away from the current one. But, Dr. Slotwiner, do you have --
DR. SLOTWINER: No, I agree.
DR. PAGE: -- further amplification on that?
DR. SLOTWINER: No, I agree. Unless, you know, there's some unexpected problems,
which is crosstalk or noise, but just for cosmetics, no. Absolutely.
DR. PAGE: And it might indeed, as Dr. Lange said, be device specific and experience
specific, but I think any, any discussion or labeling and any recommendations of what to do
would need to be based on what data there are out there and what we will learn in these
225
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
wonderful post-approval studies that we're anticipating because I would personally
anticipate that in general these would be left in place and a new device would be placed.
Is that helpful, Dr. Zuckerman?
DR. ZUCKERMAN: The comments I have just heard are extremely helpful. Thank
you.
DR. PAGE: And now we come to Question 4. Dr. Selzman, would you please read
Question 4 for us?
DR. SELZMAN: Thank you.
Please discuss your views on the clinical role of this technology in patients currently
indicated for conventional transvenous single chamber (VVI) pacemakers. In your
discussion, please specifically address the following clinical subgroups:
• Patients in sinus rhythm with symptomatic paroxysmal or permanent second or
third degree AV block
• Patients with paroxysmal or transient sinus node dysfunction
• Patients with tachy-brady syndrome
• Patients with pacemaker syndrome
• Patients in sinus rhythm and frequent pacing is not expected
• Patients with carotid sinus syndrome
DR. PAGE: Thank you.
I'm going to go out on a limb here, and first of all, I recognize that the majority of
these VVI pacemakers were put in patients who you couldn't have paced the atrium
anyway; they were in atrial fibrillation. So that was the only option for them. There are
226
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
excellent guidelines put forth by AHA, ACC, and HRS in terms of choice of device, VVI versus
dual chamber pacemaker. I'd like to reconfigure this discussion, perhaps, if the Panel
agrees, on whether this is a device that would be an option anyway for the standard VVI
indications, and then if you personally feel, in a non-typical VVI indication, you think this is
preferable to a dual chamber pacemaker, please speak to that.
But first, I'd like to just comment, is this a VVI that would be an option for when
you'd be putting in a VVI anyway, and generally, we don't put VVIs in pacemaker syndrome
patients obviously or patients who are going to require AV synchrony. But help me out in
terms of -- Panel, in terms of whether we already have guidance as to different groups,
which is very well put forth by the major cardiology and EP societies.
Dr. Lange.
DR. LANGE: Let me summarize, I think, what you said. This is an alternative device,
but it does not change the indications for VVI pacing, and I think that's a good summary.
DR. PAGE: Dr. Zeitler.
DR. ZEITLER: The only thing I'd add is under the extraordinary or unusual
circumstances in which transvenous pacing is impossible. For example, in the pediatric
populations or complex congenital heart disease for which there is no other transvenous
option, that maybe that's an additional VVI indication for this technology.
DR. PAGE: Great. So in certain populations, having access femorally is an option we
didn't have before, specifically in some cases, prior epicardial or whatever.
Other comments from the Panel about that?
So we've kind of turned around the question. Now, I want to make sure I'm
227
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
answering the question as it stands. I also -- before we get there, though, is there anybody
so enthusiastic about this device in comparison to a transvenous VVI that it would tip you
more toward trying it in populations where you might have otherwise, if you're going
transvenous, put in an AV device but you might have some preference of this device over a
transvenous system of one sort or another?
Dr. Borer.
DR. BORER: Yeah. The only problem I have with giving reign to my free enthusiasm
for this wonderful technology is that we have very little information about safety or we
have limited information about safety, and that would be a rate-limiting step here.
Otherwise, gee, sounds wonderful. So as we get more information, it can be more widely
applied for the standard indications.
DR. PAGE: Fair enough.
Dr. Lange.
DR. LANGE: The only patient group I might highlight is the one that Dr. Cigarroa
noted, that is acute renal where they're going to need hemodialysis and require an AV shot
where you don't want to be putting venous systems in. This might be -- you know, where
you typically use an AV sequential but you might go to this device instead.
DR. PAGE: So you might actually tilt towards trying a ventricular-based device with
the tradeoff of having no intravascular hardware?
DR. LANGE: Well summarized.
DR. PAGE: That's helpful.
Dr. Zuckerman, does this adequately address Question No. 4?
228
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
DR. ZUCKERMAN: Yes, it does. Thank you.
DR. PAGE: Now, we're not going to close yet because I want to make sure -- we're
not doing a vote today obviously. I want to ask the Panel if you've all had an opportunity to
express any comments, concerns regarding this device as such. And then I'm going to
specifically ask for our Industry, our Consumer, and our Patient Representative. But in
terms of the voting panelists, any other further specific comments?
Seeing none, Dr. -- Mr. Thuramalla, do you have any other comments?
MR. THURAMALLA: Just finishing remarks. So I'd like to thank the sponsors and the
FDA for their excellent presentations, and for the Panel to go through this exercise in
helping a disruptive technology come into existence. This is very helpful to the industry.
Thank you.
DR. PAGE: Thank you very much.
Mr. Frankel.
MR. FRANKEL: Just one thing that was mentioned before in terms of why, indeed,
there would be a need for a recommendation for extraction with the population that we're
talking about. So I'm just wondering, together with two of the sponsors, there's about 16
extractions that were mentioned in the data in the limited population we have at this point.
I would be interested to know why there were 16 extractions attempted, being mindful of
that very strong point of why that would be done as opposed to leaving them in place. So
that --
DR. PAGE: I think those data were included in the packets.
Dr. Lange, did you want to comment?
229
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
DR. LANGE: Many of those were for failure of the device, changing either in the
threshold or the sensing, and many were removed within a short period of time. That is,
the study presented four of those removed within 72 hours.
MR. FRANKEL: And so --
DR. PAGE: And there were infections, as well.
MR. FRANKEL: Okay. And that would be, I guess, specified in the labeling in terms of
recommendations for extraction, that would --
DR. PAGE: Say again, I'm sorry?
MR. FRANKEL: In terms of detailing the recommendations for extraction, would that
be noted in terms of a clear criteria?
DR. PAGE: I think that certainly could be considered in the package insert.
And finally our Patient Representative, Ms. Dunn.
MS. DUNN: I just want to thank the FDA and the companies that were represented
here today. As a patient myself, and a patient advocate, I am on device number four,
anticipating getting device number five. I have a biventricular ICD device. I have had lead
extraction from a staph infection and a device switch-out in my pocket. I had vegetation
growing on the leads. Extraction was performed. And I did have a cardiac tamponade. I
also had a one-inch tear in my septum.
So everything that was described here today really hit home for me. And I thank you
for the advancement. I know I'm not a candidate for this device because I do need my
biventricular pacing, but I thank you for the technology, and I look forward to hearing how
this all turns out.
230
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
Thank you.
DR. PAGE: Thank you, Ms. Dunn. And thank you for that personal testimonial and
your participation. I also want to thank Mr. Frankel and Dr. Thuramalla representing
consumers and industry. I want to thank the Panel for lively discussion and really
thoughtful engagement as we reviewed this. I want to thank the speakers who came up to
public comment. Industry, from Boston Scientific and Medtronic and St. Jude, your
presentations were just outstanding. And finally FDA for putting together the materials so
well.
This is transformative technology. It's a masterpiece of engineering. The issues of
safety and effectiveness were not assessed by us today, but the object of today was to
evaluate, assuming or if and when the device might be approved, how to learn more about
this device because we can't wait for patients who have already been enrolled to reach end
of life for their battery. To the contrary, this in my opinion holds great promise for many,
many patients.
Dr. Zuckerman, are there any other comments or questions or concerns you might
have before we adjourn?
DR. ZUCKERMAN: No, I think Ms. Dunn and you have summarized it very well. We
had a great session today with all the stakeholders actively participating. From the FDA
perspective, we obtain the information that we need. I want to thank everyone, especially
the Panel members who took time to come here today.
Thank you.
DR. PAGE: With that, this meeting of the Circulatory System Devices Panel is now
231
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
adjourned. Safe travels, everyone.
(Whereupon, at 4:14 p.m., the meeting was adjourned.)
232
Free State Reporting, Inc. 1378 Cape St. Claire Road
Annapolis, MD 21409 (410) 974-0947
C E R T I F I C A T E
This is to certify that the attached proceedings in the matter of:
CIRCULATORY SYSTEM DEVICES PANEL
February 18, 2016
Gaithersburg, Maryland
were held as herein appears, and that this is the original transcription thereof for the files
of the Food and Drug Administration, Center for Devices and Radiological Health, Medical
Devices Advisory Committee.
____________________________
TIMOTHY J. ATKINSON, JR.
Official Reporter