FOOD AND DRUG ADMINISTRATION

\+ + + + +

GENERAL AND PLASTIC SURGERY DEVICES PANEL

OF THE

MEDICAL DEVICES ADVISORY COMMITTEE

\+ + + + +

EMPHYSEMA AND ABLATION DEVICES CLINICAL ISSUES

DISCUSSION SESSION

\+ + + + +

FRIDAY,

FEBRUARY 28, 2003

The Panel was convened in the Grand Ballroom of the Gaithersburg Hilton
Hotel, 620 Perry Parkway, Gaithersburg, Maryland at 1:30 p.m., Dr.
Robert L. McCauley, Acting Chair, presiding.

PRESENT:

ROBERT L. McCAULEY, M.D. Acting Chair

DAVID KRAUSE, Ph.D. Executive Secretary

MICHAEL J. MILLER, M.D. Voting Member

DEBORAH M. BROWN Industry Representative

CHRISTINE MOORE Consumer Representative

BRENT A. BLUMENSTEIN, Ph.D. Temporary Voting Member

DEAN E. BRENNER, M.D. Temporary Voting Member

THOMAS B. FERGUSON, M.D. Temporary Voting Member

JOSEPH LoCICERO, III, M.D. Temporary Voting Member

DEBORAH SHURE, M.D. Temporary Voting Member

STEPHEN B. SOLOMON, M.D. Temporary Voting Member

JAMES K. STOLLER, M.D. Temporary Voting Member

CELIA WITTEN, Ph.D., M.D. FDA

C-O-N-T-E-N-T-S

Call to Order 4

Panel Introductions 5

Robert L. McCauley, MD, Acting Chairman

FDA Presentation 7

Introduction 7

Dr. Binita Ashar

Industry Presentations 8

Broncus Technologies, Incorporated 7

Dr. Joel Cooper

Closure Medical Corporation 18

Dr. Thomas Stevens

Emphasys Medical, Incorporated 23

Dr. Geddes

Spiration, Incorporated 35

Dr. Rick Shea 35

Dr. Matthew Brenner 36

Dr. Douglas Wood 39

Open Public Comments 44

Dr. Joel Cooper, ATS 44

Dr. Joe Putnam 45

Panel Deliberations and Address 50

of FDA Questions

Discussion of Question 1 47

Discussion of Question 2 62

Discussion of Question 3 68

Discussion of Question 4 79

C-O-N-T-E-N-T-S (Continued)

FDA Presentation 85

Introduction 85

Dr. Binita Ashar

Industry Presentations 86

RITA Medical Systems, Incorporated 86

Dr. Barry Cheskin

Dr. Steven Rosenberg 88

Open Public Comments 105

Dr. Joe Putnam 106

Dr. Patrick Sewell 112

Dr. Joel Cooper 118

Panel Deliberations and Address 123

of FDA Questions

Discussion of Question No. 1 123

Discussion of Question No. 2 138

Discussion of Question No. 3 145

Discussion of Question No. 4 152

Discussion of Question No. 5 157

P-R-O-C-E-E-D-I-N-G-S

1:25 p.m.

DR. KRAUSE: Okay, if you don\'t sit down in the next five minutes,
we\'re going to make you stay until 10:00. A little FDA humor there.

\[Laughter.\]

All right, I was going to read the conflict of interest and temporary
voting status again, but I don\'t really need to because this afternoon
there\'s no vote. So these people don\'t need to deputized, which is
good. I read the conflict of interest this morning, so I\'m not going to
do it again.

So, in that case, I would like to turn the afternoon session over to Dr.
McCauley, our Chairman.

CHAIRMAN McCAULEY: Good afternoon. My name is Dr. Robert McCauley. I\'m
Professor of Surgery and Pediatrics at the University of Texas Medical
Branch in Galveston and Chief of the Plastic Surgery Services for
Shriners Burns Hospital in Galveston.

This afternoon the Panel will be making recommendations to the Food and
Drug Administration regarding clinical concerns involving two classes of
medical devices: those intended to treat emphysema and those intended
for ablation of lung tumors.

The next item of business is to introduce the Panel members, who are
giving of their time to help the FDA in these matters, and the FDA staff
at this table. I\'m going to ask each person to introduce him or herself
stating his or her specialty, position, title, institution, and his or
her status on the Panel, starting with my near left.

DR. SHURE: My name is Deborah Shure. I\'m Professor of Medicine at the
University of Texas Health Science Center at Houston, and I\'m Director
of a multidisciplinary program in pulmonary vascular disease there. I\'m
a pulmonologist and I\'m a consultant to the Panel.

DR. MILLER: I\'m Michael Miller. I\'m a Professor of Plastic Surgery at
the University of Texas M.D. Anderson Cancer Center in Houston, and I\'m
a member of the Panel.

DR. BLUMENSTEIN: My name is Brent Blumenstein, and I\'m not from M.D.
Anderson.

\[Laughter.\]

I\'m a private consultant on the Panel, a biostatistician.

DR. STOLLER: My name is Jamie Stoller. I\'m a lung doctor. I\'m at the
Cleveland Clinic, where I am a member of Pulmonary and Critical Care
Group.

DR. BROWN: I\'m Debera Brown. I\'m with Broncus Technologies in
California, the Vice President of Regulatory Affairs, and I\'m a regular
Panel member as the industry representative.

MS. MOORE: My name is Christine Moore. I\'m the consumer member of the
Panel, and I\'m the former Dean of Student Services at the Community
College of Baltimore.

DR. WITTEN: I\'m Dr. Celia Witten, the Division Director of GRND in FDA.

DR. FERGUSON: I\'m Tom Ferguson from Washington University in St. Louis,
a Meritus Professor of Surgery there, and I\'m a consultant to the
Panel.

DR. BRENNER: I\'m Dean Brenner. I\'m a Professor of Internal Medicine
and Professor of Pharmacology at the University of Michigan. I\'m a
medical oncologist, and I presume I\'m supposed to advise on oncologic
things here, and I\'m a consultant.

DR. LoCICERO: I\'m Joseph LoCicero. I am a thoracic surgeon. I\'m
currently the Chair of the Department of Surgery at the University of
South Alabama in Mobile, and I\'m a Panel member.

CHAIRMAN McCAULEY: I would like to remind public observers that while
this portion of the meeting is open to public observation, public
attendees may not participate except at the specific request of the
Panel.

We are now ready to hear the FDA presentation. The FDA is going to give
us some background information for this topic.

DR. ASHAR: Thank you, Dr. McCauley.

Good afternoon. My name is Binita Ashar. I\'m a Medical Officer at FDA.
We have asked you, the Panel, the General and Plastic Surgery Devices
Panel, to consider clinical trial issues concerning the application of
devices placed in local areas of the lung for the treatment of
emphysema.

As you know, the present treatment options for patients are evolving.
Common treatment includes medical management, occasionally lung
transplantation for severe cases, and potentially lung volume reduction,
which is still under study.

There has been some interest in developing devices placed in areas of
the lung to achieve local physiological changes in the lung as a
treatment for emphysema. Device designs, as discussed in the literature,
include the use of fibrin-based glues, occluded stents, medical
adhesives, and inter-bronchial valves.

The purpose of this session is to obtain the Panel\'s thoughts on
clinical trial issues to be considered when studying devices that
produce local pulmonary physiological effects for the treatment of
patients with emphysema.

Following the presentations made by the sponsors this afternoon, we will
be asking you, the Panel, to comment on a number of questions, including
an appropriate control group, safety parameters, efficacy endpoints, and
duration of followup.

Thank you very much and, Dr. McCauley, I will hand over the questions to
you for review by the Panel after the presentations made by the
sponsors.

CHAIRMAN McCAULEY: We will now hear from some members of industry in
regards to this topics. Please come up in this order: The first would be
Broncus Technology; followed by Closure; followed by Emphasys Medical,
Incorporated; followed by Spiration Incorporated.

Bronchus Technologies, Incorporated.

DR. COOPER: Good afternoon, Mr. Chairman. I\'m Joel Cooper. I\'m a
thoracic surgeon. I am Chief of Cardiotheracic Surgery at Washington
University School of Medicine. I\'m here in several capacities.
Primarily, I\'m as a representative for Broncus, a company to which I
took a proposed intervention and a project which I have been working
with them to develop.

I also have other sort of roles. I consult for Emphasys, one of the
companies which will be presenting. I have a relationship with a company
called Synovis, which has a product we use in volume reduction surgery,
which is a staple line reinforcement which I developed some years ago
for volume reduction surgery, so I could be perceived as having an
interest in volume reduction surgery. I\'m also here as Vice President
and President-Elect of the American Association for Thoracic Surgery, as
their representative.

The items that I will be discussing are shown here. These are the
headings of the subsequent slides, some of the issues that you wished
discussed.

I need to introduce this with a few words about emphysema. Chronic
obstructive pulmonary disease, the fourth leading cause of death in the
United States, is quite prevalent. However, the term \"COPD,\" or
chronic obstructive pulmonary disease really carries two different
disease populations under that rubric. One is emphysema and one is
airways disease, or what is called chronic bronchitis or asthmatic
bronchitis.

For many of the therapies for COPD, the distinction is not too
important, but for device therapies, which are proposed to treat
emphysema, it is a critical distinction to be able to make. Even among
the pulmonary population I must say that this distinction is not always
perceived, and many patients are referred for treatment of emphysema
who, in fact, do not have significant emphysema but who have the other
form of COPD, the airways disease, the chronic bronchitis.

Emphysema specifically refers to destruction of the fabric of the lung,
a loss of its physical elastic properties, and a loss of the gas
exchange surface on the alveoli. As a person with emphysema has
progressive disease, they are limited by the gas exchange problems;
oxygen and carbon dioxide exchange is limited, and that may limit their
activities. But, in the end, when they are crippled by emphysema, it is
the mechanics of breathing, the persistent overinflation of the
hyperexpanded chest, the distorted diaphragm and chest wall, the effort
of breathing, and the associated dyspnea or sense of pervasive
breathlessness, which cripples these individuals.

And the goal of treating emphysema by any means has always been an
attempt to reduce what is called dynamic hyperinflation, the oversize of
the chest, which these patients have. They are trapped in the state of
permanent hyperinflation, and no amount of forced expiratory maneuver
can empty the air out of their chest and allow them to take a deep
breath.

The treatment options for emphysema are, and will continue to be, mainly
medical management, antibiotics, bronchodilators, steroids, all designed
to try to improve expiratory flow from the patient with emphysema and
with asthmatic bronchitis, and it will continue to be the mainstay.

We were fortunate in 1983 to be able to be successful with the initial
lung transplants in humans which were used for a variety of diseases,
including emphysema, and emphysema continues to be one of the main
indications for lung transplantation. For those patients, any pattern of
emphysema is suitable because you are removing the lungs.

But when you look at specific therapies, the pattern in which the
destruction occurs is extremely germane to the treatment being
considered. Volume reduction surgery, something we developed that began
10 years ago, was based upon observations in transplant patients and
requires that the patient have a particular pattern of emphysema. We
call that heterogeneity. One part of the lung very badly destroyed;
that\'s the part that\'s removed, to allow the remaining lung, less
destroyed, to function better and to improve the respiratory mechanics.

The volume reduction surgery, five presented randomized trials already,
two more in press, in addition to the NETT trial, 200 publications, all
showing its value, has generated a fair amount of interest. The NETT
results, soon to be published, will confirm the previous findings, I
understand.

Because of the success of volume reduction surgery, which taught us that
you can change the mechanics of a patient who is crippled from severe
emphysema, and by changing those mechanics, you can alter the quality of
life dramatically, that has led some to look at alternative proposals to
try to achieve the same benefit ‑‑ you will hear from some of those this
afternoon ‑‑ an attempt to achieve the benefit of volume reduction
surgery by in some ways reducing the volume of the targeted,
overextended, overdistended lung.

The program that I am working with at Broncus is a totally different
concept, and that is it\'s an attempt to provide, through yet another
group of patients, an alternative to medical therapy when there is no
existing one. Those patients are those who have a fairly homogeneous
pattern, top to bottom, of severe emphysematous destruction, who are not
candidates for lung transplant because they are too old or have
co-existing morbidities, who are not candidates for volume reduction
surgery or one of its substitutes because they do not have that
heterogeneous pattern of emphysema.

So for an intervention which is designed for people who have no
alternative, we would argue that the only possible control you have is
continued medical management when evaluating these new therapies. If you
are proposing a therapy as an alternative to an existing therapy, then
you may, in fact, come up with a difference as to what should be the
control group.

I want to emphasize again that for homogeneous emphysema, currently,
medical management is the only option. These are severely-disabled
patients. They cannot take a shower easily or at all. It takes an hour
to get dressed. They cannot visit the grandkids. They are trapped with a
hyperinflated state. They just want to put a gun to their head, and they
will accept almost any risk if they could be provided a period of relief
from the disabling dyspnea which they have.

One of the questions that you are addressing this afternoon is, how do
you evaluate therapies? I would argue that it depends on who is your
target population. What alternatives do they have? What\'s the nature of
your intervention?

The history of the last century is filled with devices and procedures
promoted for the relief of breathlessness in patients with severe
emphysema which ended upon the waste heap of history, and for one
reason: All of these procedures, glomectomy, phrenicectomy,
chostochrondrectomy, radical denervation, all promoted to relieve
symptoms, had only subjective benefit, no objective, verifiable benefit
to correlate with the subjective benefit.

And the Santayana has taught us those who fail to learn the lessons of
history are condemned to repeat them. When you are dealing with dyspnea
and breathlessness, and you propose to improve it, you must have
something objective, at least a function measure which is
physiologically logical in terms of the intervention and, ideally, one
quality-of-life or subjective improvement.

The patient doesn\'t come to you and say, \"Dr. Cooper, my FEV1 is
killing me and my residual volume is out of sight.\" They say, \"I
can\'t get dressed. I can\'t take a shower. I can\'t breathe.\" Nothing
is more important than subjective benefit, but it cannot alone be
trusted because of the sham effect that you can have, unless there is a
physiologically-relevant, objective measurement which can also be
monitored.

In looking at what you might choose, one spirometric measurement,
whether it\'s the vital capacity, the force vital capacity, or the FEV1,
I think is very relevant, and a 15 percent improvement in any of those,
I would argue, is a relevant improvement.

I personally believe that the residual volume \[Dr. Cooper blows air out
of his lungs\], the amount of air that\'s left after the maximum forced
improvement, is a very difficult measurement to make in anybody. You
have to have a body box. In these patients, it is very difficult to
make.

But I would argue that, if you could do it and do it accurately, it is
probably the most relevant because the size of your chest when you\'re
breathing is what really determines your work of breathing and your
sense of breathlessness. So I believe that is important to measure, but
I recognize it takes specially-trained technicians, and not all patients
can do it. So I would argue for a spirometric measurement as perhaps a
surrogate.

And then at least one measurement of function or quality of life or
subjective benefit, be it a well-verified, quality-of-life
questionnaire, a dismal using the MRC scale, or a functional test. Some
of these are more eloquent, but, again, very complicated.

Again, for homogeneous emphysema, looking at safety, when you discuss a
safety issue, and what is the risk that a patient should be subjected
to, again, I would argue that you must look at whether or not there\'s
an acceptable alternative to the proposed new treatment.

If there is no alternative, and if the patient is severely disabled, and
particularly if the patient has a limited life expectancy, then your
standard may be one thing. If the patient isn\'t as disabled, if there
is an alternative therapy, but maybe this is being proposed because
it\'s less risky, then I think you may have to set a different standard.

I would only argue that you must look at the target population for these
different devices and interventions before you decide where the
risk/benefit ratio lies. One thing is in your favor, in discussing these
things: The natural history of emphysema is very well-described.

Nobody stays the same. Everybody gets worse at a predictable rate. Life
expectancy for the patients who will be considered for these
interventions, medium survival is less than three years, and for the
homogeneous, severe patients, probably about a year and a half.

In terms of safety ‑‑ others will talk about this more than I have time
to ‑‑ there are obvious things you need to look for in terms of these
interventions, whether it\'s hemoptysis, which can be serious;
pneumonia; sacerbation of their respiratory status, intubation, air
leaks, and death, but death is not the worst endpoint in our patients
who are subject to these operations, be it transplant or volume
reduction; know that. The worst thing is to be made worse and to end up
ventilator-dependent and more miserable than you start out with.

So it is important, again, to look at the disease you are treating, the
intervention, the target population for these in making your decision. I
don\'t think, in terms of followup, you are addressing that. I would
argue the same thing. if you have no alternative, if life expectancy is
short, as in severe, homogeneous emphysema, three to six months of
benefit may be very worthwhile. It\'s like a patient with cancer of the
esophagus when we put in a stent, so they can swallow and have a
reasonable dignity and quality of life, even though it may be only for a
matter of months.

On the other hand, if you are looking at an alternative to an existing
therapy, then your period of followup clearly has to be longer to
justify an alternative in comparison with the current standard of care.

At any rate, I thank you very much for the opportunity of presenting,
and if there is an opportunity to answer any questions later in the day,
I will be pleased to do so. Thank you.

CHAIRMAN McCAULEY: Are there any questions from the Panel members for
Dr. Cooper?

\[No response.\]

We will now proceed with the presentation by Closure Medical,
Incorporated.

DR. STEVENS: Hello. My name is Tom Stevens. I\'m Director of Regulatory
Affairs for Closure Medical Corporation. We are here today to talk about
our endobronchial occlusion device.

With me today I have Joe Barefoot, my boss, Vice President of Regulatory
Affairs and Quality Assure at Closure Medical; Jeff Clark, Vice
President of R&D for Closure; Kevin Kovitz, interventional pulmonologist
from Tulane University Medical Center could not be with us today, and
David West, Vice President of Qintas Consulting.

We have heard just now about the benefits of lung volume reduction
surgery. The current modalities of achieving this are median sternotomy,
as well as video-assisted thoracic surgery, or VATS. Currently, surgical
mortalities of 16 to 25 percent have been reported for the lung volume
reduction procedure; zero to 9 percent for the VATS procedure up to a
period of a year after the procedure has been performed.

We are looking at potential alternatives to the surgical procedure.
Bronchoscopic procedures to achieve ongoing reduction are believed to
possess less risk associated with morbidity and mortality compared to
the surgical intervention.

The Closure medical device depends on placement of occlusive plug using
bronchoscopy and is expected to result in segment-specific atelectasis,
reducing lung volume. Closure\'s endobronchial occlusion device is
expected to offer, through atelectasis, a less-invasive, lower-risk
modality of achieving ongoing reduction than the surgical therapy.

The Closure medical device is a liquid that is delivered through the
catheter and polymerizes in place within the segment in the lung. It is
composed of a proprietary cyano acrylate formulation that is combined
with an activator or a polymerization initiator, viscosity modifier, and
a radio-opaque agent.

Delivery of procedure: The bronchoscope is introduced into the desired
lobe with conscious sedation. The balloon catheter is positioned within
the target bronch segment, and the delivery syringe is attached and the
liquid is delivered through the catheter. Subsequently, the catheter and
bronchoscope are removed, once polymerization has been achieved.

We have evaluated this device in a pre-clinical model. Our objectives:
to provide proof of concept for an occlusive medical device, to achieve
safe and effective atelectasis at the segmental level. Our objectives
also included development of an associated procedure for placement of
the device as well as pre- and post-operative therapy to manage the risk
of infection.

Pre-clinical study design was a goat model used to provide an accessible
tracheal bronchus and an isolated upper lobe, rigid bronchoscope and six
French Berenstein occlusion balloon catheters were used, and the
occlusive plug was placed into the proximal tracheal bronchus.

The design included a seven-day antibiotic treatment pre- and
post-placement, endoscopic and x‑ray analysis at approximately seven
days and ninety days post-treatment, after which the animals were
euthanized for lung explant, culture, and histopathology.

This is a bronchoscopic view of the tracheal bronchus to the lower
right, and you can see the occlusion device in place at day ninety. In
this picture it is in place and intact.

This is a photograph of the explanted lung. The segment here is where
the occlusion device is placed, and we were happy with this result.

So our animal study, what we concluded from that was that we were able
to demonstrate a concept of an occlusive device to achieve atelectasis.
We were successful in developing a procedure and device formulation to
achieve the desired placement and retention of the plug, and also were
successful in managing the infection risk, using the sterile product and
the antibiotic therapy.

The issues for FDA for the study design, from our point of view, need to
focus on the necessary and sufficient information to demonstrate safety
and effectiveness; define the expectations for clinical utility, and
balance to achieve the appropriate level of scientific rigor with
consideration of the practical restraints of undertaking these studies.

Specifically, questions for FDA, and with the help and guidance of the
Panel, are: Are there appropriate objective performance criteria or
other scientific means for designing studies of safety and effectiveness
that obviate the requirement for active control studies; that is, the
surgical intervention?

If control studies are required, what would be the appropriate control,
surgical lung volume reduction or medical management? Answer the
question of: How are the subjects to be recruited and retained? Are the
inclusion and exclusion criteria to be based strictly on the NETT
protocol or are there other criteria that can be based on the NETT
experience? What are the appropriate clinical endpoints: pulmonary
function, quality of life, or others? And what is the appropriate study
duration?

That concludes the presentation of Closure Medical.

CHAIRMAN McCAULEY: Does anyone on the Panel have any questions for Dr.
Stevens?

DR. LoCICERO: Yes, I do. While we\'re not here today to discuss the
pre-clinical trial as such, you did present something that might affect
the length of followup or the type of followup. Can you comment on how
the cyano acrylate is molded? Is this done outside of the body or is
this done inside of the body?

DR. STEVENS: It\'s done inside of the body. The cyano acrylate is mixed
with the other components after the bronchoscope has been placed, then
introduced through the catheter as a liquid into the segment, where it
then polymerizes within a period of a few minutes. So it\'s formed in
place.

CHAIRMAN McCAULEY: Any other questions?

\[No response.\]

We will now proceed with Emphasys.

DR. GEDDES: Good afternoon. My name is Dr. Geddes. I\'m a Professor of
Respiratory Medicine and Pharmacology at the Royal Brompton Hospital in
London. I am speaking on behalf of Emphasys, though I am not part of
Emphasys. I\'m not a company person. I\'m not a regulated person.

I run an emphysema clinic, and we have experience in both volume
reduction surgery and early experience with the endobronchial valve
system that Emphasys has developed. It is for that reason that I have
been asked to talk about my views as to the future ideal clinical trial.

I am just starting a combination of all the randomized control trials
published for volume reduction surgery to date. This does not include
the NETT study and does not include the other two that Joel Cooper
mentioned in press.

Just to give an indication of what can be achieved in these patients, an
improvement of FEV1 measured between 15 and 30 percent, while the
control, the medical control group, are declining. One has to remember
that these patients are getting worse during periods of study.
Six-minute walking distance improved or declining in the control group,
but a significant mortality in the surgical group, a significant
mortality in both groups, but more in the surgical group. So any
treatment that could provide similar or possibly less benefit with less
morbidity and mortality is certainly worth exploring.

The endobronchial devices that we have used, have been using, and I just
want to show this slide as an example to make one simple point. Look at
the x‑ray top left and compare it with the x‑ray bottom right. There you
see emphysema in the upper lobes, a very black lung at the top right.
After placement of the valves, look at this one. You see the diaphragm
has come up, and this lung shows loss of volume and expansion of some of
the lung that was not expanded before.

The reason I am showing that is just to make the simple point that
endobronchial devices can work at volume reduction. So the question then
is: Is that going to provide patient benefit and are they safe?

The safety experience with these valves is now based on 91 patients with
365 valve insertions. These are in pilot, uncontrolled studies, allowing
a period of observation of 14,000-odd patient-days. So there is building
already quite a lot of information about these devices.

I have summarized the adverse effects that have so far been reported:
one death that was probably procedure-related, infection in the occluded
segment; three important episodes of infection, and eight episodes of
pneumothorax, three of which lasted more than a week.

There have been some late events, which I have classified separately.
For example, a death at ninety days from interstitial perforation is
unlikely to be related to the device.

So this begins to define some of the safety measures that should
certainly be assessed as any trial goes on.

And I just want to share with you the experience we have in a very
limited group of nine patients in whom we have tried this treatment as a
real treatment. These are people who we selected for volume reduction
surgery, but did not go forward for surgery, either because they were
too sick or because they refused surgery.

Looking in green, you can see the changes that followed bronchoscopic
placement of the valve as compared with our own controlled clinical
trial of volume reduction surgery. Now this is not a randomized group. I
just want to make the simple point that the types of changes that we are
getting with the bronchoscopic approach are comparable with those that
can be achieved with the surgical approach.

The patients are not the same and our entry criteria are different. So I
don\'t want to say that the treatments are in any way equivalent; just
that similar sorts of measures of improvements can be achieved. They are
not always achieved. We have four start out of nine; three didn\'t get
any benefit. So we are still learning.

So if we then go on to what studies might be done, and what outcome
measures might be appropriate to use, this has largely been covered.
They are already quite conventional. You can take these from the volume
reduction studies and others: A physiological measure, an FEV1 always is
the conventional one, although it has its faults. Some measure of
exercise performance. The six-minute distance has been most commonly
used, but other maximum exercise or endurance exercise tests may be
better.

Some measure of quality of life, we use the St. Georges Respiratory
Questionnaire. It\'s probably the best available and is more appropriate
for these patients than a global quality-of-life measure.

Then I would propose that a tertiary measure of hospital days would give
information that I would find useful for what the patients are having to
endure following the randomization to whatever the control and active
groups are, and also it is a surrogate for costs as well as patient
unpleasantness.

I think the outcome measures are relatively straightforward. What I find
more difficult is what the exact trial design should be. As a clinician,
these are the questions that I want to answer:

Does the system, whether it is a valve or any of the others, work? Is it
safe? And then we also need to know ‑‑ and these come in smaller print
because they are secondary questions ‑‑ we need to know what are the
ideal patients. I think we only learn that by experience, not by theory.
It may well be that we will want to do a comparison with surgery at some
stage. But until we know who the ideal patients for each group, it would
be quite inappropriate to use surgery as a comparison group. The results
will depend on selection of patients rather than the treatment itself.

Already we have some information. I know that these can work. I don\'t
know if they work well enough because we don\'t have an adequate control
group.

Is it safe? I know the Emphasys valve is probably safe with a number of
92; a previous number of 91 you saw. It\'s come up to 92 because we did
another patient yesterday morning. The long-term safety and the rare
event safety events, obviously, will need larger groups.

Selection criteria will depend on more experience and probably will be
gained from a longer period than the initial controlled trial, and a
comparison with surgery, I\'m sure, will be interesting at some stage in
the future, but not yet.

My own view is that these devices, if they do work and are safe, are
likely to find their place as a trial of treatment before surgery but
not be used instead of surgery. The patients, when you talk to them
about it, they say, \"If there is a way that might be simpler and safer,
then I would like to try it first, but if it doesn\'t work, can I go on
to the other?\" And that is probably what any of us would say.

So there are three clinical trial designs that I think are possibly
worth considering. One would be bronchoscopic volume reduction against
surgical. I think it\'s premature, but that would be a possibility.
Another would be just to use the patients as their own controls and
compare pre and against post, and the third would be to use
bronchoscopic volume reduction against best medical therapy, following
the tradition set by volume reduction surgery.

My own personal view is that the first one is premature until we know
better what the selection criteria should be and who are the ideal
patients for each. Then possibly randomize those in whom it is a real
option, one or the other.

The pre and post without an adequate other non-treated control group I
think is probably inadequate because we won\'t be able to make valid
conclusions about all the outcome measures. My own preference would be
to go for the bronchoscopic insertion of the device against best medical
treatment, but there are problems.

And the problems are that you have a treatment with surgery, which
already has a lot of controlled trial data to suggest that it works in a
patient group who do not have a lot of time. So I think any trial design
would have to take that into account, and we would need to define entry
criteria well, so that those who were clearly suitable for surgery
didn\'t go into this.

We would include surgical candidates and those in whom it was equivocal
as to which was the best treatment, which would be the majority. We
would do a primary comparison at six months, by which time you would
know whether the thing has worked, and also you would have given the
patients enough time for the benefit to be worthwhile. Even three months
is worthwhile to these patients.

But in those who did not improve, then surgery would need to be allowed.
I think it would be unethical to ask these patients to remain in a
control trial for years, during which they are likely to die without
ever having access to a treatment which has a possible benefit. There
would need, then, to be a long surveillance period after the trial to
make sure that late and rare side effects were properly picked up.

I would hope that we would be able to do these things relatively soon
because there are millions of patients like that for whom we do not have
a treatment at the moment, and these devices do, in our own experience,
offer real potential benefits.

We have one patient who, having had a bronchoscopic insertion, refused
to go on the television to report the benefits because he would now lose
his disability benefit because he was able to do so much more.

\[Laughter.\]

So, at a purely anecdotal level, this can work. I would like to be able
to get to the position where we know that it does work and for enough
people. Thank you. That\'s all I have to say.

CHAIRMAN McCAULEY: Thank you.

Are there any questions from the Panel for Dr. Geddes? Dr. Ferguson?

DR. FERGUSON: Yes, that was very nice. All of these presentations do not
mention in the protocol one of the things that I have been most
impressed with in the lung volume reduction group that I\'ve seen at
Washington University, and that is the positive benefits that you get
with several months of intense medical therapy over and above what we
call medical therapy, in terms of getting the patients ready for
whatever they\'re going to have.

I think it\'s important to emphasize that that is a standard for lung
volume reduction surgery, and I would not like to see that lost as we
talk about other devices.

DR. GEDDES: Could I just respond?

CHAIRMAN McCAULEY: Do you want to comment on that?

DR. GEDDES: I completely agree with that, and it is essential because
these patients are sometimes neglected. In our own trials, both volume
reduction and of the endoscopic approach, they have all been through a
period of months of optimization treatment, including formal physical
rehabilitation. So I think that\'s essential. Some of the patients no
longer are interested at the end of that time.

CHAIRMAN McCAULEY: Other questions? Dr. Miller?

DR. MILLER: Yes, I\'m not familiar with the device you\'re talking
about. Is it a physical device that totally occludes the airway?

DR. GEDDES: It\'s equivalent to a metal stent with a plastic surround
but a duck-billed valve in the center to allow air to come out of the
occluded segment, but not to go in. So it is not complete occlusion. It
is occlusion on inspiration, but airflow possible on expiration. So
mucous or air can get out of the occluded segment.

DR. MILLER: Does it cause atelectasis in the distal lung the way the
occlusive device does?

DR. GEDDES: What it has done in half of the patients, formulate
atelectasis of the lobe we\'ve been targeting in some partial
atelectasis; in others none at all. Patient selection to achieve
atelectasis is an important consideration.

DR. MILLER: Can it migrate or can you take it out once you put it in?

DR. GEDDES: You can take it out. They have been taken out as late as, I
think the latest is three months after insertion. So far, migration has
not been a problem. They expand on placement, but those are a good
example of the long-term surveillance requirements because I think, in
fact, there will be those sort of problems occasionally. It hasn\'t
occurred yet.

DR. MILLER: Thank you.

CHAIRMAN McCAULEY: Dr. Shure?

DR. SHURE: Most foreign bodies would have significant granulation tissue
and fibrosis by three months. Is this Teflon or something else that
would prevent that?

DR. GEDDES: Yes.

DR. SHURE: You say it can be removed at three months?

DR. GEDDES: Well, that\'s right. Again, that is the experience so far
with the longest period of insertion that I personally have looked at,
is now nine months afterwards, and there is no granulation tissue at
that time.

DR. SHURE: No granulation tissue?

DR. GEDDES: No.

CHAIRMAN McCAULEY: Thank you.

We\'ll now hear from Spiration, Incorporated.

DR. SHEA: Good afternoon. My name is Rick Shea. I am President and CEO
of Spiration, Inc. Spiration was founded in 1999 to develop medical
technologies for the treatment of lung diseases.

For this project, Spiration has assembled a scientific advisory board of
over 20 experts. These slides that Lori is showing here depict some of
them. We have arranged for two of these advisors to address the
questions posed to the panel.

Dr. Matthew Brenner is Chief of Pulmonary Medicine and a Professor of
Medicine at the University of California in Irvine. Dr. Brenner has
published extensively regarding his research on emphysema and the
effects of lung volume reduction surgery in various models, including
experimental models of emphysema.

Dr. Douglas Wood is Professor and Chief of General Thoracic Surgery at
the University of Washington in Seattle. Dr. Wood has substantial
experience in both lung volume reduction surgery and interventional
bronchoscopy, and has published extensively on the clinical aspects of
lung volume surgery, lung cancer, and the use of tracheobronchial
devices to treat airway obstruction.

Dr. Wood participated as a co-principal investigator for the
NIH/CMS-sponsored National Emphysema Treatment Trial, as well as the
companion study of cost-effectiveness of lung volume reduction surgery,
sponsored by the Agency for Health Care Policy and Research.

Spiration has also two physicians on staff who are here today to address
the Panel\'s questions. Dr. Steven Springmeyer, our Medical Director, is
a pulmonologist and interventional bronchoscopist and a Clinical
Professor of Medicine at the University of Washington.

Dr. Xavier Gonzalez is our Vice President of Research. Dr Gonzalez has
supervised all the pre-clinical in vivo and ex vivo testing for
Spiration\'s intra-bronchial valve system.

I would now like to introduce Dr. Matthew Brenner.

DR. BRENNER: I thank you, and good afternoon. I will begin with a short
animation showing the use of the Spiration intra-bronchial valve system,
which I\'ll now refer to as the IVV. This animation shows delivery,
deployment, and removability of the IVV device.

The IVV device is a one-way valve delivered under topical anesthesia
with conscious sedation to selected regions of the bronchial tree using
a flexible bronchoscope. It is designed for rapid, simple deployment.

Once the device is in place, it\'s designed to limit flow of air into
the distal diseased portions of the lung. The valve is designed to allow
mucous to exit the targeted area, to minimize the potential obstruction
that might lead to pneumonia. Pneumonia is a concern as a possible
complication of airway obstruction with any intra-bronchial device.

The valve can easily be removed via flexible bronchoscopy. The ease of
removability was designed specifically to increase patient safety in the
event of complications, incorrect placement, or lack of therapeutic
benefit.

My comments will specifically address Question No. 2 regarding the
safety parameters to be evaluated in the clinical trials of these
devices. The process of pre-clinical investigations of new devices is
important to analyze and predict the safety factors needed to be
addressed in clinical studies.

I and the other members of the scientific advisory board of Spiration
have recommended a rigorous and complete characterization of the safety
profile of the IVV device in pre-clinical studies, including delivery,
deployment, and removability, before the company proceeds to clinical
trials in these very fragile patients.

Spiration designs studies in healthy, in vivo animal models to provide
specific information that will help predict responses that may be
observed in human airways with the IVV device. The company is conducting
progressive, acute, and chronic studies. In this pre-clinical work,
Spiration has implanted over 500 devices using three different species
for periods of one, three, and six months. The company has safety data
regarding the removal of over 100 devices for periods of up to six
months.

In summary, pre-clinical studies remain an important step to establish
the safety of devices before moving to clinical trials. As a result of
conducting these pre-clinical studies, the companies identified and
analyzed key safety parameters listed in this slide that should be
required prior to clinical studies of new intra-bronchial devices in
emphysematous patients.

Thank you, and I would like to now introduce Dr. Douglas Wood, who will
discuss clinical study design of intra-bronchial devices in emphysema
patients.

DR. WOOD: Thank you, and good afternoon. In this presentation I am
representing the members of the Spiration Scientific Advisory Board.

Under current eligibility criteria, only about 10 to 20 percent of
emphysema patients are eligible for surgical treatment. There are no
surgical alternatives for the remaining 80 to 90 percent of emphysema
patients who are suffering from a progressive disease with no known
cure.

In considering the target population for initial pilot studies, the
population may differ based upon differences in device design, risk
profile, and physiologic mechanism of action. For the pilot clinical
study of the Spiration intra-bronchial valve, it is the opinion of the
Scientific Advisory Board that the initial pilot studies should be
confined to patients with hyperinflation, severe heterogeneous, upper
lobe emphysema who do not qualify for LVRS or transplantation and who
are able to tolerate bronchoscopy.

Patients will be required to complete the program in pulmonary
rehabilitation prior to enrollment to match the majority of LVRS studies
and to establish a post-rehabilitation baseline to serve as the most
legitimate pre-treatment control.

To address Question No. 1, we believe that the appropriate control group
would be patients receiving best medical management, including pulmonary
rehabilitation. LVRS would be appropriate as a control group if the
device risk profile approaches that of surgery or if device implantation
precludes subsequent LVRS.

The results of pilot studies and the published results of the NETT
randomized clinical trial will help guide the design of pivotal clinical
studies.

Regarding Question 2, the most important aspect of the initial clinical
studies for these devices is the need to demonstrate safety. There is
now an extensive body of literature regarding safety of LVRS. The
published data should serve as a guide for evaluating new,
minimally-invasive procedures for the palliation of end-stage emphysema.

As scientific advisors, we agree with the adverse outcomes defined in
Question 2 and recommend adding the need for device removable and/or
surgical intervention as additional adverse outcomes.

With regard to the measures of effectiveness asked in Question 3, we
agree with the FDA\'s proposed measures, including improvement in FEV1,
six-minute walk, maximum exercise capacity as measured by cycle
ergometry, and quality-of-life and dyspnea scales.

We recommend including measurements of lung volumes, a standard test
that provides objective evidence of reduced lung volume. However, the
proposed variable of length of hospital stay is unrelated to device
effectiveness; it may be a surrogate for device safety, but is largely
influenced by the study protocol.

The degree of clinical improvement achievable with these intra-bronchial
devices has not been established and should first be evaluated in a
well-controlled pilot clinical study. It is anticipated that the NETT
will provide a consensus of the investigators regarding the degree of
improvement or decline that will be considered clinically-significant.
The pilot study data can then be combined with these results to
establish reasonable endpoints for a pivotal clinical study.

Relief of dyspnea is the primary clinical motivation for treatment in
most patients, and these studies should include subjective measurements
of dyspnea and quality of life.

Regarding Question 4, followup is needed to assure acute and chronic
safety as well as to evaluate persistence of efficacy. Duration of
followup is very much dependent upon the device design, the risk
profile, and the reversibility of the procedure.

For the IVV device that has established a substantial body of data from
pre-clinical studies and has the ability to be removed, we think acute
and chronic safety can be determined in three months. Devices or
procedures that have not been demonstrated to be reversible may require
longer followup before determining safety.

Regarding the followup for effectiveness, we think the benefits of the
IVV device may be evaluable within one month of treatment. This should
be confirmed at three months after treatment. The chronic safety and
effectiveness can then be evaluated during post-approval followup that
conform to the guidelines for implantable devices.

In conclusion, I hope this has adequately answered the questions
submitted to the Panel. The IVV device and other minimally-invasive
technologies may offer improvement of symptoms in patients not eligible
for surgery and in the future may provide effective palliation with
lower risk than surgery.

We thank you for the opportunity to provide input into your
deliberations, and we offer to address any additional questions that you
may have.

I also just wanted to introduce two additional members of our Scientific
Advisory Board that are with us in the audience. Dr. Roger Yusen is a
pulmonologist and an Assistant Professor of Medicine at Washington
University School of Medicine in St. Louis, and Dr. Yusen in the
audience has authored several publications on patient selection for LVRS
and long-term outcomes after surgery.

Dr. Dan Sterman is the Director of Interventional Pulmonology and an
Assistant Professor of Medicine at the University of Pennsylvania. He
has authored a number of publications in the area of lung cancer and
interventional pulmonology.

Thank you.

CHAIRMAN McCAULEY: Are there any questions from the Panel for the
members of Spiration, Incorporated?

\[No response.\]

We will now proceed with the open public comment session. All persons
addressing the Panel speak clearly into the microphone, as the
transcriptionist is dependent upon this means of providing an accurate
record of this meeting.

We are requesting that all persons making statements during the open
public hearing session of the meeting disclose whether they have
financial interest in any medical device company. Before making your
presentation to the Panel, in addition to stating your name and
affiliation, please state the nature of your financial interest, if any,
and disclose if anyone else besides yourselves paid for your
transportation or accommodations.

We will begin with those individuals who have notified the FDA of their
request to present in this forum. Dr. Cooper?

DR. COOPER: Thank you. The ATS, which I am representing, appreciates the
opportunity of being invited here to participate and to be able to
answer questions.

I don\'t really have any specific comments to make other than to say
that the organization is very interested in the process, very willing to
help in any way, shape, or form with the design, the establishment of
standards, and the evaluation of this, and is particularly concerned
with the process of introduction of new technologies in a responsible
fashion into the community.

We would like to assure that the process assures that, once devices are,
in fact, made available, that that introduction of the device is
something which is really beyond the FDA I believe, is done in the
fashion which patients are fully informed and very aware of the risks
and benefits which must be established, I believe, before the FDA
finally approves these devices.

So I don\'t have other specific comments to make other than that we
appreciate participating in the process and are happy to avail you of
any expert advice that you may wish to seek from the cardiothoracic
surgical community. Thank you.

CHAIRMAN McCAULEY: Dr. Putnam?

DR. PUTNAM: Good afternoon. Thank you, Mr. Chairman. My name is Dr. Joe
B. Putnam, Jr., and my practice is dedicated solely to general thoracic
surgery in Houston at the University of Texas M.D. Anderson Cancer
Center.

As a surgeon, Professor of Surgery, Deputy Chairman, Program Director,
and Clinical Investigator, I have focused on the specific problems of
patients with lung cancer and other pulmonary diseases for the past 15
years. I serve as Chair of the Thoracic Oversight Committee for the
American College of Surgeons Oncology Group, which is a National Cancer
Institute-funded cooperative group improving the care of cancer patients
through prospective, multi-institutional clinical trials, specifically
examining the surgical and multidisciplinary treatment of cancer.

I also serve as Chair of the Work Force on Clinical Trials for the
Society of Thoracic Surgery. I have been involved in over 40 clinical
trials related to thoracic surgery over the course of my career as
primary investigator, co-primary investigator, and collaborator.

Thank you for the opportunity to be here today to address the Panel\'s
posed questions for devices for the treatment of emphysema. For
disclosures, I have received non-restricted grant funding from
Radiotherapeutics, recently purchased by Boston Scientific, and from
RITA Medical Systems, for the conduct of pre-clinical and clinical
trials, respectively. My transportation has been subsidized by the
Society of Thoracic Surgery.

Question 1: the appropriate control group for clinical evaluation.
Because the NETT trial is the largest trial to date for the assessment
and treatment of end-stage lung disease, the design and structure of
this trial would be appropriate to follow. A subset of patients within
this trial should have some benefit and should pose the gold standard
for which comparisons are made in any new clinical trial. The results of
this NETT trial should be available within the next 30 to 60 days, and
the recommendations would be to assess the results of this trial
carefully prior to establishing treatment and control groups.

It is imperative that the results of any and all trials, whether
positive or negative, Phase 1 or greater, be published in a timely
manner. Trials must be optimally performed on a national level at
multiple centers.

Finally, educational programs for devices must be made available to the
participants in the trial to ensure consistency of care and application.

Question 2: clinical devices for safety. The endpoints presented,
rehospitalization, COPD exacerbation, and so forth, are excellent
endpoints to monitor. Again, because the NETT trial is the largest to
date, endpoints monitored in this trial must also be considered for
future trials if a meaningful comparison is to be done.

Future endpoints must be objectively defined prior to the study
origination through peer-reviewed publications or consensus conferences
addressing such endpoints. Common procedure-related toxicities may be
developed for use by all clinical investigations, such as has been
proposed by the common surgical toxicities through the National
Institutes of Health.

Question 3: the merits of the parameters in evaluating effectiveness of
such devices. These included pulmonary function tests, six-minute walk
tests, and so forth. The clinical significance of percent changes relate
to the endpoint in question, so it is a bit premature to discuss what
would be appropriate changes in the absence of the context of the trial.

The maximal oxygen consumption, a management of the cardiopulmonary
axis, how well the body absorbs, transports, and uses oxygen, as well as
the diffusion capacity, the DLCO, are currently easily available and
objective measures of pulmonary reserve.

Question No. 4: the duration of followup. Short-term followup, less than
six months, is usually presented. However, 12 months, 18 months, and
longer really define the issues of long-term safety and efficacy.

As the NETT trial has proposed, a minimum of six months is required.
Many patients in the NETT trial have been followed for five years.
Long-term followup is obviously required for late events.

From the Society of Thoracic Surgeons, I would like to mention to the
Panel that our National Cardiac Database, the largest in the world with
over 2 million patients entered to date, including over 525 hospitals
and 1,500 individual surgeons, has allowed thoracic surgeons to improve
their patients\' care.

Recently, a post-market evaluation of transmyocardial revascularization
techniques, funded by the FDA, in association with the Society of
Thoracic Surgeons, was highly successful. The TMR procedure was tracked
in over 2,500 patients over a two-and-a-half year period alone or in
conjunction with cardiac bypass. This study is now closed, and the
outcomes are pending.

The Society of Thoracic Surgeons and its Work Force on Clinical Trials
welcomes the opportunity to assist our patients and the FDA in its quest
for improvements in health care and to balance the considerations of
clinical, ethical, and economic outcomes.

Thank you for the opportunity to discuss these issues.

CHAIRMAN McCAULEY: Is there anyone else wishing to address the Panel?

\[No response.\]

Thank you. Since there are no other requests to speak in the open public
hearing, we will provide with the general Panel discussion, including
discussion of the FDA\'s questions.

Are there any general comments from the Panel at this time?

\[No response.\]

We will proceed with the FDA questions.

Question No. 1: \"What is the appropriate control group for clinical
evaluation of these devices?\" ‑‑ has two separate parts to it. \"For
which patients would LDRS be an appropriate control group, and for which
patients would medical management be an appropriate control group?\"

Dr. Ferguson, you have been asked to lead the discussion of this
question.

DR. FERGUSON: First, let me say that the presentations from the
companies and the thought that they have put into it, in my view, is
right on target in terms of appropriateness and discussions of safety
and efficacy.

To answer, however, the question, I think it is much too soon to decide
what are the appropriate control groups. This was brought up by Dr. Wood
and some others.

To me, the control groups would, for a long time in the future, have to
be those individuals who are not candidates for any other type of
surgical procedure, LVRS, transplant, or others that might come on the
scene, but those are the ones here.

I think that my answer to this would be that the appropriate control
group for a long-term time in the future would be those patients who
have received maximum medical benefit under medical therapy.

So I have skirted the first part of that and gone directly to the
second.

CHAIRMAN McCAULEY: Dr. Brenner, any comments?

DR. BRENNER: From an oncologist\'s point of view? No.

CHAIRMAN McCAULEY: Dr. LoCicero?

DR. LoCICERO: Pretty soon we\'re going to have information concerning
lung volume reduction from the National Emphysema Treatment Trial which
may actually eventually affect what we decide as far as using this as a
control group.

However, it\'s probably not appropriate to use these devices for ‑‑ have
a control group of lung volume reduction against these devices because
these devices are not intended to be a complete treatment as lung volume
reduction, as they\'re not affecting ‑‑ most of them, as far as I
gather, do not affect all lobes, and only portions of the lung, and may
not be equivalent to lung volume reduction surgery. So, in that case, it
would be inadvisable to use lung volume reduction as the control.

Additionally, the death rate or the mortality rate for the operation is
measurable and these devices show a much lower mortality rate. This
would set up an unduly-difficult ‑‑ or an unduly-easy hurdle for these
particular products in comparison to that approach and, again, may be an
inappropriate match.

Concerning the second point, best medical therapy versus this type of
device might be an appropriate control. All of these patients will
deteriorate at the same rate. It allows us an opportunity to look at
divergence based on their deterioration.

CHAIRMAN McCAULEY: Dr. Shure?

DR. SHURE: Well, I think there are several aspects of this, and some of
it may overlap with effectiveness. I\'ll try not to do that too much.

At least some of these devices are said to be an alternative. That\'s
how they are proposed in the presentation, as an alternative to LVRS. I
think one has to ask the question of, how are these areas being
targeted? Are they all heterogeneous cases. Except for Dr. Cooper\'s,
they seem to be. Well, how do we know that in a segmental obstruction
you\'re getting the areas that you would want to get? I don\'t think
that was clarified and would be a source of concern.

I think, ideally, NETT would be a control. NETT is not going to
repeated. One could consider cohort matching of these patients in a
large multicenter trial of all the devices. I think it\'s important that
whatever be done here be multicenter because there will be differences
in the patient population and levels of skill. But I think that would be
ideal.

I\'m not sure that that\'s possible, though, because there are going to
be more factors about here, and retrospective cohort matching may be
difficult. So I think we are left with a medical control. We do have
good data for what the deterioration is in this patient population. So
that\'s good.

I think I agree with whoever said that we need optimal medical
management for at least six months prior to this. So I think that would
serve as the best control.

I think a number of things need to be put in here that would make it
analogous to NETT, if we are looking at them, which is CT grading,
excluding pulmonary hypertension, measurement of FEV1, and so forth.

I think in terms of starting any of these studies you need to define
crossover to LVRS, when that would be considered, when it would be
considered appropriate. So I think those are the issues, and I think
just because of the feasibility, you would need a multicenter,
randomized, controlled trial using medical group as a control.

CHAIRMAN McCAULEY: Dr. Miller?

DR. MILLER: This area is not one that I am particularly expert in, but
from what I understand of this, it would seem that you have not a
homogeneous group of patients here. The patients who are at various
stages of disease who require different treatments at whatever stage
they are, and I think that the proper control group would be that group
that would ordinarily get a treatment for whatever stage they are when
you propose to use one of these devices.

So the competing alternative to the device is what they would get at
that level of disease. So I guess the answer to the first question is,
it depends on the patient and what their alternatives are and what you
are comparing to in terms of the treatment.

CHAIRMAN McCAULEY: Dr. Blumenstein?

DR. BLUMENSTEIN: If the results from NETT are to be known in a couple of
months from now ‑‑ is that what I heard? ‑‑ it seems like we are having
this meeting two months early, because I would imagine that a great deal
will be learned from NETT, probably not the first two-month
presentation, but some of the other analyses that would follow the
initial analysis and the announcement of the trial, and so forth.

In particular, some of the analyses of subgroups ‑‑ I don\'t mean that
in the sense of isolating them, but the relationship between treatment
effect, the interactions between treatment effect and group
identification.

It seems to me there are analogies here also with advanced stage cancer,
for which there\'s no alternative, and that there may be some of the
regulations that govern these cancer trials today, the accelerated
approval type of things or some of the single-arm, acceptance of
single-arm studies in situations where there are no alternative
treatments, some of the models there might apply in this situation.

Again, all of those depend on how well you know your historical data,
and the historical data, at least to some extent, may come out of NETT,
and it may be worthwhile to wait a bit.

But one thing that occurred to be here also is that, even if you are in
a group, if you\'re studying a group for which lung reduction volume
surgery ‑‑ did I say that right? I\'m not so facile with this. But for
which that is inappropriate, that a randomization between early use of
these devices versus a later use of these devices would gain you
something very important, and that is to give you an initial, at least
an initial randomized data comparing the immediate effect of the
installation of these devices.

I assume that the procedure time is fairly short on these things, I\'m
gathering from the little animation that I saw. I\'ve never done one, so
I can\'t tell.

So I would assume that randomization between early versus late might be
something that could be done fairly quickly, and you wouldn\'t be
delaying the group randomized to a delay treatment very long, but at
least you would, then, develop that randomized data that would allow you
to assess in an unbiased way the immediate effect of the device.

CHAIRMAN McCAULEY: Dr. Stoller?

DR. STOLLER: Well, I would echo Dr. Ferguson thanks to the presenters. I
think that the issues have been framed very carefully.

My own view is at the end of the day both effectiveness and efficacy of
these devices in the minds of patients are going to be framed by the
clinical choices that patients have. And irrespective of the pending
results of NETT, I think the appealing patient choice will be that of a
non-surgical procedure unassociated, as Dr. LoCicero has pointed,
presumably unassociated with the same short-term mortality rate, one
would at least hope. So I think that consideration frames a strong
preference for a medically-managed control group.

That said, I think one of the potential appeals of a bronchoscopic
approach is, as we have heard with regard to some of the devices, its
reversibility. So the reversibility at least allows the possibility of
crossover at a later time, undoing and potentially crossover to a
surgical intervention that would not preclude surgical candidates from
the medically-managed groups.

So that my own sense of the inclusion criteria would be to be, in fact,
broad and to not exclude potentially surgical lung volume reduction
candidates who are being medically managed at the time from candidacy in
the trials, recognizing that they may be allocated to a control group.

CHAIRMAN McCAULEY: Ms. Brown?

DR. BROWN: I\'m sympathetic to the FDA and the companies that are trying
to design the studies today, given that the NETT trial results aren\'t
out. If the NETT trial results are coming out in two months,
unfortunately, the FDA in general has 30 days to do almost anything, and
they have to make decisions based on the information they have today,
rather than two months from now. So just to let the Panel know that I\'m
not sure the FDA gets to wait for future scientific data that may be
helpful.

In addition, I think that it is important with these studies to
carefully think about the options that the patients do have. The
homogeneous patient has a different option than the heterogeneous
patient. With the procedures that are bronchoscopic, they are going to
carry more risk than the medically-managed patients, but, on the other
hand, the surgical procedures carry a whole lot more risk, but the
efficacy is going to fall somewhere probably in between. So that is
going to impact how the FDA thinks about the safety of these devices
with respect to both medical management and surgery.

CHAIRMAN McCAULEY: Ms. Moore?

MS. MOORE: I have nothing to add to what\'s been said already, so I
pass.

CHAIRMAN McCAULEY: Dr. Shure?

DR. SHURE: One other comment that I forgot to make was the procedure
that I think involves actually collapsing the lung, washing with
surfactant, and so forth, and then the glue. That\'s a fairly dramatic
procedure for the patient, and I think one might want to consider sham
bronchoscopy with a lavage as a control in that study as a possibility,
just because they have gone through something similar. It\'s analogous
to having surgery and feeling you\'ve gone through a lot.

CHAIRMAN McCAULEY: Dr. Ferguson?

DR. FERGUSON: I would like to reiterate what Dr. Stoller said. I think
pegging any of these devices to lung volume reduction is the wrong thing
to do. They\'re all different. They\'re a different approach, and I
don\'t, frankly, see how the results of the NETT study, whatever they
show ‑‑ I think we know what they\'re going to show ‑‑ but whatever they
show have much impact on what we\'re talking about here today.

CHAIRMAN McCAULEY: Dr. LoCicero?

DR. LoCICERO: I\'ll just expand on that a little bit. To limit the
indications to whether or not this works against lung volume reduction
ignores the vast majority of patients who don\'t qualify for lung volume
reduction. This also may affect the company\'s ability to recruit
patients and gather data in any kind of a timely manner.

Dr. Stoller?

DR. STOLLER: Thank you. I guess I would like to make one other comment
with regard to candidacy in the context of homogeneous versus
heterogeneous lung function. There\'s a population ‑‑ and many who know
me will anticipate an interest of mine in my comment ‑‑ but there\'s a
population of patients with alpha 1 antitrypsin deficiency who, in fact,
have hetero disease, but it\'s in the wrong direction and not easily
amenable to surgical lung volume reduction. In fact, the relatively
embryonic experience with these patients, and not in a controlled way,
suggests rather disappointing surgical results.

So it seems to me the opportunity exists, and I would urge careful
thought about the potential inclusion of patients with alpha 1
antitrypsin deficiency, in which there is, in fact, heterogeneous lung
disease, but it\'s basally distributed and, therefore, not easily
amenable to the conventional surgical approaches that have been
undertaken to address them.

So these devices, in a funny way, offer an opportunity to look at a
heterogeneous emphysema population that\'s in a funny way been excluded
from consideration and for whom benefit may be conferred. So that would
be something that I would urge attention to as these pivotal trials are
being considered.

CHAIRMAN McCAULEY: Dr. Witten, it appears that the Panel does not feel
that lung volume reduction surgery would be an appropriate control group
and that the appropriate control group for these devices would be
patients that have had maximized medical therapy. Does that satisfy
your ‑‑

DR. WITTEN: Yes. Thanks for the discussion.

CHAIRMAN McCAULEY: Thank you.

We will now move to the second question which has been posed to the
Panel by the FDA. \"What are the most important safety parameters to be
evaluated in clinical trials of these devices?\"

Dr. Shure has agreed to lead off this discussion.

DR. SHURE: I think many of the parameters were very reasonably discussed
by the presenters. I would like to make one comment at the beginning,
before going on to detailing those. That is that I think that what we
are dealing with is we are dealing with a chronic illness. So we have to
look at both acute consequences of the intervention, plus chronic
consequences, because these are chronically-ill patients. So we need to
look at both short-term and long-term endpoints.

I think these are probably analogous to what we\'ll talk about under
efficacy, but we perhaps could look at composite endpoints or parameters
of death; air leak greater than seven days; bleeding requiring
transfusion or reoperation or a need for mechanical ventilation;
pneumonia, looking at both the acute and chronic in terms of frequency
of pneumonic episodes; need for hospitalization; number of hospital
days; need for reoperation to remove the device if migrates; respiratory
failure as a consequence of the device ‑‑ that would be long-term ‑‑
decrease in FEV1. I mentioned reintervention because of migration.

I think people have said that these devices don\'t migrate, but I think
we really need to assess that. I don\'t know if they radio-opaque. I\'m
assuming they are, but I think they need to be looked at
bronchoscopically, probably at intervals of at least three, six, nine,
and twelve months. I would propose something on that order.

Secondarily, perhaps decreasing quality-of-life index or decrease in
dyspnea, but I would view the other ones as I mentioned as primary
safety issues.

CHAIRMAN McCAULEY: Any comments, Dr. LoCicero?

DR. LoCICERO: I agree pretty much with all of what Dr. Shure has said. I
would also add that the device that is formed within the body may pose
slightly different safety endpoints, which might include local heating
effects, which may be measured by bleeding or some other effects on the
bronchus. This may also pose some long-term effects, which may require
us to look at this particular device for a much longer period of time.

CHAIRMAN McCAULEY: Dr. Brenner?

DR. BRENNER: I have no comments.

CHAIRMAN McCAULEY: Dr. Ferguson?

DR. FERGUSON: I agree with Dr. Shure. It seems to me that one of the
things that is going to become an important consideration here, and I\'m
not speaking for or against any device, believe me, but it is the fact
that, is the device removable? And all of the things that have been
mentioned in terms of the easing, and so on, are going to be important
parameters down the road affecting what patients are selected, just any
number of things.

CHAIRMAN McCAULEY: Ms. Moore?

MS. MOORE: I think Dr. Ferguson just mentioned the point that I was
going to mention. One of the presenters did suggest that we add to this
list the ease of administering and removing the device. I would concur
with him on that.

CHAIRMAN McCAULEY: Ms. Brown?

DR. BROWN: Just one comment about the serious adverse events: With
respect to patients who rehospitalized after the procedure is done and
COPD exacerbation kinds of information, it is my understanding that,
since these patients have an ongoing disease state and they\'re
continuously deteriorating, that that\'s something that we expect to see
in this population. So that when we do a comparison between treatment
and control, hopefully, we will be able to sort out what\'s
device-related and what\'s not. But we do expect to see those things in
these patients.

CHAIRMAN McCAULEY: Dr. Stoller?

DR. STOLLER: Again, I agree with Dr. Shure\'s comments. My notion is
that an evaluation of the complications ought to carefully attend to
complications of the presence in the airway of a foreign body, of which
these all are. That would obviously subsume outcomes such as, you know,
hemoptysis infection, both acutely and chronically, as well as
complications relating to the procedure itself.

Patients with emphysema are characteristically at higher risk, it seems
to me, with regard to bronchoscopy. These procedures are longer than the
traditional diagnostic bronchoscopies, I would imagine. So one would
have to capture complications of the bronchoscopic intervention
independent of the placement of a device in assessing the complications
of the procedure.

Then, of course, I think as has been very nicely stated by all of the
presenters and Dr. Shure and other members of the Panel, you know, the
intermediate-term complications would surely to capture
rehospitalization, intubation, mechanical ventilation both invasively
and non-invasively, and death, frankly. I agree with the notion about
the need to remove the device by virtue of complications as a
consequence of the placement of a foreign body in the airway.

Clearly, one would want to capture the crossover rate; that is to say,
which is ultimately a testimony to clinical efficacy and patient
preference. Patients who go on to have a device and then ultimately find
themselves electing based on results of the available clinical trials
and the NETT trial, whatever that shows, could be forthcoming, who elect
to go on to surgical intervention as a lung volume reduction
opportunity.

So I think it has been nicely stated by all: The assessment of
complications needs to be very broad-reaching because this represents an
intervention not conventionally available to patients with relatively
severe emphysema.

CHAIRMAN McCAULEY: Dr. Blumenstein?

DR. BLUMENSTEIN: I don\'t have anything to add.

CHAIRMAN McCAULEY: Dr. Miller?

DR. MILLER: I think in terms of looking at the complication, I think one
thing that should be considered is how difficult it is to treat the
complication once it occurs, rather than just scoring it occurred.
Because I can certainly imagine pneumonia occurring behind an
irremovable plug of glue in the airway is going to be much more
difficult than just having a pneumonia behind a removable valve that
suddenly you can drain that segment. So I think some examination of that
would be important.

DR. SHURE: Days of hospitalization or need for surgery could be part of
that.

CHAIRMAN McCAULEY: Dr. Witten, it appears that two points have really
come up relative to Question 2: complications related to the foreign
body in the airway in and of itself versus the complications associated
with procedure. These have been secondarily broken down to acute
consequences and chronic consequences. The parameters that have been
identified include death, bleeding, mechanical ventilation, pneumonia,
hospitalization or rehospitalization, reoperation, respiratory failure,
decrease in FEV1, migration of the device, time periods for evaluation
being three, six, nine, and twelve months, with secondary endpoints of
decrease in dyspnea and improvement in quality of life.

Does that satisfy you?

DR. WITTEN: Yes. Thank you.

CHAIRMAN McCAULEY: We\'ll now move to the third question. \"What
endpoints, among those listed and any others not listed, would be
important to demonstrate device effectiveness? Pulmonary function,
six-minute walk test, maximum exercise capacity, quality of life,
dyspnea questionnaires, length of hospitalization?\"

For this question, Dr. Stoller has agreed to be the lead person.

DR. STOLLER: Well, thank you. I appreciate the opportunity to comment.
Again, I think these issues have been very nicely laid out by the
discussants.

My own view of this is that the assessment of primary and secondary
outcomes really should take its lead from the design of available, in
fact, surgical trials, including NETT, and which I think has been nicely
discussed. The spirit in which the outcomes were designed took into
consideration that this is really a palliative procedure. So one needs
to capture outcomes that relate to functional capacity and patient\'s
experience of this disease, while, of course, not neglecting the
complications, as we\'ve discussed, in long-term survival.

My own sense I think has been discussed really by many others: that the
primary outcome measures must include some measurement of exercise
capacity. We have been asked to comment on the minimally-important
clinical difference, and I\'ll come back to that as I go through the
individual outcomes, at least my best assessment of those. I will try to
gauge those comments by what information I\'m aware of in the literature
that guides some comment in that regard.

But I think that with regard to functional status, the major contenders,
if you will, would be maximum exercise capacity is done on a bicycle
exercise test, as has been done in NETT, as well as an assessment of the
six-minute walk, for which there are, in fact, standards now published
and some assessment of minimally-important clinical differences that
comes from work by Redelmeier and Guyatt that are included with the
recent ATS standards document on six-minute walk.

I think that a disease-specific quality-of-life measure needs to be
included, as has been done in several of the studies, the randomized
trials that have been discussed; certainly, in the St. Georges enjoys
reasonably popularity, is self-administered, and would certainly satisfy
such a measurement in my view.

In addition, it enjoys some assessment of the minimally-important
clinical difference, that difference being in the literature as four
units, although more conservatively other studies have taken a somewhat
more aggressive delta, if you will, and have insisted on an eight-unit
outcome measure as a clinically-important difference. So I think
there\'s some room for discussion about that, but I think that that\'s a
reasonable disease-specific, quality-of-life measure.

Others should be collected, I think, but, of course, in the design of
pivotal trials and the assessment of power calculations, one has to
anchor these on the targeted outcome measures.

Then, finally, I think as has been amply discussed, no matter what the
outcome, one needs to have some sense of physiologic plausibility.
Physiologic outcome measures are not sufficient, I think as has been
pointed out nicely by Dr. Cooper. Patients don\'t come to see us with
regard to, you know, FEV1 is better and I completely embrace that
notion.

By the same token, if there is a benefit, one has to understand what are
the physiologic underpinnings by which one could understand that. So
that requires some assessment, in my view, of airflow and lung volumes;
in particular, spirometry because it\'s widely done, highly quality
controlled.

My view is that it would need to be done in a
maximally-bronchial-dilated state, recognizing the high prevalence of
reversible airflow obstruction in patients with COBD, well demonstrated
in the IPPB trials, and even in alpha 1 antitrypsin deficiency, one
would have to look at post-bronchial dilator FEV1 in a standardized way,
as well as a measurement of lung volumes, including residual volumes, as
I think is pointed out, would be important.

Now, having said that the primary outcome measures should really be
threefold ‑‑ exercise capacity in some dimension, quality of life, and
physiology ‑‑ clearly, the other outcome measures that, again, have been
included in many of the available randomized trials, including survival,
should absolutely be included. It would weigh towards the
long-as-possible followup, as one may see different kind of temporal
trends in mortality-related results, as well as to the natural history
of the disease affected by the placement of the device.

I think that going down the actual list and trying to address the
minimally-important clinical differences, with regard to pulmonary
function, in particular FEV1, there are several choices here. This has
been approached in several ways.

My own view is that one would want to assure a magnitude of difference
at least large enough to exclude the reversible component of airflow
obstruction that one sees. By conventional definition, in terms of
defining a bronchodilated response in these patients, that number has
characteristically been for the FEV1 200 ml and 12 percent, as a delta
large enough to say that this difference exceeds what one might expect
from the aggressive bronchodilated management of these patients, again
recognizing that the prevalence of reversible airflow obstruction is
very high.

So I would favor something along those lines in terms of a magnitude of
change. Having said that, the only paper of which I am aware that has
addressed this head-on in terms of ascertaining what the
minimally-important clinical difference that is recognizable to patients
is the work by Redelmeier and Guyatt. That speaks to about a 3 to 4
percent predicted rise in the FEV1 as the minimally-important difference
that could be clinically recognized, subjectively recognized, by
patients as they talk to their colleagues in a rehab program. \"Am I
better than my colleague in terms of the impact of rehab on me?\"

The delta that was required in their study was about 3 to 4 percent,
depending on whether you look at the decrement and the increment or the
increment alone.

With regard to the six-minute walk, again, the data that really come
from the same group defined a delta, and that\'s been stated in the ATS
summary, of about 54 meters, as I recall. Again, if it\'s on the
clinical improvement side, it\'s a little higher, about 70 meters of a
six-minute walk increment to be the minimally-important clinical
difference. This is an embryonic literature, I would hasten to add, but
what little exists I would bring to bear in this discussion.

With regard to the maximum exercise capacity, again, I would take
guidance from the kind of dichotomous assessment of outcome that have
been used in conventionally-available surgical trials, and in NETT, as I
recall, that difference is a 10-watt increase in bicycle testing
exercise capacity. We\'re not commonly using the shuttle walk test in
this country, but that, of course, has been looked at as well.

I don\'t have strong feelings about SF‑36 in terms of the overall health
dimension, although I am aware that that has been looked at. For
example, in Dr. Geddes\' randomized trial, as I recall, the surgical
lung volume reduction group experienced on average a 22-unit rise, which
was statistically significantly different.

I\'m not aware of literature that addresses the minimally-important
clinical difference. So I really can\'t comment there.

With regard to length of hospital stay, I would regard that as something
important to capture, but it is certainly not something that one would
power a trial of such an intervention.

CHAIRMAN McCAULEY: Ms. Brown?

DR. BROWN: With respect to the endpoints, I agree with Dr. Stoller with
respect to that there are documented and validated quality-of-life
measures, the St. Georges questionnaire, and SF‑36. There is literature
to describe what\'s considered clinically-significant.

So I\'m not going to talk about exactly what those numbers are, but I
agree with the numbers that you have presented. I believe that is pretty
well supported in the literature.

With respect to FEV1, the ATS guidelines discuss two potential
standards. One is for bronchodilator changes. That\'s the 12 percent,
200 millimeters. An alternative is the 15 percent that\'s discussed with
respect to what is considered clinically-significant over a year for
normal patients. So 15 percent is an alternate without the
200-millimeter criteria.

And the six-minute walk, the Redelmeier paper discusses 54 meters, but
those are for patients who, on average, at baseline can walk 360 meters.
So I think that the baseline for the patients should be taken into
consideration. That\'s a 15 percent improvement, and so maybe some
consideration should be made for other baseline walking distance for
those patients and their severity.

CHAIRMAN McCAULEY: Ms. Moore?

MS. MOORE: Nothing to add.

CHAIRMAN McCAULEY: Dr. Ferguson?

DR. FERGUSON: Nothing to add.

CHAIRMAN McCAULEY: Dr. Brenner?

DR. BRENNER: Nothing to add.

CHAIRMAN McCAULEY: Dr. LoCicero?

DR. LoCICERO: One thing that we didn\'t mention so far is length of
hospital stay, and that really is not an indicator at all of this
particular device, and probably will be too inaccurate and too little a
variation to include.

We really, Dr. Cooper, representing Broncus, really articulated it best,
and that is, there really are two endpoints. One is functional and one
is physiologic. Everyone measures FEV1, and so that makes it a good
endpoint. We do have, as has already been brought out, some reasonable
data concerning that.

The other is functional, where there remain some differences of opinion,
and it might be something that could be considered a secondary endpoint
with two or three different potential variables as a measure.

CHAIRMAN McCAULEY: Dr. Shure?

DR. SHURE: I agree with everything that Dr. Stoller said. I think in
terms of the six-minute versus the MVo 2, the MVo 2 is certainly better
standardized, which makes it a little better perhaps, but the six-minute
walk is something that most centers can do without any trouble.

The one thing that we might consider suggesting as well, though, is
something I think was looked at in that, which is a decrease in oxygen
need. That would be a secondary endpoint, reflecting perhaps both an
objective endpoint and quality of life. That could be assessed by a room
error Pa02 of greater than 60 with exercise, because that would allow
patients not to walk around with oxygen, and it would perhaps make them
happier than almost anything.

CHAIRMAN McCAULEY: Dr. Miller?

DR. MILLER: I wonder if it would be appropriate to include something,
some measure of the pace of the disease, if you have affected the
natural history of the disease. I mean, you can insert one of these
devices, and maybe measure one of these things at a point in time, but
if the patient deteriorates over two years instead of six months, that
may be worth noting.

CHAIRMAN McCAULEY: Dr. Witten, it appears that ‑‑

DR. WITTEN: You have one more.

CHAIRMAN McCAULEY: Oh, did I miss one? I\'m sorry. Dr. Blumenstein,
forgive me.

DR. BLUMENSTEIN: I\'m not being nearly as contentious this time as I was
in this morning\'s session.

\[Laughter.\]

I was going to suggest that the NETT trial, one of the things that
struck me, as I was reading the description of it, is that they\'re
employing quality-adjusted life-years. I think that we\'ll learn a lot
of good reference data and methodological techniques from how they
handle the data there in this particular disease setting.

There are also other methodologies, like

QTWIST, and so forth, that may help us understand the tradeoff between
quality of life versus shorter life.

CHAIRMAN McCAULEY: Dr. Witten, it appears that there are parameters or
classes of parameters that have been discussed: those which are clinical
parameters of improvement versus physiological parameters of
improvement.

All of the parameters listed under Question 3 appear to be appropriate,
except for length of hospital stay. Additional parameters that may be
included: decreased need for supplemental oxygen.

Does that satisfy?

DR. WITTEN: Thank you.

CHAIRMAN McCAULEY: We\'ll now move to Question 4. \"The duration of
followup should allow adequate safety and effectiveness assessment of
these permanently-implanted devices in a chronically-ill population.
What is the appropriate duration of followup for a pivotal clinical
study of these devices?\"

Dr. LoCicero has agreed to lead off this question.

DR. LoCICERO: There are really three different intervals of evaluation
required. One is the immediate evaluation, looking at post- or
interprocedure complications. That would be the day of the procedure,
first to evaluate bleeding pneumothorax, et cetera, some of the things
that have already been mentioned.

The second is potential post-procedure reactions which may occur within
the first few days following the procedure, the implantation of the
device. This typically is the first two to three days, when we might
develop atelectasis or other problems, and also potentially-delayed
hemorrhage or pneumonia, which might develop at approximately seven to
ten days. So for procedure-related events, we need to look at the day of
the procedure two to three days later, seven to ten days later.

In terms of evaluation of effectiveness, the first real time that we can
evaluate these devices is, as has been presented today, would be at
approximately one month. The NETT trial has evaluation points at three
months, six months, et cetera.

What we see from some of this data is that there is a plateau that
occurs at around six months. Since our control arm is going to
deteriorate at the same rate and our patients are going to deteriorate
at the same rate, we would probably be able to get a reasonable
evaluation within six months. So that this might be the time when we
would have maximum benefit from the device prior to deterioration of the
patient.

We also want to be able to give that patient the opportunity to go on to
some other form of treatment. So I would recommend that our endpoint for
effectiveness be six months.

CHAIRMAN McCAULEY: Dr. Brenner?

DR. BRENNER: No comment.

CHAIRMAN McCAULEY: Dr. Ferguson?

DR. FERGUSON: No.

CHAIRMAN McCAULEY: Ms. Moore?

MS. MOORE: No.

CHAIRMAN McCAULEY: Ms. Brown?

DR. BROWN: I think that the length of followup should be considered
separately, depending on the severity of the disease, so patients who
have fewer options perhaps would have a shorter length of followup than
patients who have more alternatives.

CHAIRMAN McCAULEY: Dr. Stoller?

DR. STOLLER: I agree with Dr. LoCicero. I think that the consideration
with regard to the length of followup has to take into account the need
to assess both short-term and intermediate-term, if you will, outcomes
with regard to assessing effectiveness, but also needs to take into
consideration the fact that patients who fail this approach may be
candidates for other approaches such as surgical volume reduction.

The length of followup cannot be so long that it actually puts these
patients at risk with regard to the natural history of their disease,
when they\'re already starting at a highly-obstructed level for which
the five-year ‑‑ we heard numbers before. The five-year survival of
patients whose FEV1 is less than a liter, the five-year mortality rate
is about 50 percent.

So that trading off the desire to have longer-term outcomes versus the
need to capture efficacy, I would agree with what was said. I think six
months is a very reasonable balance between maximizing benefit, but not
disallowing patients from crossing over to other interventions if they
remain in such a pivotal trial for the full duration of expected
outcome.

CHAIRMAN McCAULEY: Dr. Blumenstein?

DR. BLUMENSTEIN: I think it would be important to also explore the
possibility of use of outcomes such as failure-free outcome ‑‑ I mean
failure-free survival; that is, the duration of time until an
alternative therapy has to be implemented, in which case it may require
maybe an active follow-up period through the suggested six months,
perhaps with a little less intense followup following that, if that were
appropriate.

CHAIRMAN McCAULEY: Dr. Miller?

DR. MILLER: I think the efficacy and the safety should probably have
different lengths of followup because the efficacy, you want to know
that immediately, if it\'s working. But if a patient gets stabilized and
does well on one, I think you want to continue the safety study for a
longer term, because they have this permanent device in their airway and
there may be some long-term problems.

CHAIRMAN McCAULEY: Dr. Shure?

DR. SHURE: I agree with Dr. Miller\'s comment. I would feel more
comfortable with a minimum of one-year followup in terms of safety and
allowing crossover to LEVRS at six months. I think there are different
issues.

I\'m personally concerned with the long-term issues of occult infections
in a space that\'s been deliberately collapsed and having a foreign body
in for that period of time, with issues of migration and proximal as
well as distal infection and hemorrhage.

CHAIRMAN McCAULEY: It appears that the two issues of safety and efficacy
basically mean a few time intervals. In terms of safety of these
products, that a time period of seven to ten days, which would cover the
operative and immediately post-operative and sort of peri-operative
period within a hospital or outside of a hospital within seven to ten
days would be needed.

In addition, most of the six-month followup which has been recommended I
think is based on the NETT trial, where a patient\'s performance has
plateaued out in six months. However, some of the Panel members are
concerned about longer-term followups of I think six to twelve months
followup in this patient population is what I\'m hearing.

Does that satisfy your answers to that question?

DR. WITTEN: Yes, thank you.

CHAIRMAN McCAULEY: Right now we\'ll take a 15-minute break.

(Whereupon, the foregoing matter went off the record at 3:15 p.m. and
went back on the record at 3:34 p.m.)

CHAIRMAN McCAULEY: This afternoon we will address clinical issues
regarding medical devices used to ablate lung tumors. We are now ready
for the FDA presentation.

DR. ASHAR: In this next session we would like to focus on the topic of
lung tumor ablation devices. Presently, there are a number of ablation
technologies on the market that FDA has cleared with a general
indication for soft tissue ablation.

For a device to obtain a more specific indication, however, we expect
that a clinical study for this new indication be performed to
demonstrate device safety and effectiveness. At this time no ablation
device has been cleared for the indication of treatment of lung tumors.

The purpose of this session is to obtain your recommendations regarding
the role of thermal ablation devices in the treatment of lung cancers.
We would also like to obtain guidance from the Panel regarding the types
of clinical studies that would need to be performed to demonstrate safe
and effective use of local ablation technologies for the treatment of
lung tumors.

Following the sponsor\'s presentation, FDA will be asking the Panel to
comment on a number of questions pertaining to the current role of these
types of local treatments, the appropriate efficacy endpoints,
appropriate imaging modalities, the length of followup, and treatment of
patients who would otherwise operative candidates using these types of
devices.

Thank you.

CHAIRMAN McCAULEY: Does anyone on the Panel have any questions?

\[No response.\]

We will now hear from some members of industry in regards to this topic.
The first presenter is RITA Medical Systems, Incorporated.

DR. CHESKIN: Good afternoon. My name is Barry Cheskin, and I\'m the
President and Chief Executive Officer of RITA Medical Systems. I want to
thank you for the opportunity to speak before the Panel today.

Our company, RITA Medical, is a company that is built around
minimally-invasive surgical devices for treating patients with various
kinds of tumors. We have the device, as has been indicated, that has
been marketed since 1997 for the ablation of soft tissue. It was cleared
by the FDA for the specific indications of unresetable liver lesions, as
well as painful bone metastases, and is currently used by physicians
around the world for a number of applications today, including lung
tumors. It is estimated that about 40,000 of these cases have been done
to date, primarily in the area of treating unresectable liver lesions.

Just to give you a sense, the system consists of a source of energy, a
radio frequency generator, as well as a single-use, minimally-invasive,
surgical tool which you see pictured there, which is used to actually
deliver the radio frequency energy to the tumor or to the site that is
to be destroyed.

The device, the needle electrode is inserted directly into the tumor. A
secondary array of wires is deployed from the tip of that needle. Radio
frequency energy is used to energize those electrodes. Temperature
sensors are used in our device to sense the temperature of the tissue as
it\'s being heated up to ensure that it reaches a sufficient temperature
to destroy the tissue. The result, as we have demonstrated, is a very
repeatable, spherical area of tissue ablation.

Our purpose in being here today, as we have discussed, is to review the
clinical issues related ultimately to marketing clearance of this device
for this indication. RITA has been discussing this indication with FDA
for some time now, and we believe there\'s already strong clinical
evidence to support safety and effectiveness of this device in this
application. We hope that today\'s meeting will lead us to a consensus
on a clear path for FDA marketing clearance for these devices in the
lung application.

I would like to now turn things over to Dr Steven Rosenberg, who will
give a summary of our clinical experience and discuss some of the
clinical issues, and, hopefully, answer some of the questions that FDA
has raised.

DR. ROSENBERG: Hi. I\'m Steve Rosenberg. I\'m the Chief of Surgery at
the National Cancer Institute, a position I\'ve had for the last 27
years. I need to emphasize that I\'m not here in any official capacity
of the government. I do this as an approved outside activity. I have no
equity in RITA, but I am a consultant to RITA. This is the only company
that I consult for.

I became involved with RITA several years ago because, as a surgeon who
cares for cancer patients, I was really interested in finding innovative
ways to treat patients that could not be dealt with adequately
surgically, and that is patients that had metastatic cancers to the
liver that were not surgical candidates.

I became very interested in this technology as a relatively low
morbidity method for the ablation of metastatic cancers in the liver,
helped RITA develop that application, and it is now virtually standard
of care. It has been used in well over 40,000 patients and represents a
very effective modality for the control of liver metastatic and primary
liver tumors in patients that are not surgical candidates.

It\'s with the interest in seeing that this modality can be brought to
bear similarly for patients with tumors in the lung, who currently have
no other treatment modalities available to them, that I would like to
discuss some of the data for the use of this treatment in the lung. I
firmly believe that its potential applications in the lung are the
equivalent potentially to those in the liver, and that it\'s a modality
that patients who have no other alternatives deserve to have available
to them.

So the targeted patient population here currently have very few options.
We\'re talking about patients with pulmonary metastases that are less
3.5 sonometers who are non-surgical candidates, generally because of
co-morbidities, that have lung-predominant disease and refractory to
other treatments.

So I do not think that this kind of treatment should be advocated now
for patients who have surgical resections available to them. This is for
those patients who are non-surgical candidates and who do not have
effective treatments available.

Similarly, patients with non-small cell lung cancer that are small,
again, that are non-surgical candidates on a refractory or treatments or
are not candidates for radiation, either because they have already had
it or the heart is in the radiation field in patients with cardiac
compromise. So with the modality for the use in patients with cancer
that currently do not have other effective options.

Now, as with any local treatment, the primary, and in fact the only,
endpoint is the tumor control, the local control of that lesion. This,
of course, is exactly what we believe has been achieved in the liver as
well.

We measure tumor control in oncology by either stabilization or decrease
in tumor size. This is a standard criteria that is used to evaluate any
chemotherapy regimen and other local therapies such as radiation
therapy. We use the same exact criteria for this application as well.

Now the imaging modality to determine effectiveness is CT imaging,
computerized axial tomography, which is recommended as the standard for
evaluation of tumors in the lung, but basically tumors in virtually any
location for cancer patients. The standard methods that are used to
measure tumor responses, there are two standard methods that are used:
the one now recommended by the World Health Organization for all studies
in oncology as a response evaluation criteria in solid tumors or the
RECIST criteria, which are guidelines which measure the longest diameter
of a lesion and measure either its stability or decrease, based on that
longest diameter.

Other criteria use the product, some of the product of perpendicular
diameters of lesions, and that\'s another way of measuring tumor
response and local control that basically gives equivalent results.

When this treatment is applied to lesions in the lung, the criteria that
one uses to determine whether or not the treatment is effective is
basically a one-month response rate, which is typically accepted for
patients with chemotherapy. Most definitions of response in medical
oncology insist that a lesion be controlled for at least one month. Now
that\'s often not a sufficient criteria, and, in fact, the criteria that
we\'re proposing for local tumor control is an evaluation at six months
after treatment.

The tumor doubling time for metastatic tumors has been studied in dozens
of papers. For metastatic cancers it\'s on average a median doubling
time anywhere from 40 to 136 days in multiple publications, and for
primary tumors it varies in different publications from 67 to 134 days.

So with this doubling time, it\'s our feeling that for the cancer
patient a tumor that either does not grow or has decreased in size over
a six-month period represents a very clinically-meaningful response.
Obviously, if a tumor is growing over a six-month period, then that
would not represent an effective treatment. But stability or decrease
over a six-month period would certainly be clinically beneficial for
most patients, given the doubling time of tumors.

Now the overall experience supporting the use of this ablation technique
in patients with lung tumors is actually quite extensive, as you can
see. Because the device is available to surgeons, many have just begun
using it to treat lung tumors. We will particularly talk about a
treatment that RITA has had considerable involvement, and that is the
treatment of Lencioni with 62 patients.

But, as you can see, there are many other investigators, including
several that have published their work and papers that were made
available to you, who have used this technique for lung tumor ablation,
and I believe shown that it can be an effective treatment for patients
with lung tumors that meet these criteria. That is, non-surgical
candidates or tumors that are less than 3.5 centimeters.

I believe that the information that\'s been obtained not only in our own
RITA study, but in other studies that have been reported at meetings and
in the literature, show that CT-guided radio frequency ablation is safe
and can successfully destroy lung tumors, that there\'s minimum
morbidity ‑‑ we\'ll look at some data in a moment ‑‑ that typically
resolves within 24 hours, most often does not require any intervention.
In fact, this can often be performed as an outpatient procedure, and
that RF ablation may prove to be a viable alternative for patients who
cannot be treated by surgery or who are refractory to other forms of
treatment.

RITA has sponsored a trial at three non-U.S. sites, and then an
independent investigator basically used the exact same protocol for a
clinical trial at UCLA. Again, these were non-surgical candidates. The
endpoint for clinical effectiveness was a six-month tumor response on CT
scan. We\'ll talk about the results in 62 patients. They had 79
different applications of 102 lesions, but 49 of the lesions are not
evaluable for tumor response at six months.

As you\'ll see, we believe this to be a safe and effective method for
tumor destruction and a kind of modality that patients that have no
other alternatives available to them, who have a metastatic cancer or
non-resectable primary lung cancers should have available to them.

The general patient characteristics, as you can see, the median age of
the patients in this experience of 62 patients that have been carefully
followed and carefully evaluated, is 64 years. You see the number of
lesions that were treated. Again, the diameter of the lesions that we
feel should be treated that can be completely ablated is 3.5 sonometers,
given the fact that the probes that are available can cause ablatants
that are, in fact, substantially larger than 3.5 centimeters.

We used the RECIST tumor criteria. Again, this is a standard criteria
that, as states here, is advocated by the World Health Organization. A
partial response is any response that causes more than a 30 percent
decrease. A stable disease is less than a 20 percent increase. So we
very rigidly used these World Health Organization criteria in evaluating
these patients.

Now the results, in comparing these lesions, can be looked at in two
ways. Clearly, the most credible way to look at the lesions is to
measure the lesions prior to treatment and then six months later measure
the lesions again to see if they have grown.

You can see that 20 percent of the lesions had completely disappeared on
x‑ray; 22 percent had decreased, had had an objective partial response
by classic oncologic RECIST criteria, and that is greater than a 30
percent decrease, and another 24 percent had stable disease; that is,
did not grow.

So you can see that the number of patients that could be effectively
treated and benefitted using this criteria of comparing a post-treatment
lesion to a pre-treatment lesion was 67 percent. Almost two-thirds of
the patients showed clinical benefit.

Now another way to look at the data is to compare the six-month value at
one month. I don\'t believe this is quite as valid, but I do want to
present this information because the lesion that is created by the radio
frequency ablation, as you will see in one example, does cause an
inflammatory lesion that appears to be maximum at one month.

So if you wanted to compare to the maximum inflammatory size, you could
see that at six months ‑‑ that is, five months later ‑‑ 93 percent of
the lesions had either disappeared, decreased, or were the same size.

This is an example of what one might typically see. You can see a
2-sonometer lesion on the left that received radio frequency ablation.
Again, this can be done under conscious sedation, under CT guidance. It
can be minimum morbidity procedure.

You can see at one month the ablated area that has been created is
larger than the original lesion, but you can see, as often happens in
the lung, as lesions disappear, the lung collapses around them, the scar
decreases, and you can see that lesion has substantially decreased, if
not disappeared, by three months later. So the general criteria we use
are comparing to the pre-treatment lesion, not the one-month size, but
you can see the reason for analyzing it both ways.

Complication rates from these procedures, again done in a conscious
patient, can be performed as an outpatient, are quite minimal.
Pneumothorax, anytime one puts a needle in the chest, it\'s always an
opportunity to obtain a pneumothorax. There was a 19 percent incidence
of pneumothorax that required a chest tube, generally for just one day;
very rare pleural effusions. One patient had pneumonia. But these were
all minimum morbidity complications in this series of the treatment of
79 lesions, and could be easily managed.

So, in summary, I do believe that the clinical evidence in the patients
that have been treated thus far does support the safety and
effectiveness of the treatment; that non-surgical patients who are
refractory to treatment or aren\'t candidates for radiation could
benefit from this, and that physicians could very readily benefit from
access to radio frequency ablation tools, when appropriately instructed
on the use of this device, just as they now use it as part of the
standard care of patients that have cancers that have spread to the
liver. I think cancers that spread to the lung could be equally
effectively treated.

So, very specifically, then, the FDA posed five questions that I would
like to at least provide our suggested answers to. The first question
dealt with the request to discuss the ablation as a means of local
control, to describe the specific patients for which this treatment
might be appropriate.

So our feeling is that RFA would be appropriate for patients with
primary or metastatic cancer to the lung that\'s less than 3.5
sonometers, because we can very reliably create an ablated lesion larger
than that, but who are not candidates for surgical resection. Surgery
is, obviously, the standard treatment for patients that do have
resectable, even metastatic, lung tumors and should be applied when the
patient is a candidate for surgery.

The second question dealt with the appropriate endpoint for the study
and the appropriate, in my view, as is the case throughout the field of
oncology, is that clinical effectiveness should be judged by the
stability or decrease in the treated lesions.

The third question dealt with the imaging modalities that would thought
to be appropriate. Of course, throughout oncology for cancers at any
location, CAT scans are a standard way to evaluate these lesions, and we
do believe that by evaluating the size of lung lesions, which can be
easily measured quite accurately by CAT scan in the lung, that
pre-treatment measurements and measurements at six months is the
appropriate evaluatory mechanism to assess effectiveness of these
lesions.

The fourth question dealt with the evaluation occurring at what
duration, what duration would be suitable. We do believe, given the
doubling time of metastatic and primary lung tumors, an evaluation at
six months is sufficient to assess safety and effectiveness, as we have
shown in some of the data that I have presented, since the majority of
untreated lesions will progress during this six-month period.

The final question which was posed, and that is the appropriate control
group, endpoints, and duration of followup for a clinical study of the
device to be used in place of surgical resection. I would advocate that
right now this should not be used in place of surgical resection. If a
patient is a surgical candidate, they should have surgery. We do not
plan to treat patients who are candidates for surgical resection and
want to have available the use of this technique for patients who are
not surgical candidates and do not have other effective options
available to them.

Well, thank you for your very kind attention.

CHAIRMAN McCAULEY: Are there any questions from the Panel for RITA
Medical Systems, Incorporation?

DR. FERGUSON: I have a question. You have to forgive my ignorance,
Steve, but the effectiveness of this device, as I understand it, is
related to the temperature that is developed in the lesion. My question
to you is, given the difference in blood flow surrounding a lesion in
the liver and the relative insulation that you have in the lung, have
you developed parameters for different temperatures?

DR. ROSENBERG: It\'s a good point. We can measure the temperatures
because there are probes that are present, because of temperature
measurements that are contained in the probes, but this is the reason
that we, in fact, ablate an area beyond the size of the lesion, which is
why we would only treat lesions that are 3.5 sonometers.

In the studies that were performed in experimental animals and the
clinical data do indicate that you can destroy tissue beyond a
3.5-centimeter diameter. This, of course, was all done in experimental
animals before these clinical efforts were undertaken.

CHAIRMAN McCAULEY: Dr. Shure?

DR. SHURE: The increasing size of the area surrounding the lesion at one
month, have you looked at what that is? Is that edema? Is that necrosis?
What\'s going on there?

DR. ROSENBERG: It mainly represents an inflammatory process, because,
after all, you are destroying this tissue by heat. And macrophages,
other inflammatory cytokines, come into that location. So it does
represent inflammation, which is why it does resolve so quickly.

CHAIRMAN McCAULEY: Dr. Miller?

DR. MILLER: Does it matter where the location of the lesion is? I mean,
can you treat a lesion up against the hilum versus one that\'s
peripheral?

DR. ROSENBERG: One would have to be careful not to treat lesions that
are near major vessels. Now it turns out vessels are, of course, heat
sinks. So they do protect themselves to some extent. But, clearly, we
would not advocate the use of this for a lesion that was next to a major
structure in the medial sternum or in the pulmonary hilum. Most lung
metastases, of course, are not in that location.

CHAIRMAN McCAULEY: Dr. Blumenstein?

DR. BLUMENSTEIN: If we were talking about a drug or a biologic agent or
something like that, we would be talking in terms of patient benefit,
but, yet, you\'re advocating here that you\'re just going to measure
tumor response as a basis of a marketing approval for this device. I am
wondering why you would change.

DR. ROSENBERG: Well, this is a local treatment. Of course, we are
talking about patients who had metastatic disease, and I would use the
analogy of metastatic disease in the liver.

There\'s been virtually no study performed with controls that are
untreated to show that virtually any surgical resection of a liver
metastases prolongs survival. That study has never been done.

The resection of lung metastases is standard procedure, and I am sure
there are many tens of thousands of those procedures that are performed
each year standing, that if one has a limited amount of metastatic
cancer, taking it out or controlling it is better than leaving it in to
grow. But, again, despite the fact that many tens of thousands of those
procedures have been done, there\'s never been a clinical trial that has
compared patients who have otherwise resectable lesions be compared to
patients ‑‑ that had them resected being compared to patients that
don\'t have them resected.

So there\'s the general acceptance in the field of oncology that if you
can control a tumor, make it shrink or keep it from growing, that you
will benefit that patient. It is exceedingly difficult in patients with
metastatic or unresectable cancers to do survival studies which compare
to no treatment.

The only patients that we plan to treat here that patients that do not
have other options. So I would say that is fairly standard. In fact, it
is absolutely standard in the field of oncology. I would say 95 percent
of all of the chemotherapy drugs that have been approved have never been
shown in randomized trials to prolong survival compared to no treatment.

CHAIRMAN McCAULEY: I would like to introduce Dr. Solomon. Dr. Solomon,
can you please tell us your specialty, title, institution, and your
status with the Panel, prior to your question.

DR. SOLOMON: My name is Steve Solomon. I\'m a Radiologist at Johns
Hopkins, and I am a consultant to the Panel.

The question I just had for you is, have you looked at other imaging
endpoints such as contrast enhancement or Houndsfield unit change to
suggest that you\'re successful?

Additionally, another thing that we will talk about later is PET imaging
and whether that has played a role in the analysis of success.

DR. ROSENBERG: Yes, I\'m delighted you mentioned that, because I think
there are a lot of potential ways to measure effectiveness: Houndsfield
units certainly could be used. PET scans can be used, although it\'s
hard to quantitate the size of a lesion.

But there\'s no substitute for measuring the lesion and showing that
it\'s not growing or it goes away, and the CAT scan is certainly the
best way to do that. You can accurately a lesion certainly much more
accurately than you can on a PET scan, as you know.

If it goes away or it shrinks, I think that is evidence that will
probably surpass many of these other measures, but they could presumably
be used in conjunction with it. I would urge, however, that if this gets
approved, that CAT scan measurement of the size ‑‑ there\'s no
substitute for seeing a cancer shrink or go away.

CHAIRMAN McCAULEY: Any other comments from the Panel?

\[No response.\]

Thank you.

DR. ROSENBERG: Thank you, Dr. McCauley.

CHAIRMAN McCAULEY: We will now proceed with the open public comment
sessions. All persons addressing the Panel speak clearly into the
microphone as the transcriptionist is dependent upon these means of
providing an accurate record of this meeting.

We are requesting that all persons making statements during the open
public hearing session of the meeting disclose whether they have
financial interest in any medical device company before making your
presentation to the Panel. In addition to stating your name and
affiliation, please state the nature of your financial interest, if any,
and disclose if anyone besides yourself paid for your transportation or
accommodations.

We will begin with those individuals who have notified the FDA of their
request to present in the open forum. The first presenter is Dr. Putnam.

DR. PUTNAM: Mr. Chairman, thank you for the opportunity to present to
the Panel. I previously introduced myself and stated my affiliations and
disclosures beforehand. Should I repeat them?

CHAIRMAN McCAULEY: No.

DR. PUTNAM: Thank you.

I have, just for the purposes of review, I have received non-restricted
grant funding from Radiotherapeutics Corporation, which has been
purchased recently by Boston Scientific. I have also received
non-restricted grant funding from RITA Medical, also for studies. These
reflect both pre-clinical and clinical studies, respectively. I have no
financial affiliation with them, nor with any competing groups.

The use of radio frequency ablation for primary metastatic lung tumors
is investigational, and its use outside of prospective clinical trials
is not warranted. Clinical trials, as the Panel has proposed, should be
carefully designed to address the critical issues of patient safety and
treatment efficacy with this technology.

Patient followup must be of sufficient duration to determine frequency
and time before reoccurrence of subsequent disease, either primary or
metastatic.

How do we distinguish between primary carcinoma of the lung and its
treatment and patients with secondary tumors or metastasis to the lung?
These clinical trials to develop efficacy and safety, appropriate
patient selection, indications and applications should be addressed.

The issues which should be addressed in the development of these
protocols should include selection of patients. I agree with Dr.
Rosenberg who, by the way, was my Chief when I was a Surgical Fellow at
the National Cancer Institute ‑‑ always happy to follow your professor.

The surgical evaluation must be performed by a thoracic surgeon. Simply
to say that a patient is not a surgical candidate is overly simplistic,
and there is no single clinical criteria which excludes a patient from
surgery.

Combinations of FED1 and DLCO together have shown to be of great
significance. However, no single criteria, nor combination of criteria,
have completely identified a population who can be considered
non-surgical candidates.

Surgery as the primary therapy should be considered, as Dr. Rosenberg
mentioned. However, radiation therapy, either external beam or
three-dimensional conformal therapy, would be considered, either with or
without chemotherapy, would be considered appropriate management as a
second line in patients who are not deemed otherwise to be surgical
candidates, in patients with primary lung cancers.

However, in patients with pulmonary metastatic disease, surgical
management alone frequently fails because we are using a mechanical
technique, surgical resection, to treat a biological problem. As a
thoracic surgeon who has spent the last 20 years trying to understand
the surgical management of pulmonary metastasis, I realize the
limitations of such a mechanical approach.

The peripheral location of pulmonary metastasis can be easily resected
with thoracoscopic resection or with open thoracotomy resection. Even
so, there is a frequent incidence of patients having recurrence, even
with the best technology.

The ability to state that this should only be used in patients who are
not surgical candidates suggests that, once approved, any patient or
physician who feels that this technology should be applied is certainly
eligible to receive this treatment, potentially to the detriment of the
patient.

The indications for application and reapplication of this technology
must be considered. Is a single application appropriate or are multiple
applications of radio frequency ablation appropriate? What about the
variability and the completeness of the resection? Even though the
technology suggests that the entire area is ablated, is this area
ablated completely?

It is easy to show that there is complete ablation which occurs in
pulmonary parenchyma. However, in patients with tumors in the lung,
complete ablation may not occur, and there may be inconsistent killing
of cancer in this area, suggesting that these patients may have rapid
recurrence and that they may require additional management in a
compromised pulmonary field.

The second question of the appropriate endpoints would be survival and
also local control at two years. Patients with limited-stage disease,
such as stage 1 disease, and stage 1A and stage 1B lung cancer, for
which this would be appropriate, patients with tumors 3 centimeters or
less in diameter, or stage 1A lung cancer, patients with greater than 3
centimeters, stage 1B, they have a five-year survival when treated
surgically of about 60 percent.

So a six-month followup would be too short. Most recurrences, both local
or metastatic, would occur within the first two years. I would suggest
that two years would be the minimum endpoint for both survival and for
local control.

The required followup would also be important to identify secondary
procedures that may be required for treatment, such as radiation therapy
or other chemotherapy.

The injury to adjacent structures, either bronchi or vessels, certainly
exists, as well as the potential exacerbation of the malignancy. In my
conduct of a clinical trial examining the role of radio frequency
ablation in a study where patients who would otherwise undergo complete
resection of their metastasis were initially treated with radio
frequency ablation and then resected. We found that the completeness of
ablation is related to size, location, and consistency of the primary
tumor.

In contrast to the mucous-producing colorectal carcinoma and hepatic
metastasis, lung tumors, both primary and secondary, can have a wide
range of tissue consistency, which may prevent accurate placement of the
ablation catheter needle array.

A second major limitation which should be addressed is that
micrometasasis to local and regional lymph nodes will remain untreated,
and this micrometasasis cannot be diagnosed with certainty using
conventional radiologic or radiopharmaceutical diagnostic procedures,
and have variable location involving the bronchi, arteries, and
pulmonary vasculature.

The limitations require sufficiently long-term followup to determine the
efficacy of the procedure versus standard therapies.

CHAIRMAN McCAULEY: Dr. Putnam, could you summarize your comments,
please?

DR. PUTNAM: I can.

The imaging modalities of CAT scan and PET scan are certainly
appropriate. Pathologic biopsy, however, may be necessary to confirm
adequacy of treatment.

The appropriate control group is unclear at this time, given that many
patients, that most patients can be treated with appropriate primary
therapeutic modalities.

Thank you.

CHAIRMAN McCAULEY: Thank you.

Are there any questions for Dr. Putnam?

\[No response.\]

Our next presenter is Dr. Sewell.

DR. SEWELL: All right, good afternoon. My name is Patrick Sewell. I\'m
an Assistant Professor of Radiology and Surgery at the University of
Mississippi Medical Center in Jackson, Mississippi.

I am here as an independent proponent of radio frequency ablation of
lung tumor, and my travel is not compensated industry and I have no
ownership/stock in any of the radio frequency companies nor the imaging
companies that I\'m going to discuss.

I have devoted the last four years to image-guided, minimally-invasive
surgical thermal ablations of a variety of tumors in a variety of
organs. The encompass clinical partners that are equally involved from
neurosurgery, orthopedics, GYN oncology, medical oncology,
cardiothoracic surgery, and abdominal surgery or hepatic surgery.

They all involve some form of image guidance, ultrasound, CT, MRI, and
the vast majority of them are done in the operating room.

Approximately 300 patients a year are admitted to or come to my
University for these treatments. I have eight ongoing IRB-approved,
monitored clinical trials for these therapies in humans and some in
animals as well, to investigate the uses of these technologies.

I don\'t know if I mentioned they involve laser cryo high-frequency
ultrasound, focused ultrasound, and, of course, radio frequency
ablation. So what I am going to, of course, talk to you about today is
the RFA.

I agree with many of the comments made previously by both Dr. Rosenberg
and Dr. Putnam. The clinical trial that Dr. Rosenberg described is
essentially what I embarked upon about three-and-a-half years ago. I
began to treat primary and secondary malignancies with CT-guided radio
frequency ablation. I have to stress that the image guidance is probably
one of the most important ‑‑ is of equal importance as the ablation
technology because it is what allows the precision or the focused
delivery of this destructive process. There have been some clinical
trials, as Dr. Putnam alluded to, that did not use CT guidance, and
those, of course, are not as successful.

Dr. Rosenberg\'s description of primary cancer, non-surgical candidates
are exactly the candidates treated by myself at the University. I have a
team of cardiothoracic surgery, pulmonology, and medical oncology that
evaluate the patients if they are primary or non-small cell lung cancer,
and if they are deemed unresectable by the cardiothoracic surgeon, then
they enroll in this therapy. The vast majority of them have exhausted
chemotherapy and radiation or they have declined radiation and
chemotherapy.

So I want to show you a couple of slides to illustrate the potential.
This is a non-small cell lung cancer pre-RFA, and this is the scar 36
months later. Now I have approximately 16 patients that are a
year-and-a-half out that are stage 1 or 2, and the data, survival data,
on that group is the same as surgical, although it is only one year. But
keep in mind these are pulmonary cripples who are the sickest of the
sick. So I think that illustrates significant potential.

However, overall, what I wanted to do with this investigation over the
last three-and-a-half years is to clearly define the safety because the
efficacies can be very complicated, but the safety is pretty clear. What
are the complications?

When I looked at the data pooled on 180-something patients over that
time period, in the peri-operative period, and I\'m not talking about ‑‑
I\'m talking about days in the hospital and shortly thereafter ‑‑ the
major complications are COPD exacerbation, 2.2 percent with some of
those very severe in these very sick patients, and intraparenchymal
bleeding, 0.4 percent.

Now there are some minor complications such as pneumothorax. When you
treat a single lesion, it can be less than 5 percent. For multiple
lesions, obviously, every time you poke the pleura, the risk goes up,
and it can be 50 percent or higher when you start going above five
lesions in one treatment session.

Pleural effusion, which is more of a nuisance, except in the patients
with significant COPD and already on oxygen, atelectasis, and loss of
any functional lung can be a significant detriment. Then an acceptable
infection rate, and what one would expect in colonized pulmonary tissues
with necrotic tissue.

I believe that the main benefit, the clearest benefit for the
application of this technology is for pain management or pleural-based
tumors, albeit primary or secondary.

The application of RF energy is well-documented. It destroys tissue
effectively and precisely. The ability to target and enhancing primary
pleural-based tumor growing into the chest wall and resulting in pain,
and end up with a necrotic area that\'s slightly larger, and immediate
pain relief upon the release the following day is a significant advance
to patients when their options are surgical resection, which would be
pretty much a nightmare in this patient; radiation therapy, which this
patient had failed.

In addition, the thermal ablative processes are not cell-type-specific,
unlike radiation or chemo. It doesn\'t have to radiation-sensitive. If
you heat cell tumor or not to 60 degrees Celsius, it incurs reparable
damage and dies within 24 to 48 hours. It is easily done with local
anesthesia, often on an outpatient basis.

Additionally, the complications of treating the painful pleural-based
tumors are extremely low. Pneumothorax is less than 1 percent. It\'s
almost zero because the vast majority of the time you can get to the
tumor without traversing aerated lung. Bleeding is very low. Pleural
fusion is not even significant, and abscess or pneumonia is, again, a
very small percentage.

Now keep in mind I preselected very sick patients who are pretty knocked
down from chemotherapy. So their infection rate is probably going to be
higher than if you did this to just a normal person and created a
necrotic area.

CHAIRMAN McCAULEY: Dr. Sewell, we\'re going to have to ask you to
summarize your comments.

DR. SEWELL: Okay. The results are immediate and sustained pain relief
and preservation of lung function by targeting and destroying a viable,
enlarging lesion that would otherwise consume functioning lung.

So, in summary, I think RF ablation of lung tissue is an accepted
treatment for soft tissue tumors with proven results, and it has shown
very low morbidity and mortality, and it does preserve lung function and
reduces pain in inoperable pulmonary malignancies, which results in a
significant quality-of-life maintenance or improvement.

Thank you.

CHAIRMAN McCAULEY: Thank you.

Are there any questions for Dr. Sewell?

\[No response.\]

Is there anyone else wishing to address the Panel? Yes?

DR. COOPER: I\'m Joel Cooper. I spoke this morning, representing, again,
the ATS, and I have no financial interest or conflict or association in
this situation.

We\'re all aware of how very vulnerable end-stage cancer patients are to
any proposed new or innovation, how often they have flocked to an
unsubstantiated treatment, and how high the standard must be if we are
going to propose anything for this unfortunate group of patients.

Dr. Rosenberg, in his presentation, mentioned individuals who are not
surgical candidates but another time he mentioned those who have no
other option. I just wanted to emphasize that there is a standard of
care for solitary pulmonary lesions in patients who are not operable,
and that is radiation therapy, with or without chemotherapy. I would
presume, therefore, that his comments related to \"no other options\" is
in fact the operative one.

We\'re also all aware of the fact that off-label use of FDA-approved
devices, often treatments promoted on the Internet by physicians, by
companies, often patient-driven, sometimes physician-driven, unfiltered
information which attracts patients to a particularly unproven therapy
is, unfortunately, something which our Association views with great
alarm, and it just puts an added burden, we believe, on the Panel and on
the FDA to assure that these types of innovations for end-stage disease
be viewed in a very scientific fashion and, in fact, be approved only
when there is solid weight of evidence, because of the potential for the
misuse.

I would echo Dr. Putnam, and I would say that he is more of an expert
than I am because he has more personal experience than I have, but I
would echo his comments, the importance of exhausting all other
modalities, of making certain that traditional therapies are exhausted,
and making certain that the patient has been offered those, and
certainly in a trial there should be standards whereby the patient is
assessed by a competent, experienced thoracic surgeon.

Dr. Sewell\'s comments in one of the particular cases was that surgery
would be a nightmare for that particular patient. I\'m not sure that I
would agree, but I don\'t know the details of that patient that he
referred. He showed a case of right upper lobe cancer. I don\'t know
whether that patient was a candidate resection or not, but I would argue
that this be very carefully evaluated when pivotal studies are done, to
make certain that safeguards for the patients are in place, that in fact
there is no alternative therapy during the period of time that the
patient is going to be considered for this particular therapy.

We would all be delighted to have an additional modality to treat
patients with cancer for whom we now have no alternative therapies, but
I would only urge caution in making certain that, indeed, high standards
are maintained.

Thank you again for the opportunity of having our Association have input
into your process.

CHAIRMAN McCAULEY: Thank you.

Dr. Rosenberg?

DR. ROSENBERG: You know surgeons love to operate, and we have at least
three very distinguished surgeons on this Panel. We\'re not advocating,
and I would not advocate, the use of this modality now in place of
surgery for patients who are surgical candidates.

Now I don\'t, frankly, see the logical consistency in some of the
arguments that were made. Dr. Putnam is an expert; I have enormous
respect for him. In fact, I author, as some of you know, a 3,000-page
textbook of oncologic treatment which is the most widely-used text in
the world. In fact, I asked Dr. Putnam to actually write the chapter,
which he did for the last several editions, on the treatment of lung
metastases.

In fact, in that chapter he, as would any thoracic surgeon, advocates
vigorously, and has advocated in that chapter, the resection of
pulmonary nodules in patients with metastatic disease, because there are
patients that have cancers that are metastatic to the lung that have
gone on to survive 25 years. It is hard to imagine that they would
survive 25 years if you allowed the cancer to keep growing.

It is an absolute standard of treatment to resect pulmonary metastatic
nodules. If a patient is not a surgical candidate, radiation therapy is
virtually never used for metastatic cancer to the lung. It is used for
primary lung cancers. If a patient is not a surgical candidate, they
have no other options.

Radio frequency ablation has been shown to be able to completely ablate
those lesions. So a surgical resection in a surgical candidate is
reasonable. You would certainly think RFA, RF ablation, would be
reasonable in that same situation when patients are not surgical
candidates.

These are the exact arguments that we heard before the approval of this
modality for the treatment of metastatic cancer to the liver. We know
that patients that have metastatic cancer to the liver from colorectal
cancer that have less than three lesions have a 25 percent five-year
survival. In the absence of that surgery, that survival is probably less
than 5 percent.

So the control of isolated metastatic lesions, although never, to my
knowledge, in oncology ever, not a single trial has been conducted in
randomizing patients to that treatment versus no surgery have ever been
conducted, it\'s absolutely standard of care.

I think for thoracic surgeons who are concerned that this would be used
in place of surgical resection, I agree completely it should not be, and
I agree with Dr. Putnam and I agree with the other comments that were
made. That is not what is being proposed.

What is being proposed is very simple, and it seems to me
extraordinarily logical. If surgical resection helps a patient that is a
surgical candidate and you have an identical situation in a patient who
is not a surgical candidate, we have a modality that can ablate that
lesion. This should not be considered in place of surgery; it should be
considered as yet another tool. It\'s just a scalpel that can be applied
with minimum or as an outpatient and should not be considered as a
replacement for surgery.

CHAIRMAN McCAULEY: Thank you.

We will move now to the discussion of the FDA questions. Do we have
the ‑‑

DR. WITTEN: Can I just make one comment as we move to the questions? I
just want to remind everybody just to focus the discussion on the
questions as they would relate to any of these devices for ablation of
lung tumor. Although I think it is extremely helpful that a sponsor of a
device presented their particular data, we\'re not here to discuss that
particular dataset, but these questions as they relate to level of
evidence for devices for ablation of lung tumors.

CHAIRMAN McCAULEY: The first question. I am going to ask Dr. Brenner to
read the first question and start off the discussion.

DR. BRENNER: \"Please discuss where you believe the coagulation necrosis
is a means of local control may fit into the current treatments for lung
cancer. Local control may mean reduction, stabilization, or a decrease
in the growth of tumor size. Please describe specific patients for which
this treatment may be appropriate in terms of extent of disease, size of
tumors, and evidence of failure of treatments.\"

I think that the discussion that we heard points out a number of major
issues that the agency is going to have difficulty with. They are
essentially the heterogeneity of this disease that you are trying to
treat, lung tumors or lung cancer.

Now, first of all, let\'s break this down a bit because I think from a
regulatory point of view that is going to be important. We are talking
about primary tumors of the lung; in other words, tumors that are the
result of growing out of epithelial sources usually, but not always, of
the lung, bronchio epithelial.

That\'s a primary tumor, and there are multiple histologies. Some
histologies are generally more aggressive; some are less aggressive. For
example, a squamous cell tumor can have a very long natural history of
five years. So you can ablate a squamous cell primary or not ablate a
squamous cell primary; survival is the same.

So, therefore, there\'s a concern right away about the concept of using
decreasing size as a primary endpoint simply because of differences in
natural history. So there can be different histologies.

Now there\'s one histology that was not mentioned, and I need to mention
it. That\'s small cell lung cancer. Small cell lung cancer is considered
a metastatic systemic disease at one set and is, therefore, not
considered for local ablation, local control, because of the systemic
nature of the disease and the rapid mortality.

However, there are occasional instances where small cell tumors locally
can be very destructive and, in fact, sometimes local and even systemic
treatments might not be useful, particularly in the recurrent stage, and
I will get to that in a few minutes. So there is histologic variability.

The second issue is there is stage. Stages are meaningful because they
predict prognosis, but they also predict whether the disease is systemic
or not systemic. If the goal was local control and one has systemic
diseases, the rate-limiting step, I\'m not convinced that trying to
control a local disease, a systemic disease with a local modality is
going to be useful in the long run, and, in fact, most of the advocates
here agree with that, since they focused more on the local disease.

However, there is likely to be a role for this modality in control
symptoms of quality-of-life indications that were not mentioned here,
except very briefly. I\'m a little surprised about that because I think
that that would be a group of patients who might really benefit.

The question is, what would be the standard by which one would utilize
to approve on the basis of a palliative indication or quality-of-life
indication, rather than on the basis of a size or a complete response or
an efficacy indication, a survival indication.

So, with those kinds of comments in hand, I\'m going to break down the
stages and the types and give you at least my own view in terms of
addressing this question as to who would fit, so to speak.

Let\'s talk first about the curative intent, so to speak, or the
complete ablation. That would be generally what was described by the
speakers as the 3.5-centimeter primary stage 1, non-small cell lung
cancer. The intent would be essentially a complete response or a
complete ablation of the tumor.

I personally do not accept a partial response as a surrogate for
survival unless there is a type of extenuating circumstance such as a
prolonged time to recurrence, and we will get into that much later. I\'m
poaching a little bit on two, but I think that it has to be in terms of
describing who the cohort would be. So that would be one group that has
already been discussed.

I think that that is a legitimate group. If there\'s no surgical
availability, if there\'s no surgical option, I agree with that. Surgery
should be the primary modality, I agree with that.

In terms of stage 2, that\'s a real tough one. The reason is that some
stage 2\'s are resectable. My own interpretation of the literature for
stage 2 is that, since they generally have lymph nodes in the hilar
regions, that for the most part, although some are resectable, 85
percent of the lymph nodes means that there is systemic dissemination.

Sometimes survival related to local controls is more related to
histology and biology than it really is to the ablational procedure. But
one could argue that a stage 2, potentially a 2A, might also fit in a
resectability group, which means that if they do not have a surgical
option, they could also be eligible for this and might be a cohort.

Stage 3\'s, the primary care, primary ablational indication; these are
generally almost all individuals who have disease that will be
systemically disseminated on diagnosis. However, the use of cytotoxic
and radiation approaches, either in combination or in sequence, seem in
a few of these groups to have ablated the tumor systemically. And if
there are many times a central recurrence, there could conceivably also
be a local ablational indication for this. I heard nothing of this here,
although I could conceive of a trial that could actually be designed
around this.

Stage 4 are generally systemic tumors and, therefore, for the purposes
of ablational approaches for survival endpoints, I do not feel that this
would be cohort that would be useful for regulatory purposes. However,
such patients do have palliative needs, and if there are things like
chest wall tumors and pain from primaries, this cohort could certainly
be used, but only on a palliative indication.

Then there is a cohort of patients who are either recurrent or
obstructive, who either have received maximal radiation and do not have
that available to them, who might be candidates for palliative maneuvers
to either reduce the size of the tumor, to release the obstruction, or
to have pain control as an endpoint. That was alluded to by our final
speaker, and I think that is a potential cohort.

So we break all these different cohorts. You can see there are multiple
small cohorts, and each one of these, if one is going to want to get an
indication, we have to design a trial for that endpoint. So to restrict
it to just a CR-type endpoint or some type of reduction, tumor size
endpoint, unresectable tumors, to my mind, are resectable tumors in a
small size primary that is not surgically eligible seems a somewhat
restrictive approach to the regulation, to the potential proof of
whether or not this concept would be useful.

In terms of the concept of control of metastatic tumors, in other words,
cancers that are metastatic to the lung that are not primaries from the
lung, I have major concerns with that as an indication. First of all,
these, too, are a whole variety of different primaries. One could have a
renal cell primary that is metastatic to the lung that might have three
or four mets, many times a surgical resection. If they are not resected,
some of these patients have prolonged survivals. As Dr. Rosenberg notes,
there is no data to show whether or not resection really is efficacious
or not.

On the other hand, some other tumors may be colon cancers might grow,
but usually the survival limitations in many of these patients are not
the lung primaries themselves, but, rather, they are metastatic sites
different, different sites other than the lung. The same with breast
primaries, for example.

So to say to lump all metastatic tumors together and argue that one
could definitively or provide some type of evidence that there is real
efficacy in terms of survival endpoints on the basis of reduction or
ablation of metastatic lesions from a heterogeneous group of tumors
without defining exactly what the primary source of this tumor,
problematic, and I personally would be uncomfortable with that as an
indication.

CHAIRMAN McCAULEY: Dr. Brenner, we appreciate the complexity of your
comments. However, I\'m not sure whether or not you defined the extent
of disease in which this therapy may be utilized.

DR. BRENNER: Stage. In other words, stage. Stage 1 would be a local
regional tumor that meets the size definition. Stage 2 would be a tumor
that would be larger but would have a lymph node in the hilum. Stage 3
would be one that is invasive in the chest wall or obstructive. Stage 4
would be metastatic.

In terms of size indications, I think that is related as much to the
placement of the needles, and I think that the sponsors define that as a
3.5-centimeter lesion, but not necessarily because other groups, and in
fact the literature that was provided to us did not restrict the size
for palliative indications. So that is why there is complexity here.

There\'s multiple potential regulatory endpoints.

CHAIRMAN McCAULEY: Are there any other comments from Panel members?

DR. LoCICERO: Just one. We\'re confusing here patients who are operable
and those who are not operable. Those who are operable fit in point No.
5, which we have not gotten to yet. We\'re talking strictly about
inoperable patients here.

CHAIRMAN McCAULEY: Other comments?

DR. MILLER: I guess I just to be clear that, when we say the patient is
inoperable, it\'s because of medical contraindications? It is not
because of the nature of their tumor? Am I correct in assuming that?

DR. BRENNER: Stage issues. In other words, generally, stage 1 would be
operable tumors for the most part; in other words, on the size and
location basis.

DR. SHURE: Which would be operable versus resectable differences.

DR. BRENNER: Operable/resectable.

DR. SHURE: Could I just add that stage 2 disease might be one, if
you\'re adding it to this, since there is nodal involvement, it would
need another modality. It couldn\'t be a sonomodality.

DR. BRENNER: Yes, for the most part.

CHAIRMAN McCAULEY: Other comments from Panel members?

Dr. Witten, it appears that the answer to Question No. 1 in terms of
extent of disease would be basically patients who are inoperable with
lesions less than 3.5 sonometers. Is that the consensus of the Panel?

DR. BRENNER: No.

CHAIRMAN McCAULEY: Stage 1?

DR. BRENNER: Oh, stage 1, okay. But there are other ‑‑ to me, that\'s
not the ‑‑ the question is broader than that. I mean it seems to me
you\'re asking a much broader question than that.

It says, in terms of the size of tumors and which tumors might be useful
from a regulatory purpose. For example, a palliative indication.

DR. WITTEN: I think it is going to be hard to summarize Dr. Brenner\'s
answer, but I think it\'s very helpful to us in terms of the Panel
having answered our question.

DR. LoCICERO: One point, and that is that stage 1 cancers are less than
3 centimeters in size. T1 lesions are less than 3 centimeters. So
although you\'re talking about 3.5, that gets you in a stage 2.

DR. SOLOMON: I guess the other comment is I\'m not sure ‑‑ you seem to
be very negative on the metastatic opportunity, and I think that if you
look at what is current surgical treatment for metastatic, certain
metastatic lesions are surgically operated on now. If it\'s a patient
who is unable to be operated on because of other co-morbidities, and
where you would ordinarily decide that surgery is an option, I think
that some of these ablations may be considered an option, too.

DR. BRENNER: It gets to really what the standard of efficacy is here.
Dr. Rosenberg strongly argues that removal of lesions is efficacious in
the long run, and that might be true, I believe, for some malignancies,
but it might not be true for other malignancies. How does one
distinguish that in a regulatory issue? That, to me, is the question.

In other words, if one is attempting to define efficacy as a regulatory
endpoint and one is utilizing a very heterogeneous lesion ‑‑ in other
words, metastatic from what? How about a sarcoma versus a renal cell
carcinoma? Any metastatic lesion?

Are we allowed to ask people to respond, particularly Dr. Rosenberg? Is
he going to be given an opportunity to respond?

CHAIRMAN McCAULEY: Dr. Witten?

DR. ROSENBERG: Am I allowed to comment? Am I allowed to comment?

DR. WITTEN: It\'s up to the Panel, the Chair.

CHAIRMAN McCAULEY: Yes.

DR. ROSENBERG: I would make just two simple points. One is we need to
distinguish non-operable from a non-surgical candidate, because a
patient might well have an operable lesion, but if they\'re not a
surgical candidate because of co-morbidities, then, of course, they
don\'t have an option available for therapy.

Now this question that you raise, Dr. Brenner, is one that comes up
frequently in terms of the resection of metastatic disease to the lung.
But I do not think you could find one out of a hundred oncologists, be
they medical or surgical, who would advocate that patients with solitary
or two lung metastases who have refractory to chemotherapy treatments
should not have those lesions resected. It is absolute standard of care
in this country, and any oncologic textbook would advocate the removal
of those lesions, as Dr. Putnam has and as I\'m sure an thoracic surgeon
on this Panel would advocate.

Now there haven\'t been randomized trials to demonstrate its benefit,
but the first time, the first patient actually that ever had resection
of a lung metastasis with renal cell cancer went on to survive 30 years.
Patients with sarcomas and pulmonary metastases that are less than 3
have five-year survivals and ten-year survivals in excess of 20 percent.
It\'s absolute standard of care.

If we start questioning now whether or not it\'s reasonable to try to
treat isolated metastatic disease to the liver or to the lung, we\'re
flying in the face of what 99-plus percent of oncologists would advocate
as standard of care in this country in the year 2003.

DR. BRENNER: It has to be specified that it is a, quote, \"isolated\"
metas. In other words, one or two. Generally, I think that there would
be a fair amount of resistance if you go above two as a standard of
care, and particularly for a regulatory purpose.

DR. ROSENBERG: You know, again, it does vary a little bit for histology,
but, in general, you\'re right. I would think generally often in the
liver one calls four as a cutoff. Most thoracic surgeons might consider
three or four, but I\'m sure Dr. Putnam has probably resected twenty
lesions in the lung, because very often you get into the lung and you
find more than you thought were there.

Those patients have, with a definite incidence ‑‑ and I\'m talking now
about hundreds of papers, maybe 500 publications, that would show those
patients have in a small incidence very long-term survivals.

CHAIRMAN McCAULEY: Any comments from the Panel?

DR. MILLER: Just one more question for you. Where does radiotherapy fall
into priority of options here? As you mentioned, surgery, and if not a
surgical candidate, then this is an option, but how about radiotherapy?

DR. BRENNER: I think that really gets into the design of a pivotal
trial, because that would be the alternate arm.

DR. SEWELL: I would like to reiterate and comment that the issue of
which metastatic lesion to treat, what type of met, is complicated. The
only clear indication, as I indicated on my last slide, would be pain
reduction or pain elimination for maintenance or improvement of quality
of life.

In the middle of that, and on the middle ground is an asymptomatic
single met and two patients, one that can tolerate surgical resection,
and that\'s what they\'re offered and that\'s what they get. The other
has co-morbidity, congestive heart failure, pulmonary disease from
whatever cause. Should we deny them radio frequency ablation of that
metastasis, knowing that it\'s their only documented metastasis, knowing
that radio frequency ablation is very extremely reliable and documented
to destroy focal areas of tissue with the hope that both of those
patients, that is their only metastatic disease, which we have no
control over, but what do we do in that case?

And then the third point, primary disease, no one tonight has advocated
treating any primary tumor that can be resected, as determined by the
resection experts, cardiothoracic surgery. That is universally agreed
upon, and I think it will be for 20 more years, until we get long-term
data as to what this does.

But what about those patients like the one I showed that lived three
years after I destroyed his four lesions on his right side? Ultimately,
he died of congestive ‑‑ tumor-free, after he had failed chemotherapy
and refused radiation, and at the age of 88. I think that\'s a valid use
of this technology, and I don\'t think it should be restricted.
Certainly it\'s subject to abuse, but can we really control that?

CHAIRMAN McCAULEY: Dr. Witten, do you think this has been adequate
discussion, so that we can move on to the second question?

DR. WITTEN: Yes, thank you.

CHAIRMAN McCAULEY: Thank you.

The second question, please. I\'m going to ask Dr. Shure to read the
second question and lead off with her comments.

DR. SHURE: The second questions is, \"Please discuss what you believe to
be the appropriate endpoints for study to demonstrate the effectiveness
of ablation devices for the treatment of primary and secondary lung
malignancies; i.e., increase in survival, reduction in tumor size,
improvement in symptoms, improvement in quality of life.\"

I would like to combine ‑‑ some of this has been covered already in the
previous discussion, but I would like to add one thing in here, which is
safety as well as effectiveness, because I don\'t think that\'s covered
throughout our discussions.

And I have some concerns with the safety of this technique in the lung,
despite the study that was presented. I think there are some things,
based on what I\'ve seen of lung ablation in my time at the University
of Mississippi.

Patrick, I know that you presented your selected series, but I think it
may have left out some of the patients that I have seen. You did report
the hemorrhage in an article, but I think we have to consider hemorrhage
requiring intubation or transfusion. We need to report death because
there was that death and there have been other deaths.

Prolonged mechanical ventilation from respiratory failure in this group
of patients is an important complication that has occurred and needs to
be reported. I think we need a large series to look at that.

I was aware of four patients while I was at the University of
Mississippi who had significant complications, including prolonged
mechanical ventilation, infection, and sepsis. I think we need to look
at this within 30 days of the procedure, not just acutely, which may
account for the differences that we see here.

So I think hemorrhage, mechanical ventilation, pneumothorax where they
early degraded in seven days, death, and infection are important.

These patients, as has been pointed out, who are candidates for this
have very poor respiratory status and very low FEV1s. The claim has been
made that this is safer than radiation. I think we have to establish
that. We say that radiation decreases the FEV1. I think we need to do a
prospective analysis of these patients as we treat them that does show
that they don\'t drop their FEV1 in response to this treatment, and that
needs to be both short-term and long-term.

One might expect a short-term reduction, as we have seen with surgery,
but they shouldn\'t lose function over a six-month to one-year period,
we would hope, other than their natural disease, of course, but that can
be looked at in a controlled population. So I think those are important
things related to safety.

In terms of effectiveness, I agree with what was said. I think tumor
size alone is not a significant parameter to look at. I think it has to
be looked at as part of the endpoint, but unless it is offering the
patient some benefit, either in terms of quality of life, palliation of
symptoms, or improvement in survival, it is not a meaningful parameter
to follow. It needs to be followed, but survival needs to be looked at,
as it is in most studies of chemotherapy and radiation.

I think local recurrence is an important thing to look at as well. I
think those would be primary.

I think secondary parameters of the efficacy would be quality of life
and, as I mentioned, FEV1 could be included in there. So that would be
my impressions of what needs to be looked at.

CHAIRMAN McCAULEY: Any other comments from Panel members? Yes?

DR. BRENNER: I would like to amplify a number of things and also to make
a few extra comments.

I concur with Dr. Putnam\'s points that an appropriate endpoint here is
a survival surrogate. In my opinion, a survival surrogate for a lung
primary is a complete response, not a partial response. Partial
responses have been notoriously unuseful and unpredictive of survival as
the endpoint.

So if one is choosing, I would concur a complete response. This,
however, is an interesting modality because the preliminary data that I
have seen appear to create a conundrum where there is no complete
response, but there\'s actually ablation of the primary. Therefore, one
sees a lesion that doesn\'t progress.

That is why a time period, time to failure, which Dr. Blumenstein
mentioned initially, would also be considered a reasonable surrogate for
a non-small cell lung cancer with an expected time of progressive. Time
to failure is the con-oncologic term.

In fact, this modality ‑‑ I think we should, as new targeted therapies
are coming about, consider that as a potential surrogate as well,
assuming that there is no other metastatic sites that go along, that
come along during that period of time.

What is an appropriate time to failure in most lung cohorts? It\'s six
months. So that a time-to-failure endpoint I think would actually be a
valid endpoint, even if there is not a complete response because of the
preliminary data that we\'re seeing.

So I think that, from a regulatory point of view, we have to understand
that non-small cell lung cancers progress very rapidly, that time to
failure in stage 2s and higher are common, and even stage 1s will
usually fail within a year. So that would be a design issue that I will
get into later.

So, in fact, even though there are generally rules and cytotox ODAC has
generally held survival endpoint, not a time-to-failure endpoint, for
common solid tumors, with a modality like this, with a different
potential mechanism of action, I think we have to be open-minded on this
issue.

Quality-of-life surrogates I agree upon, but I do have some additional
endpoints that I think are worthwhile that oncologists have used in the
past for indications, and they are pain, pain endpoints. And I alluded
to the palliative issues in patients who have, for example, large chest
masses that are in pain.

Most of these patients have pain, and we have used pill counts, total
dose of narcotics over daily times as reasonable surrogates. I think
reduction usually at least of 50 percent were sometimes regulatory; it
has been 100 percent, in other words, a complete cessation of narcotics
for a period of time, usually a month, as a quality-of-life surrogate
that you can really hit the nail on.

Another potential quality-of-life surrogate, particularly in these folks
who might have obstruction or fevers, would be a loss of fever. Then the
real difficult one, but one that many have found to be reproducible,
even though it\'s been difficult to bind, is the Karnofsky performance
status. As controversial as that is, it\'s surprising how it holds up in
just about every analysis.

What we would be looking for is an improvement in the Karnofsky
performance test that is real, not a 10 percent improvement where you
power your study up with a thousand patients so that you prove a 10
percent improvement in Karnofsky performance test, but were somebody has
a very low Karnofsky performance test, bed-to-chair existence, and is
able to then get up to an 80 or 90 percent performance test, although I
don\'t know that that has been used in a regulatory situation.

People have used the SF‑36 for a partial regulatory indication as well.
So that has already been mentioned.

And then pulmonary function apropos to the previous discussion, to me
that\'s a black box, but it could be defined by our experts on the Panel
as a potential surrogate, particularly saturation in the palliative
situation.

CHAIRMAN McCAULEY: Other comments from the Panel?

\[No response.\]

Has there been enough discussion, Dr. Witten, to address the Question
No. 2?

DR. WITTEN: Yes, thank you.

CHAIRMAN McCAULEY: We\'ll move on to Question 3. Dr. Solomon, I\'m going
to ask you to read Question 3 and lead the discussion.

DR. SOLOMON: \"Please discuss the imaging modalities that you believe
would be appropriate to assess tumor size during these studies.\"

I think if we look at the possible imaging modalities, you can divide
them into sort of anatomic and physiologic. I think anatomic
measurements would be size, as Dr. Rosenberg described.

However, one of the problems that comes up with ablation technologies is
that after a procedure, immediately afterwards, the lesion appearance
could be larger than when ‑‑ you saw some of these in the initial images
that Dr. Rosenberg showed us, that at one month the lesion looks
actually bigger than it was initially. So size can be somewhat confusing
at different times. So you probably need to follow that over time.

I think that if we look at the physiologic aspects of imaging, and that
would include Houndsfield unit change and contrast enhancement, as well
as glucose metabolism, as in PET imaging, you actually are going to get
a much more realistic opportunity to evaluate these lesions.

So that I think on a practical sense, most people have access to CT
scanning, and I think that\'s probably the way things should go. We
should use CT to measure size.

I would add using the Houndsfield units. I would also add using contrast
enhancement because I think in previous experience with other parts of
the body, if there is an area of enhancement, it is suggestive of
recurrence. Then if you do see this area of enhancement, perhaps a
biopsy would be a good endpoint to say, hey, this is actually an area of
residual recurrent tumor.

PET imaging has shown to be very valuable in looking at post-ablation
imaging, and recent literature in The Journal of Clinical Oncology
suggested that it actually was very helpful in looking at success of
treatment of liver lesions. So I would suspect that in the lung we would
appear to have similar results. So I would advocate considering PET
imaging with glucose metabolism, FDG tracer, as a second alternative to
CAT scan.

So, again, to summarize, CAT scan, measuring size over time, but also
use contrast enhancement; also use Houndsfield units. Additionally, I
think that PET imaging would be a valuable tool and using biopsy as a
tool to confirm areas of increased enhancement or perhaps increased FDG
uptake.

CHAIRMAN McCAULEY: Any comments from the Panel?

Dr. Witten, does Dr. Solomon\'s comments ‑‑ I\'m sorry, Dr. Brenner?

DR. BRENNER: I wanted to state my concern about using PET as a
regulatory tool to suggest that the mass that you\'re seeing is not
viable unless there are data compelling to demonstrate that that is,
indeed, the case. In other words, linked biopsy data.

Since I don\'t know the literature in that field, I would like to bring
that up and ask whether there is compelling information that supports
that position because that would be an important regulatory point, I
think.

DR. SOLOMON: I guess I would say that I don\'t think the data is clearly
‑‑ it hasn\'t been shown at all in the lung. There are a few case
reports of using PET as a tool for looking at post-ablation in the lung.
There is definitely good data coming out as far as liver ablation, but I
think that perhaps it would be a tool that could be used in conjunction
with biopsy to confirm areas of residual.

DR. BRENNER: Then my advise to FDA would be that, if PET is to be used,
it has to be accompanied by a biopsy in order to verify that there is,
indeed, stasis; in other words, ablation, and that that is not viable.

CHAIRMAN McCAULEY: Comments? Dr. Stoller?

DR. STOLLER: I would just make the perhaps overarching comment that the
challenge in this conversation is, as I think has been pointed out, the
incredible heterogeneity of populations for whom this might be made
available. It seems to me that, perhaps in contrast to the earlier
discussion, which had its own subtleties about different patient
populations, this particular conversation is complicated by the fact
that, if there were three or four patient populations ‑‑ heterogeneous,
homogeneous ‑‑ in the prior discussion there are perhaps dozens, if not
hundreds, of patient populations for whom this issue would be framed.

That said, I think the comments about primary outcome measures have to
be focused completely on the patient population and focused question for
which the issue is being channeled. So, in my own mind, perhaps the
simplest, and in the context of comments that have been made about
trying to avoid vigilantly making this modality available as a primary
curative ‑‑ as a surrogate for a primary curative modality when there is
ample experience in, for example, bronchogenic carcinoma of resection or
even radiation therapy, avoiding any opportunities, I think Dr. Cooper
had pointed out, to allocate patients to this treatment when there are
conventionally-available modalities is absolutely improper. I agree with
that comment completely.

That said, on the other end of the spectrum there are patients who have
metastatic bronchogenic to the lung who have either a high degree of
symptoms, whether it be pain related to some pleural disease or perhaps
even hemophilus, et cetera, for whom a very clear palliative indication
might exist that goes beyond radiation therapy or even local
bronchoscopic opportunities.

So, in that context, the outcomes, to my mind, would have nothing to do
with, in fact, size or PET FDG agreement. It would have to do with
control of the symptom that was the indication for the procedure.

So I\'m aware that I may not be helping to drill down on the agency\'s
questions about this, but I would submit that the complexity of
answering this question has to do with the incredible heterogeneity of
the patient populations for whom this modality might be made available.

To my way of thinking, the simplest answer would be confine it to a
group in which a palliative indication is offered, which I think is
largely the sense of comments made by many of the discussants before.

In that regard, one might focus perhaps less on the physiologic function
or even survival, because survival is an unlikely outcome benefit in
that particular context, but more around symptomatic control. I
personally think that perhaps functional status is unlikely to be
dramatically improved, and I would discount the contribution of any
pulmonary physiologic measurement, as I think that would be highly
unlikely and difficult to understand in terms of its biologic
contribution, even if demonstrated.

DR. SHURE: I meant a lack of decrease, you know, not hurting them by the
procedure.

DR. STOLLER: I completely agree with that comment. My comments are not
directed at safety, and I agree with Dr. Shure\'s comments completely
about concerns, you know, the temptation to enter this vicious cycle of
technology about tumor growth, repeat invasion, repeat pneumothorax. I
mean this is a cascade on which these patients sometimes find
themselves.

I think one of the important cautions, I think echoing comments by other
discussants, is that the question ought to be vigorously framed to avoid
a cycle of technologic interventions to these patients without
demonstrable benefit.

CHAIRMAN McCAULEY: I think many of those issues were addressed in the
safety and efficacy question. Right now we are focusing primarily on
tumor imaging.

Dr. Witten, do Dr. Solomon\'s and Dr. Brenner\'s comments satisfy you at
this point?

DR. WITTEN: Yes, thank you.

CHAIRMAN McCAULEY: We\'ll move on to the fourth question. Dr. Brenner,
can you take the lead and read the fourth question?

DR. BRENNER: Now with all this heterogeneity, let me see if I can break
it down and clean it up.

There are a number of proposed designs that might work here. Let\'s take
the group that was primarily discussed by our initial presenters.

They would be the group of stage 1, resectable but inoperable, non-small
cell lung cancer. Standard of care in those folks would be considered
radiation alone. So that a study design would be randomization.

Before I go forward, I would argue that any pivotal trial design, in my
opinion, would need to be randomized and randomly allocated, the reason
being, otherwise, there would induce selection bias into the design
study, and Dr. Blumenstein could probably help with that some.

But for the cohort that was described by the industrial sponsors and two
representatives, the group I believe they are really targeting are the
resectable, inoperable group with medical contraindications. The
standard of care I would think would be radiation.

Therefore, an appropriate design would be radiation versus radiation
plus heat. Plus, this modality, I don\'t know how you could not provide
radiation in either arm. So one would have to evaluate the contribution
of the heat. That\'s problematic in terms of the local control of the
lesion, because one might argue that the radiation might be successful
in such a large number, particularly in stage 1, that the burden of
proof would require a large cohort in order to get the power to deal
with complete ablation.

I don\'t know what other panelists would think of a radiation versus
radio frequency ablation alone as a standard design, with radiation
available for failures, but I think that one has to realize that that ‑‑
and it was already mentioned by the Panel members this is not an
entirely risk-free procedure with some early reports of some 70 percent
pneumothoraces with chest tubes, some bleeding episodes.

So I agree. I concur. That kind of design would also allow good toxicity
profile.

CHAIRMAN McCAULEY: Dr. Shure, do you have any comments, as this
partially relates to the question that you outlined and answered
previously?

DR. SHURE: Duration of followup with regard to safety and efficacy,
well, I think with regard to safety, I think one has to look at least a
30-day followup. I don\'t think ‑‑ it has to be looked at as an
operative procedure and look at 30-day complications at least.

In terms of the FEV1, which does concern me that this hasn\'t been
looked at in this population, I think that should be at least a
three-to-six-month followup.

I think in terms of survival, and if we are talking about treating with
stage 1 disease who are otherwise inoperable, but would be resectable, I
think you need a minimum of one-year followup. I think in the oncology
world, it would be more like a three-to-five-year followup.

Given that these patients have bad lung disease, I think one should
require in a controlled study that the original cohorts be followed
until death.

CHAIRMAN McCAULEY: Thank you.

Dr. Witten, has that been enough discussion to satisfy answers to
Question 4?

DR. WITTEN: Well, I think Dr. Brenner has something.

CHAIRMAN McCAULEY: Dr. Brenner?

DR. BRENNER: Yes, I was going to argue for a two-year endpoint, per Dr.
Putnam\'s comments. I agree that two years is appropriate for this
cohort as a followup, as a survival endpoint, with a secondary endpoint
of followup to death.

I think there are other designs that would be useful from a regulatory
point of view that would be a palliative design, where one would use
recurrent patients who have lesions that are symptomic in prior
radiation fields who would benefit from a palliative endpoint, and that
would be randomization between this modality and best supportive care.

I think there would be a large population for such a design. Not only
that, but I think that the risk/benefit ratio would be perhaps even more
favorable because people, because of their distress, would be willing to
accept more risk compared to, say, the stage 1 group. So that is another
design that I think is reasonable.

CHAIRMAN McCAULEY: Are there other comments from Panel members?

DR. SOLOMON: I mean this is a therapy that is a local therapy. So I
guess we have to keep in mind that what you\'re expecting out of this
therapy is going to be a local response. Therefore, sometimes you might
consider looking at the imaging findings of the local therapy or the
biopsy findings of that local therapy to prove that it actually worked
the way you expected. That is local control.

Obviously, the endpoint of why we are doctors and why we treat patients
is for other issues, such as survival and quality of life, and things
like that. Obviously, quality of life will be another endpoint that is
shorter-term.

I guess the question of whether or not this works for survival-length
time periods, you are going to be looking at very long time periods.
Maybe the comparison should be made with surgical resection of mestastic
lesions and see how it compares against that. Maybe that would make it a
more reasonable time course because a two-to-five-year time course may
be too impractical.

DR. BRENNER: A palliative endpoint would simply be pain; for example,
number of pills. That might be just as useful. You might not even need,
for example, a size. As a matter of fact, a size estimator would be of
less interest to me than a quality-of-life endpoint, because we\'re not
treating, in essence, size; we\'re treating symptoms to a palliative
endpoint. So I would find that a standard that I could live on the basis
of benefit, benefit here being quality-of-life benefit rather than
survival benefit.

So I pose two proposed designs. One is an efficacy survival endpoint for
the primary ‑‑ for the resectable, inoperable group, but also then a
palliative design which would not have a survival endpoint, but a
quality-of-life endpoint, which I would find to be of benefit.

CHAIRMAN McCAULEY: I think these were issues that Dr. Shure brought out
in Question No. 2 as primary endpoints in evaluating efficacy of this
particular treatment.

Has this discussion been beneficial for you, Dr. Witten, to move on to
Question No. 5?

DR. WITTEN: Yes, thank you.

CHAIRMAN McCAULEY: Question No. 5, I\'m going to ask Dr. LoCicero to
read that question and lead the discussion.

DR. LoCICERO: The answer\'s longer than the question. \"Please describe
the appropriate control group endpoints and duration of followup for a
clinical study of an ablative device that is to be used in place of
surgical resection of lung tumors for patients who would be considered
operable.\"

I think we have had a huge discussion already concerning this issue,
that operable patients should receive surgical resection, and that at
this time this device is not to be used in those patients.

CHAIRMAN McCAULEY: Any other comments from Panel members?

DR. WITTEN: Well, I am just wondering, as I had mentioned, that we\'re
not talking just about the particular device of this particular sponsor.
So I suppose one question would be, does your answer mean that you
don\'t consider that an ablation study for patients in place of an
operative would ever be appropriate and, if so, why not? Or if that\'s
not the answer, then a discussion of the question, which, like I say,
may not apply to this particular device, but ablation devices in general
would still be helpful.

DR. LoCICERO: There are a variety of ablation devices, photodynamic
therapy, laser, ultrasound, radio frequency, focused IMRT, et cetera,
all potential ablative devices for operable patients, but operation or
surgical resection remains the standard. No one here has questioned
that, even those who have used other devices.

The only study that I\'m aware of that looked at ablative devices was
using photodynamic therapy in Japan, where they gave the photodynamic
therapy followed by resection. In that case, the tumor was removed,
appropriate operation was performed, and then it was looked at under the
microscope to see if there were any remaining viable cells. That would
be the only situation where this could be used or applied, as far as
I\'m concerned.

DR. WITTEN: So what you\'re saying is that a first stage would be to
look and see if there are viable cells at resection? Suppose the sponsor
performed that; they did that stuff, and they found that there weren\'t
viable cells. Then would there be a next stage, and what would that
trial look like?

DR. LoCICERO: I think that would not be a primary trial for approval of
such a device, and that would have to be a preliminary step on the way
to much further studies. But as far as expanding indications at this
point, this would really be not an indication. Nobody at this point
considers ablative therapy to replace surgery in operable patients.

DR. SHURE: Can I make one quick comment to echo what Dr. LoCicero said.
I think one way to look at this is that there have been numerous studies
that have shown that removing a nodule, removing a wedge, doing a wedge
resection, or doing a segmentectomy do not have as good a survival as
lobectomy.

All this can be, at best, is removing a nodule. That\'s all. It\'s
local. It\'s local, very, very local therapy. So even at its best, it
couldn\'t replace a lobectomy as we see the disease now.

CHAIRMAN McCAULEY: Other comments from Panel members?

\[No response.\]

Dr. Witten, does that satisfy your answer to Question 5?

DR. WITTEN: Yes.

CHAIRMAN McCAULEY: The FDA would like to thank all of the Panel members
for giving their time and efforts for the discussion of this product.

This meeting is now adjourned.

(Whereupon, the proceedings were concluded at 5:18 p.m.)