transcript: feb. 18, 2016 (pdf - 857kb)

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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

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CENTER FOR DEVICES AND RADIOLOGICAL HEALTH

MEDICAL DEVICES ADVISORY COMMITTEE

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CIRCULATORY SYSTEM DEVICES PANEL

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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

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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

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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

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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

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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

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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

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INDEX PAGE FINAL COMMENTS

Industry Representative - Naveen Thuramalla 228 Consumer Representative - Naftali Frankel 228 Patient Representative - Debbie Dunn 229

ADJOURNMENT 230

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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

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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

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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

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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

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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.

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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.

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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-

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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

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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.

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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.

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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

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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.

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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

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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

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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

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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

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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.

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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

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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

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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

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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

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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

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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

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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

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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.

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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

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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

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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.

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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

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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

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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

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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

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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,

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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?

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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

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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

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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. 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,

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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

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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

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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

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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.

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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

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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

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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

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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

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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

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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

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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,

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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.

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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

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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,

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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.

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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.

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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

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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.


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.

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DR. PAGE: Thank you. Dr. Lange.

(Off microphone response.)


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.

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DR. BRINKER: 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.

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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. 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

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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. 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

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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.

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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

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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

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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

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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%.

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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,

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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

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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

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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.

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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

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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

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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.


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.

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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

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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?



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

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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. 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

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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. 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.

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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?

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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. STEINHAUS: Is that sufficient?

DR. PAGE: Yes, that's perfect. Thank you very much.

Dr. Karasik.

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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

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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

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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. 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.


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.

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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

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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

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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

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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

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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

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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.

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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

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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

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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

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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

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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,

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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.

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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?

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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.

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MR. HUBBARD: Oh, I'm sorry.


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. 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

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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. 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.


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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 --

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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

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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.


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.

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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,

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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

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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

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sites, etc., so this won't take 100 hundred years but will be done very quickly?

DR. CARLSON: Thank you, Dr. Zuckerman.


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.

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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 --


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. LANGE: Both industry sponsors mentioned that their devices were MRI

compatible, and after lunch, if you could tell us what that means.

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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?


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.)

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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

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federal registration. Each speaker will be given 10 minutes to speak.

Back to you, Dr. Page.


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

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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.

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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.

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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.

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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.

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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

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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

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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

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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

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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.

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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

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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

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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.


DR. PAGE: Thank you, Dr. Ip.

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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.

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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

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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

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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?


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

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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

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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

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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.

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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. 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%

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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. 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. 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

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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. 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

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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

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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.

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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.

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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. 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

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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. 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.

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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. 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. 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.

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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

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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

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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

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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. 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

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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

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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. 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

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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.

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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

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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. 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.

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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.

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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.


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

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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. 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.

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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

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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.


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

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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

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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.


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.

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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

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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

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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.

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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.


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

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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

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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. 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.

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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. Cigarroa and then Dr. Borer.

DR. CIGARROA: So it certainly relates to the issue of cardiac perforation. I, too,

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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. 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

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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.


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

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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. 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

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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

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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?

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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.


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

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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

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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.


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

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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

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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,

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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,

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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.


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

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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. 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

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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.

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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

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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.


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

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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.

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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.


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

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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.

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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. 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.

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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. 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?

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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

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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

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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,

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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

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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. 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 --

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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?

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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.

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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.


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.)

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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

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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.


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.

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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?


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?

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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.


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

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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

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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

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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

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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).

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(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.


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.


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

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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. Lange.

DR. LANGE: The clarification is for many individuals that we're going to present this,

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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. 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?

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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

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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

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having in mind, Kurt?


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.

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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

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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?

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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

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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

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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

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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

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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.

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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,

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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. 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

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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

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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?

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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.

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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

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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.


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. 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

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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. 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.

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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

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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


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

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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. 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

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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. 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?

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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.


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?

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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.

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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

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adjourned. Safe travels, everyone.

(Whereupon, at 4:14 p.m., the meeting was adjourned.)

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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

transcript: feb. 18, 2016 (pdf - 857kb)

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