UNITED STATES OF AMERICA

\+ + + + +

FOOD AND DRUG ADMINISTRATION

\+ + + + +

MEDICAL DEVICES ADVISORY COMMITTEE

\+ + + + +

GENERAL AND PLASTIC SURGERY DEVICES PANEL

\+ + + + +

GAITHERSBURG, MARYLAND

\+ + + + +

THURSDAY,

JULY 24, 2003

\+ + + + +

8:50 a.m.

\+ + + + +

The Panel met in Salons A, B, & C, Grand Ballroom, at the Gaithersburg
Hilton Hotel, 620 Perry Parkway, Gaithersburg, Maryland, with Robert L.
McCauley, M.D., Acting Chair, presiding.

[PRESENT]{.underline}:

ROBERT L . McCAULEY, M.D., Acting Chair

MICHAEL A. CHOTI, M.D., Voting Member

[PRESENT (Continued)]{.underline}:

MICHAEL J. MILLER, M.D., Voting Member

BRENT BLUMENSTEIN, Ph.D., Temporary Voting Member

RAYMOND J. LANZAFAME, M.D., Temporary Voting Member

ANN MARILYN LEITCH, M.D., Temporary Voting Member

JOSEPH LoCICERO, M.D., Temporary Voting Member

DEBERA M. BROWN, Industry Representative

LeeLee DOYLE, Ph.D., Consumer Representative

DEAN E. BRENNER, M.D., Consultant

FRANCINE HALBERG, M.D., Consultant

DANIEL B. KOPANS, M.D., Consultant

STEPHEN SOLOMON, M.D., Consultant

CELIA WITTEN, Ph.D., M.D., FDA, Division Director DGRND

DAVID KRAUSE, Ph.D., Executive Secretary, Division of General,
Restorative & Neurological Devices/ODE

[ALSO PRESENT]{.underline}:

BINITA S. ASHAR, M.D., Division of General, Restorative & Neurological
Devices

GEORGE M. BURDITT, Kelsey, Inc.

KAMBIZ DOWLATSHAHI, M.D., Professor of Surgery, Rush Medical College,
Kelsey, Inc.

KEYVAN FARAHANI, Ph.D., NIH/NCI

ROBERT GATLING, Office of Device Evaluation, FDA

NEIL R. P. OGDEN, Branch Chief, General Surgery Devices Branch

JUDITH E. O\'GRADY, RN, MSN, RAC, Senior Vice President, Regulatory,
Quality and Clinical Affairs, Integra LifeSciences Corporation

JOHN D. PAULSON, Ph.D., Vice President Quality Assurance and Regulatory
Affairs, Johnson & Johnson Wound Management, a Division of Ethicon, Inc.

LENE RETBØLL MÜLLER, Director of Quality Assurance, Medical Devices,
Ferrosan A/S

[ALSO PRESENT (Continued)]{.underline}:

STEPHEN P. RHODES, MA, Branch Chief, Plastic and Reconstructive Surgery
Devices Branch

[C O N T E N T S]{.underline}

[PAGE]{.underline}

Deputization of Temporary Voting Member 7

Conflict of Interest Statement 8

Panel Introduction 11

Update Since Last Meeting, Stephen P. Rhodes 14

[Reclassification of Absorbable Hemostatic19]{.underline}

[Agents and Dressings]{.underline}:

Industry Presentation:

John D. Paulson, Ph.D. 19

Lene Retboll Muller 35

Judith E. O\'Grady, R.N. 43

FDA Presentation:

David Krause, Ph.D. 54

Panel Deliberations and Address FDA Questions 76

Reclassification Questionnaire and Vote 107

Presentation of Dr. Keyvan Farahani 158

Panel Introduction 161

Open Public Comment 165

[Clinical Issues in Regards to Medical Devices]{.underline}

[for the Ablation of Breast Tumors]{.underline}:

FDA Presentation:

Binita S. Ashar, M.D. 166

Industry Presnetation, Kelsey, Inc.:

George M. Burditt 173

Open Panel Discussions and FDA Questions 209

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

(8:38 a.m.)

DR. KRAUSE: Good morning. We are ready to begin this, the 62nd meeting
of the General and Plastic Surgery Devices Panel.

My name is David Krause. I\'m the Executive Secretary of this panel, and
I\'m also a reviewer in the Plastic and Reconstructive Surgery Devices
Branch.

I\'d like to remind everyone that you are requested to sign in on the
attendance sheets which are available at the tables just outside the
doors. At the table out there you may also pick up an agenda, a panel
roster, and information about today\'s meeting.

The information includes how to find out about future meetings through
the Advisory Panel phone line and how to obtain meeting minutes or
transcripts.

Before I turn this meeting over to Dr. McCauley, I\'m required to read
two statements into the record. One is the deputization of temporary
voting members, and the second is a conflict of interest statement.

Now, only panel members who are attending this morning portion of the
meeting will need to be deputized because there will be a vote. This
afternoon\'s portion of the meeting will not have a vote. So those
members do not need to be deputized.

Pursuant to the authority granted under the Medical Devices Advisory
Committee charter, dated October 27th, 1990, and as amended August 18th,
1999, I appoint Brent Blumenstein, Raymond Lanzafame, Ann Leitch, Joseph
LoCicero as voting members of the General and Plastic Surgery Devices
Panel for this meeting on July 24, 2003.

In addition, I report Robert McCauley to act as Temporary Chair for the
duration of this meeting.

For the record, these individuals are special government employees and
consultants to this panel or other panels under the Medical Devices
Advisory Committee Act. They have undergone the customary conflict of
interest review and have reviewed the materials to be considered at this
meeting.

And this appointment is signed by Dr. David Feigel, who is the Director
of the Center for Devices and Radiological Health.

Okay. The following is the conflict of interest statement.

The following announcement addresses conflict of interest issues
associated with this meeting and is made part of the record to preclude
even the appearance of an impropriety. To determine if any conflict
existed, the agency reviewed the submitted agenda for this meeting and
all financial interests reported by the committee participants.

The conflict of interest statutes prohibit special government employees
from participating in matters that could affect their or their
employer\'s financial interests. The agency has determined, however,
that the participation of certain members and consultants the need for
whose services outweighs the potential conflict of interest involved is
in the best interest of the government.

Therefore, a waiver has been granted for Dr. Michael Choti for his
interest in a firm that could be affected by the panel\'s
recommendations. Dr. Choti\'s waiver involves consulting on a
competitor\'s unrelated product for which he receives an annual fee of
less than \$10,000. The waiver allows this individual to participate
fully in today\'s deliberations.

A copy of this waiver may be obtained from the agency\'s Freedom of
Information Office, Room 12A-15 of the Parklawn Building.

We would like to note for the record that the agency took into
consideration other matters regarding Drs. Choti, McCauley, and Solomon.
Each of these panelists reported past or current interests involving
firms at issue, but in matters that are not related to today\'s agenda.

The agency has determined, therefore, that they may participate fully in
all discussions.

In the event that the discussions involve any other products or firms
not already on the agenda for which an FDA participant has a financial
interest, the participants should excuse him or herself from such
involvement, and the exclusion will be noted for the record.

With respect to all other participants, we ask in the interest of
fairness that all persons making statements or presentations disclose
any current or previous financial involvement with any firm whose
products they may wish to comment upon.

Those are the two statements. I\'d also like to say that anyone
addressing the panel or any panel members when they speak, please speak
clearly into the microphones so that the transcriptionists can fully
understand your statements.

And one other thing before I turn the meeting over to Dr. McCauley. I
would just like to thank Dr. McCauley for his service to this panel.
This is Dr. McCauley\'s last meeting unless we happen to have another
one before August 31st, which would be really hard to schedule at this
point. So I told Dr. McCauley that he\'s free to do any outrageous
things he wants because it\'s his last meeting and we can\'t fire him.

(Laughter.)

DR. KRAUSE: So anyway, Dr. McCauley, please.

ACTING CHAIRPERSON McCAULEY: Good morning. I\'m Robert McCauley, and
I\'m the Chief of the Department of Plastic and Reconstructive Surgery
at Shriners Burns Hospital and Professor of Surgery and Pediatrics at
the University of Texas Medical Branch in Galveston.

And as Dr. Krause mentioned, I am currently the Acting Chair for this
session.

Today the panel will be making recommendations to the FDA on the
proposed reclassification of absorbable hemostatic agent and dressing
products from Class III to Class II and on clinical concerns involving
medical devices intended to ablate or remove breast 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
here at this table.

I\'m going to ask each member to introduce himself or herself, state his
or her specialty, position, institution, and his or her status on the
panel. That includes voting members, industry or consumer
representatives, or deputized voting members.

I would like to start with my immediate left.

DR. LANZAFAME: Hi. I\'m Raymond Lanzafame. I am a general surgeon. I am
currently the Director of Laser Medicine and Surgery at the Rochester
General Hospital in Rochester, New York, and I am a deputized voting
member of the panel.

DR. LEITCH: I\'m Marilyn Leitch. I\'m a surgical oncologist in the
Department of Surgery at University of Texas Southwestern Medical School
in Dallas. I\'m the Medical Director for the Center of Breast Care
there.

DR. CHOTI: I\'m Michael Choti, surgical oncology, general surgery at
Johns Hopkins Hospital in Baltimore, Maryland, and I\'m a voting member
of the panel.

DR. BLUMENSTEIN: I\'m Brent Blumenstein. I\'m a biostatistician in
private practice, and I\'m a temporary voting member.

DR. DOYLE: I\'m LeeLee Doyle. I\'m the Associate Dean for Continuing
Medical Education and Faculty Affairs at the University of Arkansas
Medical Sciences College of Medicine. I am a Ph.D. researcher, and I am
a non-voting member. I am the consumer representative.

MS. BROWN: I\'m Debera Brown. I\'m the Vice President of Regulatory
Affairs for Bronchus Technologies. I\'m the industry representative and
a non-voting member.

DR. WITTEN: I\'m Celia Witten, Division Director of DGRND, which is the
FDA reviewing division for these products.

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

DR. LoCICERO: I\'m Joe LoCicero. I\'m a thoracic surgeon. I\'m Professor
and Chair of Surgery at the University of South Alabama and Director of
the Center for Clinical Oncology of the Cancer Research Institute of the
University of South Alabama, and I\'m a temporary voting member.

DR. KRAUSE: And I\'m Dave Krause, and I introduced myself before.
Thanks.

ACTING CHAIRPERSON McCAULEY: I would like to note for the record that
the voting members present constitute a quorum as required by 21 CFR,
Part 14.

The panel will now hear an update of activities related to the General
and Plastic Surgery Devices Panel since the panel\'s last meeting in
February of 2003. The update will be presented by Mr. Stephen Rhodes,
Branch Chief of the Plastic and Reconstructive Surgery Devices Panel
Branch of the Division of General Restorative and Neurologic Devices.

Mr. Rhodes.

MR. RHODES: Thank you, Dr. McCauley.

I am Stephen Rhodes, the Branch Chief here of the Plastic and
Reconstructive Surgery Devices Branch.

Welcome, members of the panel and members of the public and
manufacturers to this one-day meeting of the General and Plastic Surgery
Panel.

This panel last met on February 28th of this year, at which time you
recommended that a pre-market approval application for a facial
augmentation device, Artecoll, be approved with conditions.

FDA continues to work with the sponsor, Artes Medical, on this
application.

And in the afternoon you discussed clinical trial issues related to
devices designed to treat emphysema.

On March 11th, the agency approved a panel tracked PMA supplement for
Inamed\'s Cosmoderm and Cosmoplast devices. These are injectable
implants made from human collagen intended to treat soft tissue contour
defects, such as wrinkles and acne scars.

On March 20th, the agency published a proposed rule to classify silicone
sheeting for scar management as Class I devices. This panel recommended
this classification in our meeting last July.

On June 3rd, the agency published a Class II special controls guidance
document for multiple surgical suture devices.

And today you will make a recommendation on a proposed reclassification
of absorbable hemostatic agent/devices, and in the afternoon there will
be a discussion regarding clinical trial issues for devices designed for
the percutaneous removal of breast tumors.

Panel members, we appreciate your commitment, and members of the public
who have requested time to address the panel, we appreciate your
comments.

Thank you for your attention.

DR. KRAUSE: Thank you, Mr. Rhodes.

We will now proceed with the first public comment session of this
meeting. 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 interests in any of the medical device companies. 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 FDA of their
request to present to the open session.

We have no one. Is there anyone else wishing to address the panel?

(No response.)

DR. KRAUSE: Okay. With that out of the way, since there are no other
requests to speak to the open public hearing, we will now proceed with
the open committee discussion.

ACTING CHAIRPERSON McCAULEY: No, we have you on the schedule.

DR. KRAUSE: We would begin the discussion of the reclassification of
absorbable hemostatic agents and dressings with a presentation of Dr.
John Paulson, Vice President of Quality Assurance and Regulatory
Affairs, J&J Wound Management, a Division of Ethicon, Incorporated.

His presentation will then be followed by that of Ms. Lene Retboll
Muller, who is also the Director of Quality Assurance and Medical
Devices, Ferrosan A/S, and then Ms. Judith E. O\'Grady, Senior Vice
President, Regulatory, Quality, and Clinical Affairs, Integra
LifeSciences Corporation.

The FDA presentation and reading of the FDA questions will then follow
these presentations. Then we will have a general panel discussion of
this topic followed by more focused panel discussion aimed at answering
FDA questions.

Before we complete the reclassification work sheet and supplemental work
sheet, we will have a public comment period. Then we will complete the
reclassification work sheet and supplemental work sheet.

The vote on these work sheets will actually constitute the panel\'s
recommendation to the FDA.

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

We will now begin with Dr. Paulson\'s presentation.

Dr. Paulson.

DR. PAULSON: Dr. McCauley, Dr. Witten, Dr. Krause, and members of the
panel, we\'d like to thank you for the opportunity to comment today.

It will take us just a moment to get the presentation up on slides.

Per the request to disclose my affiliations, they\'ve been duly noted by
Dr. McCauley and are present. I\'m an employee of Johnson & Johnson and
a shareholder of Johnson & Johnson.

What I\'d like to talk about today in a very brief time frame is a
summary of the presentation from last year. We noticed that only a
couple of the panel members that were present during last year\'s
discussion are here again today. So we\'ll go over some of the high
points that were discussed last year; review briefly the recommendations
of that panel; talk about regulatory classifications; and substantial
equivalence in Class II regulation implications for products entering
the market. We\'ll discuss special controls which are the centerpiece of
regulation under Class II, and recommendations for the panel\'s
considerations.

I\'ll talk specifically today about Surgicel, although we\'re here to
talk about several different types of absorbable hemostats. Surgicel is
a leading product in this category. It is an oxidized, regenerated
cellulose product in different physical forms, including fabric, a
densely knitted fabric, and a fibrillar material.

It\'s used adjunctively in surgical procedures for control of capillary
venous or smaller arterial bleeding and rapidly stops bleeding by acting
as a matrix for formation of a clot that\'s readily absorbed from the
site of implantation with minimal tissue reaction.

And since we have so many surgeons in the room, I doubt that you need
much further detail about this well known product.

Just to briefly mention that the starting material for manufacture of
this is cellulose from wood pulp. Wood pulp contains about 50 percent
cellulose by mass, and in order to arrive at a purified cellulose, it
has to be decomposed essentially and then recomposed into regenerated
cellulose, commonly known as rayon, and that\'s a very common commercial
process.

What\'s not so common is then the oxidation of that product under very
controlled conditions with nitrogen tetroxide to form oxidized
regenerated cellulose, which as you can see has substituted carboxylic
acid functions for alcohol functions at Carbon 6, the glucose molecules
which make up the cellulose.

So cellulose is the oxidation reactant. The major reaction product is
ORC, oxidized regenerated cellulose, which you see on the left. But
there are also a number of other reaction products which turn out to be
significant in some regards.

I call your attention to the two and three ketone ORCs at the top of the
slide, and while the efficacy of ORC is typically related to the main
reaction product, we understand from recent publications that the two
and three ketone ORCs are controlling in respect to degradation in the
body so that the biological absorption of the body is related to the two
and three ketones.

Okay. I\'m going to briefly talk about some of the mechanisms of action
of Surgicel, the physical and chemical attributes which control it, and
the ways in which they\'re governed by existing standards and
specifications for Surgicel. And I\'ll call your attention to the
multiple mechanisms of action that are listed on here, which include
physical and mechanical actions in tamponade, food absorption, swelling
and gel formation, and then surface interactions with proteins,
platelets, intrinsic and extrinsic pathway activation.

These are associated with physical and chemical properties of Surgicel
which are listed in the column in the middle, and then if we refer to
the U.S. Pharmacopoeia, a common reference for attributes that control
pharmaceutical products, which is how this product was originally
approved, we see that USP specifies none of the physical and mechanical
properties listed here. It describes only some of the chemical
properties noted under surface chemistry.

So those attributes are in relation to hemostasis. In relation to
biocompatibility, and important consideration since this is, in effect,
an absorbable implant which is frequently left behind in the body, I\'ve
mentioned just a few toxicity endpoints that are of importance. I\'ve
mentioned some of the Surgicel properties that relate to these
toxicology endpoints, and I\'ve shown here the USP requirements for
these elements that are important to biocompatibility.

And the point of these two slides is to say that there are important
biological interactions of these products that are controlled by
physical and chemical properties, but not well described by U.S.
Pharmacopeia requirements or other standards.

Those of you who use U.S. Surgicel get a consistent product. We are, in
fact, the only manufacturer of oxidized regenerated cellulose product in
the United States, but there are products which claim to be ORC and in
some cases are ORC from different parts of the world.

This is Cellulostat from China and Taiwan. It says it\'s oxidized
regenerated cellulose.

This is ORC from Europe, a product called Curacel, and here is some
analysis of these products, and you can see that I\'ve highlighted in
yellow and italics some differences among these products that could be
clinically important or may just be chemically important, but there are
differences among the products that you can see.

And I\'ve also lined up in the column on the far right the USP
specifications for these, and you can see the areas where it is
controlled and some areas of differences where USP requirements do not
provide controls.

I\'ll call your attention particularly to Cellulostat, which claimed to
be ORC, but according to spectoral identification and identification
tests, it does not appear to be ORC at all.

As we evaluate products in the laboratory, we use a standardized swine
spleen incision model using a standardized incision. We use digital
compression and measure time to hemostasis.

Here you can see Surgicel nu-knit applied. You can see that there is a
fluid absorption, hemoglobin oxidation which causes a darkening of the
material and gel formation or false clot under which true clotting
occurs.

We use this model to compare our own products with other products and to
study innovations in this area.

Here we\'re showing some of the time to hemostasis results that are
achieved when we compare products. Surgicel nu-knit, as I mentioned, is
a heavier, denser knit of product that achieves hemostasis in
approximately three minutes. Two replicates with Surgicel demonstrate
hemostasis in about eight minutes, Curacel in approximately ten minutes,
and Cellulostat failed to achieve hemostasis in greater than 12 minutes.

And so we believe that this model, which is reasonably standardized and
a good indicator of effect on blood clotting, does indicate that there
are meaningful differences in performance among these products.

This slide is here just as a reminder that we\'re dealing with oxidized
regenerated cellulose, which I told you absorbs with minimal tissue
reaction in a very brief period of time. Cellulose itself does not
absorb from the body. The body is incapable of breaking down cellulose
and results in chronic inflammation and nonabsorbed material.

Here\'s a cut and suture two years after implantation, and you can see
the inflammation. This is put in here to call to attention that
cellulose itself, were it to be in completely oxidized, were it to be
unabsorbed, is undesirable for an object. It does not perform or absorb
from the body, and as surgeons, you\'re well aware of its adhesiogenic
and inflammatory properties.

Okay. Last year, in summary, of the information that we provided last
year, Surgicel is, indeed, an absorbable hemostat that has a long
history of safety and effectiveness, as I\'m sure Dr. Krause will tell
you. It has complex chemistry and processing, which create unique
product properties, multiple physiologic interactions required for
safety and effectiveness, and that other ORC products are not equivalent
in terms of time to hemostasis, physical properties and chemical
composition.

And finally, the recognized standard existing in the marketplace, the
U.S. Pharmacopeia, does not address many critical product attributes.

At last year\'s advisory panel meeting, the panel was concerned about
the divergent nature of the technologies. We\'re talking right now about
Surgicel, which is derived from cellulose. Other presenters will talk to
you about gelatin and still others about collagen products.

These are very divergent products in terms of their nature, chemistry,
and potential impacts on surgery. There are issues about inequality of
products that I\'ve just reviewed with you and control over complex
product attributes.

Last year the panel voted four to three to table the action on
reclassification and requested FDA to work with industry to develop
guidance and address concerns, and they requested that this guidance
document be returned to the panel for review before reclassification
recommendation was made.

Briefly I\'ll go through classification, which I\'m sure Dr. Krause will
do. Class I is not under consideration here. It\'s the class of products
where general controls, such as good manufacturing practices or quality
systems regulations are sufficient to reasonably assure safety and
effectiveness.

Class II products are those where reasonable assurance of safety and
effectiveness require general controls, including pre-market clearance
and design control, plus some or all of the following. I particularly
call to your attention development and dissemination of guidelines,
including possible clinical data requirements and others which are
listed.

Class III, the class in which these products currently exist, are not in
Class I due to their medical importance and cannot be assured safe and
effective on the basis of general controls and not in Class II because
insufficient information exists to assure safety and effectiveness using
special controls.

We argued last year that because the U.S. Pharmacopeia did not provide a
full spectrum of requirements in key areas for this product that this
product should remain in Class III, but I think that was not necessarily
the sentiment of the panel here, and the issue that came back is
defining the special controls that were needed to assure these products
remain safe and effective in the future.

Under Class II regulation the process of market entry is decided on the
basis of substantial equivalence. The types of changes which occur under
Class II regulation include changes in chemical composition, physical
form, indications for use, contraindications, instructions for use,
performance specifications, and methods of manufacture and
sterilization.

So unlike the movement of a prescription pharmaceutical that\'s unique
and innovative to a generic form where the chemistry, indications for
use remain identical, that is not necessarily the case as we move from
Class III to Class II in devices. Substantial changes to these products
and their uses can be anticipated and should be anticipated in preparing
this guidance document.

We believe there are also issues about indications for these products
versus data. Surgicel has been on the market for more than 40 years, was
originally supported by clinical studies involving over 500 patients in
numerous surgical specialties, and subsequently there are hundreds of
published reports of Surgicel in a variety of surgical procedures, all
of which combine to provide assurance about its safety and
effectiveness.

Its indication for use is surgical procedures, and as we proceed now to
begin to consider substantial equivalence, this raises questions about
what does it take to be substantially equivalent to a product who is
indicated in the world of surgical procedures.

These are some specific surgical uses of Surgicel supported by clinical
data. They include neurological, cardiac including grafts, vascular
including grafts, gynecologic, orthopedic, abdominal, thoracic, ENT and
others.

While all of these represent hemostasis controls, when you get beyond
hemostasis, there are procedurally related controls, some of which I\'ve
listed. For general surgeons, we have tissue response absorption,
adhesions in wound healing. In neurologic, we have neurotoxicity;
pyrogenicity since the central nervous system is especially vulnerable
to bacterial pyrogens; tissue reactions, absorption, adhesions,
migration, compression of nerves and vessels due to product swelling in
confined spaces.

In cardiac and vascular surgery, we have a tendency to rebleed, tissue
response, compatibility and effectiveness with grafts and sutures,
adhesions and fistula formation.

In gynecologic surgery, consider if you will just ovarian tissue
response and adhesions which are very important in preserving
reproductive capability.

With orthopedic surgery, tissue response, absorption, cyst formation,
interference with bone formation are items that are already listed in
labeling for these products, but need to be considered carefully as we
think about future products that may be dissimilar in the regards I
mentioned earlier.

In ophthalmic, we have tissue reaction, postop. response, plus
neurologic concerns, and in urologic surgery, efficacy in the presence
of urine, absorption, urethral and ureteral obstruction, and calculus
(phonetic) formation.

And the point of going through this is to say we\'ve got these very,
very broad indications. Yet when you get to specific surgical uses,
there are unique and special attributes and performance requirements
that come into play.

So with all of this in mind, what are some considerations? We\'ve got
diverse materials and technologies, broad indications in general surgery
and surgical specialties. These are critical medical applications,
considered neurosurgery and cardiovascular surgery, as well as all of
those that I\'ve mentioned.

These are implantable, absorbable materials of biologic origin, and we
can anticipate significant change in future products.

Our recommendations are that indications be limited to those with
adequate data provided rather than all established uses of products with
a long history of safety and effectiveness. I don\'t know of any other
category of products that could gain an indication as broad as the one
we\'ve just reviewed without substantial data in the relevant specialty
surgeries.

We believe that specialized biocompatibility studies related to the
tissues and uses in surgical specialty are advisable and should be
required and that clinical studies in the general surgery and the
individual surgical specialties, for example, neurologic, cardiovascular
and gynecologic, studies should be conducted as part of the substantial
equivalence demonstration.

Thank you.

ACTING CHAIRPERSON McCAULEY: Are there any questions for Dr. Paulson?

(No response.)

ACTING CHAIRPERSON McCAULEY: We will now move on and hear the
presentation by Ms. Muller.

MS. MULLER: Good morning. My name is Lene Muller, and I\'m representing
Ferrosan. It\'s a Danish company, and we have our products distributed
here in the U.S.

And with regards to the economical interest, I\'m an employee at
Ferrosan in Denmark.

And I\'d like to thank the committee for giving me the opportunity to
represent Ferrosan at this FDA hearing.

I hold the position as Director of Quality Assurance and Regulatory
Affairs at Ferrosan A/S.

The objective of my presentation is to go through the most critical
factors of absorbable gelatin based hemostats; to touch briefly on the
safety profile or surgical and spongosinal (phonetic) products; and have
a look at the existing controls in the USP, Pharmacopeia; and also
address issues of consideration for future regulation or guidance.

The products that are manufactured by Ferrosan is the spongostinal
(phonetic) products which is absorbable gelatin sponge which we\'ve been
producing since 1947 for the European market, and recently in 2002, we
also launched Spongostan powder for the CE market.

In the U.S. market, we have surgical products, which is absorbable
gelatin sponge USP, which is PMA approved back in September \'99.

We also have surgical powder, and the PMA supplement was approved in
September last year.

Does Ferrosan find a reasonable assurance for safety and effectiveness
for absorbable gelatin based hemostatic agent as a Class II device?
Well, the answer is for the existing product, yes, due to the massive
documentation that is in place, due to the PMA registration and the
registration we have in the rest of the world.

For similar or new products or new materials we don\'t find this same to
apply.

You can ask the question: why is the safety profile for this type of
product very good? And there are some answers to that, and I think one
of the very important ones are the clinical and the animal studies, and
those are the toxicity and the biocompatibility.

We also have controls of the animal derived raw materials and the
manufacturing processes, and this is dues to many years of experience
and very thorough knowledge both in production and in use.

When we look at some of the most critical factors for absorbable gelatin
based hemostatics, well, the effectiveness of the product is well
documented through clinical studies, and the toxicity and the
biocompatibility has been conducted in animals with satisfactory result.

And the raw material controls includes a risk assessment of infectious
materials due to the animal origin of the material, and I think that\'s
a very important part when you deal with raw materials of animal origin
because we are all aware of the possibility of viral activity or prions.

And finally, I\'ve mentioned that absorbable gelatin Spongostan and
power are sterilized and packed in material that provide a sterile
barrier, and that, of course, goes for a lot of other medical devices.

But I think the three top are the most critical factors for the
absorbable gelatin based hemostats.

When we look at gelatin as a material, we know that it\'s very sensitive
to slight changes in the manufacturing or sterilization process, which
could create varying product characteristics which lead to product
performance issues. It could be a tendency to swell or absorbency.

When we look at the products prior to, for instance, sterilization or
different types of sterilization or different types of sterilization
cycles or the power used for the Epping sterilization, we know that it
affects the absorbency of the gelatin products.

We are all also aware of some of the other products on the market. There
is instances where formaldehyde is used. We know they\'re used to harden
the product of the absorbable gelatin sponge, and I think that is a very
important implication for tissue compatibility.

When we look at the PMA application that we made, we had performed
clinical investigation for Surgifoam absorbable gelatin sponge USP prior
to the FDA approval. We performed the clinical investigation at
multi-sites with 281 patients involved, and the clinical investigation
included general surgery, cardiovascular surgery, and orthopedic
surgery, and was also compared to an existing hemostatic agent.

The safety and effectiveness for neurological use has been supported by
a study involving 700 cases in the EU. Also we\'ve performed animal
studies using the spinal model for comparing Spongostan and Surgifoam to
the existing product.

We\'ve performed a wide range of toxicity and biocompatibility studies
that are listed here, all with satisfactory result.

We also conducted a risk assessment of the raw material due to the
animal origin, and we find that the anti-infectious treatment of the
Porcine raw material during the extraction of the raw material is very
important.

We also do a very careful selection of raw material sources and
processing. All of the herds and animals are under very careful
veterinarian control and surveillance.

We have traceability from the animals to the raw materials, and we also
do vendor surveillance and audits.

When we receive the material, we go through a very thorough receipt
control.

Based on these critical factors, Ferrosan handles and regards the
absorbable gelatin based products in line with our pharmaceutical
products. We tend to handle them in the same manner.

The product development and the manufacturing is performed in compliance
with the FDA quality system regulation, including design control.

Our manufacturing site is in Copenhagen, Denmark, and it is FDA
registered. We also have had an FDA pre-approval inspection, and we have
routine inspection by the FDA. We send in annual reports and PMA
supplements for changes.

When you look at Spongostan and Surgifoam absorbable gelatin sponge
safety profile, we have a history of more than 50 years of safe use of
Spongostan in Europe. The adverse event per sold unit is very low. It
reflects actually three cases in more than 300,000 sold units, and so
far we have had no product recalls.

However, we think and believe that some of this is due to the current
stringent controls and the clinical validation prior to the FDA
approval.

When you look at the controls in place right now in the USP, when you
look at the gelatin raw material monograph, it is from the national
formula, and the monograph is intended to use for gelatin used in
manufacture of capsules or tablets.

Some of the parameters listed here are relevant also for the implants,
but I think that if the monograph should reflect the purpose of this
type of use of gelatin, there could be other things to take into
consideration when you\'re thinking of the animal origin as an implant.

These are the parameters that are included in the USP monograph for the
Finnish product, the absorbable gelatin sponge, and I think that that
doesn\'t cover all of the critical factors that I just brought to your
attention previously.

When you look at some of the issues that we think that is necessary to
take into consideration, it is the design control, especially the
clinical trials and the animal studies, the toxicity, the
biocompatibility, and the risk assessment of the origin of the animal
raw materials, special labeling, physical performance including water
absorption, swelling, digestibility, reconfirmation, dimension, and
density, and also the stability studies.

My conclusion is if the reclassification is being implemented, I think
that identical materials, if not processed in the same manner, may have
varying product characteristics, and additional special controls are
deemed to be incorporated in the guidance to cover the critical factors,
especially with regards to effectiveness and the animal origin.

Thank you.

ACTING CHAIRPERSON McCAULEY: Are there any questions for Ms. Muller?

(No response.)

ACTING CHAIRPERSON McCAULEY: Thank you, Ms. Muller.

We\'ll now move on to the presentation by Ms. O\'Grady.

MS. O\'GRADY: Good morning. My name is Judy O\'Grady. I\'m the Senior
Vice President of Regulatory Quality and Clinical Affairs for Integra
LifeSciences Corporation.

I\'d like to thank Dr. Witten, Dr. Krause, and other members of the Food
and Drug Administration, Dr. McCauley as Chairman, and other members of
the General and Plastic Surgery Devices Advisory Panel for allowing me
the time to speak at this public advisory committee meeting regarding
reclassification of transitional Class III devices, the absorbable
hemostatic agents and dressing devices intended to hemostasis during
surgical procedures.

The objective of my comments today is to give a brief summary of the
presentation and comments made to this advisory panel in July of 2002
and recommendations to FDA for issuance of final guidance document for
special controls for transitional Class III devices, absorbable
hemostatic agents if reclassified to Class II.

In summary of the comments that were presented, absorbable hemostatic
agents, the current classification in FDA and the United States is
they\'re classified as Class III pre-market approval required, which is
a PMA. In the European Union the classification is the same. They\'re
Class III, and this is due to the fact that the devices have a
biological effect or are wholly absorbed or mainly absorbed.

Devices that are in direct contact with the CNS, heart, and major
vessels, and all devices manufactured using products of animal origin
are placed in the same category.

In Canada, they have a similar classification in the European Union and
as well as FDA. They are surgically invasive, intended to be absorbed in
the body, and again, any type of medical devices incorporating products
of animal origin.

In Japan, a similar classification and data requirements of the FDA and
EU, as well as a clinical trial is required.

Australia, again, similar classification data requirements as FDA and
the EU, and the rest of the world, most countries have very similar
classifications for any absorbable hemostatic agents, and in fact, some
countries classify absorbable hemostatic agents as pharmaceuticals.

Some of the data that was submitted to FDA in support of PMAs for
absorbable hemostatic agents, full line of biocompatibility studies.
I\'m not going to read all of these, but there were some specialized
studies, specifically genotoxicity studies, also studies looking at the
immunogenic potential. Many implantation and absorption studies, and
then additional testing, such as mechanical testing, swellability,
compression, and that is if these products are going to be used around
vessels or in and around the spinal cord so that as they absorb fluid,
that they don\'t apply any type of compression.

And then if it\'s a product of animal origin, viral safety studies, as
applicable.

Animal studies, implantation studies evaluating rate of absorption,
foreign body reaction, incidence of infection, incidence of adhesion
formation, and incidence of any other tissue reaction, and hemostatic
studies in an animal model.

Clinical trial data. There have been multiple clinical trials conducted
on these product lines. Some studies have involved up to 550 patients
looking at general cardiovascular, neurosurgical, OB-GYN, urological,
burn and plastic surgery procedures and the controlled population being
of other marketed hemostatic agents.

Some of the parameters that were evaluated during these studies were
time to hemostasis, adherence to the site, pliability, handling, overall
performance, and then looking at postoperative bleeding, hematoma
formation, and postoperative evaluation evaluating adverse events.

Manufacturing. These products are manufactured in compliance with FDA
quality system regulations, which are good manufacturing practices.
Facilities, FDA registered, ISO 9001 certified.

Since these products are PMA products, pre-approval inspection is
required, and also there\'s routine inspections of the manufacturing
facility for compliance with FDA quality system regulations.

Annual reporting requirements to the PMA and PMA supplements for any
significant changes to the process, procedures and testing of the
products.

Recommendations to FDA regarding reclassification. Recommend strongly
that if FDA reclassifies absorbable hemostatic agents from Class III to
Class II, that it includes special controls. Class II devices are
defined in Section 513 of the FD&N Act to include any devices for which
reasonable assurance of safety and effectiveness can be obtained by
applying special controls.

Only general controls will apply to Class II devices unless special
controls are established by regulation. Special controls may include
special labeling requirements, mandatory performance standards, patient
registries, post market surveillance.

Reclassification should only occur with issuance of an FDA final
guidance document to assure continued safety and effectiveness profiles.
Current FDA approved PMAs, PMA supplements remain in place and viable,
and that the confidential information, such as manufacturing data,
remain confidential, not available for release under FOI.

Guidance documents should include, of course, standard information and
description of the devices and the principle of action of each of the
device components. If collagen is a component of the hemostatic agent,
it should comply with FDA guidance document in medical devices
containing materials derived from animal sources.

Looking at the type of collagen, tissue, and species, country of origin,
processing of the collagen, viral inactivation studies, and the BSE/TSE
risk analysis.

Biocompatibility testing should be in accordance with FDA guidance. Use
of international standards, ISO 10993, looking at the battery of
biocompatibility studies, but also including mutagenicity studies,
immunogenic potential, biodegradation studies, and other studies as
indicated by the type of biomaterial.

[In vitro]{.underline} as well as [in vivo]{.underline} hemostasis
studies.

Preclinical studies should also include implantation to look at the rate
of absorption, foreign body reaction, incidence of infection, incidence
of adhesions, and incidence of any other tissue reaction.

Clinical experience. There should be a summary of any clinical
experience. The sponsor should demonstrate that the hemostatic agent
will perform as safely and effectively as another legally marketed
absorbable hemostatic agent.

Clinical data for hemostatic agents composed of materials for which have
not been previously used as implantable, absorbable hemostatic agents
should be provided from a multi-center clinical trial.

Clinical data should be obtained for high risk surgical procedures where
postoperative bleeding adverse events are especially critical, such as
neurosurgery, ophthalmic surgery, and others as indicated.

Clinical data should demonstrate that hemostatic agent performs
similarly when compared to another legally marketed hemostatic agent.

Clinical studies should evaluate if indicated time to hemostasis, days
of adherence, ease of handling, and critical, which would be
postoperative, evaluations of postoperative bleeding, infection,
hematoma formation, wound dehiscence and any adverse events.

Sterilization should include the method of sterilization validation
studies. A sterility insurance level of ten to the minus six, and
description of the monitoring of the sterility for each lot and
description of the packaging or the product to maintain sterility.

Again, on sterility, if radiation sterility, the dose should be
indicated. If the method is ethylene oxide sterilization, the maximum
levels of ethylene oxide, chlorohydrin, and ethylene glycol residues
which remain in the device should be identified and comply with the
maximum limits proposed in the [Federal Register]{.underline} and also
in AAMI, ANSI, ISO guidance document 10993.

Pyrogenicity testing. The pyrogen level of the final sterile device
should be less than .06 endotoxin units per mL, and this is specifically
for any neurosurgical use or in contact with cerebral spinal fluid.

Product expiration testing, data should support the expiration date for
the product and should be submitted, and stability studies should
monitor the critical parameters of the device to insure that it will
perform safe and effectively over the lifetime of the product.

Manufacturing should comply with FDA quality system regulations,
including design controls. Submission should contain information on the
device reagents and processing, device specifications, product release
testing, residual levels of manufacturing agents, such as any
leachables, residual levels of heavy metals, pyrogen levels, packaging,
sterility.

Summary. Reclassification from Class III to Class II should only be with
special controls and an FDA guidance document in place to insure
continued safety and effectiveness profiles. The current approved FDA
PMAs for absorbable hemostatic agents should remain in place.

Specialized clinical and preclinical studies should, at a minimum,
address concerns related to use and surgical specialties, such as
neurosurgical, cardiovascular, and other specialized procedures.

Thank you very much.

ACTING CHAIRPERSON McCAULEY: Does the panel have any questions for Ms.
O\'Grady? Yes.

DR. LoCICERO: Your company has made a specific recommendation for
pyrogenicity level for neurologic use. Do you make recommendation for
pyrogenicity levels for other uses?

MS. O\'GRADY: Yes, I do. The pyrogen level, I know the collagen
hemostatic agents manufactured by a company all meet the level for
neurosurgical use, which is .06 endotoxin units, but I believe there
could be some other requirements if the product was not going to be used
in neurosurgery for endotoxin units. But they all should be
nonpyrogenic.

ACTING CHAIRPERSON McCAULEY: Are there any other questions from the
panel?

(No response.)

ACTING CHAIRPERSON McCAULEY: We will now hear the FDA\'s presentation.

Thank you, Ms. O\'Grady.

MS. O\'GRADY: Thank you.

ACTING CHAIRPERSON McCAULEY: We will now hear the FDA\'s presentation by
Dr. Krause.

DR. KRAUSE: Before I start, I\'d like to welcome all of you, especially
Dr. McCauley, panel members, Dr. Witten, attendees from industry,
attendees from the FDA and all other attendees who have taken their time
to attend this meeting of the General and Plastic Surgery Devices Panel.

My name is David Krause. As well as being the Executive Secretary of
this panel, I\'m a reviewer in the Plastic and Reconstructive Surgery
Devices Branch in the Division of General Restorative and Neurological
Devices, and I have been the lead reviewer on quite a few PMAs for the
absorbable hemostatic agents.

Today FDA would like the panel to consider reclassifying the absorbable
hemostatic agents from Class III to Class II.

Okay. Basically I will focus on the following topics. I\'d like to begin
with a general definition of absorbable hemostatic agents as it is now
in the 21 CFR. I\'d like to go on to FDA\'s beliefs as to why Class II
would be appropriate for hemostatic agents. I\'d like to give a brief
history of absorbable hemostatic agents and summarize what was the
panel\'s recommendation at the last panel meeting.

I\'d like to then discuss special controls document, present MDR
reports, and what risks FDA feels need to be addressed, and finally,
give you FDA\'s proposal for the absorbable hemostatic agents.

The 21 CFR, which is the Code of Federal Regulations, at this time
defines absorbable hemostatic agents as a device intended to produce
hemostasis by accelerating the clotting process of blood, and then it
says it is absorbable, and it\'s presently Class III.

That\'s a pretty nebulous and very general description of the hemostatic
agents, but I think it\'s intentionally so, so that products that fit
that general description can be looked at for the use as a hemostatic
agent.

FDA believes that the reclassification to Class II is appropriate for a
number of reasons, but the two most important and, I think, the most
appropriate or clearest reasons are these two, which basically are that
the device specifications and the performance characteristics, which
includes bench testing, animal testing, and clinical data that are
needed to evaluate and control the safe and effective use of these
devices, are well understood after years of experience.

Secondly, down classification meets the FDA\'s mandate to apply the
least burdensome approach to regulating medical devices. One of the
factors that\'s taken into account when the FDA considers Class I, Class
II, or Class III or a number of the factors is kind of a combination
that includes, number one, the risks associated with the device, but
also the experience, and there are devices that are Class III and
require a PMA that are not very risky devices, but how they work is not
very well understood.

These devices, how they work, you know, with the length of time that
they\'ve been around are fairly well understood by the industry as well
as the agency when it comes to regulation.

A brief history of the absorbable hemostatic agents is that up until the
device amendments were signed by President Ford in 1976, these were
regulated as drugs. They required a new drug application to the Center
for Drugs and were reviewed as drugs and those types of studies that the
Center for Drugs would use were the types of studies that were done in
order to assess these products.

After the signing of the device amendments, a number of devices \-- I
think there were about 16, but I\'m not sure \-- were transferred to the
Center for Devices, and most of them I think wound up in Class III for
regulation via pre-market application or what we call a PMA. The
hemostatic agents were one of those.

If you look back through history and you look at the products that have
been marketed in the United States as absorbable hemostatic agents,
Oxycel, Surgicel, Avitene, and Gelfoam have the oldest applications.
Oxycel and Gelfoam have been on the market the longest, both since the
early to middle \'40s. Surgicel was approved by the Center for Drugs in
1960. Avitene was approved in 1976.

But all of these, as you can tell by the N number, were submitted to the
Center for Drugs as new drug applications.

Later, as the Center for Devices began to regulate these products, you
notice the P numbers appear, and Avitene, another form of Avitene,
Collastat, Superstat, Instate were the earliest products to go through
the PMA process at the Center for Devices.

These were followed closely by Helistat, Novacell (phonetic) or Novacol
\-- excuse me \-- Hemostagin and Surgifoam, and finally FloSeal and
CoStasis.

Oxycel, which was on the first slide, is no longer being sold in the
United States. Superstat is also no longer being marketed in the United
States. Hemostagin, which was on the slide previous to this one, is no
longer being marketed, and an interesting fact about these two products
is that both of these incorporated the licensed bovine thrombin as part
of this product. So these were \-- the FloSeal matrix and CoStasis, both
included thrombin as a component, and they both used the licensed form
of bovine thrombin.

There was a panel meeting July the 8th, 2002 \-- I\'m sorry. It says
2003 up there \-- which discussed this topic. At the time the discussion
on reclassification was tabled so that a contents of a guidance document
could be evaluated.

Each of you have got basically what we would intend to put into such a
guidance document in the memo that we sent you, as well as posted on the
Web for anyone else to look at.

Basically the purpose of a special controls guidance document is to
express or to convey to industry what is the current thinking within the
agency at this time. These types of documents are subject to updates,
and they\'re not considered requirements per se, but they do lay out the
kinds of information that the agency believes needs to be provided in
order to establish substantial equivalence.

In general, a special controls guidance document would be laid out as
I\'ve shown here. We\'ve provided you with the suture guidance document
as kind of a guide, and if you noticed, it was slightly different, and
you know, these undergo constant modification as to how the agency
thinks these sections should be labeled and, you know, types of
information.

But each update is intended to be better than the last. So hopefully it
happens that way.

Section 1 would be where general information, including a brief
explanation of why the guidance document has been written, a device for
which the guidance document has been written, references to the [Federal
Register]{.underline}. It identifies previous guidance documents that
are superseded by this guidance document and things like that would be
in Section 1.

Section 2 would be where the FDA believes that special controls combined
with general controls are sufficient to provide reasonable assurance of
safety and effectiveness and includes a brief summary of other sections
by stating where you would be able to find information on regulations,
risks, things like that in the guidance document.

Also, the background section would identify Web sites and other guidance
documents that would give advice on the submission of a 510(k),
including a rationale for least burdensome approach to device
regulation.

The third section, which is the content and format of an abbreviated
510(k) submission, is a boilerplate section which only talks about
abbreviated 510(k)s and really wouldn\'t apply to this type of a 510(k).

Section 4 is the scope section where it identifies products,
regulations, the product codes, and other things that are specific to
this particular product type.

Section 5 of the guidance that we\'re proposing for the absorbable
hemostatic agent products at this time would be the section where we
would list the risks to health. Here FDA would identify the specific
risks to health that are generally associated with the use of an
absorbable hemostatic agent and also identify the measures that are
recommended to mitigate these risks.

In a few minutes I\'ll be addressing risks and mitigation, and you\'ll
see that table there.

Section 6 is a very detailed section which discusses the material and
the performance characterization, and I don\'t want to go through that
in great detail. That\'s in the handout that we had sent you and the one
that we posted up on the Web, but I think the industry representatives
did a really good job of pointing out the types of criteria that would
go into that section.

Basically it would talk about material or information on the material
itself, you know, the exact questions that were posed. You know, is the
herd regulated? What are the BSE/TSE, you know, transmissible agents,
viral inactivation? Are all of those things addressed? That would be in
that particular section.

There would also be manufacturing information which would take into
account the types of information that Dr. Paulson was talking about with
Surgicel, where the pH and the degradation of the material and all of
those types of things would be monitored through careful studies and
would need to be submitted in a 510(k) to let us see, you know, that
that information is understood.

Sterility, the USP definition, does or does not the product meet that?
Those types of things would all go in that section.

Final device information, is it cross-linked? Is there a cross-linking
agent? How much? How much is residue?

For instances, some of the older hemostatic sponges maybe have been
cross-lined with glutaraldehyde. So some glutaraldehyde information
would then be necessary because everyone knows that glutaraldehyde is
toxic.

Shelf life information would go into that section, et cetera. These
would be all of the pre-clinical types of bench top testing data that
would be assessed in Section 6.

Section 7 would deal with animal testing, and here for example, I can
just read you what\'s in there at this point. It says, \"FDA recommends
that you provide animal studies modeling each surgical application for
which the absorbable hemostatic agent is to be indicated. For example,
for general surgical use, we would recommend that animal testing include
arteriolar, venous and capillary bleeding from various tissues and
organs. For the arterial bleeding we recommend that you provide specific
data to support this indication.\"

And then other similar indication we would want people to monitor
infections, hematomas, coagulopathies that are as a result of the use of
the hemostatic agent, increased wound healing times, et cetera. That\'s
the type of information that we would want to see in the animal testing
section.

Finally, Section 8 deals with clinical testing, and there\'s a long list
of the types of information that we would be looking for there. I\'ll
just go through a little bit of it.

It says, \"A clinical study should be designed to compare the safety and
effectiveness of the new device to a legally marketed predicate device.
In most cases such comparisons should be made between absorbable
hemostatic agents manufactured from similar materials with similar
indications for use.\"

So if somebody were manufacturing a device made of regenerated oxidized
cellulose, considering that there\'s only one on the market in the
United States, we would expect to see clinical data comparing that new
product to the predicate product, which in that case would be Surgicel.

Also, a study should be conducted at enough institutions to assure that
the observations made regarding the safety and effectiveness of the
devices will be significant in spite of technical and procedural
differences likely to be encountered when the device is marketed. And
that section goes on and gives basically that type of advice.

Section 9 of the guidance document at this time is the section on
sterility, which is a boilerplate section which basically refers to
guidance documents that are in existence for how to assess sterility and
to, you know, validate, et cetera.

I think Ms. O\'Grady did a really good job of covering the kinds of
information that that guidance document asks for.

Biocompatibility is also boilerplate. It refers to the same document
that Ms. O\'Grady pointed out, which is the ISO 10993. The section on
labeling, again, is boilerplate. It includes the suggestions for
prescription use devices, that they must carry the statement caution
\"federal law restricts this device to sale by or on the order of a
physician.\" In most cases these would be being used in the surgical
theater. So it\'s not really something that\'s going to be sitting on a
shelf in a drugstore.

And the other advice is given on instructions for use, and the
instructions should include adequate information regarding the
contraindications, warnings, and precautions in order to address the
identifies risks to health and a clear explanation of the device
technological features and how it is to be used.

And as a sample of that type of labeling, I gave you the labeling for
Surgifoam, which was discussed in one of the previous industry
presentations so you have an idea of the type of labeling we\'d like to
see for these devices.

In preparation for this discussion, I reviewed the MDR reports as listed
in the FDA tracking system, and it\'s important to note that up until
1992 there was no real tracking system. Beginning in 1992, the tracking
system was voluntary up until 1996 at which it became mandatory that
medical device failures, events that were a problem were reported to the
FDA.

So you know, you can guess that a lot of this information is under
reported. However, I think what I\'m pointing out to you here is what\'s
been reported to the FDA, and when you consider that there probably have
been millions of uses of these devices during this time, there is an
amazingly small amount of what we call medical device reports which
report problems with the device as perceived by those using them, you
know, surgeons, hospital staff, et cetera.

This list is complete up until June 13th, 2003, which is when I accessed
the system to get the data.

There were more than the 59 reports that I have here, but as I read
through them carefully, I noticed that some of them were for bone wax,
which is not considered an absorbable hemostatic agent. It doesn\'t have
the same product code. At this point it\'s an unclassified device
that\'s somewhere else, but I think by mistake some of those were put
down here. So those I eliminated.

And I also eliminated devices which were used for femoral artery closure
which have their own product code and somehow got lumped in with these.
I think there was maybe like 50 of those, and I\'m not sure why they put
in there, but I went through and I weeded those out.

And so this is what I came up with, which it could be off by a few in
either direction, but I think it\'s a fairly good estimate of the MDRs
reported, and you can see hemostasis failure up until a couple of years
ago, there was only one reported, and the most recent ones, I think, is
people expect more from these newer hemostatic agents, and they are
trying them on a lot of places where they before wouldn\'t have used
them, and so I think there are a few more failures in the last couple of
years.

Deployment failures, those are basically the person can\'t figure out
how to put the thing together. So I thought that was interesting.
That\'s one of the main ones. So that\'s not really a problem with the
device. It\'s a problem with somebody being all thumbs, you know, like
Richard Nixon or something.

Abdominal infection, sinus infections, paralysis. In most cases this is
probably due to off-label use. Most of these products are labeled very
carefully that you shouldn\'t stick them in small spaces because they
swell, and these are probably where people did just that. They stuck
them in small places. The device swelled. There was some nerve damage
and paralysis follows.

Oral infections, granulomas, abscesses. As you can see, there\'s very
few of these reported.

Additionally there were a number of other foreign body reactions,
allergic reactions, et cetera, you know. Like I said, I found a total of
59, and I could be off by ten either way, but I think it\'s a pretty
accurate portrayal of what\'s out there in the MDR system.

Okay. By searching the literature, going through the MDR reports,
reading through the labeling for absorbable hemostatic agents that are
presently marketed, and also looking through the SSEDs of PMAs that are
in our files and on record, I was able to identify the following
potential risks, and basically we are proposing the control that\'s in
the right-hand column.

So for uncontrolled bleeding we believe that animal studies and/or
clinical studies can be used to assess the hemostatic capability of the
products, hematoma formation, again, animal studies, product labeling,
infection and fever, animal studies, product labeling, sound dehiscence,
product labeling, foreign body reaction, inflammation, edema, granuloma.
As you can see, these are some of the proposed methods.

Adhesion formation, failure to be absorbed, interference with methyl
methacrylate adhesion. That\'s kind of an old one that\'s been around
for a long time if you go through the labeling of these devices. It
turns out that some of the collagens may inhibit the adhesive properties
of the methyl methacrylate.

Aspiration into transfusion filters, and we believe most of these or a
lot of these can be addressed with product labeling.

Product failure due to anticoagulation therapy. Again, that\'s something
that can be assessed or at least surgeons who are going to use the
product can be warned in the labeling that they should be careful if the
patient is on anticoagulation therapy.

Some of these devices actually work quite well on patients who are on
anticoagulation therapy, but still it\'s a good warning to make doctors,
surgeons keep an eye on patients.

Others were, you know, using in small spaces; the possibility of
embolization if somehow accidentally the device is injected into a blood
vessel. Device swelling, allergic reactions, again, those all can be
controlled for.

Products with thrombin. Every product that has thrombin in it has a
large boxed warning, and the boxed warning is a recent addition to
thrombin, and it\'s because the potential for cross-reactivity of
antibodies that are made to the bovine factor Va cross-reacting with the
human factor Va and the coagulation cascade and thus resulting in a
potential coagulopathy.

In the two products that we looked at that had thrombin, we saw none of
this, but we do require the boxed warning to go on the label for people
to be on the lookout for this.

And the second additional risk was all of the problems that we saw where
people were complaining that they couldn\'t put the devices together
were for the two latest PMAs, which were syringe type devices that
required some putting together and apparently they didn\'t read the
instructions or whatever and couldn\'t put the device together, but
it\'s not a big deal.

So the FDA\'s proposal is that the absorbable hemostatic agent product
be reclassified to Class II, and we are recommending a special control,
and in this case it would be a detailed guidance document.

The present listing for absorbable hemostatic agent is the one I read
you the definition before. It\'s Class III, requires a PMA. The proposed
new identification would be absorbable hemostatic agent, surgical. The
definition would remain the same, and it would be Class II with the
special control guidance document as previously indicated.

That\'s the end of my presentation. During your discussion these are the
questions that we would like you to discuss, and we can read them later
when you get to that discussion.

If anyone has any questions, I\'d be glad to answer them.

ACTING CHAIRPERSON McCAULEY: Are there any questions from the panel for
Dr. Krause?

(No response.)

ACTING CHAIRPERSON McCAULEY: Dr. Krause, will you now read the FDA
questions? We will not address the questions at this time, but will
address them in our later deliberation.

DR. KRAUSE: Okay. The questions are as follows:

Please discuss the proposed reclassification of the absorbable
hemostatic agent and dressing products. Please also discuss what
descriptive information and intended use should be included in the
classification identification.

Second, please discuss the risks to health for the absorbable hemostatic
agent and dressing devices.

And, third, are there any other risks to health for these devices that
have not been identified?

Thank you.

ACTING CHAIRPERSON McCAULEY: Thank you, Dr. Krause.

This is a good time to take a break. We\'ll come back in 15 minutes.

(Whereupon, the foregoing matter went off the record at 10:02 a.m. and
went back on the record at 10:25 a.m.)

ACTING CHAIRPERSON McCAULEY: We will now proceed with some additional
time for open public comment. 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 this meeting disclose whether they have
financial interests in the medical device company before making a
presentation to the panel. In addition to stating your name and
affiliation, please state the nature of your financial interest, if any,
and disclosure if anyone besides yourself paid for your transportation
or accommodations.

Are there any individuals wishing to address the panel at this time?

(No response.)

ACTING CHAIRPERSON McCAULEY: Since there are no other requests to speak
in the open public hearing, we will continue with the open committee
discussion and the FDA questions.

We will start with the panel deliberation portion of this session. Are
there any comments currently from the panel?

Dr. Miller, do you have any comments you would like to add at this time?

DR. MILLER: I think I was present for our last discussion of this. I
remember it very well, and I remember being made nervous by some of the
presentations about the manufacture of these devices and the possibility
of less thorough and complete standards being applied by companies.

But I think that with the guidelines that we discussed I feel very
comfortable with the sort of parameters that were listed for a guidance
document.

ACTING CHAIRPERSON McCAULEY: Are there any other comments from panel
members?

Dr. Blumenstein.

DR. BLUMENSTEIN: Well, I feel more like a consumer rep. here than a
statistician, but I guess I have two concerns. One is the system by
which events are recorded, the data that was put up from I forget the
name of that system.

DR. KRAUSE: Oh, the medical device recording, MDR?

DR. BLUMENSTEIN: Yes. It\'s very difficult for me to assess the meaning
of the data because, number one, I don\'t have a denominator and, number
two, I have no idea regarding the tendency to actually report events
that do happen and to properly classify them.

Is there any way I can get a better description of that database and
what requirements there are for it and any assessment about the
possibility of missing a significant number of events or anything like
that? Can anybody speak to that?

DR. KRAUSE: That\'s actually a good question, and we anticipated last
time that that question would get asked, and we had somebody from that
group over here. It\'s the office, I think, of \-- what is it? I can\'t
remember the name of it. Surveillance and Biometrics actually, and there
was somebody here that was ready to explain all of that, and since
nobody asked last time, we didn\'t ask them to come this time and now of
course, the question. So it\'s Murphy comes back and gets us once again.

DR. WITTEN: Well, I think that we can though say something about that
system. So I\'ll say something to address your question, which is that
system really isn\'t designed to look at incidence rates. It isn\'t
designed to look at rates of events because there is certainly a
question about what gets reported, and there\'s certainly, you know, a
question about how many of these devices are used, and it\'s a large
number.

I think what that system is primarily good for is for identifying new
types of adverse events that people don\'t expect. So, in other words,
in general I think if somebody uses these products and they \-- they may
or may not work as well as the physician would like to see it work, but
if the types of problems that he or she is having with the use of the
products is within their experience of what, in general, they would
expect with this product, in general, that wouldn\'t be something that
that physician would tend to report.

So what we look for from that system is more identification of new types
of things. So when Dr. Krause presented that list, it is more with an
eye to looking at whether or not FDA has been able to identify the known
risks with the device to make sure that the special controls that are
proposed in the guidance document address all of the risks that were
identified.

And I don\'t think that there was any intention to draw any conclusions
about how frequently adverse events occur with these products. You
wouldn\'t get that from the MDR system.

DR. BLUMENSTEIN: Yeah, and I didn\'t expect that either because I\'m
aware of the voluntary nature or more or less voluntary nature of this,
but there\'s issues about attribution and whether, you know, a
particular event that might happen in a clinic somewhere, whether it
actually gets correctly attributed, if there is that concept and so
forth.

But really it\'s my second question that reflects back on this first
question that\'s of more concern, and you raised the issue about whether
the design of that system is to identify new things that are happening.
So I gather the data is presented and you look at the particular things
that have been reported, and you\'re not surprised by what\'s there, and
you\'re pleased that there\'s not something that\'s new and unusual or
like that.

My second question really has to do with, you know, what kinds of
changes in technology over the next few years are going to lead to
possible interactions with these devices, perhaps new drugs used during
surgery or new techniques used during surgery or immediately post
surgery that might interact with the absorbability or tendency for
infections.

I don\'t know. I\'m just making things up. I\'m just a biostatistician,
but are there any concerns in those directions and whether this system
will be able to pick those up in sufficient time to react to them and so
forth?

DR. WITTEN: Well, I think that that might be a good question to ask your
fellow panel members in terms of what kinds of things they might be
concerned about, but I guess, you know, one question I would have would
be as far as the reclassification whether that proposed reclassification
\-- whether or not, you know, Class III or Class II, we would be likely
to get the type of data pre-market to address those kind of questions
differently.

In other words, is there a difference for that kind of question between
the two classifications?

I don\'t really know. I can imagine some situations where the MDR system
wouldn\'t pick up some interaction or would pick up others just because,
you know, a lot of times you have something happen where if the event is
remote from the application site, it\'s probably less likely to be
reported as an adverse event.

In other words, if there were something that happened systemically to
the patient, I can\'t imagine what it would be that were related to an
interaction, yes, people would be less likely to report it. If it was
something that happened at the site, they\'d probably be more likely to
notice it, but it\'s really hard to address that except to say I\'m not
sure how that relates to the classification, which is really a question
of what kind of information, you know, we need. It relates to what kind
of information we need about the product to put it on the market and
regulate it on the market.

I\'m not sure what difference the answer would be depending on the class
of the product.

DR. BLUMENSTEIN: Yeah, I appreciate that the reclassification may not
make any difference with respect to the interaction with other
technologies and other techniques and so forth, but my issue is whether
the system is sufficient to guard against those kinds of things because
my sense is that the technologies are really changing quite rapidly in
terms of things that are used during surgery and so forth, or at least
that\'s what I see from my surgical friends.

And so that\'s the source of my question, is whether you feel like that
there\'s sufficient mechanism in place to identify things that could be
rather devastating, given the wide use of these devices.

DR. WITTEN: I don\'t think I have anything to add to what I have already
said.

DR. KRAUSE: If I could add, the warning label that\'s on products with
thrombin and thrombin packaging itself was something that was picked up
through the report, not the device reporting system, but reporting
systems that showed that there was a very small subpopulation within the
general population of people treated with thrombin who did develop these
antibodies, and so the response to that was to put this warning on the
labeling to warn, you know, the physician in charge to keep an eye out
for these coagulopathies which could be induced by using thrombin.

And it\'s very rare, but it was picked up through some kind of a, you
know, monitoring system. So that\'s an example of the system working.

ACTING CHAIRPERSON McCAULEY: Sorry. Are there any other comments?

DR. CHOTI: Could I make a comment, Robert?

This question I brought up last time perhaps to address to Dave is just
still I think the definition or identification is still somewhat
nebulous, and, Dave, you mentioned that there\'s kind of a reason to
keep it vague, and I think that makes sense, but I\'m still concerned
that this idea of absorbable hemostatic agent intended to produce
hemostasis is, as we move into the future with new products and perhaps
polymers, over the years it has been fairly consistent, subtle
variations perhaps in these products, but recently now with the addition
of thrombin and autologous platelets, there will be new devices, perhaps
polymers or that are completely distinct.

Similarly, the vibrant sealants which have a different role, the Tissiel
(phonetic) and HemoCure products and so forth may have a different role
and don\'t fit into this category, but they are absorbable. They do
provide hemostasis, and are there opportunities to get other devices or
other products to fit into this classification based on this definition?

DR. KRAUSE: Do you want to answer that?

DR. WITTEN: Yeah. You know, if a new product with the same intended use
in a new technology, if a manufacturer wants to submit an application
for something that\'s got a new technology and the same intended use,
then, you know, we would look at the product and look at the comparison
to the product that\'s on the market and see whether the kinds of
questions that we would, you know, ask about the differences in
technology and what effect it has on performance could be addressed by
data, and so, you know, we have a flow chart algorithm to go through.

You know, what are the questions that this new technology raises and can
it be addressed by data?

So that, as Dr. Krause said in his presentation, that data, you know,
could be benchtop characterization for a newer technology that might
well not be enough. That could include animal data, and if that isn\'t
enough, then that can also include clinical data.

So we do see, you know, clinical studies as part of the potential
spectrum of data that we would look at to evaluate what effect a
difference in technology has on whether or not we can clear the product
as substantially equivalent in performance to the products on the
market.

ACTING CHAIRPERSON McCAULEY: Are there any other issues that the panel
would like to discuss?

Dr. Leitch.

DR. LEITCH: Do the details of the guidelines address the pyrogenicity
issues that were raised by Ms. O\'Grady in terms of that level of
detail?

DR. KRAUSE: Yes, they do.

MS. BROWN: I wanted to make one comment about pyrogenicity. I know that
there\'s a level for neurosurgical use, but I believe for medical
devices there\'s a less stringent level for general surgical use, and so
we probably should have the two levels represented.

DR. KRAUSE: Just to address Ms. Brown\'s comment, when the product is
indicated for the general surgical use, which excludes neurological use
and we go by the regular standard for medical devices; if, however, a
company would like us to remove the neurological exclusion or add a
neurological indication, then we would go to the pyrogenicity level,
that is, you know, for neurological use, which is the .06.

ACTING CHAIRPERSON McCAULEY: Other issues, other questions?

(No response.)

ACTING CHAIRPERSON McCAULEY: At this point we will begin the focused
discussion of the FDA questions. Can we have the questions placed on the
screen for us?

The first question proposed to the panel states: please discuss the
proposed reclassification of absorbable hemostatic agent and dressing.
Please also discuss what descriptive information and intended use should
be included in the classification identification.

We\'ll start with Dr. Lanzafame.

DR. LANZAFAME: Bear with me for a moment because I\'m new to the panel,
but from my vantage point as an end user and a researcher what I would
like to see most is what the composition of the agent is, what its
indications, contraindications and so on are included in the labeling.

The issue of pyrogenicity, what are the particular cautions? Is there
cross-reactivity with other materials? And are there any special use
applications? For example, insertion in minimally invasive strategies
and so on may render the material difficult to use.

From the perspective of the quality control information, I believe that
the information that is required and requested in at least the portions
of the controls guidance document adequately cover those sections. So I
won\'t discuss those further at this time.

ACTING CHAIRPERSON McCAULEY: Dr. Leitch.

DR. LEITCH: I think that the proposed reclassification is not
unreasonable, but with the special controls guidance document. I think
that answered a lot of the concerns I had with respect to ongoing safety
for new products that come into the field that resemble or are not
exactly the same.

And then with respect to the intended use issues, I do think the
differences at different sites need to be carefully explicated and that
as new devices come up that there be the requirement to address those at
the individual sites where specific problems have been recognized.

And it seems to me that most of the, you know, serious complications
that are realized relate to some of these special sites, such as the
neurologic sites and nerve compression. There\'s been little data to
suggest there are significant antibody reactions.

So I think one of the biggest things is this application at different
site, that that needs to be \-- attention needs to be kept to that. I
think the general surgical use doesn\'t seem to be as much an issue as
some of the other special sites.

ACTING CHAIRPERSON McCAULEY: Dr. Choti.

DR. CHOTI: I agree that I think with these special controls as outlined
I feel better about the reclassification to the Class II in this
situation.

I think there are some variability in the special controls with each
device. I think that as far as the intended use and descriptive
material, I do think that Ann suggested that it needs to be site
specific where it\'s applied and also with each different device there
may be some variability based on how different it is and what some of
the information, clinical or animal data, suggests as to what
descriptive materials.

So that should be defined based on the material, but I think if that\'s
clearly specified in the special controls, I think that it\'s reasonable
to move ahead with that.

One question I do have regarding advice recommendation, how strict are
some of these things in the special controls using the words
\"recommend\" something or \"advise\" something?

DR. WITTEN: Is what you\'re asking what does the FDA with this special
guide and how do we use it?

DR. CHOTI: Right.

DR. WITTEN: In terms of how we use it, the classification process and
the guidance document address or list the kinds of risks that we see
with these products, you know, that we\'ve experienced, and the guidance
document gives a mechanism by which the sponsors can address those
risks.

Now, they may choose not to follow exactly what\'s in the guidance. What
they need to do is address the risks that are listed in the guidance.

So if there is some other way that they can do it, for example,
sometimes we might list or suggest some specific kind of testing, and
the sponsor may choose to do other testing. If we think that that
testing also addresses the risk that\'s identified in the guidance
document, then we would review that.

So it\'s an option. You could think of it as a list of risks that have
to be addressed and a menu of options, you know, suggesting what we
think is the best way to address or a way to address those risks.

And I think in general, you know, you have to look at these guidances
and take them fairly seriously because, you know, it\'s a path. It\'s,
you know, an algorithm to get to market for their product.

ACTING CHAIRPERSON McCAULEY: Dr. Blumenstein.

DR. BLUMENSTEIN: I have nothing to add.

ACTING CHAIRPERSON McCAULEY: Dr. Doyle.

DR. DOYLE: I think that most of the things that I have to say have been
said, too. I think that the thing that struck me most as a consumer rep.
is the fact that the guidelines, I think, have to be very clear that
because of the differences in the materials of which these are made, if
you\'ve seen one, you\'ve seen one. And I think it\'s very important
that the guidelines are specific, and they do seem to be covering the
various types of material, particularly, of course, those made from
animal, tissues from animal origin.

ACTING CHAIRPERSON McCAULEY: Ms. Brown.

MS. BROWN: I agree that down classification in Class II with special
controls would be appropriate. The quality system regulations are pretty
good at controlling the manufacturing processes and assuring that as
changes are made, design controls make sure that the products are
reasonably safe and effective.

The biocompatibility standards for these products are pretty well
understood and described.

I think Dr. Paulson covered very nicely that effectiveness can be looked
at pretty carefully in animals, in the animal models. That\'s understood
pretty well.

With respect to intended use, I don\'t know if \-- was this the time to
talk about intended use or were we going to \-- okay.

I think that out of the blocks the intended use should be the general
intended use that was the kind described for Surgifoam with an exclusion
for neurological ophthalmic and neurological, unless data is collected
specifically to take those exclusions out.

I think all of the products that have come to market even under PMA have
had those exclusions and have had to come up with some kind of specific
data to address those, and I think that\'s still a good idea.

ACTING CHAIRPERSON McCAULEY: Dr. Miller.

MS. BROWN: And those are my comments.

ACTING CHAIRPERSON McCAULEY: Sorry.

DR. MILLER: I think that these products have been around for so long and
there aren\'t a lot of ambiguities about how they work or what happens
to them. I think that it\'s very reasonable to lower their level of
regulation that they\'re subject to, and I think that the guidelines
that have been suggested, I think they address the concerns that have
been talked about today and that we discussed last time, and it seems
sensible to me.

ACTING CHAIRPERSON McCAULEY: Dr. LoCicero.

DR. LoCICERO: As the last person to sort of summarize, we\'re really
talking about does it meet the definition of Class III anymore, and that
is the devices for which insufficient information exist to determine
there\'s safety and effectiveness, and there are few products around
with this kind of history, and we do seem to have sufficient information
at this point.

So I\'m very comfortable with the down classification.

ACTING CHAIRPERSON McCAULEY: Dr. Witten, it appears that the panel is in
favor of down classification of absorbable hemostatic agents and
dressings to Class II with site specific requirements, particularly with
respect to general intended use and neurosurgical use.

Does that satisfy your requirements for that question?

DR. WITTEN: Yes. Thank you.

ACTING CHAIRPERSON McCAULEY: The next question for the panel to discuss
will be the risks. Please discuss the risks to health for the absorbable
hemostatic agent and dressings.

We will start with Dr. Leitch.

DR. LEITCH: Well, I\'ve got into that a little bit before. I think that
primarily where we\'re seeing them is then the application to enclose
spaces with respect to neurologic injury.

And I guess what I would say, you know, a lot of times you might think
that that would be a confined to a neurologic site surgery, but I think
other sites should be aware that if they put it into a closed space even
though they\'re not, quote, operating on the nerves, that they could
experience complications relative to compression injury.

And so for me that seems to me to be the biggest concern that I have
outside of some of these other issues of manufacturing performance which
I think ought to be encompassed in the guidelines.

ACTING CHAIRPERSON McCAULEY: Dr. Choti.

DR. CHOTI: I think that really minimal risks to health that have been
identified; I think they have been. The current products are well
characterized with regard, I think, to health risks, which are minimal.

The issue, again, though is what is the future, and in other devices, as
newer, combining with other products and so forth, I think we\'re going
to just have to anticipate risks to health that we don\'t know about
currently.

But I think certainly of the products we\'ve seen the risks are minimal.

ACTING CHAIRPERSON McCAULEY: Dr. Blumenstein.

DR. BLUMENSTEIN: I have nothing to add.

ACTING CHAIRPERSON McCAULEY: Dr. Doyle.

DR. DOYLE: I think Dr. Choti said everything I wanted to say.

ACTING CHAIRPERSON McCAULEY: Ms. Brown.

MS. BROWN: I noticed in the Surgifoam package insert there\'s a
statement about should not be used in instances of pumping arterial
hemorrhage, and I was curious as to whether that was a precaution that
was going to end up in most package inserts.

So I\'ll just open up. From my own experience with products like this,
that pumping arterial hemorrhage challenges these devices quite a bit.
So that might be an area that either there\'s a caution or there\'s data
collected to address that.

ACTING CHAIRPERSON McCAULEY: I think it has been previously stated that
the use of these devices is primarily for hemostasis, obtaining
hemostasis, which is not controlled by just the standard surgical
methods.

Dr. Miller.

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

ACTING CHAIRPERSON McCAULEY: Dr. LoCicero.

DR. LoCICERO: In terms of the health risks, I think there really are
two. One Dr. Leitch has outlined extremely well, and that is putting
this into closed spaces, and that may be an issue of education that the
manufacturers can take to the treating physician. It is a very low \--
the rate is extremely low, and it\'s possible that many physicians have
not experienced it, nor have they had the education about that issue.

And that would be something the manufacturers could bring to the
physician.

The second is either failure of the device or failure to control
hemorrhage for whatever reason. The intention is to control hemorrhage,
and it\'s usually pretty clear. It\'s either going to do it or it
isn\'t, but there are situations where using the device covers up the
hemorrhage, and one of the complications that\'s listed is hematoma as a
result of continued bleeding, and it\'s unrecognized bleeding that might
occur.

And this is, again, an issue of surveillance by the physician and
recognizing that the product may or may not be able to control all
hemorrhage.

ACTING CHAIRPERSON McCAULEY: Dr. Lanzafame.

DR. LANZAFAME: I think most of the comments have been well addressed. To
echo what Dr. Choti said, really more from the perspective of newer
agents that may be coming to the marketplace, while the previously
identified risks look at inflammation, edema, wound dehiscence,
generally speaking foreign body reaction and inflammation are only part
of the wound healing cascade.

And as some of these strategies might be used in impaired hosts or
oncologic applications, future products may need to look at their
influence in some of these special states, which may not be generic.

ACTING CHAIRPERSON McCAULEY: Dr. Witten, it appears that several issues
have come up relative to the risk of health for absorbable hemostatic
agents and dressings. Three that come to mind appear to be concerns of
the use of these products to enclose spaces, also the risk of
unrecognized hemorrhage, which is continuing, and a third appears to be
related to the process of wound healing.

Are these issues enough to satisfy your concerns relative to Question
No. 2?

DR. WITTEN: Yes. Thank you.

ACTING CHAIRPERSON McCAULEY: The third questions: are there any other
risks to health for these devices that have not been identified?

We will start the panel discussion with Dr. Choti.

DR. CHOTI: Well, as we\'ve just heard, one which I\'m always concerned
about not so much with this device, but the oncologic risk, the risk of
cancer occurrence as this can be applied in areas of ablation, areas of
cancer, and that\'s an endpoint we never see because you can never
really track it easily. It applies to a variety of oncologic strategies.

Again, this hemostatic agent, it\'s not its main purpose, but it\'s a
risk to health, that is, does it seed cancer cells, does it, you know,
this kind of thing. It\'s extremely hard to measure and we\'ll really
never know that, but I think that\'s something that one always needs to
keep in mind as a long-term health risk of a variety of types of
devices.

ACTING CHAIRPERSON McCAULEY: Dr. Blumenstein?

DR. BLUMENSTEIN: I have nothing to add.

ACTING CHAIRPERSON McCAULEY: Dr. Doyle.

DR. DOYLE: I guess the answer to that is I hope there aren\'t any that
we don\'t know, but there may be. I think, with new things coming along,
we have to be constantly vigilant.

ACTING CHAIRPERSON McCAULEY: Ms. Brown.

MS. BROWN: I have nothing to add.

ACTING CHAIRPERSON McCAULEY: Dr. Miller.

DR. MILLER: I have nothing to add, but I just have a question. We\'ve
discussed new devices. I just want to be clear in my own mind. If
something totally new comes up that falls into this category, say, some
synthetic polymer that is unlike anything that\'s ever been created
that\'s designed to do what these devices are designed to do, that would
no longer be substantially equivalent; isn\'t that correct? And it would
have to be treated differently than these, you know, collagen devices
and that sort of thing?

DR. WITTEN: It depends. What we do is we look at the devices on the
market, and we look at the new device proposed for market and see
whether the new device raises any new types of questions that we
wouldn\'t ask about the old devices.

In other words, you know, if the questions that we would ask about a new
proposed device are just, you know, does it control the bleeding, the
questions that we relate to the risks that we\'ve just discussed, then
what we would then do is see whether we could address those questions by
data.

Now, if it raised some new types of questions, and I\'m not sure what
those would be because we haven\'t seen those products yet, but I\'m
sure that, you know, you could imagine something sufficiently novel
that, you know, there are some new types of questions about it.

Then we would. It wouldn\'t fall into this. But the answer is, yes, it
depends. So the answer is, yes, if there\'s a product made of a new
material that is not fit exactly in this descriptive classification,
what we would do would be to evaluate it against the existing products
to see whether, you know, the kinds of questions that we would ask about
that kind of product are similar to the kinds of questions we ask about
the existing product or it\'s sufficiently novel to raise new types of
questions.

So I guess that\'s clear, I hope.

ACTING CHAIRPERSON McCAULEY: Any other questions, Dr. Miller?

DR. MILLER: I don\'t think so.

ACTING CHAIRPERSON McCAULEY: Dr. LoCicero?

DR. LoCICERO: Excuse me. I\'d like to echo Dr. Doyle\'s comments. The
eye does not see what the mind does not know. So we need to be very open
and vigilant about potential new complications.

ACTING CHAIRPERSON McCAULEY: Dr. Lanzafame.

DR. LANZAFAME: I have nothing to add.

ACTING CHAIRPERSON McCAULEY: Dr. Leitch.

DR. LEITCH: I have nothing to add. Thanks you.

ACTING CHAIRPERSON McCAULEY: Relative to the third question, Dr. Witten,
it appears that outside of the development of new devices which may
interact positively or negatively with the hemostatic agents, there are
no significant health concerns that can be identified at this time.

Does that satisfy your requirements for that question?

DR. WITTEN: Yes. Thank you.

ACTING CHAIRPERSON McCAULEY: The next item on the agenda will be to
reclassify questionnaires and votes. We will complete the classification
questionnaire and the supplemental data sheet.

Dr. Gatling from the Office of Device Evaluation will assist us as we go
along.

After panel discussion of each question, I will note your answer for
each blank on the data sheet, and Dr. Gatling will record it on the
overhead for us. We will vote on the completed questionnaire and
supplemental work sheet. It will become the panel\'s recommendation to
the FDA.

Are there any questions before we proceed?

(No response.)

ACTING CHAIRPERSON McCAULEY: Let\'s begin. Dr. Gatling, will you proceed
with the questionnaire, please?

MR. GATLING: Yes. My name is Bob Gatling. I\'m the Director of the
Program Operations Staff in the Office of Device Evaluation.

Normally we would have a presentation to talk about classification and
reclassification and how that all fits together, but given where you are
in your deliberations, Dr. Witten and Dr. Krause, do you want to just
proceed right to the questionnaire and the supplemental data sheet?

DR. WITTEN: No, I don\'t think so.

MR. GATLING: Do you want me to go over a few of the slides then?

I\'m just going to highlight a few of the slides that I have in my
presentation here. Normally Marjorie Shulman of the 510(k) staff
presents this presentation. These are her slides, and it\'s geared
toward classification of devices that were on the market before 1976,
which is not applicable today.

It\'s also for reclassification, which is applicable today.

These are the kinds of things that she would normally go through. A
little background material. The medical device amendments of 1976
established a classification procedure for devices. It set up the 33
classes, Class I, II and III, and at the time that the medical device
amendments were passed, it was charged to FDA to classify every product,
every medical device that was on the market beginning in 1976. So we had
a big task in those early days.

The law also provided for reclassification based on new information of
those devices, which is more applicable today.

These are some other laws that are listed that have been passed in 1990,
FDAMA in 1997, and a more recent one, medical device user fee of 2002.

Pre-amendments versus post amendments information. Just to give you a
little bit is those that were before 1976 were classified. This
particular product was a transitional device as Dr. Krause mentioned
earlier and automatically placed in Class III. You did not have to go
through a classification process.

To keep moving through these things, so the reclassification of the
pre-amendments, and we may reclassify pre-amendments devices in a
procedure that parallels the initial classification, and that\'s going
to be the questionnaire in the supplemental data sheet plus the panel
deliberation, and it\'s based on new information.

And now that we have kind of come to this point with these products
being on the market since the 1940s, I think there\'s a lot of
information to base this information on.

Post amendment devices, not applicable for this one. Again, another
slide.

Class I. It has been reiterated in some of the earlier presentations
today what a Class I device is, and these are where general controls are
sufficient to provide that reasonable assurance of safety and
effectiveness. This is the lowest class of regulatory control.

And these general controls include prohibition against adulteration and
misbranding, the pre-market notification 510(k) requirements, banned
devices, good manufacturing practices, registration and listing, record
keeping and repair, replacement, and refund, general control.

Class II devices are ones where the general controls in Class I are not
sufficient to control the risk to health, and so it provides for special
controls which adds onto the general controls to control these different
risks associated with it.

And with those two, general controls and special controls, the risks to
health are sufficiently addressed, and these special controls can
include performance standards of the various types, post market
surveillance studies, discretionary studies if we want to do that,
patient registries, and traceability and development dissemination of
guidances, which is the main point, I think, that you\'ve been talking
about today.

And you can get very detailed into that guidance document of the kind of
information that companies need to present to FDA in their marketing
application, and you are very detailed in yours, including design
controls.

Recommendations could include special labeling. I think you have some of
those things in tracked devices.

Class III where this device currently exists is where there\'s
insufficient information to determine the safety and effectiveness of
the device. I think at the time in 1976, that since they were undergoing
review as new drugs, that the agency felt that those should move right
into Class III and stay in that category until reclassified. So I think
we\'re at a different point today than we were back at that time.

And the new information that we should be considering is should be valid
scientific evidence, and these are the kinds of information that\'s
considered valid scientific evidence in clinical trials.

A recommendation for the initial classification and a reclassification
of this panel meeting is what we really need, and we\'re going to be
using some tools today, this questionnaire and the supplemental data
sheet to capture the information that\'s needed as part of the
reclassification.

And these are just some detailed things that we will actually go through
with those particular ones, and at this point, unless there are any
particular questions, I would like to go ahead and move to the
questionnaire and the supplemental data sheet.

And what I recommend we do is we go through. Some of these are like
identify the risk to health. You can just refer back to the discussions,
what\'s been provided in your information that you received prior to the
panel, and any additional risks that you\'ve identified as part of your
discussions. We don\'t have to relist that. We can capture that from the
record.

Okay. I handed out the supplemental data sheet and the questionnaire.
We\'ll go through the questionnaire first.

Okay. So I\'m just going to kind of skip through some of these we note.
Go to Question 1. Is the device life sustaining or life supporting?

I\'m assuming no. Yes? I need to answer the questions. I\'m sorry.

ACTING CHAIRPERSON McCAULEY: All those who voted yes on the first
question raise your hand.

(Show of hands.)

ACTING CHAIRPERSON McCAULEY: Those who vote no?

(Show of hands.)

ACTING CHAIRPERSON McCAULEY: Could we get a recount?

Those who voted yes?

DR. LEITCH: Could I ask a question?

ACTING CHAIRPERSON McCAULEY: Sure.

DR. LEITCH: Are there some specific definitions of those two things,
life sustaining and life supporting?

DR. KRAUSE: I\'ll try to address that, and, Dr. Witten, since it\'s your
area, you might want to add onto that.

A life sustaining and a life supporting device is where if there\'s a
failure to perform as it should could lead to death or serious injury.
So I think you have to look at the application, what these things are
used for, to maybe answer that, and sometimes maybe it\'s yes and
sometimes no.

ACTING CHAIRPERSON McCAULEY: Okay. Are there any other questions before
we take a vote on this question?

Those panel members who voted yes?

DR. MILLER: Could I ask one question before we vote?

ACTING CHAIRPERSON McCAULEY: We\'ll get through this.

DR. MILLER: I mean, I can envision a situation where it would be life
threatening if this device failed. So if there is a situation where
that\'s true, does that make it a life sustaining and life threatening
device?

But in many situations it fails and it\'s not life threatening, it\'s
just a problem that you can fix. So which wins in each classification?

DR. KRAUSE: Yeah, I think it\'s the general use of the device. It\'s
not, you know, if there\'s one out of a million situations or something
like that. It\'s the general use of the device, if the general way the
device is used isn\'t life sustaining or life supporting.

DR. MILLER: Okay. Thank you.

ACTING CHAIRPERSON McCAULEY: Are there other questions relative to this
issue before we vote?

DR. BLUMENSTEIN: Yes. So the phrase \"device failure\" was used. Now,
device failure could be the misapplication of the device by the person
like the surgeon or it could be that the manufacturer \-- there\'s a lot
of this device that is incorrect.

Which applies here? I mean, if there\'s a bad lot that causes
infections, that causes death, then it seems to me that that\'s
definitely life threatening, but does that apply to this question?

DR. KRAUSE: I don\'t think so because the way the question is worded is
or the intent is if the device is made correctly according to
specifications and used in the way it\'s labeled, does it function the
way it\'s supposed to function? Is it life sustaining or is it not?

So it\'s not looking for the exceptions to the rule. It\'s basically a
question for the general use of the device, the general manufacture of
the device if everything is done according to specifications and the
indications for use.

ACTING CHAIRPERSON McCAULEY: Other issues?

(No response.)

ACTING CHAIRPERSON McCAULEY: Once again we\'ll try this question again,
Dr. Gatling.

MR. GATLING: Okay.

ACTING CHAIRPERSON McCAULEY: Those who vote yes to Question 1.

(Show of hands.)

ACTING CHAIRPERSON McCAULEY: Those who vote no?

(Show of hands.)

MR. GATLING: Okay. Question 2, is the device for use which is of
substantial importance in preventing impairment of human health?

ACTING CHAIRPERSON McCAULEY: Those who vote yes?

(Show of hands.)

ACTING CHAIRPERSON McCAULEY: Those who vote no?

(Show of hands.)

MR. GATLING: Okay. Thank you.

Question 3, does the device present a potential unreasonable risk of
illness or injury?

ACTING CHAIRPERSON McCAULEY: Yes?

(Show of hands.)

ACTING CHAIRPERSON McCAULEY: No?

(Show of hands.)

DR. KRAUSE: Oh, by the way, everybody should be filling out their
particular form as to how they\'re voting so that we can collect them in
the end, except for the non-voting members.

ACTING CHAIRPERSON McCAULEY: Question No. 4.

MR. GATLING: Okay, Did you answer yes to any of the above? Yes, you did.
Go to six.

Is there sufficient information to establish special controls in
addition to general controls to provide reasonable assurance of safety
and effectiveness?

ACTING CHAIRPERSON McCAULEY: Those who vote yes?

(Show of hands.)

ACTING CHAIRPERSON McCAULEY: Those who vote no?

(Show of hands.)

MR. GATLING: Okay. Thank you.

Okay. Question 7, if there\'s sufficient information to establish
special controls to provide reasonable assurance of the safety and
effectiveness identified below, the special controls needed to provide
such reasonable assurance for Class II, and this includes listed on the
form guidance documents, performance standards, device tracking, testing
guidelines, and then other.

And if the information that\'s provided in the pre-panel information and
your discussion is sufficient in your mind, then you can consider that.

ACTING CHAIRPERSON McCAULEY: Is there any discussion of this question
before we proceed?

DR. LEITCH: Could I ask a question about Number 5? Did the panel vote
yes to Number 5? Did I get that correctly?

Because if yes, that\'s a Class I.

DR. KRAUSE: No. What happened was when we voted on Items 1, 2, and 3,
one of those was yes. So we skipped to six.

DR. LEITCH: Okay.

DR. KRAUSE: Okay?

DR. LEITCH: Okay.

DR. KRAUSE: So there was no reason to vote on five.

DR. LEITCH: Okay.

ACTING CHAIRPERSON McCAULEY: Will the guidance document provide
sufficient information for special controls related to absorbable
hemostatic agents?

How many vote that a guidance document is sufficient?

DR. MILLER: Can we \-- may I ask a question? Can we just say in this
whole section to refer to our discussion that we had and have that be
sufficient for all of these?

ACTING CHAIRPERSON McCAULEY: Dr. Witten, is that reasonable?

DR. WITTEN: Yes.

DR. BLUMENSTEIN: I just had one comment. I heard several people mention
education as being important here, and what I can\'t recall just offhand
is was that covered in the guidance document.

DR. KRAUSE: Education is specifically not covered in the guidance
document, but if you look at the very back of your packet of
information, there\'s the labeling for the product Surgifoam, and you
can see that the labeling is very detailed, and it talks about, you
know, when you apply the device once hemostasis is achieved, that you
should remove as much of the device as possible.

So that\'s kind of stuff that has been learned by education over the
years of using these devices, and we would insist on basically that kind
of labeling for these devices. It\'s very informational. It includes all
of the precautions, all of the warnings, all of the, you know,
contraindications and things like that that we have discussed.

DR. CHOTI: So the discussion, your presentation, Dr. Krause, is a
guidance document. It\'s not a performance standard, tracking or any of
these others. It\'s only a guidance document; is that right?

DR. KRAUSE: Right, right.

ACTING CHAIRPERSON McCAULEY: Question?

DR. CHOTI: So perhaps we should vote on whether these other \-- so the
guidance document is perhaps as discussed. The question is whether these
other controls should also be included for any of them.

ACTING CHAIRPERSON McCAULEY: Dr. Witten, can you clarify this for us?

DR. WITTEN: Well, we\'re asking you to identify the special controls
needed to provide such a reasonable assurance, and what we have proposed
in our discussion is that we have a guidance document that we think
covers, you know, the special controls that we think is needed to
provide reasonable assurance of safety and effectiveness.

If there are any other things that you think, you know, are also needed,
then you certainly are free as a panel to suggest what those are, but
our suggestion was and is the guidance document.

But I\'d be glad to answer any questions about the other things listed
on this list if you\'d like.

ACTING CHAIRPERSON McCAULEY: Dr. Krause, do you have any comments to
add?

DR. KRAUSE: No, I agree with Dr. Witten.

ACTING CHAIRPERSON McCAULEY: Dr. Blumenstein.

DR. BLUMENSTEIN: Well, I\'d just like to ask what device tracking is.

DR. WITTEN: Yes. Device tracking means that the device can be tracked to
the patient so that every time that a device is used, the manufacturer
is informed of who it was used in and is able to locate that patient so
in case that later something turns out with the device that they want to
contact that patient, they can get in touch with them.

So I\'m not actually \-- to be honest, there are not a lot of tracked
devices. I\'m not sure exactly what they are, but, for example, if you
had an implantable heart device that if it failed the patient would be,
you know, at risk of death on failure and the sponsor discovered some
mechanical problem with their device and wanted to be able to get in
touch with those patients to let them and their physicians know, it
would enable them to know in whom that product was used.

DR. BLUMENSTEIN: So this is not like putting a cell phone in there so
that it can be tracked and the patient can be located at any moment
then, right?

DR. WITTEN: No, but it is to be able to specifically be able to identify
those patients.

DR. BLUMENSTEIN: Right. No, I understand now. Thank you.

ACTING CHAIRPERSON McCAULEY: Are there any other questions?

Dr. Leitch.

DR. LEITCH: Well, with respect to the education issue, you know, we\'re
referred to the Surgifoam insert, and the issue I raised of, you know,
these other sites, but then, for example, for general surgical use where
you might be using it in a closed space or you might have some extremity
surgery and you\'re using it on a tendon, but you\'re not repairing a
tendon, but it\'s in the vicinity of a tendon or if you\'re running down
this list quickly to look at the contraindications, you might not
realize that particular issue because it\'s kind of subsumed under sites
that the person wouldn\'t be operating on, and so I think that\'s what,
you know, we\'re mentioning in education, that some of these things may
be unknown to people who don\'t operate in those sites, but yet they
could be pertinent to a site where they are operating even though it\'s
not a neurologic procedure.

ACTING CHAIRPERSON McCAULEY: Any comments from anyone else?

(No response.)

ACTING CHAIRPERSON McCAULEY: Would it be prudent to ask whether or not,
as Dr. Choti suggested, that the panel members can vote multiple times
on the same question because there are different issues that are
addressed in each one of these items?

DR. KRAUSE: Well, I think anyone can suggest any of those methods for
the special control, and you don\'t only have to have one. You can
certainly have more than one, and if there\'s one that\'s not listed
there that you think should be considered as a special control for that
type of device, you can add it under \"other.\"

ACTING CHAIRPERSON McCAULEY: Do any of the panel members feel that
performance standards need to be part of the controls?

(No response.)

ACTING CHAIRPERSON McCAULEY: Device tracking, is that an issue for
special controls?

(No response.)

ACTING CHAIRPERSON McCAULEY: Testing guidelines, are those issues for
special controls?

(No response.)

ACTING CHAIRPERSON McCAULEY: There\'s no comment from the panel. So it
appears that none of the three mentioned items are required special
control issues.

Does the panel have any other special control issues that need to be
addressed under \"other\"?

(No response.)

ACTING CHAIRPERSON McCAULEY: Then we can move on to the next question.

MR. GATLING: Okay. Question No. 8 has to do with performance standards.
Since you are not recommending a performance standard, it\'s not
applicable. The same thing with Number 9, not applicable.

Number 10, for a device recommended for reclassification to Class III,
identify. That\'s not applicable.

Okay. The next page. Identify the needed restrictions only upon the
written authorization of a practitioner licensed by law to administer or
use the device, used by persons with specific training or experience in
its use, used only in certain facilities or other.

ACTING CHAIRPERSON McCAULEY: Are there any issues relative to Question
No. 11?

(No response.)

ACTING CHAIRPERSON McCAULEY: No.

MR. GATLING: Well, I think one of the main things there, should it be a
prescription device.

ACTING CHAIRPERSON McCAULEY: I\'m sorry?

MR. GATLING: Should it be a prescription device? That would be a needed
restriction.

ACTING CHAIRPERSON McCAULEY: Any discussion from panel members?

DR. MILLER: When you say prescription, I mean, you don\'t write a
prescription for something you use during a surgery. But I think a
person needs to be trained to use it, of course, and needs to be
licensed to use it. I mean, a physician, a surgeon needs to have the
training. I don\'t think he needs to have a special facility. Any
surgical situation would be appropriate.

Would you check off those two boxes?

MR. GATLING: Okay. Generally for this particular question what we\'re
looking for is whether it should be restricted to prescription use
versus over the counter. That\'s where the distinction comes in. And
it\'s prescription even though it\'s used in surgery. There\'s a
presumed prescription at that point.

The others having to do with training is one where you feel that before
a physician can actually use the device, some sort of a training program
\-- he or she needs to go through that and actually use that. That\'s
where these restrictions come in.

DR. MILLER: Like specifically training on that device or \--

MR. GATLING: Yes, correct.

DR. MILLER: \-- surgical training in which the device is a part of what
you\'re trained to use?

MR. GATLING: That\'s correct. It\'s very specific to this device, not
general medical or specialty training.

DR. WITTEN: Let me just clarify. When you use something in surgery, even
though you\'re not writing a prescription for it, I mean, you know,
it\'s like asking for a medication during surgery. It\'s considered a
prescription because, you know, you\'ve got a nurse. You\'ve asked for
it and you\'re administering it, that kind of thing.

DR. MILLER: I understand.

DR. LoCICERO: I might also add that this is a ubiquitous use product,
and so during our training we use it ubiquitously. So I\'m not sure that
we need special training.

ACTING CHAIRPERSON McCAULEY: Other comments from the panel members?

MS. BROWN: I think with regard to the training the current products
under PMA don\'t require training to my knowledge. So to start adding it
at this point probably doesn\'t make sense.

ACTING CHAIRPERSON McCAULEY: I agree. I think that as Dr. LoCicero
mentioned, this product is used ubiquitously, and if we\'re down
regulating it to a lower class, it seems we\'re going backwards to
require training.

DR. MILLER: I guess I considered surgery, you know, training. A surgeon
should put it in.

(Laughter.)

ACTING CHAIRPERSON McCAULEY: Are there any other comments from panel
members?

Dr. Leitch.

DR. LEITCH: Well, the issue of prescription versus not, I mean, are you
asking us to make a discrimination of, you know, could this be used by
the lay public as a Bandaid or something like that? Is that \--

MR. GATLING: That\'s what this question would address, and it would be
available at your local pharmacy for anybody to pick up on the shelf and
take home and use.

DR. KRAUSE: Yeah, I think what it\'s talking about is would it be
labeled with the federal law requires, you know, that this be used only
by a licensed practitioner, that type of labeling, which would
ordinarily be considered the prescription labeling as opposed to
over-the-counter labeling where anybody could apply it.

ACTING CHAIRPERSON McCAULEY: Dr. LoCicero.

DR. LoCICERO: As we went through our discussion this morning, was it not
the FDA\'s recommendation that this be restricted to use by physician?

DR. WITTEN: By a practitioner.

DR. LoCICERO: Practitioner. Sorry.

ACTING CHAIRPERSON McCAULEY: Can we proceed to a vote on this question?

Just on the first item which states that only upon written and oral
authorization of a practitioner licensed by law to administer use of
this device, those who say yes.

(Show of hands.)

ACTING CHAIRPERSON McCAULEY: The next question: use only by persons with
specific training or experience in its use. Those who vote use?

(No response.)

ACTING CHAIRPERSON McCAULEY: Those who vote no?

(Show of hands.)

ACTING CHAIRPERSON McCAULEY: We have a unanimous vote of yes for the
first question and a unanimous vote of no for the second question.

The third question states whether or not this product should be used
only in certain facilities. Any discussion before we vote?

(No response.)

ACTING CHAIRPERSON McCAULEY: Those who vote yes?

(No response.)

ACTING CHAIRPERSON McCAULEY: Those who vote no?

(Show of hands.)

ACTING CHAIRPERSON McCAULEY: That again is a unanimous no.

Dr. Gatling, does that complete the questionnaire?

MR. GATLING: Thank you very much. That\'s great.

Now we can move to the next document, the supplemental data sheet.
Generic type device is the name of the product as we\'re discussing
today in this advisory panel. Device and implant, and that\'s defined as
in the body for greater than 30 days.

Dr. Witten, how is this currently listed? Is it listed as an implant?

DR. KRAUSE: It\'s absorbable, and the time to full absorption for some
of these is close to 30 days. So it\'s kind of \--

MR. GATLING: I would say probably no then.

DR. KRAUSE: What\'s that?

MR. GATLING: I would say no, it\'s not an implant given that.

DR. KRAUSE: Okay.

MR. GATLING: It\'s less than 30 days.

Indications for use. You had an identification. Is that sufficient or do
you want to have anything in addition to what was up there?

ACTING CHAIRPERSON McCAULEY: Any comments from the panel?

DR. KRAUSE: I think Ms. Brown had a suggestion earlier which was dealing
with here\'s the indication.

MS. BROWN: Well, to use either the indication that\'s in Surgifoam\'s
package insert, which is at the back of the package. Also I know that
other companies that have gone before have had intended uses that
didn\'t have the language dealing with capillary, venous, and arteriolar
bleeding.

But I do think the indicated use statement should, unless there\'s
specific data to address it, have neurological, ophthalmic and
neurological exclusions just because that\'s historically what these
agents have had.

DR. KRAUSE: So the panel can vote to use the indication as stated in the
Surgifoam labeling or any variation. So if you think it should be
different than that, you can certainly say that or you can just agree
that that\'s an appropriate indication.

It\'s in Tab 7, and that\'s the general indication that these devices
are approved. The wording may be slightly different, but that\'s the
general idea, is that these devices are used in general surgical
applications with those exclusions when conventional means fail.

And the conventional means are ligature, cautery, pressure, and those
types of things, or it\'s impractical which means if a surgeon would
like to \-- needs to stop bleeding, but it\'s in a place where he can\'t
get a cauterizing iron or he can\'t get a suture. Then you would want to
use one of these devices, and that\'s basically what the intent is of
that indications for use statement.

MR. GATLING: Also, I\'d like a clarification that you had a device
identification that\'s currently in the CFR. Are you comfortable with
that wording, given the reclassification of that? re there any changes
needed to that?

DR. CHOTI: Just for clarification, that was the statement that this was
used for stopping bleeding and that is absorbs.

MR. GATLING: Right.

DR. CHOTI: And that\'s the general definition.

MR. GATLING: Are there any changes to that that you would recommend?

DR. CHOTI: No.

MR. GATLING: Okay. Identification of ‑-

ACTING CHAIRPERSON McCAULEY: Before we move on \--

MR. GATLING: Oh, sorry.

ACTING CHAIRPERSON McCAULEY: \-- we need to take a vote as to whether
that is an acceptable indication for device labeling.

DR. LEITCH: Are we talking about identification or indication?

ACTING CHAIRPERSON McCAULEY: Identification or indication. I\'m sorry.

MS. LEITCH: Because there\'s identification, which is \--

ACTING CHAIRPERSON McCAULEY: That\'s next.

MS. LEITCH: \-- absorbable \-- that\'s next?

MR. GATLING: No, this actually really should capture the identification
that\'s going to be put into the CFR, and that\'s why I asked that, to
clarify your recommendation on the current \--

ACTING CHAIRPERSON McCAULEY: So that question basically is not on the
questionnaire, but we are voting now for the identification.

MR. GATLING: Right, and also your indication statement. That\'s a good
thing to have for the labeling part of it.

DR. LEITCH: So if I understand the identification is absorbable
hemostatic agent, surgical, is an absorbable device intended to produce
hemostasis by accelerating the clotting process of blood during surgical
procedures. That\'s identification?

MR. GATLING: That\'s correct.

DR. LEITCH: Okay. That\'s different than indication, which is the
intended use.

ACTING CHAIRPERSON McCAULEY: Well, we\'re saying that that\'s
identification, which Mr. Gatling is asking, which is not part of the
questionnaire.

DR. KRAUSE: Do we have a question on that, Bob?

MR. GATLING: No, actually this data sheet is both the initial
classification and for reclassification, and it\'s a dual use document.

DR. KRAUSE: Okay. So we\'re saying that Number 4 is both asking about
the indication for use and the product identification?

MR. GATLING: Correct. During initial classification usually what you\'re
working with is the current indication, which we then develop into an
identification for regulatory purposes. So this document tries to
capture that.

And I want to clarify that the reclassification of this generic type
that is proposed today, is there any changes to the current
identification that we\'ve already developed in the original development
of the CFR?

ACTING CHAIRPERSON McCAULEY: I think we\'re going to review the CFR
identification of hemostatic agents and dressings and see if that\'s
acceptable to panel members.

DR. KRAUSE: This is the identification, product identification that
we\'re proposing, which is I think identical to what it is now.

DR. LEITCH: It doesn\'t have \"dressing\" in it, right?

DR. KRAUSE: Right. We took the word \"dressing\" out. We just wanted to
say absorbable hemostatic agent, surgical because the fact is that there
are certain sound dressings that have hemostatic properties, and those
are not in this classification. So we thought the name was confusing. So
we just thought it would be appropriate to change it to surgical.

DR. CHOTI: I still have a little bit of a problem with this
identification in its vagueness. You know, why doesn\'t bone wax or
fibrin sealants fit that classification in some way?

So it\'s a vague definition that just includes absorbable clotting
process, hemostasis, but I just can\'t think of a better way to phrase a
definition or identification.

MR. GATLING: When we developed the identification, what we wanted to try
to do is capture the broad category of the devices so that things would
fit in there naturally. If you make it so restrictive that when new
products are coming in you can\'t use that category, they end up falling
out into a different regulatory category. So that was the reason that
the identifications were kind of broad even though when we actually get
the files and we\'re reviewing those they may fit in there and the
category kind of expands and gets narrow depending on the particular
product.

So we try to keep it big, but we can use the very specific things that
we need to be.

DR. WITTEN: Also, I\'ll just say that fibrin sealant is a biologic
project, and when we\'re reviewing these if it\'s something like bone
wax where the indications for use wouldn\'t fit in with the predicate,
then it doesn\'t fit in with this category.

In other words, this is an identification of the category, but then when
you get an application, you review it in comparison with the other
products that are in that category, and in comparison with their
labeling, their intended use and what they\'re made of.

So it doesn\'t mean that somebody would just come with a product that
could fit into what you term, you know, vague or we\'d call it broad
category, and that means they get on the market. They need to make a
case in comparison with a specific product that already exists in that
category.

DR. KRAUSE: Right, and also, bone wax doesn\'t meet that definition
because it does not accelerate clotting. It merely acts as a tamponade.
It just blocks bleeding. It doesn\'t really induce hemostasis, which
these products do.

DR. CHOTI: It\'s somewhat semantics. I mean, a hemoclip, an absorbable
hemoclip, you know, yes, that just blocks the vessel, but ultimately it
does inhibit the clotting cascade to some degree.

Again, it\'s semantics. I don\'t know of a better definition. I agree
there are advantages to keeping it broad, but it\'s a little bit
problematic.

ACTING CHAIRPERSON McCAULEY: Is the identification of hemostatic agents
as outlined by Dr. Krause in this slide, is that acceptable to the
panel?

(Show of hands.)

ACTING CHAIRPERSON McCAULEY: Yes. Okay. Now we can move on to
indications.

MR. GATLING: Thank you.

One clarification. What happened to dressings? Because I know this is
going to come up as we proceed with a reclassification. Are you
including the dressings in this? No? Okay.

Okay. Question 5 is the identification of any risk to health presented
by the device, and I think you all have a nice list if you want to just
refer back to that one.

DR. KRAUSE: Oh, we\'re just going to have a vote on the indication now.

MR. GATLING: Oh, sorry.

ACTING CHAIRPERSON McCAULEY: Could we have a recap of indications for
use in the device labeling?

DR. KRAUSE: Let me read an indication. Absorbable hemostatic agents are
used, dry or saturated, with sterile sodium chloride \-- and that part
doesn\'t need to be in there \-- as indicated for surgical procedures,
except urologic, ophthalmologic, and neurologic for hemostasis when
control of bleeding by pressure ligature or other conventional
procedures is ineffective or impractical.

ACTING CHAIRPERSON McCAULEY: Can we have a vote on indications or at
first is there any discussion about the indications for this product?

DR. CHOTI: Just one question regarding urologic, ophthalmologic and
neurologic.

ACTING CHAIRPERSON McCAULEY: Yes.

DR. CHOTI: Is there evidence to suggest it\'s \-- I mean, should we have
discussion regarding whether that should be excluded?

ACTING CHAIRPERSON McCAULEY: Dr. LoCicero?

DR. LoCICERO: I think from all of our discussion this morning that it\'s
included with specific guidelines. We spoke specifically about
pyrogenicity and the level that is required for neurologic. So we
actually have included it, and so my suggestion is that we leave that
piece out of the indications, and our guideline, our controls are going
to take care of that issue.

ACTING CHAIRPERSON McCAULEY: Any other discussion?

DR. WITTEN: So I missed that. So is the intended use going to not have
exclusions or have exclusions? I don\'t understand what the intent is
right now.

DR. LoCICERO: I would suggest that we leave out that phrase because, in
fact, it is indicated in those three areas. It is used in those areas.
So it doesn\'t make sense to exclude that from the indications.

MS. LEITCH: And it would be the manufacturer\'s responsibility to say
the circumstances in which, you know, they have data to say it
shouldn\'t be used, and this particular manufacturer has indicated these
sites, but I don\'t think everyone who would do a hemostatic agent would
think it wasn\'t useful in the other site.

So I think that, you know, some sites have raised concern, and that any
new product would have to address concerns in those sites. But I think
to put the identifier as indication to exclude sites when a new product
might be okay for those sites wouldn\'t be appropriate, but yet \--

ACTING CHAIRPERSON McCAULEY: But these are all labeling issues.

Dr. Lanzafame.

DR. LANZAFAME: Yes. Having dealt with this before, just a reality check.
Am I correct in presuming that each intended use and indication for use,
which indeed are labeling issues, the more specific they become across
devices and products, the more specific the controls on the part of the
manufacturer in terms of providing data to actually support those
indications?

DR. WITTEN: Well, I think that\'s generally the case. The situation is
we don\'t actually need a vote on this. I think these recommendations
for labeling, and you know, we\'ll take what you said into account while
we look at the labeling guidance, but what we would do is exactly, you
know, like what you\'ve suggested, which is for a specific product look
at what the predicate device labeling is, look at that device\'s
labeling and see whether, you know, if there are differences we need
additional information to support those differences.

So I think, you know, we\'ve had some discussion about that, and I think
we can move on sine we don\'t need that for the supplemental data sheet.
We don\'t need a vote on that; is that right?

MR. GATLING: That\'s correct. This is a recommendation of how the
wording should be.

DR. WITTEN: Right. So I think we can go on to talk about the
identification of risks, and that\'s what we need a vote on from you
all, I mean, unless there\'s some additional comments. But I think as
was just stated, this would be something we would look at for the
labeling of that specific product because, as you just said, when we
reviewed that specific product.

ACTING CHAIRPERSON McCAULEY: So we\'re on identification of any risk to
health presented by the device, correct?

DR. WITTEN: Yeah, and you can refer back to your prior discussion.

ACTING CHAIRPERSON McCAULEY: Yes, we can actually refer that back to one
of the questions that we answered in the earlier FDA session. Is that
acceptable?

DR. WITTEN: It\'s acceptable to us if it\'s acceptable to the panel.

ACTING CHAIRPERSON McCAULEY: Is that acceptable to the panel?

(No response.)

ACTING CHAIRPERSON McCAULEY: Let\'s move on to the next question.

MR. GATLING: Okay. Recommended advisory committee\'s classification and
priorities. So classification, Class I, II or III.

ACTING CHAIRPERSON McCAULEY: Does everyone agree with Class II? Yes or
no? Those who vote yes?

(Show of hands.)

ACTING CHAIRPERSON McCAULEY: The vote is unanimous for Class II, device
reclassification.

MR. GATLING: There\'s another question here regarding priority, and it
has to do with performance standards, and since there\'s no performance
standard.

It\'s not an implant or life supporting. So we skip Number 7.

Number 8, a summary of information including clinical experience or
judgment upon which classification recommendation is based, and you have
a lot of information. You can refer to the information that you have in
your clinical experience if you want.

ACTING CHAIRPERSON McCAULEY: We can also, if it\'s acceptable to the
panel, we can also refer this question to the earlier discussions with
the FDA, if that\'s acceptable. Okay.

MR. GATLING: Okay. Identification of any needed restrictions on the use
of the device, special labeling banning prescription use. This is where
the prescription thing comes in again and any special labeling which you
may have which you could refer back to the guidance document as part of
your special controls. There\'s a labeling section in there, I believe.

ACTING CHAIRPERSON McCAULEY: Does the panel object to referring back to
the guidance document for labeling issues?

(No response.)

ACTING CHAIRPERSON McCAULEY: No? Then we can move on to the next
question.

DR. WITTEN: Move on to 11.

MR. GATLING: Okay. If the device is recommended for Class II, recommend
whether FDA should exempt it from pre-market notification. In other
words, we would not see a pre-market submission for these types of
devices if you vote to exempt it.

ACTING CHAIRPERSON McCAULEY: Any discussion from the panel?

DR. BLUMENSTEIN: My form says Class I.

DR. WITTEN: We skipped Question 10. We\'re moving on to Question 11.

DR. BLUMENSTEIN: Oh.

DR. CHOTI: Would you just clarify something for me? So if it\'s this
Class II, it\'s still possible to have a \-- is this where we\'re
deciding whether one can still have a PMA in this class?

DR. WITTEN: No. What Question 11 says is do you think that the
manufacturer should submit an application to us prior to going to
market, 510(k) Class II application, or do you think they can go to
market and just, you know, follow the guidance and the special controls
without submitting an application?

So exempt means no application and not exempt means we review it before
market.

Yes? Oh, sorry. Yes.

DR. BLUMENSTEIN: My issue here would be the surveillance. If they just
go to market without notification, does that mean they\'re not under
surveillance?

DR. WITTEN: Well, if they go to market without notification, that means
we don\'t review the information regarding their product prior to going
to market, which in general for these, you know, I don\'t know of any
other exempt devices that are \-- I mean, I can\'t think of any.

We do have some Class II exempt devices. I\'m sorry I can\'t come up
with some examples, but exempt means we don\'t review the information
regarding the product, but all of the devices are subject to \-- these
Class II devices would be subject to MDR requirements. In other words,
there would still be the other requirements in place regarding good
manufacturing practices and needing to submit adverse event reporting.

But the question is: do we review the data in the application and review
the labeling before it goes to market?

ACTING CHAIRPERSON McCAULEY: Dr. LoCicero.

DR. LoCICERO: Now, one of the things that we\'ve been hearing all
morning is that the FDA has assured us that they would review the
information, look at the indications, be sure that the product addresses
the specific concerns about health issues related to the indication.

So I think it would be imperative that we make this nonexempt.

ACTING CHAIRPERSON McCAULEY: Any other discussion?

(No response.)

ACTING CHAIRPERSON McCAULEY: Those in favor of making this nonexempt or
further devices nonexempt from pre-market notification? Nonexempt.

(Show of hands.)

ACTING CHAIRPERSON McCAULEY: The vote is unanimous for nonexemption.

MR. GATLING: Thank you.

Question 12, existing standards applicable to the device, subassemblies,
components or device materials. I don\'t recall. Were there any
referenced in the guidance document at all?

DR. WITTEN: Yes. There is a biocompatibility standard referenced in the
guidance, and you could answer this question just by saying standards
referenced in the guidance. That could be your answer to this question.

ACTING CHAIRPERSON McCAULEY: Any objection to the panel for proceeding
in that direction of following the special guidance document standards?

Any objections?

(No response.)

ACTING CHAIRPERSON McCAULEY: None.

Does that conclude the supplemental form?

MR. GATLING: Yes. Thank you very much.

ACTING CHAIRPERSON McCAULEY: Okay. Is there a motion to accept the
classification work sheet that\'s filled out with the recommendation of
Class II for absorbable hemostatic agents intended as an adjunct to
hemostasis when control of bleeding by ligature or conventional
procedure is ineffective and impractical?

DR. LANZAFAME: So moved.

DR. LoCICERO: Second.

ACTING CHAIRPERSON McCAULEY: There\'s a motion by Dr. Lanzafame and
seconded by Dr. LoCicero. Can we have a vote at this time?

All in favor?

(Show of hands.)

ACTING CHAIRPERSON McCAULEY: The vote is unanimous.

The motion of the panel unanimously is that absorbable hemostatic agents
intended as an adjunct to hemostasis will control the bleeding by
ligature or conventional procedures is ineffective or impractical, to be
classified into Class II.

Are there any further discussions?

(No response.)

ACTING CHAIRPERSON McCAULEY: At this point I\'d like the panel members
to just briefly state why they voted as they did. We\'ll start with Dr.
Lanzafame.

DR. LANZAFAME: I voted in that fashion based on personal experience, the
discussion and deliberations today, and also based on the information
provided prior to the panel meeting.

ACTING CHAIRPERSON McCAULEY: Dr. Leitch.

DR. LEITCH: I voted this way based on the review of the information that
we were presented, the presentations by the manufacturers, and the
long-term use of these agents with good safety and few serious adverse
events reported.

DR. CHOTI: I agree. I voted this way based on experience and the
information presented.

ACTING CHAIRPERSON McCAULEY: Dr. Blumenstein?

DR. BLUMENSTEIN: I want to note, first of all, this is one of the rare
events where the statistician votes with the rest of the panel.

(Laughter.)

DR. BLUMENSTEIN: Second, I voted this way not based on experience
because I\'ve never used one of these devices, but I\'ve been assured
that the surveillance for future uses and adverse events and so forth is
as good as it can be within reason, and I haven\'t been shown anything
that indicates that this shouldn\'t be reclassified.

ACTING CHAIRPERSON McCAULEY: Dr. Miller?

DR. MILLER: Yes, I voted based also on personal experience and on our
discussions today.

ACTING CHAIRPERSON McCAULEY: Dr. LoCicero?

DR. LoCICERO: I voted based on experience, the information presented
today, and a review of the definition of Class III, which these devices
no longer meet.

ACTING CHAIRPERSON McCAULEY: That concludes our morning session. We will
break and return or reconvene this afternoon at one o\'clock.

(Whereupon, at 11:55 a.m., the meeting was recessed for lunch, to
reconvene at 1:00 p.m.)

A-F-T-E-R-N-O-O-N S-E-S-S-I-O-N

(1:08 p.m.)

DR. KRAUSE: Before we get into the official afternoon program, I\'ve
asked Dr. Keyvan Farahani of NIH/NCI to come and discuss some new,
interesting funding that\'s available through the Cancer Imaging
Program, which may be applicable to some of the devices and some of the
research that\'s going on in the field that\'s going to be discussed
today.

So as soon as they have Dr. Farahani\'s slides set up, I\'m going to ask
him to go before we start the official afternoon\'s session. So just
bear with us until we get the computer set up, and then we\'ll have Dr.
Farahani.

(Pause in proceedings.)

DR. FARAHANI: Good afternoon. My name is Keyvan Farahani. I\'m Program
Director for Image Guided Diagnosis and Therapy Branch of the Cancer
Imaging Program, formerly known as Biomedical Imaging Program of the
National Cancer Institute.

I would like to thank Dr. Krause and Schultz for this opportunity to
introduce to you an initiative that\'s going to be announced shortly, in
the next few months, that is a program for small business grants for
integration and clinical evaluation of technologies for image guided
interventions.

I only have a couple of slides that I will go through quickly.

There has been many advances in the last ten years or so in combining
imaging with drug or inertial (phonetic) delivery systems that have
assimilated the need for development and optimization of these systems
for clinical evaluation.

We view image guided interventions as, indeed, separate categories of
imagine guided biopsies, image guided surgeries, and image guided
therapy.

The majority of research thus far has focused on development of
component technologies for various interventional techniques. So
there\'s a lack of integrated and optimized IgI systems, and that\'s one
of several obstacles in advancement of image guided interventions of
cancer.

There\'s also a realization for complexity of IgI methods that is
expected to increase as the new technologies come on line. These
technologies include molecular imaging, miniaturized electromechanical
systems and robotics.

So we feel that there\'s a need to extend beyond feasibility trials in
some of these techniques.

The purpose of this program announcement is to promote integration of
component technologies in image guided interventions and help support
their subsequent clinical trials in order to deliver these technologies
into the bedside.

So we realize that these tasks of system integration and clinical trials
require extended financial support, and this program is designed to do
that and meet some of these needs.

The technological scope of this initiative would include integrational,
interventional, and monitoring devices onto imaging platforms, such as
MRIs, CT, or ultrasound. The clinical applications would include tumors
of solid organs, including brain, lungs, liver, the breast, et cetera.

So with that in mind, I\'m here to answer any questions after the
program or any time, and there\'s my contact information. I\'ll be happy
to discuss anything with you.

Thank you.

DR. KRAUSE: Thank you.

ACTING CHAIRPERSON McCAULEY: Good afternoon. I\'m Dr. Robert McCauley,
and I am Professor of Surgery and Pediatrics at the University of Texas
Medical Branch in Galveston and Chief of the Plastic Surgery Services
for the Shriners Burns Hospital also in Galveston, Texas.

I\'m currently serving as Acting Chairman for this session.

This afternoon the panel will be making recommendations to the Food and
Drug Administration regarding clinical concerns involving devices
intended to ablate or remove breast tumors.

Since we have new panel members, I\'d like to take this time to
introduce the panel members who are giving of their time to help the FDA
in these matters and the FDA staff at the table. I\'m going to ask each
person to introduce him or herself stating his or her specialty,
position, institution, and his or her status on the panel as a voting
member, industry or consume representative, or deputized voting member.

I would like to start to my right with Dr. LoCicero.

DR. LoCICERO: I\'m Jose LoCicero. I am a thoracic surgeon. Currently I
am professor and chair of the Department of Surgery at the University of
South Alabama, the Director of the Center for Clinical Oncology in the
Cancer Research Institute of the University of South Alabama, and I am a
deputized voting member.

DR. SOLOMON: I\'m Steve Solomon. I\'m a radiologist at Johns Hopkins,
and I\'m a consultant to the panel.

DR. HALBERT: Hi. I\'m Francine Halberg. I\'m a breast cancer radiation
oncologist at the Marin Cancer Institute and clinical associate
professor at UCSF, and I\'m a consultant to the panel.

DR. KOPANS: I\'m Daniel Kopans, Professor of Radiology at Harvard
Medical School and Director of the Breast Imaging Division at the
Massachusetts General Hospital, and I\'m a consultant to the panel.

DR. BRENNER: Dean Brenner from the University of Michigan, Professor of
Internal Medicine and Pharmacology. I\'m a medical oncologist and
pharmacologist responsible for the Cancer Prevention Program at the
University of Michigan Cancer Center.

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

DR. WITTEN: Celia Witten. I\'m the Division Director of the Division of
General and Restorative and Neurological Devices at the FDA, which is
the reviewing division for these products.

MS. BROWN: I\'m Debera Brown. I\'m the Vice President of Regulatory
Affairs for Bronchus Technologies. I\'m the industry representative and
a non-voting member of the panel.

DR. DOYLE: I\'m LeeLee Doyle. I\'m the Associate Dean for Continuing
Medical Education and Faculty Affairs at the University of Arkansas for
Medical Sciences, College of Medicine. I\'m the consumer representative
and a non-voting member on the panel.

DR. BLUMENSTEIN: I\'m Brent Blumenstein. I\'m a biostatistician in
private practice. I\'m a temporary voting member.

DR. CHOTI: I\'m Michael Choti, surgical oncologist at Johns Hopkins
Hospital and associate professor of surgery and oncology, and I\'m a
voting member on the panel.

DR. LEITCH: Marilyn Leitch. I\'m a surgical oncologist, Professor of
Surgery at UT Southwestern Medical Center in Dallas, the Medical
Director for the Center of Breast Care there, and I\'m a temporary
voting member.

DR. LANZAFAME: Hi. I\'m Raymond Lanzafame. I\'m a general surgeon. I am
the Director of Laser Medicine and Surgery at the Rochester General
Hospital in Rochester, New York, and I\'m a temporary voting member.

DR. KRAUSE: My name is David Krause, and I\'m the Executive Secretary of
the panel.

ACTING CHAIRPERSON McCAULEY: We will now proceed with the open public
comment session for this afternoon. 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 of the medical device companies.

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 the
transportation and accommodations.

We will begin with those individuals who have notified the FDA of their
request to present in the open session.

There is none?

DR. WITTEN: No.

ACTING CHAIRPERSON McCAULEY: Okay. Is there anyone else wishing to
address the panel at this time?

(No response.)

ACTING CHAIRPERSON McCAULEY: We will now move to the FDA presentation.
Dr. Binita Ashar of the FDA is going to give us a presentation at this
time.

Dr. Ashar.

DR. ASHAR: Thank you.

Good afternoon. My name is Binita Ashar, and I\'m a general surgeon with
FDA\'s Center for Devices and Radiological Health.

I would like to provide a brief introduction for this afternoon\'s open
session where you will be providing your recommendations regarding
clinical trials designed to examine the safety and effectiveness of
thermal ablation devices for the local treatment of breast cancer in
lieu of local resection.

There are several technologies that have been described in the
literature as using a minimally invasive approach to introduce thermal
energy into a breast cancer in order to produce irreversible cell
damage. These devices include radio frequency ablation, focused
microwave, focused ultrasound, interstitial laser photocoagulation, and
cryoablation.

Many of these devices have been cleared by the FDA and are marketed for
the general indication for soft tissue ablation. For a device to obtain
a more specific indication, however, we expect a clinical study for this
new indication demonstrating device safety and effectiveness.

At this time no thermal ablation device has been cleared by the FDA
specifically for the treatment of breast cancer. FDA, therefore, is
seeking the panel\'s input regarding clinical studies that may be
conducted in order to support such an indication.

We believe that an open forum such as this is the best way to initiate
this process, and we wish to thank all of those who are participating in
this meeting.

With that, I would like to provide a broad overview of where we have
been and possibly where we are going. As you know, in the late 1980s, a
number of studies, the largest being the NSABPO6 trial, demonstrated
that there was no difference in the disease free and overall survival
between patients treated by total mastectomy versus lumpectomy with
radiation therapy.

It was these results that began the minimalist era of surgical
management of breast cancer in the late 1980s.

In 1996, this panel, the FDA General and Plastic Surgery Devices Panel,
convened to discuss the role of stereotactic breast biopsy devices in
the diagnosis of breast cancer.

As an aside to their primary topic, they did briefly touch on some
clinical trial issues regarding the use of stereotactic breast biopsy
devices for therapeutic breast cancer excision. However, they did not
provide a full discussion that can be used to address the issues that we
are facing here today.

At that time, the panel felt that patients should not receive
therapeutic resection using a stereotactic biopsy device outside of the
confines of a controlled clinical trial, and that the ultimate endpoint
for such trials would be the local failure in the preserved breast.

The panel discussed the duration of follow-up, and depending on the risk
for recurrence, entertained following patients anywhere from two years
to 15 years.

The purpose of today\'s session is threefold. First, we would like the
panel to consider the level of evidence that would be required from
feasibility studies involving breast cancer thermal ablation followed by
open excision before moving to pivotal studies involving breast cancer
thermal ablation without excision and simply following patients for
cancer recurrence.

Second, we would like to obtain the panel\'s recommendations regarding
the framework for pivotal studies examining the safety and effectiveness
of thermal ablation devices for ablating breast cancer in lieu of local
resection.

Finally, as treatment of patients with breast cancer today involves a
multi-disciplinary approach, we would like the panel to comment on the
effects of thermal ablation when combined with radiation therapy,
chemotherapy, and radiographic evaluations.

Oftentimes when a device is demonstrated as safe and effective in one
population, efforts are made to expand the use of the technology to a
broader population of patients. For example, in your discussion today,
you could focus on cancers less than two centimeters having a low risk
for recurrence.

However, how would your recommendations change if the tumor, for
example, was larger than two centimeters with a more aggressive
histology?

Therefore, for each of the following questions please remember to make
recommendations specifying the appropriate patient population and
discuss under which circumstances repeat initial feasibility studies of
ablation followed by open resection should again be undertaken prior to
extrapolating the results to a broader patient group.

You have all been given the questions that FDA has requested that you
address during this discussion, and these questions are provided on the
subsequent slides. I will run through them briefly here, and then Dr.
McCauley can take over the presentation.

This first question deals with the level of evidence that would be
required in moving from a feasibility study that treats the breast
cancer by ablation followed by resection to a pivotal trial that treats
the breast cancer by ablation in lieu of resection.

The second question addresses the pivotal trial framework for studies
aimed to demonstrate thermal ablation device efficacy in providing local
breast cancer treatment in lieu of lumpectomy.

The third question deals with the effect of thermal ablation on the
surrounding tissue affecting the chemo and radiosensitivity of the
surrounding tissue.

And the final question deals with the ability to radiographically follow
the tumor during the time of treatment and subsequently after receiving
a thermal ablation.

Thank you very much for you attention, and I will turn the discussion
over to Dr. McCauley.

ACTING CHAIRPERSON McCAULEY: Thank you, Dr. Ashar.

Are there any questions for Dr. Ashar? Yes.

DR. KOPANS: Just on your last point, it shouldn\'t just be to
radiographically follow, but to follow by imaging because ultrasound is
effective, MRI is effective as well.

DR. ASHAR: Excuse me. Yes, it would be including all radiographic
modalities.

ACTING CHAIRPERSON McCAULEY: Any further questions?

(No response.)

ACTING CHAIRPERSON McCAULEY: We will hear from some members of industry
with regards to this topic. Will the representative, Mr. George Burditt,
from Kelsey, Incorporated please begin your presentation?

MR. BURDITT: Dr. McCauley, Dr. Witten, Dr. Krause, and members of this
very distinguished panel, my name is George Burditt, and I\'ve been
asked to be the spokesman for a group of experts representing Kelsey,
and for the record, of course, we\'re all being paid by Kelsey. I\'m not
sure a lawyer needs to tell you he\'s being paid, but I must admit I\'m
being paid for this presentation.

The other members of this panel of experts that I\'ve had the pleasure
of working with are Dr. Kambiz Dowlatshahi, M.D., F.A.C.S, professor at
Rush Presbyterian Medical School. He introduced stereotactic core needle
biopsy to the United States. He has pioneered interstitial laser therapy
for breast cancer treatment and is a leader in this field.

Phil Lavin is a biostatistician, an eminent biostatistician particularly
in the field of the subject we\'re talking about today, clinical studies
for devices.

Chris Brauer, former of the Office of Device Evaluation, is also an
expert in this field, particularly concentrating in women\'s health
issues, which are, of course, so important in the subject that you all
are considering today.

Dave West, who is with ODE for many years, as I\'m sure you know, and
his associate Chris Sloan, who is with us here today or consulting with
us, they are both now with Quintiles.

And we also are pleased to have Linda Jewel of Siemens here with whom
we\'re working closely and Tyco has been working with us.

And I must saw as a lawyer who has been practicing food and drug law for
50 years, I\'m particularly pleased to have such an outstanding group of
experts supporting me in this whole project.

As I poignantly know from personal experience, the most dreadful
sentence a woman can hear is, \"You have breast cancer.\" My wife heard
that sentence when she was 39 years old, and in those days she had the
state-of-the-art treatment, which is mastectomy with excision of the
axillary nodes, and that was accepted as the method of treatment.

Since that time detection methods have increased substantially. As the
Society for Women\'s Health Research said, as you can see in this slide,
breast cancer really gives women a double dose of fear, of course fear
of dying, but then equally important, the fear of disfigurement from
treatment.

This slide shows the incidence of detection of small breast cancers. The
only application of ILT is for breast cancers of 1.5 centimeters or
less. So we\'re talking about small cancers here.

This slide, which is from a 1990 study, shows that in 1990, 25 percent
of the tumors detected in women\'s breasts were one centimeter or less,
and Dr. Dowlatshahi thinks that now that figure 13 years later is
probably nearer 50 percent.

The developments in detection of breast cancer, all of the things that
have just been mentioned, the ultrasound, color Doppler ultrasound,
developments in mammography, all of these other diagnostic and detection
procedures have been developed enormously over the last few years as you
all are well aware.

But the treatment of breast cancer has not followed suit. It simply has
lagged behind, and as the National Cancer Policy Board said, serious
problems exist with the quality of cancer care provided to women with
breast cancer in the United States.

There was a [Time]{.underline} magazine article that expressed this same
dichotomy between the development of breast diagnosis and treatment of
breast cancer, and Dr. Gralow from Hutchinson said, \"We may be far over
treating our patients,\" and that\'s particularly true because of the
increase in the percentage of the small tumors.

Let me turn now to this ILT treatment specifically. It\'s a new
treatment option. It is clearly not a universal replacement for
lumpectomy. Lumpectomy does have defects, as you are well aware. There
are risks with it.

I saw one study that over a period of 20 years lumpectomy with radiation
and with chemo had a 20 percent failure rate after 20 years, and without
any supplementary treatment it had a failure rate of 40 percent.

Women in the United States deserve an alternative to a procedure that
has a failure rate as high as that.

Here\'s a diagram of the device, and Dr. Dowlatshahi, who is an expert
with lasers, is going to focus the laser on that slide so that you can
see specifically the things I\'m talking about.

Using stereotactic imaging, the location of the tumor is precisely
determined. That\'s the blue in the center.

Small metal markers are inserted in the periphery of the tumor for
accurate visualization and follow-up. Those are those five little black
points that you can see.

Two needles are inserted into the breast, one bearing the laser probe
\-- that\'s the one on the left \-- together with fluid infusion at the
tip to keep it cool, not over 100 degrees Centigrade, and the other
bearing the temperature monitoring probe. That\'s the one that has the
five dots on it.

Stereotactic imaging confirms the proper placement of the needles. The
doctor is watching the whole placement of the needle on his screen.

Power supplied to maintain the central temperature of 80 degrees to 100
degrees Centigrade during treatment.

Well, I pushed something here, and I haven\'t the slightest idea what I
pushed. Help.

Dr. Lavin is not only an expert in biostatistics, but he\'s also an
expert in \-- thank you, Tim. Thank you, Phil. Sorry. Beg your pardon.

But power is applied to maintain the central temperature in the core at
between 80 and 100 degrees Centigrade, never over 100, and the saline
solution I mentioned is on the tip to make sure it doesn\'t go over 100,
and the surgeon has real time monitoring through five sensors, with the
five sensors that you can see throughout the 2.5 centimeter sphere.

The procedure is automated. It has continuous control through the
procedure. The surgeon is in complete control of it. You end up with a
transcript of the treatment and a patient record.

The great advantage of this is that it\'s replicable, evaluable, and
controllable. It\'s a standardized procedure.

After the procedure axillary node biopsy is performed, and radiation and
chemotherapy is administered as needed, just as it is now.

This is a chart that shows one of the things that the surgeon is looking
at during the procedure. This is a display. The left column, the tall
one with the red at the top of it, is the temperature inside in the
center of the tumor.

The five bars are the temperatures recorded by each of those five
sensing points on the needle, which you saw in the diagram. This is an
example of the control the surgeon has when he\'s administering this
procedure.

These are mammographic images, pre-ILT on the left, post ILT on the
right.

This is a color Doppler ultrasound, which to me was very impressive. On
the left it shows the blood vessel feeding the tumor right in the
center. The white is the blood vessel. On the right the blood vessel is
gone. This is post treatment, right after treatment. There\'s no delay
in this. It is after treatment. As you can see, the blood vessel has
been totally ablated.

Let me switch now to patient selection for the study. This is a list of
at least some of the criteria that we would propose that you consider in
your recommendations and which we would like to propose to the agency.

The lesion, as I said before, must be not greater than 1.5 centimeters.

[In situ]{.underline} or invasive cancer must be established by core
needle biopsy.

The lesion has to be well defined and clearly visualized so that you
will have that .5 centimeter zone around the tumor.

There\'s no radiotherapy or chemo applied before because that would
throw it off.

And the baseline diagnostic mammograms, ultrasound, color Doppler
ultrasound would be taken prior to treatment.

How do you know if that damned spot is out, as Shakespeare might have
said with this process? One month following the treatment, the patient
is examined thoroughly, mammogram, ultrasound, color Doppler ultrasound,
core needle biopsies of the treated tumor at the center and at three,
six, nine and 12 o\'clock positions, and pathological examination of the
tissues taken from the core needle biopsies.

As far as follow-up and monitoring is concerned, we would propose three,
six, nine, and 12 months follow-up for everybody in the study with a
mammogram, ultrasound, and if there\'s any area suspicious anywhere in
the tumor, additional core needle biopsies would be performed, and of
course, everyone would go through annual screening mammography
thereafter.

As far as investigators, and this is also very important because it may
be unique for this particular kind of a study, experience breast
specialists only would be enrolled as the investigators. They must be
experts at image guided core needle biopsy.

Dr. Dowlatshahi will personally train every one of them, detailed
training in the operation of the device and procedure, and the initial
procedures by the investigators would be supervised. Dr. Dowlatshahi is
going to actually go to the center where every one of these
investigators is performing his work and at least the first, and maybe
more than one, but at least the first one, Dr. Dowlatshahi will
personally participate in the therapy, and hopefully that will show that
there will undoubtedly be at the beginning a resection of at least the
first one.

And incidentally, I should thank Dr. Ashar for her beautiful
presentation to you all. That was most helpful and certainly spells out
the issues that you will be facing.

We would hope that you would not require because of the circumstances of
this whole situation a separate feasibility study followed by a separate
pivotal study. We would propose that you run in the feasibility study
into the pivotal study bey requiring, as we propose to do, that the
first patient, at least the first and maybe more than one, not only have
the ILT, but also have a lumpectomy, and that will help establish the
efficacy. It will help establish the training has been successful. It
will give everybody the comfort factor that you would normally get with
a feasibility study.

But this laser is not a new event. As you\'re well aware, lasers are
used in all parts of the body now, and this is the first time it has
been proposed for use in treating breast cancer, but it\'s not like
it\'s bringing something off the moon all of a sudden to use a procedure
that\'s never been used before. It\'s a well established procedure, and
the laser that\'s being used is a well established laser. Hopefully it
will show the ablation of the tumor and the half a centimeter margin
rounded.

For clinical trials we would propose a multi-center study obviously to
test for effectiveness, and in this particular circumstance, patient
satisfaction and cosmesis, which are really far more important in a
study like this and for this kind of a device than for most surgical
devices. The clinical trials would collect safety data on every facet of
safety that\'s known to mankind, adverse events, failures, local
recurrence, everything that would normally be done, and it\'s very
important not only to Kelsey, but to everyone in the United States that
we have a total safety report.

Hopefully this would demonstrate that the tumor has been ablated and
that the patient satisfaction is guaranteed with the procedure and with
breast appearance, and again, because of this unique procedure, because
of the quality of life.

We propose that you consider that we have a one-year study one year
after the last patient is enrolled so that every patient in the study
would have at least one year of treatment. As a matter of fact,
everybody would have more than one year except for the last patient
enrolled. So while it\'s one year, it\'s one year only starting with \--
the year doesn\'t start until the last patient is enrolled.

My own personal feeling, this is probably the most important slide of
all. We propose a long-term post market follow-up of all treated
patients for 20 years. That is, in a sense because we\'re asking for the
one year period for the pivotal study, but we want to make sure that 20
years later this process is successful.

Incidentally, 20 years is also what\'s the number in 20-year studies on
lumpectomy. So it would give us something to compare.

The long-term follow-up would include a registry of all treated
patients, keeping track of everybody. I\'m in a registry like that for
another medical device. So I know it works. There are registries like
this. It\'s not a new concept, but it would be applied to this specific
device.

And the registry and the follow-up would include new patients admitted
to the study post clearance. It would not stop just with those enrolled
in the first year.

Ladies and gentlemen, thank you very much. ILT is a major step in the
treatment of breast cancer. It will help close the gap between the huge
advances in detection and the relative inaction in the field of
treatment of breast cancer.

It has been a great pleasure for me to see these experts and to listen
to them and hear them explaining all of the benefits of this to women
throughout the United States, and we urge you to consider these very
carefully. We know you will. We appreciate very much the action of the
FDA in picking such an outstanding panel to hear us.

We\'ll be here all afternoon if you have any questions of any of we.
We\'d be delighted to try to answer.

Thank you very much.

ACTING CHAIRPERSON McCAULEY: Thank you, Mr. Burditt.

Do we have any questions from the panel regarding this presentation.

DR. KOPANS: More of a comment. I\'m not sure there\'s actually an
answer. I think it\'s important to realize that stereotactic guidance,
the actual anterior and posterior margins of the lesion are not
determinable using stereotaxis. So I assume that the technology is being
used with the thought that there will be a spherical volume of ablation,
and you\'re assuming that the anterior and posterior margins are going
to be within that sphere.

I think there\'s a little bit of question whether that\'s going to be
true or not.

MR. BURDITT: A very good question. We\'ve tried to address it in a
couple of ways. One is it will only be a defined tumor. If it\'s one of
these tumors that\'s kind of splattered around, not eligible for the
study; won\'t be included.

Second, because of the follow-up and because of these enormously
improved detection methods, if anything is missed, there\'s always the
possibility of going back in and doing a lumpectomy or any other
procedure that\'s necessary.

Furthermore, it\'s anticipated that there will be radiation and chemo as
there is with lumpectomies. We\'re not trying to avoid that. Those will
still be in there. So that\'s certainly something that Dr. Dowlatshahi
is very well aware of. That\'s why he\'s proposing half a centimeter
margin beyond what you can see as the end of the tumor.

But you\'re right. Tumors are irregular in shape, and therefore, we\'re
trying to reach that question by focusing specifically on these smaller
tumors that are well defined.

Thank you, sir.

ACTING CHAIRPERSON McCAULEY: Dr. Lanzafame.

DR. LANZAFAME: Yes. Can you provide some further detail on the spacing
between the thermal probe and the laser probe?

And secondarily, I\'m assuming that the process is a photothermal
process and is also related to the wavelength. Given that fact, do you
have any specific information on the scattering characteristics of the
metallic clips and the thermal probe?

MR. BURDITT: On the first question, the needles are parallel, as you can
see in the diagram. They will be a millimeter or a millimeter and a half
apart, but parallel. As a matter of fact, Dr. Dowlatshahi did one just
the other day under his IRB approval, and the first time the second
needle didn\'t go in right, and they had to modify the second needle.

Incidentally, the lady was totally satisfied.

DR. LANZAFAME: So in other words, the thermocouple is one millimeter
away from the laser source and not at the edge of the sphere as it\'s
shown in the diagram? Am I understanding that correctly?

MR. BURDITT: Kambiz.

DR. DOWLATSHAHI: George, I think I\'d better step in.

MR. BURDITT: I appreciate.

DR. DOWLATSHAHI: Thank you for your great presentation.

Regarding the distance between the two needles, currently we\'re using
one centimeter in order to give that zone of ablation. The eventual size
of the zone of ablation is about two and a half centimeters in diameter,
between two and a half to three centimeters, which will encompass the
1.5 centimeters.

Going back to your question regarding the effect of the laser beam on
the metal markers, these are steel markers which are used for carotid
inclusion. I don\'t think it is going to affect the reflection. Is that
what you were saying?

DR. LANZAFAME: Actually it\'s the other way around. Is there a
scattering or interference?

In other words, one issue would be black body absorption, which is what
I think you\'re addressing. The other would be scattering or shadowing
at the opposite end relative to your source, whether it\'s spherical or
cylindrical.

DR. DOWLATSHAHI: In terms of you mean affecting the coagulation of the
tissue?

DR. LANZAFAME: Right.

DR. DOWLATSHAHI: I have not seen that happen. In practice, the only 54
patients that I treated and removed serial resection by a pathologist
did not show any escape or failure of the malignant cells around the
markers.

I think Dr. Kopans has one question.

ACTING CHAIRPERSON McCAULEY: Dr. Blumenstein.

DR. BLUMENSTEIN: So there\'s a point here where you use the term \"post
marketing.\" So I assume that this is your registration trail that
you\'ve described here.

DR. DOWLATSHAHI: Yes.

DR. BLUMENSTEIN: So I failed to identify the primary endpoint. I didn\'t
see anything about a sample size, and I gather this is not a randomized
study. So what is your reference data? What is your criterion for
success?

MR. BURDITT: It is not a randomized study. We\'re proposing a single arm
study. I like to think in my terms that you don\'t really need a control
group. How would you get a control group? You can\'t have a group of
people who aren\'t going to be treated. That would obviously be
unethical.

To have a group of people on a particular treatment that\'s in existence
doesn\'t really serve much purpose. The test is: is it successful? And
we\'re proposing a Bayesian type study that would focus on this group
only.

We have not talked about numbers. The reason we haven\'t is that we want
to discuss this matter very carefully with FDA. Of course, we have
numbers in mind. They\'re a little confidential, for one thing, but we
also want to discuss with FDA what FDA thinks is a reasonable number to
have in the study.

We want to discuss the number centers, the number at each center. This
equipment is quite expensive, and we can\'t have 50 centers. In the
first place, Dr. Dowlatshahi is going to train everybody at every
center, and it\'s not feasible to have that many.

It will be a few centers carefully selected with experienced physicians,
and the number at each center we\'ll work out with FDA in our proposal.

ACTING CHAIRPERSON McCAULEY: Dr. Brenner.

DR. BRENNER: So in your design, if I\'ve got it right, you\'re going to
do re-needle biopsies, but you\'re not going to resect because I presume
you\'ve already published that. Is that what you\'re suggesting?

And if so, if that\'s true, if I got you right, then how do you know
that you actually ablated beyond a centimeter or half centimeter margin
that you\'re claiming to ablate for a regulatory endpoint?

I\'m confused.

MR. BURDITT: Well, the answer lies in all of these enormously improved
diagnostic detection techniques. The physician is going to be looking at
this regularly, one month with a careful follow-up with all of the
diagnostic tools that we know about, and regularly throughout the year
so that we can answer these questions.

We don\'t believe there will be any splatter or anything caused by the
five markers. We don\'t believe that anything is going to happen. Dr.
Dowlatshahi has not seen them in the 54 patients he has done, and what
we plan to do is watch carefully for those things.

That\'s an excellent question. That\'s obviously the kind of thing we
have to watch about.

DR. BRENNER: So your argument is that the imaging is sufficient to rule
out any kind of cells that are viable; that the imaging will pick all of
that up. Is that your argument?

MR. BURDITT: Yes, sir.

DR. BRENNER: Thank you.

MR. BURDITT: And it will be continually improving. Even that advanced
procedure isn\'t stopping.

Yes, sir.

DR. KOPANS: Well, just as an imager, that doesn\'t work. There\'s no
imaging test that really can accurately tell you. Certainly microscopic
disease and even fairly gross disease may be viable, and there\'s no
imaging test that can tell you its viability or nonviability.

I do have a question. You\'re saying that you\'re going to have a
thermal injury of three centimeters, two and a half to three centimeters
in diameter. Breasts in compression in stereotactic devices, I haven\'t
looked at the numbers, but they\'re down around four centimeters that
allow biopsy.

What kind of distance do you need for the lesion to be from the skin
surfaces so that you don\'t affect the skin surfaces?

DR. DOWLATSHAHI: One centimeter.

DR. KOPANS: One centimeter at both ends? Because that\'s kind of triple
the number of individuals you can treat.

DR. DOWLATSHAHI: I realize that, but I think if the lesion is close to
the skin, it\'s possible to cool the skin by ice or by spray, and
that\'s, in fact, what I have done in the past. In the far posterior
part of the lesion close to the chest wall, that, again, has not been
any problem, but I think the point that you\'re raising is correct. The
small breasted women who in compressed form will have the thickness
between the skin, the front and the back reduced significantly may not
be suitable for this, but in practice we have not had any burns on
either side.

DR. KOPANS: The other point, again, for the panel is that when you\'re
doing a stereotactic positioning of anything, the lesion doesn\'t always
fit in the center of the compressed volume. So you may have a four
centimeter thick breast, but the lesion could be a half a centimeter
from the anterior-posterior skin.

So just another issue that you\'re going to have to deal with.

DR. DOWLATSHAHI: But my response to that was that that may well be true.
I agree with you, but there has not been any scalding of the skin apart
from the very early days when the fluid dripped back onto the skin.

Now we\'re quite aware of that, and we take care of it by cooling the
skin. In fact, there\'s going to be a thermal sensor on the skin.

DR. KOPANS: Just one more follow-on. Sorry.

And that is that one of the things I haven\'t seen in the reports on the
various ablation technologies is really evidence that cosmesis is
preserved. I mean, I take your word for it. I just wonder though if this
amount of heating even just under the skin, if the skin is preserved, do
you end up with puckering and so on?

I would suggest that there be some way that you monitor the cosmetic
results in any of the tests that are done.

DR. DOWLATSHAHI: The patients will be photographs before and after. The
break has not occurred, except in one case in my experience, and this
is, of course, the patient who has had treatment and been followed up.
Those early 54 cases, they all underwent lumpectomy or mastectomy.

ACTING CHAIRPERSON McCAULEY: Dr. Brenner.

DR. BRENNER: Well, pursuing the cosmesis endpoint since that seems to be
a major theme in all of these presentations and documents, I\'d like the
speakers if they could to address the question of whether or not
there\'s a validated, reproducible method of measuring cosmesis for the
breast as an outcome because that seemed to be problematic, at least to
me.

DR. DOWLATSHAHI: I think that that is correct. As I said, the
photographic or the taking pictures from the breast before and after
surgery or after treatment is one way. I think there are some other
methods of developing the patient\'s satisfaction is probably going to
be also an issue here, which is something to be considering.

I don\'t have a definite answer for you right now.

DR. BRENNER: I think the radiation oncologists and perhaps the plastic
surgeons might have \-- I know there are scales that have been used. I
don\'t know the validation for those, but it might be something to
discuss with those folks.

DR. HALBERG: Sir Dr. Harris Tarvard (phonetic) has written extensively
on assessing cosmesis after radiation therapy, and I\'m sure those same
scales could be used in your work.

Since I have the microphone, could I ask a question at this point?

ACTING CHAIRPERSON McCAULEY: Sure.

DR. HALBERG: I was wondering if you have information from the color
Doppler ultrasound about the blood flow in the tissue immediately
adjacent to the ablated zone.

DR. DOWLATSHAHI: Immediately afterwards there is increased flow to the
vessels surrounding the ablated area. There is hyperemic, as you expect,
intense hyperemia which is shown by color Doppler. We usually wait for a
few days for that reaction to subside before evaluating the tumor.

So what I can tell you for sure is that the vascularity of the tumor is
abolished totally. Sometimes the tumor does not have much vascularity,
and we enhance that by giving an enhancing agent, such as \--

DR. HALBERG: I was actually more interested in maybe a month out after
the initial hyperemic and increased blood flow changes, if there\'s a
zone of decreased blood flow that you\'re left with. I don\'t know if
you\'ve done those color Dopplers prior to lumpectomy and how long
you\'ve waited, you know, what your longest interval has been from the
doing the laser treatment to the lumpectomy.

But I\'d be interested in the longer term blood flow in that region.

DR. DOWLATSHAHI: The longer term, if we look at these two or four weeks
or even six weeks, it diminishes. The flow, the amount of flow in the
vessels diminishes, but undoubtedly there is a cut point between the
vessels in the normal unablated tissue and the ablated tissue.

DR. HALBERG: So the transition zone with decreased blood flow then
adjacent to the area of necrosis long term?

DR. DOWLATSHAHI: Long term there is definitely a decrease.

DR. HALBERG: Thank you.

ACTING CHAIRPERSON McCAULEY: Dr. Solomon.

DR. SOLOMON: In your lumpectomy specimens, what has been the consistency
and size of the ablated zone? Has it been something that\'s reproducible
given the power setting that you\'re using?

DR. DOWLATSHAHI: The series that we removed dated the interval between
the treatment and the removal was between three to four days all the way
up to eight weeks, and you do see the changes in terms of the acute
necrosis. The pathology is a little bit more detailed. If you wish I can
give you the several zones.

Very close to the laser you get what you call a wind effect. Further
away from the laser there is an area what we call pseudo necrosis. With
HME you don\'t get any \-- it looks as though it\'s non-treated. Further
away, one millimeter away or three millimeter away, you get total
necrosis. Further away you get hyperemia with fat necrosis. So you have
concentric circles of about two to three millimeters from the center,
which is the laser point.

DR. SOLOMON: But do you ever get smaller ones in the sense that, you
know, if you do a particular patient can you count on it always being
two centimeters in diameter or is it possible that some patient it\'s
only one centimeter? Because that\'s going to be crucial for doing an
image guided procedure.

DR. DOWLATSHAHI: Quite right. It depends on the amount of laser energy
you give. In other words, if you give about 3,000 joules, you may get up
to about one and a half or two. If you give eight or 9,000 joules of
energy, you may get about 3,000. I\'m sorry. Three centimeters.

Therefore, there is a titration between the amount of energy and the
size of coagulation.

DR. SOLOMON: And when you\'ve looked at these patients on a separate
topic of cosmesis after ablation, is there a hard nodule or something
that they can feel after the procedure in terms of scar?

DR. DOWLATSHAHI: Immediately after the procedure there is a swelling. If
the tumor was nonpalpable, the patient feels a swelling or fullness
rather in the area. We give them ice packs for the next six to 12 hours,
and the patient feels the fullness which may become even a lump over the
next six to 12 weeks, and then subsequently this will decrease and
disappear, and that mass is actually the changes you see on the
mammography.

ACTING CHAIRPERSON McCAULEY: Dr. Kopans?

DR. KOPANS: Just a follow-up on the issue that Dr. Halberg brought up,
and that is that if, in fact, the blood supply to the tissue surrounding
the ablated tumor is compromised, that could conceivably influence the
effect of radiation to any residual tumor nest that may still be viable
in the area.

So, you know, killing the blood supply is a good thing if you get all of
the tumor. It may not be a good thing if it\'s compromised at the time
of radiation therapy.

DR. DOWLATSHAHI: I think that that has a valid theoretical point. In the
cases that have been treated in this way and not removed, I have one
patient who has now gone for three and a half years. The tumor, which
was eight millimeters, was totally ablated, and she developed a small
oil (phonetic) cyst at one year, which I aspirated without any necrotic
tissue in it. In fact, I have three patients like that. The tumors are
ranging from seven millimeters to 14 millimeters, and at one year at the
cyst which was the residual evidence of cancer there was about one, one
and a half centimeters, which was evacuated subcutaneously.

DR. KOPANS: If I could just make a follow-on point to what Dr. Solomon
was, I think, getting at, and that is that the recurrence rates that
we\'re seeing now following lumpectomy surgical excision with negative
margins and radiation, our recurrence rates are down around two percent
at about eight to ten years, much lower than what was reported in BO6,
for example.

So modern surgery, modern radiation has really reduced the recurrence
rates even lower than what\'s in the literature, and I would urge FDA to
perhaps look at more modern series as a reference point.

And I think the improvement is due to the fact that we really are
looking for negative margins, and the concern that I think some of us
have on the panel is if you\'re not removing the tumor, you don\'t know
that you\'ve got negative margins, and so you have to have an ablation
technique that somehow as close as you can will assure that you\'ve
gotten all of the macroscopic margins.

Of course, the reason for radiation is that you can never be sure that
you get all of the tumor even with surgery, but I\'d had to go backwards
where we\'re seeing a marked decrease, a decrease in mortality from
breast cancer due to imaging early detection and I think better
therapeutic techniques, and I think we just need to be careful not to
lose some of the ground that we\'ve gained.

DR. DOWLATSHAHI: I think the question of margin has been extensively
evaluated recently. There was a very good review by the N.D. Anderson
group. The difference in the recurrence between eight millimeters and
five millimeters and three millimeters and one millimeters did not seem
to be significant.

If you have cancer right at the point of resection that seems to be
true. That seems to be important.

If I address the question of the markings intraoperatively as a surgeon
myself, as well as others who are in the field, we always depend on the
tactile sense to achieve about at least four or five millimeters of
normal tissues surrounding what we regard to be a cancer.

I think by imaging it is possible to evaluate that much, much better. I
think there is a fairly good correlation between the tumor size by
imaging, ultrasound or mammography, versus pathology. I think it\'s
close to 80 percent judging by the papers that I have read and judging
by my own experience.

So I think the imaging by mammography and ultrasound will give you a
good idea of the extensions of the tumor. Remember that we are going to
be very selective in the inclusion of the cases for this study,
especially when we can see the tumor as a clear moon in the sky. Those
are the ones that we\'re going to choose initially for this treatment,
and to exclude those with the extensive intraductile carcinoma, as
represented by micro calcifications for even necessary by MRI.

DR. KOPANS: But we can\'t lose sight of the fact that modern therapy has
been, I think, more successful because it\'s predicated on negative
pathological margins. We can\'t feel the margins of a tumor, certainly
the microscopic margins even at surgery, and the issue of extensive
intraductile cancer is also a problem because not all intraductile
cancer calcifies, and so you can have extensive DCIS at the periphery of
a tumor that\'s not evident by imaging, not evident even at the time of
surgery, but the pathologist says that the margin is grossly involved.

Those lesions you won\'t know about until they recur.

DR. DOWLATSHAHI: But I would like to challenge you, Dr. Kopans, with
regard to the pathology being gold standard. I don\'t think that is 100
percent true because it depends on the pain of the knife of the resident
who usually bisects these tumors and reports that the largest diameter
or the margin was clear or not clear, may not be in that knife.

In other words, the knife might have gone this and the other side of
that positive margin.

ACTING CHAIRPERSON McCAULEY: Do we have any other industry
representatives that wish to address the panel at this time?

(No response.)

ACTING CHAIRPERSON McCAULEY: I would like the panel to keep in mind that
we\'re talking more specifically about general clinical issues regarding
nonsurgical ablation of breast tumors. We do have some questions that
we\'ll have to answer that were presented to us by Dr. Ashar, but we\'ll
take a 15 minutes break and we\'ll come back and address those
questions.

(Whereupon, the foregoing matter went off the record at 2:08 p.m. and
went back on the record at 2:25 p.m.)

DR. KRAUSE: Neil, could you put up the first question, please?

ACTING CHAIRPERSON McCAULEY: This is the first question which the panel
is asked to address for the FDA. That question states: please
characterize the appropriate level of evidence or confidence level that
will be required to move from a feasibility study that treats breast
cancer by ablation followed by resection to a pivotal trial that treats
the breast cancer by ablation in lieu of resection. Include in your
discussion the following issues: accuracy of the device to target the
specific lesion, completeness of ablation, reproducibility of different
investigators, and reproducibility amongst different centers.

We\'ll start with \-- is there a lead reviewer for this question?

DR. ASHAR: I believe Dr. Leitch was going to be starting with us.

ACTING CHAIRPERSON McCAULEY: Dr. Leitch.

DR. LEITCH: Well, with respect to this question, I think the confidence
level we want, first of all, is that we can document that there is
successful ablation of all viable tumor, and I think patients would like
100 percent confidence level, and that may not be technically feasible
to get, but I would say somewhere 95 percent to 100 percent evidence of
complete ablation in a feasibility study.

And one of the studies we have for review by ISO describes a 96 percent
total ablation rate in that series. That series is small, 26 patients, I
believe; microwave; 80 percent response rate, but measured in sort of
different ways, not necessarily a pathologic complete ablation.

Dr. Dowlatshahi\'s studies, you know, originally 70 percent complete
ablation, and then ultimately in later cases higher rates of complete
ablation, but of course, that represents an experience over time and
working out the bugs of a procedure.

So within that, you want to have confidence that the tumor, in fact, is
ablated by whatever method of ablation is chosen, and the targeting
techniques, I think we have a lot of evidence from the biopsy literature
about successive targeting with respect to stereotactic radiographic
imaging, as well as ultrasound.

I think a more difficult technology for trying to target the lesion
would be that of MRI. While it\'s good to define a lesion, there are
still some issues on how to target with that device.

So I think, one, you\'ve got to figure out what technology in a given
investigator\'s hands works the best in terms of achieving ablation, and
you know, we have a number of types to review, and so that would be one
thing I think the FDA would want to address.

In terms of margins, if the lesion is not removed, you\'re not going to
have any sense of what the margin is other than what you estimate it by
some imaging technique with respect to the changes that occur in the
environment of the tumor. That\'s the only way you\'re going to be able
to evaluate a margin.

And it sounds like the investigators have looked at trying to ablate
anywhere from five to ten millimeters beyond the visible lesion. You
know, in surgery we had that pathologic evaluation of what the margin
is, the exact width, but again, to be fair to the ablationist, the
margins have been debated in the surgical literature as well, being
quite narrow in an NSABP trial with not cut across tumor cells versus
the Milan trial with quadrantectomy type wide resection.

So while we can\'t make such a big thing exactly about the width of
margins, you\'re asking different questions about margins in the
ablation without resection versus a surgical specimen which is removed
and has a measurement of the tumor from the edge.

So I think what one would have to get is from the resected data of
ablation, what does it appear to be the width beyond the evidence tumor
on imaging that you have to have your technique impact in order to end
up with ablation of the entire lesion.

Then with respect to reproducibility, again, having the technology that
a lot of people are able to do because breast cancer is frequent. These
small tumors are very frequent, and you can\'t have it be the case that
only five centers in the U.S. know how to do this if you\'re going to
have it be implemented as an important technique in breast cancer care.

So the technology would have to be evolved in a way that it could be
broadly applicable. I think from a surgical perspective, ultrasound
imaging approaches would be more broadly applicable in the surgical
community than MRI certainly, and there are certainly issues in MRI
imaging and the significance of findings that are debated just in
looking at MRI for our current methods of treatment of breast cancer.

So that has a way to go, although it may turn out to be one of the more
accurate technologies.

So those would be my comments to kind of get things started.

DR. WITTEN: Before you go around \-- I\'m sorry. Are you going to ask
everyone else to add?

ACTING CHAIRPERSON McCAULEY: Yes.

DR. WITTEN: Can I just clarify part of what that question means? Is that
okay?

ACTING CHAIRPERSON McCAULEY: Yes.

DR. LEITCH: That would be good.

DR. WITTEN: Okay. Yes. Just in case it\'s not entirely clear, what our
current thinking has been is that we want to make sure the sponsor,
before we approve a large scale pivotal trial, our current thinking is
that the sponsor would need to show that they can ablate the cancer or
the tumor predictably according to a certain predictability by
performing an ablation and then followed by a resection.

And so that leaves us with a dilemma of, you know, say we wanted that as
a feasibility study; then our dilemma is what degree of success for a
feasibility study would leave us happy to approve a pivotal study, given
a high rate of success as was pointed out of, you know, treatment of
breast cancer with conventional methods.

So, I mean, we\'ve heard from one sponsor their suggestion that a
feasibility study is not necessary, and of course, you might agree with
that point of view and you could comment on that also, but in terms of
our thinking, we\'d want a feasibility study where a sponsor performs an
ablation and then resects the lesion to look at how well they did in
their ablation. How would we characterize success of that feasibility
study or what would we want to look for?

And I think you\'ve, in part, answered that, Dr. Leitch, by suggesting,
you know, 96 percent, but I just want to make sure that everyone
understands that that is part of our question. It\'s about our lack of
comfort about knowing when it would be okay to move from one stage of
product development to the next stage.

ACTING CHAIRPERSON McCAULEY: I have one question for you, Dr. Leitch,
and that question actually is addressed to the tumor size that you think
would be applicable to this type of therapy.

DR. LEITCH: Well, I think what, you know, the investigators have shown
us is that their level of confidence \-- and this is true in some of the
other types as well \-- is probably under two centimeters, and they\'re
probably picked this 1.5 centimeter to be sure you\'re not, you know,
2.1 or, you know, that you\'re really sort of, you know, well within
that T1 tumor size.

And then the limitations which have been pointed out with respect to the
zone of whatever ablative technique, for example, in a stereotactic
device where the breast is compressed front to back, this width is going
to be limited by that way the breast is fixed.

So, you know, again, if you\'ve got a big tumor that is, you know,
essentially filling the compression device, you can\'t apply these heat
related technologies because you don\'t have the margin width front and
back.

So having a small tumor in a large breast, you know, lets you do some of
the planning, the treatment planning that would get you the dimensions
on all sides, not just four sides, but also anterior and posterior, you
know, having six dimensions covered by the ablative field, but not have
a complication related to that because you don\'t really have that
width.

So they\'re suggesting smaller tumors. Now, that makes it less valuable,
in my opinion, because a 1.5 centimeter tumor surgically resected from
the breast and the breast looks pretty good when you get finished, and
so, you know, the advantage to the patient of this technology for that
size tumor I think is going to be relatively low.

Where we need more help actually is on the people who are more difficult
to achieve breast preservation, who, you know, we think they have a
small tumor; we resect them; their margins are positive, what we were
talking about with the DCIS at the margin. Where the patient really
desires breast preservation, some of these techniques might be used to,
quote, clean up the margins and help with this periphery of tumor.

But applying it in the very small tumors, the benefits for endpoints, if
we want to look at, of, say, cosmesis, local recurrence which is going
to be low in the standard therapy in that group of patients and the
cosmesis which is very high in those patients, you know, to demonstrate
a significant difference in those is going to be very low.

So while those small tumors may work best for the achievement of
ablation, which I think is true, and it would be safest, the question
is: well, what benefit do you get out of having done it on a smaller
tumor size?

ACTING CHAIRPERSON McCAULEY: Dr. Choti.

DR. CHOTI: I think that a feasibility study, an ablate and resect
feasibility study, well designed is going to be important information
before moving forward to a pivotal trial, and how that feasibility study
is done is going to be important.

One issue, and probably a small tumor ablate and resect is the way to
go; one issue that will come up in the feasibility study is the ethical
aspect of the lumpectomy because it may be that the lumpectomy will
actually need to be or will end up being larger in that woman on that
feasibility study than the lumpectomy she may have gotten if she wasn\'t
in the trial. So that\'s something that the sponsors will need to
address.

Alternatively, it could be an ablate and resect in the mastectomy
situation, which would be a clean study, but there\'s a select number of
patients in whom she may have a small tumor and yet require a
mastectomy.

But that perhaps is one way a feasibility study could be designed.

As far as the endpoints for the feasibility study, difficult. If it\'s
designed where the resection is done immediately after the ablation,
then the \-- well, if the resection is done several days later or a week
after an ablation, then the number you end up with 96 percent necrosis
may be more accurate than in an ablate and resect in which the resection
is done immediately after the ablation, particularly in cryotherapy and
others when you don\'t see immediate histologic destruction of the
cells.

And so certainly after cryoablation, the tumor looks totally viable. So
it\'s difficult to access completeness in some therapies.

In heat thermal ablation it\'s easier immediately, but even then NADA
staining and some other parameters may need to be done to assess percent
necrosis.

The advantage though of an immediate ablate and resect feasibility study
is that this question of the margins perhaps could be more easily
assessed because you often, I think, in breast as in other soft tissue,
you may still be able to see the tumor or histologically tell the tumor
versus normal breast. So you may be able to more clearly assess the true
margin and the ability of targeting. How accurate the center of the
ablation zone is relative to the center of the tumor will give you some
feasibility information about the accuracy of targeting.

ACTING CHAIRPERSON McCAULEY: Dr. Blumenstein.

DR. BLUMENSTEIN: I take this question to mean that you really want a
number, and one number was suggested. I think you said 95 percent, did
you say?

DR. LEITCH: For ablation, tumor ablation.

DR. BLUMENSTEIN: For ablation. Well, it seems like we have to start with
what is the definition of ablation, and that has to be completely
standardized across all possible studies of this type, and I\'m not sure
how to do that. I\'m just a statistician, but you know, in other words,
I assume you\'re talking about a resection with some kind of inspection
of the margins, the surgical margins, and the definition of what
represents success versus failure.

And that\'s going to be difficult, but it seems to me on the other side
of that, once you have that definition it isn\'t a matter of how much
success you have but what constitutes failure, and I think you said 95
percent success. That\'s just something you threw out.

I play this game all the time when I try to work on trial sizes and so
forth, but what the other half of that is what constitutes failure. Is
it 80 percent, 85 percent or 90 percent?

And that has a lot to do with how large of a study one is going to have
to do. If it\'s 90 percent failure, 95 percent success and you\'re
setting up a trial to distinguish between those two hypotheses, it\'s
going to be a pretty large trial.

And so I think that, you know, we need to worry about what constitutes
failure and what constitutes success, not just what constitutes success.

I can also read this question in a very general way, and I might as well
get this off my chest. It says here, \"Was appropriate level of evidence
to move on to a pivotal trial,\" and one of the things I\'m worried
about when I look at these methodologies is all of the new things that
are going on with respect to using the tumor and characteristics of the
tumor with respect to various assays, microarray analyses and so on like
that.

What are we doing in this case because we\'re not getting the tumor?
What are we missing? And what are we missing because we\'re not doing
ancillary lymph node dissection and other things like that?

I don\'t know these things. I\'m asking more as rhetorical questions
because I hang around breast cancer enough to know that a lot of people
think these things are important.

And then there\'s one more question I have, and that is what about
autologous tumor vaccines, which seems to be an up and coming idea. And
so feasibility to move on would also seem to me to be what is it that
you\'re precluding by using this kind of a therapy as opposed to one
that actually harvests the tumor or harvests the tumor plus nodes or
whatever other things are there.

ACTING CHAIRPERSON McCAULEY: Dr. Doyle.

DR. LEITCH: Did you have a comment? Go ahead.

DR. DOYLE: As neither an expert in oncology nor sort of a Dick and Jane
on statistics compared to my companion on the right, one thing that
strikes me is that if this is something to replace the lumpectomy, then
the completeness of ablation, it would seem to me, should be the same as
the completeness of ablation in lumpectomy. So whatever is acceptable
for lumpectomy would seem to me to be the minimal confidence interval we
would accept for the completeness of ablation by any other technique.

ACTING CHAIRPERSON McCAULEY: Ms. Brown, any comments?

MS. BROWN: Coming back to Dr. Blumenstein\'s comment about the
confidence interval for a feasibility study, a 95 percent confidence
level would imply a pretty large group. So my experience is feasibility
studies tend to be smaller studies, but they lead to a pivotal study.

So I was curious what we have in mind in terms of some numbers of
patients in the feasibility study leading on to a pivotal trial.

DR. LEITCH: Well, I think for, you know, a single institution, you know,
you might be able to do something in sort of the 50 to 100, but you also
have to kind of look at the capability to do this broadly, and so I
think what some of the people that are looking at this are trying to do
are to get, you know, at least more than one institution participating
at the same time to demonstrate that you can do this.

And so one theory would be if you had a center that maybe had done 50
cases, where they had resected and they wanted to do this broader trial,
that the other institutions under their tutelage would need to
demonstrate, and my thought would be somewhere in the range of ten to 20
cases where they had ablation rates of 100 percent.

I don\'t think one case is sufficient to say, \"Well, you know, we did
one case and that was 100 percent ablated.\" I think you would need to
demonstrate with some number, and Brent can maybe give us a better idea
about what that would be, but, you know, for that part I don\'t think it
has to be hundreds.

Obviously when you get to comparing it, you know, without resection,
then you\'re talking that you\'ve got to have very large numbers of
patients.

DR. BLUMENSTEIN: Yeah, I mean, I\'ll just throw out some numbers, and I
think Robert made a very good point here about the idea that if you are
doing this kind of study it\'s really multiple institutions. So when
we\'re doing a very small study across multiple institutions, it
doesn\'t really fly very well.

But if your definition of success was 95 percent and your definition of
what constituted failure is 80 percent, then you would require about 40
patients or so. But if you fail to find success, then really what
you\'re saying is that there\'s no evidence that it\'s 80 percent or
more.

Is that success? And so the question is that you really have to talk
about that spread, the difference between what constitutes success and
what\'s your evidence of non-success.

ACTING CHAIRPERSON McCAULEY: Dr. Miller.

DR. MILLER: I think the task of the surgeon is to ablate the tumor, and
if these technologies ablate the tumor, then they can compete with an
open resection, but they have to 100 percent, I think, ablative. I think
anything less than that they lose, and so I think that the feasibility
needs to compare this as an ablative procedure and with an immediate
resection afterwards, with a 100 percent tumor ablation with the
alternative procedure.

And if an investigator proves he can do that, then I don\'t see why that
particular investigator is to be held back from doing a pivotal study
because now the whole question shifts from are you ablating the tumor
properly to what is the biological course of the disease if you ablate
the tumor in this way.

And so continuing to do feasibility studies for somebody who proves they
can ablate the tumor completely with this technology, that is not
productive unless you just move right on, and this will get to what
happens to the disease if you use this approach.

So I think I could envision a study where, you know, you had everybody
go through a period of time where they prove they can completely resect
the tumor with whatever technology we\'re talking about here, in which
they do that for a requisite number of patients.

Then you go right into the next phase with a pivotal study, and you just
sort of conduct the whole thing at the same time. I could see something
designed like that, and it would address all of these questions.

And I don\'t know what number to pick, but I know that for sentinel
lymph node mapping the magic number is 20. If a surgeon wants to start
doing sentinel lymph node mapping, if he does 20 successful mappings and
lymph node dissections, then he start doing mapping. So perhaps
something analogous to that got this.

DR. HALBERG: Can I ask a question?

How important do you think it would be for the surgeon or the
investigator performing the thermal ablation to do the lumpectomy
immediately following the ablative procedure? I mean if they did it
within a week or a couple of weeks would that make a difference to you?

DR. MILLER: I don\' know. I think either immediately \-- I guess I
don\'t know what happens to those tissues once you ablate them like
this. I think the quicker the feedback the better.

If the tissue changes so that you can\'t tell where you did your
procedure, that would be a problem, I guess, but either immediately or
if it\'s reasonable to wait, then maybe a few days, but I think promptly
to do a resection procedure after you try this approach to confirm that
you are getting a 100 percent ablation with your technique.

DR. SOLOMON: Pathologically it can be difficult to assess ablation
immediately after the ablation. So it may take 48 hours or longer until
you can actually see histologically the changes.

DR. MILLER: Okay. So I don\'t know if that\'s important then to wait the
right amount of time to be sure that you check it properly, but the
other thing about this that I\'m aware of is that the biggest problem
with it is localizing the tumor, and the misfires \-- at least I know in
the radio frequency studies, there was 100 percent tumor ablation if the
tumor was where you ablated. If you didn\'t ablate where the tumor was,
then the tumor survived.

So the problem wasn\'t getting an ablation where you put the device, but
it was properly locating the device. And so I think, you know, if the
study is designed so that the imaging method is as accurate as possible,
then that will be an important part, too.

ACTING CHAIRPERSON McCAULEY: I think that the comment I have here is
that even with the imaging devices that we currently have, there are
still going to be times when you\'re not going to be in the tumor. so
you still have to count that as a failure.

DR. MILLER: No question about. I think it becomes a question of patient
selection.

ACTING CHAIRPERSON McCAULEY: Dr. Dowlatshahi has told us that just
recently he had a problem with a case. So he\'s very experienced.

DR. MILLER: Yeah, I think that becomes a question of selection. I mean,
if you cannot identify on your imaging a discrete tumor, if you do a
core biopsy and cannot confirm that that tumor is a type which tends to
stay discrete and doesn\'t tend to be multi-focal or have diffuse
spread, like not lobular carcinoma, not VCIS, all of these things, but
you can confirm it\'s a discrete tumor; you can identify it with
confidence on your imaging; then that patient is a candidate.

If they fail any of those criteria, then they\'re not a candidate. So I
think just careful selection and then complete ablation with the
alternative, that makes sense to me.

ACTING CHAIRPERSON McCAULEY: Dr. Brenner.

DR. BRENNER: Trying to advise the agency on this issue, you know, we\'re
talking about T1 tumors here really. They\'re small. It\'s conceivable
that most of this disease is a systemic control problem, not a local
control problem. Certainly at this size I think it\'s important to
recognize that.

So this question is real important because it really is a core issue in
terms of local control.

So the way I would advise the agency in terms of dealing with the design
of Question No. 1 is the point out a number of variables I think you
need to look after.

One that has not been mentioned here is a pathology protocol. In other
words, everybody is talking about complete ablation, but how do you
define that pathologically? And I think there has to be a standardized
pathology protocol that is doable and validated across institutions and
documented concordance amongst pathologists so that when somebody says,
\"It\'s ablated. It\'s ablated,\" and that there\'s not that variation
\-- for example, if you take out a two centimeter lesion, depending on
the sectioning, you might miss islands of tumor, and I think that\'s one
advice I have for the agency to be concerned.

The second advice I have is, as has already been pointed out, this has
to be multi-institutional and has to deal with cross-culture. In other
words, different places do things differently. That has to be in some
way dealt with and standardized, and I recommend that the agency
recommend that.

The third issue is cohorts and the type of cohorts, and the question
that arises in my mind is the T2 lesion and whether or not that should
be inclusive in such a design. I would probably set some cutoff that the
technology allows, and T2, I think, includes up to five centimeters.
That might be too big.

So I think you need to be careful about the size of the lesion that\'s
being ablated, and that needs to be standardized.

And then I think that in terms of endpoints, definition, what endpoints
are we talking about? As I thought about it, there would be a pathologic
endpoint. In other words, complete pathologic ablation, and then there
would be a pathologic partial ablation endpoint, and the way one might
have to look at that might be a surface area indication and one would
want to utilize perhaps a volumetric surface area indication, and that
would be used as a quantitative endpoint in order to then deal with the
questions, particularly the two latter questions, the reproducibility
amongst different investigators and reproducibility among different
centers.

You\'ve got to standardize the pathology. You\'ve got to standardize
your surface area in terms of the amount that\'s being ablated, and then
you can do the reproducibility work and get a quantitative endpoint that
Brent can then work with. Because I think that\'s the kind of
information you need in order to say, \"Well, we\'re 85 percent
successful,\" or, \"we\'re 96 percent,\" 95 percent. You need that kind
of data.

So basically we\'re looking at pathology bins, but I also think you need
imaging bins. In other words, is there also an image outcome? Would
there be an image pathologic outcome and also an imaging partial
outcome?

And I\'m wondering. A partial response outcome and an imaging might
actually be fibrosis and not tumor, and so that\'s some information that
I think would need to be dealt with, but those are the variables that I
think the agency needs to look at in the design of a preliminary trial
that I\'ve not seen in the literature to date that I would want to look
for before I approve a pivotal trial.

Then in terms of endpoints, in terms of ablation, I think my surgical
colleagues are much better qualified to comment than I am on this.
However, I think that in terms of concordance data I\'d like to see a
concordance of about 90 percent at least for both imaging, as well as
pathologic outcomes to insure that we know what we\'re doing going into
a pivotal trial amongst different institutions.

And I\'d like to see a coefficient variation of around ten percent. Why
ten percent? Well, that\'s what we use in analytics when we want to
validate an analytical procedure.

And here I think the coefficient variations are much larger, and one
could take issue with me on that, and I\'d like Brent\'s comments on
whether that\'s a reasonable coefficient variation in terms of outcomes.

So those are the solid, perhaps regulatory kinds of points that I tried
to make in terms of responding to the agency\'s question.

ACTING CHAIRPERSON McCAULEY: Dr. Kopans.

DR. KOPANS: Yeah, a lot of the points that I wanted to make have already
been said, but let me just reinforce a couple of them.

First of all, I think it would be very important to talk in detail to
medical oncologists and radiation oncologists. The point that was
brought up, how much information do they need to provide modern care as
we\'re now talking about tailoring everyone\'s tumor therapy to their
particular tumor. We\'re not removing the tumor. The point that was made
earlier, we may be losing that information.

I think it\'s important for people who don\'t do core biopsies or needle
biopsies to realize that there\'s a very big sampling error with needle
biopsies, and what is the definition that you\'re going to accept of
adequate core biopsy? Is it spring loaded devices? Is it vacuum assisted
devices? Is it en bloc resections, whatever?

That really I haven\'t seen any real definition or standardization of
what is a sufficient biopsy and how much information is either being
lost or is sufficient, I guess, to adequately treat the tumor.

I think, again, margins have been emphasized over and over again. I just
want people to have a realistic understanding that imaging does a very
good job in defining tumors, but it does not define microscopic margins,
and ductile carcinoma [in situ]{.underline} is variably imaged even with
magnetic resonance, which is probably the most sensitive certainly to
invasive cancers. At least 50 percent of DCIS doesn\'t show up on MRI.

And for those of you who haven\'t been around as long as some of us have
been, we thought that extensive intraductile cancer was a major risk for
recurrence based on the Joint Center experience a number of years ago,
and then it was realized that there was residual tumor. The margins were
not clear, and it wasn\'t so much just that there was extensive DCIS in
the tumor.

You need to be sure that you\'ve got the vast amount of tumor out before
radiation therapy can be adequate. So, again, margins is a real tough
nut to crack. I would be of the school that if you\'re going to replace
an excisional biopsy with [in vivo]{.underline} ablation, that you need
pretty close to 100 percent certainty that you\'re ablating what the
surgeon would have taken out.

And that\'s going to be a little tricky because there\'s really no
standardization of what the surgeon takes out and what is a negative
margin. The NSABP, you know, says if there wasn\'t a cell touching the
margin, that\'s a negative margin. Mel Silverstein would say a one
centimeter margin is probably what is required. So that\'s going to take
some definition.

Also, some things to keep in mind. In modern therapy, my understanding
is that recurrences in conservatively treated patients don\'t really
start showing up until about two years. So that to have just a two-year
follow up to me is insufficient to know what your recurrence rates are
going to be.

I would say a minimum of five years. You could argue even longer
periods. I kind of like the idea of a long-term registry that was
mentioned earlier. That becomes logistically extremely difficult, I
would imagine, but you need to follow these patients up for the long
term.

And then, again, to come back, you have to have 100 percent clear
margins. How many cases that takes, I guess it\'s an infinite number if
you want 100 percent. So I\'ll defer to the statistician to determine
the exact number.

And then finally, a point that was brought up that I think needs to just
be kept in the back of our minds, and that is, you know, the reason our
recurrence rates are so low in conservatively treated breasts are
because (a) good surgical technique and (b) good radiation therapy.

And is tissue damage to the residual breast where there may be nests of
cancer cells that escape the ablative technique, are those cells because
of hypoxia in that tissue going to be more resistant to radiation and
are we, therefore, going to see more recurrences maybe further down the
line?

So, again, a whole bunch of issues I don\'t have the answers for at this
time.

ACTING CHAIRPERSON McCAULEY: Dr. Halberg.

DR. HALBERG: There are four things I want to expand a little bit on. The
first would be that when one does the study we\'re going to assess
margins, if you will, not just by imaging, but by core biopsies. All of
the information we\'re going to get on the tumors is going to be from
core biopsies, and at least one of the RF papers discussed getting a
series of core biopsies all around the edge of the tumor.

I think in the initial feasibility study it would be important to
specify how one wanted to obtain core biopsies and standardize that as
well. (a) You\'ll obtain more tissue. (b) You\'ll get some margin status
information that you could then use to help guide the subsequent pivotal
studies.

I would encourage the protocol for the biopsies prior, in the first
study as well, so that you can understand what you\'re doing with
respect to imaging and lumpectomy.

The second point that I wanted to make is that, of course, the group
that one envisions the thermal ablation devices working best for are the
T1 tumors, but I would encourage us to try and look at the largest and
ugliest tumors that one can still ablate.

In other words, where it\'s pretty well documented that the recurrence
rates at ten years with standard lumpectomy, negative margins, radiation
therapy are at most five or six percent and at experienced breast
centers probably closer to two to four percent. So those are very, very
low recurrence rates, and those recurrences are usually not seen until
five years.

Having 1,000 patients with very small tumors, following them for five
years and seeing no recurrences doesn\'t mean that you\'re successful.
It just means that you haven\'t followed enough patients out long
enough.

So I would encourage us to look at the larger end of the spectrum in
terms of patients both in the initial study and I don\'t know. You know,
we\'ll have to look at what the limits of these technologies are, but
certainly try and push things towards the larger end so that if we see
recurrences, we\'ll tend to see more of them and see them earlier.

The third point that I wanted to make, and this gets into Dr. Kopans
brought up hypoxia, and we\'ll discuss that much more extensively under
Question 4, but I think we have to address this hypoxia in the initial
study as well.

Very briefly, any time you perturb the microenvironment in tissue, you
perturb the blood supply and create hypoxia, and indeed, the ultrasound
data that was presented with laser suggests that you do create hypoxia.

So the short version is that hypoxia is well documented to induce
radiation resistance. Radiation doesn\'t work as well on tissue that\'s
hypoxic, period.

There are a series of elegant studies done many years ago by a gentleman
named Roland Holland, who looked at lumpectomy followed by \--
lumpectomy negative margins in patients who then went on and had an
immediate mastectomy. And what he did is he cut in every last breast
cell and microtomed, and found that even with lumpectomy negative
margins where you think you\'ve, quote, gotten it all, there are a
substantial number of patients that have occult satellite little
residual microscopic foci of breast cancer left behind, and the vast
majority of that residual disease is within two centimeters of the
lumpectomy cavity.

And if that is, indeed, hypoxism that you\'re creating, you worry that
the excellent results that we\'re seeing with lumpectomy followed by
radiation therapy may be compromised by some of these thermal ablation
devices.

So I think one of the endpoints, even the initial study has to be not
just local recurrence, but I\'d like to see us look at survival and
distant disease free survival as well. The question raised there is does
local recurrence impact distant metastatic disease, and that\'s
controversial with breast conserving therapy.

What is also of concern, however, is that there\'s an increasing body of
data suggesting that hypoxia changes the phenotype of cancer in general;
that if you render cancer cells hypoxic, you increase their genetic
instability. You increase their metastatic potential. You increase the
aggressiveness of cancer.

And so what you\'d want to do, even in the initial study, is track these
patients to see if there is a higher distant disease recurrence. I would
encourage that to be one of the endpoints, as well.

And those are basically the points I wanted to add.

ACTING CHAIRPERSON McCAULEY: Dr. Solomon.

DR. SOLOMON: I agree with what the panel has been suggesting, that
we\'re talking about a 95 percent or higher success rate, but there are
three other points that I\'d like to just emphasize that are a little
bit different than other people have been talking about.

The first is to recognize, again, the limitations of imaging. Recent
studies have shown that even if you biopsy and actually remove all of
the ultrasound visible tumor so that you can\'t see anything left,
there\'s residual tumor.

So that stresses the importance of margins and that you have an
acceptable wide margin of ablation beyond just seeing the lesion that
you\'re looking at.

The second point is that the placement of the needle is critical, and
there are a lot of very operator dependent issues in this particular
procedure, and, therefore, again, you would want something that would be
multi-operator, a multi-center trial to emphasize the reproducibility in
more than one person, in more than several people\'s hands.

And the third point that I want to emphasize is that when you do an
ablation, except for, let\'s say, MR thermometry in that unique case of
focused ultrasound in the MR scanner, you really can\'t tell what the
kill zone is. You can\'t see on ultrasound exactly where you \-- you
can\'t define exactly where the kill zone is.

And, therefore, I think in the lumpectomy study, it will be important to
look at the size of the ablation zone, the necrosis zone and link that
to a particular amount of power or settings on the machine so that you
can have a reproducible \-- because you can\'t tell when to stop.

The biggest problem is when do I stop ablating. So it\'s important that
you know that, okay, I\'m looking at a one centimeter tumor. The needle
is placed in the right spot. I know if I do 50 watts for X amount of
time the ablation zone is going to be two centimeters or whatever, and
that\'s going to give me a wide enough margin of error, and that\'s why
the pathology on this lumpectomy study and the size of the lesion and
the reproducibility of the lesion is going to be important.

DR. HALBERG: I apologize. There was one other point I wanted to make on
the initial study, and that is that if one is doing a lumpectomy several
days or longer after the initial ablative procedure there are ways to
assess the hypoxic zone, and it may be important to document that.

There is a commercially available kit called a hypoxia probe. Basically
what they do is they give small doses of a nitroimidazole compound 24
hours prior to the lumpectomy, and then you can use antibodies to stain
the lumpectomy specimen to see the zone of hypoxia that has been
created, and at least on a limited basis that might be an interesting
sort of surrogate marker for the hypoxic problems you might see down the
line.

ACTING CHAIRPERSON McCAULEY: Dr. LoCicero.

DR. LoCICERO: A lot of points have already been covered. Concerning
immediate lumpectomy, we know that from other ablative studies that
there can be trapped viable tumor cells within an ablated specimen, and
so we main need to have more time to know what cells have died and what
cells may survive.

Another potential is over time with ablative therapies you can see the
line of demarcation very well around four to six weeks after ablative
therapy, and that might be an easy marker for the pathologist. In fact,
it may be good to have a pathologist experienced in examination of
ablative tumors provide some information to the FDA.

Concerning reproducibility of the investigators and the site, I think we
already have several guidelines for that. Some years ago the Lung Cancer
Study Group set out guidelines for lung cancer resection and
lymphadenectomy.

More recently, we have the NCCTG, the North Central Cancer Treatment
Group, certifying surgeons to perform laproscopic assisted colectomies.
We have the information from individuals performing sentinel node
biopsies, and the American College of Surgeons\' Oncology Group
certification of surgeons performing thoracoscopy.

So any of those could be used as models to develop guidelines for
certifying surgeons and sites to be entered into a study like this.

You\'re definitely going to need to have a very dedicated monitor for
any study like this.

ACTING CHAIRPERSON McCAULEY: Dr. Lanzafame.

DR. LANZAFAME: A number of points have been made already, but if I can
be a little bit of a purist, I have a problem with the word
\"ablation.\" Ablation to me means gone immediately, removal of a volume
of tissue.

We\'re not doing that. We\'re causing coagulative thermal necrosis be it
by light energy, by radio frequency, ultrasound, by some methodology,
and we\'re leaving that [in situ]{.underline} in a living organism.

Bearing that in mind, there\'s a long history of experimental studies,
some of which our own, some of which a lot brighter minds have done,
talking about what that might do to the host in terms of sensitizing the
host, improving some parameters, making other parameters worse,
rendering tissue hypoxic.

But having said that, I think we have to keep in mind that we\'re not
physically removing tumor at least with these modalities unless we
specify on the part of FDA that that\'s going to be done as part of the
trial.

And in terms of things such as reproducibility, we have to understand
that breast tissue is certainly not homogeneous in nature, nor are the
tumors homogeneous in nature. Presumably we would want to stipulate that
we had solid tumors. We\'ve alluded to some of that, but I think that
would be very important.

We also have to understand that age, composition of breast varies, and
we would at least want to be looking at data as to whether or not we\'re
stratifying patient populations along those sorts of endpoints.

That becomes particularly important with our thermal source, light,
energy absorbed in tissue. The tissue will change as it\'s undergoing
its thermal denaturation. Presumably that\'s also occurring with the
other energy sources.

And so I think we have to be very circumspect in terms of how we do
that.

We\'ve talked about imaging methods and reproducibility thereof. To the
best of my understanding, any of the things that we\'re considering or
are about to consider are actually using standard available technologies
to do the imaging for us.

Having said that, I think we would want to stipulate very narrow
boundaries in terms of what type of device, manufacture of device,
particularly if we\'re talking about a technology that\'s going to be
applied to a stereotactic stage on someone\'s machinery.

We probably would want to be doing some site testing in phantoms and
otherwise to be certain that we\'re actually getting what we think
we\'re getting with the device.

And if we\'re talking about things like fibers and other sources,
particularly if there are things that are being used for different
purposes, we may actually want to track that particular delivery device
to be certain that its configuration is actually producing the dosimetry
that we think it is.

Indeed, there\'s been a lot of discussion about pathologic margins. As
somebody who\'s done that sort of stuff on whole organisms and human
populations, the ability to guarantee 100 percent resectability or to
verify that by the pathologist will probably take a century. We are
looking at a sample of something that we assume is a 360 degree sphere.
So folks have looked at a certain number of sections.

I think it would be naive of us to hold this group of technologies any
differently than we do surgical technologies in that respect. I think
one of the reasons that we got into the issue of looking at margins is
that those of us that put our fingers in there and manipulate things are
spreading cells around and doing other things. So I think there\'s a
crude surrogate for our inability to guarantee by some other means that
we\'re outside of that. We\'re looking at the width of a margin or a
pseudo margin of a deformable specimen.

One of the issues in terms of looking at our endpoints may actually be
along the lines as Dr. Halberg alluded to, and that would be, for
example, to do periodic sampling of that site if that site is left [in
situ]{.underline} in the patient, i.e., periodic stereotactic biopsies
at prespecified locations and in prespecified numbers.

ACTING CHAIRPERSON McCAULEY: Thank you.

DR. KOPANS: Can I make a quick comment on the margin issue and
pathology?

I think the point is well taken that our gold standard \-- and I think
it was brought up by the company as well \-- of pathologic analysis of
margins is far from perfect. If it were perfect, we wouldn\'t need to do
radiation. So I think or I hope that\'s understood.

The pathologic analysis that should be required of these technologies
should be some kind of standard pathologic analysis. Now, that said,
I\'m not sure there is a standard pathologic analysis, but the FDA maybe
needs to define what is the pathologic analysis that should be the
standard for surgical specimens and the ablative, or whatever we\'re
going to call it, technologies should have to live up to that standard.

ACTING CHAIRPERSON McCAULEY: Dr. Witten, we\'ve had an extensive of this
first question with numerous views. It would be impossible for me to
summarize them all at this time.

However, I think that if you feel we have provided you with enough
information to proceed to the next question, I propose that we do that.

DR. WITTEN: Yes. Thank you.

ACTING CHAIRPERSON McCAULEY: Could we have the second question, please?

The second question states: please provide a pivotal trial framework for
studies aiming to demonstrate thermal ablation device efficacy in
providing local breast cancer treatment in lieu of lumpectomy. Please
address the appropriate patient population with respect to primary tumor
size, nodal status, histology, mammographic findings, ultrasound
findings, biological markers, age, et cetera.

Some of these issues have already been addressed, but we\'ll briefly go
through them again.

Number two, control group. Again, this was also partially addressed in
Question 1. Assessment in terms of radiographic modalities, biopsies, et
cetera, and the frequency of such assessments.

Duration of follow-up to demonstrate efficacy of treatment in lieu of
lumpectomy.

The lead discussion panel member, again, for this question, is Dr.
Leitch.

DR. LEITCH: Well, you know, I think ultimately to demonstrate the
benefit of this that would need to be a randomized trial comparing it to
the standard treatment.

However, I think before that is done there does need to be a trial that
would simply be a single arm trial taking patients with ablation, not
resected, and looking at a number of issues in those patients before
taking it to the randomized trial environment.

And, again, we\'ve talked about the tumor size issue, which from a
safety perspective would be more in the T1 tumor size, but it\'s also a
size where we\'re less likely to demonstrate, you know, a significant
advantage, but you know, it would be a safer group of patients; that the
tumors are well demarcated by the imaging technology that\'s selected
for targeting, whether that be mammography or ultrasound; that there are
not extensive associated calcifications with the lesion.

With respect to age, I think you want the patient at least to have a
life expectancy of five years so that one could have the opportunity to
monitor outcomes. I personally would not particularly put any
restrictions on the tumor profile, but would emphasize that, of course,
all of those parameters must be obtained before the tumor is ablated in
order to guide other therapies.

The other issue which we really haven\'t talked about is the failure to
accurately stage the patient because you do not have pathologic staging
of the tumor size, which when you get into these small size tumors the
recommendations regarding adjuvant therapy begin to spin on the precise
sizing and, you know, maybe the medical oncologists can speak to that as
well.

And the control group for this type of trial, I think, would need to be
some of the more modern studies, but even then SABP and their more
recent trials indicate about a six percent local recurrence rate at ten
years, and you could use those types of study as your historical control
to look at these issues.

Radiographic assessments. In my opinion, at a minimum, again, this would
be kind of whatever you select, but I\'d probably be inclined to select
both mammography and ultrasound as sort of the standard things that
would be done in all patients, and doing that at six months intervals,
and I probably would pick a five-year period of duration.

MRI would probably be done as sort of a pilot type of study within some
of that population to look at issues of can you measure things like
hypoxia and get sort of a dynamic picture of the breast after these
types of therapies and maybe answer some of these questions about the
zone of hypoxia. So MRI not probably for everybody, but for some subset
of that patient population to look at that technology in the long-term
follow-up.

Because, again, I think you have got to say how are we going to be able
to apply this forever, and hopefully we would be able to do the
follow-up by more standard imaging, which would be mammography.

And in my view the follow-up should be at least five years for this type
of a study.

ACTING CHAIRPERSON McCAULEY: Thank you, Dr. Leitch.

Dr. Lanzafame.

DR. LANZAFAME: I have nothing to add.

DR. WITTEN: Can I ask a question of Dr. Leitch?

DR. LEITCH: Yes.

DR. WITTEN: Before you go on?

I\'m just wondering. You said that you thought there should be another
study before the pivotal study, and so I\'m just wondering what we would
learn from what stage.

DR. LEITCH: Well, the question is what you\'re going to call a pivotal
study.. You know, if you\'re going to say, well, we\'re going to take it
from we did the ablation and we verified the ablation, you know, and now
we\'re going to take it to where we don\'t do anything further. We just
do the ablation and then we compare it against standard therapy.

To me that\'s sort of the bigger jump. You could do that. You could do
that, but essentially we have no follow-up of any of these people with
ablation only to know what the outcomes of those patients are. To then
apply it in what I would think would be a very large trial, would it
not, for numbers?

So that\'s the down side of not doing, you know, a smaller study that
looks at some of these issues where you might make a decision, you know,
it\'s not worthwhile to go forward with that.

ACTING CHAIRPERSON McCAULEY: I assume what you\'re saying then is that
the actual framework for a pivotal study really is based on
standardization of the feasibility study and the results of that study
as we define as being successful, which includes not only a recurrence
rate, but also detection and standardization of determining what is true
ablation.

DR. LEITCH: I mean, the other things which we haven\'t really brought up
yet, I thought a radiation oncologist might, but you know, there\'s
other things that are coming down the pike in terms of radiation
treatment for breast cancer which is, you know, partial breast radiation
techniques which may rely very heavily on these issues about hypoxia and
that sort of thing, and so that\'s kind of coming down the pike at the
same time this is, and how do you integrate those two technologies?

And the other technology which is an advance in our breast cancer care
is sentinel node biopsy technologies, which as I was understanding from
the presentation here, that technique is done after the ablative
procedure, and I\'m wondering how the ablative procedure might alter
lymphatic drainage from the primary tumor so that you\'re mapping might
be interfered with.

And we certainly don\'t want to jeopardize that technology which we
think is a real advance for breast cancer care. So that\'s another thing
you have to take into account because, again, in these very small
tumors, all of that data, you know, that sentinel node data becomes very
important. You know, the tumor size issues are very \-- you know, the
exact tumor size issues are very important.

So those things have to be considered in this, which I suppose all of
those things could be fleshed out in a randomized trial, but the
question is really whether you want to make that kind of commitment and
maybe Brent can tell us what kind of commitment that would be in terms
of patient numbers, you know, if you went on to the randomized trial.

ACTING CHAIRPERSON McCAULEY: Dr. Blumenstein.

DR. BLUMENSTEIN: Yeah, I mean, first of all, this would have to be a
non-inferiority trial. You\'re not trying to prove that this new
ablation method is superior to standard therapy, but you\'re trying to
show that it\'s not inferior.

And as a result of that, it\'s going to be a little bit larger than a
trial that\'s perceived to be a superiority trial. I would say that we
would be talking about at least 2,000 patients or more for a trial like
this.

I was curious about the control arm and, in fact, the experimental arm
in this case. Would there be radiation therapy in both arms or one of
the arms?

DR. LEITCH: Well, I think as it has been proposed by the current
investigators, it is that they would apply radiation therapy after the
ablation. Of course, that may be a more interesting question of could
you ablate only and not radiate the patient.

But you know, again, you\'ve got to kind of do the first thing before
you could take that out. So you would be, in my thought, you would be
doing ablation plus radiation, surgery plus radiation.

DR. BLUMENSTEIN: Yeah, but I mean, what has been said here by your
proposal of doing an intermediate trial between the trial addressed in
Question 1 and this trial, a single arm efficacy trial which is more
like a Phase 2 drug trial where your primary endpoint is some
preliminary evidence of efficacy to justify going to a pivotal trial.

There\'s also all of these other issues about whether you\'re using it
in combination with radiation therapy or not, and so forth. So all of
these things are extremely important at this design phase.

ACTING CHAIRPERSON McCAULEY: Dr. Witten, do you have any further
comments?

DR. WITTEN: I don\'t. I stopped you before you went around the room
though. So other people might.

ACTING CHAIRPERSON McCAULEY: Dr. LoCicero?

DR. LoCICERO: No additional comments.

ACTING CHAIRPERSON McCAULEY: Dr. Solomon?

DR. SOLOMON: I agree with what was already said, but the only other
twist perhaps for people to think about would be what if this technology
were addressed to a positive node group. So these are people who we know
that the margins are \-- it has already spread to the nodes and the
margin positivity may not be as \-- we\'re not as sensitive to that as a
safety issue. So that may be something for people to discuss as well.

DR. LEITCH: Yeah, it\'s sort of the opposite theory that you, you know,
pick people that have sort of less to lose than a person who has a high
probability of being cured by standard therapy. You know, you pick
somebody who has less likelihood so they don\'t lose as much as the
person who is highly curable by current techniques.

ACTING CHAIRPERSON McCAULEY: Dr. Halberg.

DR. HALBERG: In thinking about this question, I realize that a great
deal of thought has gone into a very similar trial. The NSAP is in the
final stages of a review of a trial that is going to compare lumpectomy
with negative margins, and then patients will be randomized to whole
breast radiation therapy or partial breast radiation therapy, with the
outcome being local recurrence.

And that\'s really not so dissimilar to a study that would look at
thermal ablation alone versus lumpectomy with negative margins to be
followed by radiation therapy.

I would encourage the use of radiation therapy in any of these trials
because there are a number of prospective randomized trials, at least
seven well conducted trials, that show a distinct superiority to the
addition of radiation therapy even after wide lumpectomy.

And so I think that that would confuse the issue greatly and increase
the risk of recurrence in women if you considered the thermal ablation
alone. I don\'t believe that\'s being proposed.

So I think we can go back to the NSABP trial. There the proponents of
partial breast radiation therapy wanted to look at favorable T1 tumors,
women that were generally a little bit older, estrogen receptor
positive, no DCIS, well circumscribed tumors, less than two centimeters
tumors. They wanted to pick a very favorable group of women and to look
at radiating less than the entire breast and to see if that was
comparable to whole breast radiation therapy.

So they looked at what it would take to do that. They used a six
percent. They basically felt that the recurrence risk for patients with
T1 tumors at ten years was six percent based on the NSABP data that
we\'ve heard.

And then you have to ask yourself. You know, breast cancer affects
hundreds of thousands of American women a year. What kind of increased
recurrence risk are we willing to accept in an equivalency trial?

And they thought that a doubling of a recurrence risk, 100 percent
increase, was too much. So they thought a 50 percent increase might be
reasonable. In a T1 tumor, that would increase your risk at ten years
from six percent to nine percent.

To conduct that study a prospective randomized trial would have to have
6,300 patients followed for ten years because you hardly start to see
recurrences in these patients until five years. So length of follow-up
is very important in these studies, and it has to be a long length of
follow-up.

It is considered too expensive and unrealistic to have a 6,300 woman
study, and so, therefore, although it wasn\'t the first choice of the
NSABP investigators, and this isn\'t finalized either yet, but what will
probably come out is a study that includes node positive women, three
centimeters and less and including virtually any tumor type so that the
recurrence rate of ten years is at least ten percent, and there
wouldn\'t be more than a 15 percent recurrence risk in these women.

And I think that that\'s quite a parallel situation to the situation
that we have here. However, I think that there is actually the potential
to do much greater harm in the women we study here. Again, we have a
technology or breast cancer treatment which works very, lumpectomy with
negative margins followed by radiation therapy, and we know that the
outcomes are excellent in terms of local control.

We are now looking at technology which is going to create an area, a
zone of hypoxia in the area that\'s most likely to harbor residual
occult breast cancer cells. We are likely to make those cells
radioresistant, and we have the potential at least theoretically to
increase the metastatic potential.

So I think it\'s very important that we conduct an excellent, large
study with long-term follow-up on these patients.

ACTING CHAIRPERSON McCAULEY: Dr. Kopans.

DR. KOPANS: Yeah, I really have nothing to add. I think all of the
comments have been very good.

Just one point. I\'m not sure I made to clear before. Radiographic, just
in terms of semantics, means X-ray imaging. So if you\'re going to talk
about imaging modalities, get rid of the radiographic part and put in
\"imaging\" in whatever you write.

ACTING CHAIRPERSON McCAULEY: Dr. Brenner.

DR. BRENNER: I wrestled with exactly the same problems that Dr. Halberg
wrestled with: size of the trial, the fact that it would have to be an
equivalency trial, and what the endpoints would be of an equivalency
trial, and the fact that really if your endpoint is local recurrence,
that in fact you have to do at least ten-year follow-up.

And that seemed to me to be something that was really not feasible. So
then the question was what would be feasible. My concern with the node
positive study\'s ten-year follow-up endpoint depends, of course, how
many nodes because you would expect with node positive patients that a
substantial number of them were going to recur and might not have
ten-year follow-ups. Whereas in the node negatives you would have more
likely that ten-year follow-up.

So I came down on the side of node negatives rather than the node
positives, and the reason is that this is about local control, and
really local control is different from systemic control, and coming at a
medical oncologist, I\'m not entirely convinced that there\'s a huge
relationship between local and systemic control in this disease.

And, therefore, one might be able to design a trial, and this would
really be up more on Brent\'s alley than mine, where even at a five-year
point one might be able to demonstrate sufficient difference between the
arm one could identify some type of confidence interval that would be
defined as worse and, therefore, cut the trial, equivalency trial, that
might allow you to shorten the trial and, therefore, make it feasible.

So that\'s where I came down. I came down on a 20 percent change and the
95 percent confidence level towards the worst as the endpoint, the
hypothesis you want to test, and didn\'t calculate the numbers because I
figured Brent would and agreed with Dr. Halberg that you couldn\'t
ignore the radiation even though I would prefer to.

I mean, without radiation you\'re just going to have more events, and
the data suggests that that doesn\'t impact on survival too much or at
all, and so, therefore, you might be able to get away with it, but I
suspect that you probably couldn\'t.

I mean, it probably wasn\'t a doable study because IRBs would probably
balk at the idea because standard of care in the community remains, I
believe, radiation, and patients would probably not be willing to enter
the study. So you\'d have trouble with recruitment.

So I think that that design fails from just a practical point of view.
So I come down on the node negative rather than the node positive, but
otherwise mainly the same concerns Dr. Halberg has.

Now, people have been mentioning that the medical oncologists should
talk about some of the things you need in tissue. It\'s I guess on the
medical oncologist. I think out of a needle biopsy, for the most part,
or a few cores, you can usually get what you need, which is an ERPR and
HERTUNU (phonetic) assessment.

And there have been a number of studies published with proliferation
indices and looking at EGFR. Now, EGFR is going to be problematic
because in the not too distant future there are drug targets for that.
You might want to look at those.

Of course, the problem is those are amino assays, and the assays aren\'t
standardized, and you can always have the power to come back and check
that later. So I think the cores are probably going to be sufficient to
really get the data you need.

My problem that I ran into was the size question because really once you
get below one centimeter, you start to run into some problems in the
adjuvant area. The literature is really very conflicting in that area,
and I think incomplete.

I don\'t think there\'s a consensus as to whether node negative, less
than one centimeter ERPR positive lesions should really be treated. I
think that there may be a consensus about ERPR negative lesions. The
microarray data and the proteomics data are not ready for prime time,
are not going to be ready for prime time for five years. So I would just
eliminate that from any regulatory issue.

So in order to deal with that issue, I would simply exclude any mass
that\'s less than one centimeter from such a design because I just
don\'t feel that you will have sufficient data to verify that
pathologically without resecting it and, therefore, might compromise
your decision on adjuvant approaches.

So those are some of the practice design issues that I came up with.

ACTING CHAIRPERSON McCAULEY: Dr. Miller?

DR. DOYLE: Can I ask him one question?

ACTING CHAIRPERSON McCAULEY: Let\'s finish the panel comments and then
we\'ll come back to your question.

Dr. Miller.

DR. MILLER: I guess this study is different than, say, when we had to
make a decision about whether to do a mastectomy or a lumpectomy, which
was like a whole shift in mentality for treating breast cancer. This is
just looking at an alternative way to do a lumpectomy, and the main
question is: is it complete enough? Does it compare to a surgical
lumpectomy in terms of completeness of lumpectomy?

Because all of the other issues about treating patients with lumpectomy
and radiation or chemotherapy and their nodal stats and everything,
those are in my mind all unchanged. The only question is: does this do
an adequate lumpectomy to control the local disease?

So I think a trial which starts to put patients into a group that are
treated with this and followed just as we could lumpectomy patients may
be modeled after, you know, the NSABP trials to look at lumpectomy would
be suitable and just go for as many years as you need to and just treat
the patients with this as an alternative.

I feel comfortable with this if I\'m convinced that this gets the mass
out. Conceptually in my mind I don\'t see why it would be any different
than doing an open lumpectomy.

ACTING CHAIRPERSON McCAULEY: So basically what you\'re saying is that
starting a pivotal trial really is based on the feasibility or based on
the success of a feasibility study to demonstrate the accuracy of
ablation.

DR. MILLER: That\'s right.

ACTING CHAIRPERSON McCAULEY: Ms. Brown.

MS. BROWN: I don\'t have anything to add to the discussion.

ACTING CHAIRPERSON McCAULEY: Dr. Doyle.

DR. DOYLE: Nor do I.

ACTING CHAIRPERSON McCAULEY: Dr. Blumenstein, any further comments?

DR. BLUMENSTEIN: Just a couple more points here. One of the strategies
that could be used here is one of accelerated approval. In other words,
the ultimate outcome for women being treated with breast cancer is
whether they have shortened life as a result of inadequate treatment.

So it seem to me that really the definitive endpoint that one has to
discuss is survival, but it\'s unreasonable to have to wait that long.
And so the FDA has come up with a set of regulations called accelerated
approval on which there\'s a conditional approval based on a surrogate
for a definitive endpoint.

And in a trial like this, I think that one would probably want to design
it with survival as the primary endpoint, but a planned early analysis
of recurrence that would take place early on and allow the publication
of the results with respect to recurrence, but have the ability to
ultimately assess the survival difference in the trial.

And this is sort of a new style that is used under this accelerated
approval program. That\'s all I want to say.

ACTING CHAIRPERSON McCAULEY: Dr. Choti.

DR. CHOTI: I think for such a pivotal trial local recurrence should be
the primary endpoint because that\'s really what we\'re looking at, as
was mentioned, but perhaps survival as a secondary endpoint.

Ideally randomized trial, ideally T1 cancers, lumpectomy versus
ablation, all with radiation therapy, with or without positive nodes,
although perhaps chemotherapy may have an impact on local recurrence.
That\'s another question, although maybe all patients if it\'s over one
sonometer will all get chemotherapy.

The problem is as you said. The number, the power is just going to be
very hard to do that. I didn\'t know that 6,300 for ten years is a
massive study. Yes, you can take away radiation. Your event rate will go
up, but it\'s unethical.

So I think that whether to stretch the boundaries to larger tumors, the
problem with that is that these therapies, at least if you extrapolate
from other soft tissue, liver and elsewhere, the local recurrence rate
goes up with the size. So that it is a worse ablation. The efficacy of
the ablation will go up as the tumor size goes up.

And so to start doing five centimeter tumors, you\'re going to have 30
percent local recurrence rates and so forth, and it\'s probably not
going to be and it\'s also not going to be used clinically for large
tumors.

So I think that it doesn\'t make sense to do big tumors. The problem is
it\'s going to need to be a big trial.

Endpoint local recurrence, assessment, I think standard imaging, perhaps
adding some newer imaging modalities, and probably serial biopsies,
definitely if there\'s anything suspicious, and probably some program to
assess with, you know, standard biopsies, that would be an option, and
then salvage lumpectomy or salvage mastectomy if recurrence occurs.

An alternative to explore is a nonrandomized trial with T1 all radiation
and then just compare local recurrence to historic controls. That would
be one way to perhaps shorten the number and then just see if you
achieve six percent or less local recurrence rate in that setting. Then
that could perhaps be a model of proving nonequivalency, and I think the
duration needs to be long, five, ten years.

Any other further comments from the panel members? Ms. Brown.

MS. BROWN: Would there be a way to design it so that approval on a
pivotal trial could be done after one or two years with the requirement
for a long post approval follow-up so that if something emerged later
you\'d be able to spot it?

DR. BLUMENSTEIN: That\'s what I wa talking about in terms of \--

MS. BROWN: It\'s a little different. This would be actually a frank
approval after one or two years of follow-up and then a post approval.
So I think it\'s what you were talking about, but I think there is a
mechanism in place for FDA to do something like this.

DR. BLUMENSTEIN: Well, I think that under the accelerated approval I
think it\'s called a conditional approval, but it carries all the
weight, as I understand it, of a full approval, but you are obliged to
do the long-term follow-up on the surrogate endpoint to validate that it
was, in fact, a valid endpoint.

And with respect to what you were saying about primary versus secondary,
the reason that I when I stated it called the survival endpoint primary
is just simply because that you want to size the trial to ultimately
know the answer with respect to survival because that\'s what\'s
important.

To say that there\'s a planned early analysis with publication of
results in submission to the FDA of local recurrence as an early
endpoint, that is in a sense a primary endpoint. It\'s just that the
advantage of a trial of that nature is that you have already set up the
mechanism for validating the long-term endpoint, and so the patients are
already in the trial. They are already being followed and so forth like
that.

So you ultimately get the validation without having to initiate a second
trial. And let\'s just think about that for a minute. If you had to
initiate a second trial after a short-term trial on a surrogate endpoint
like recurrence, it would be unethical to randomize at that point.

Now, with respect to what you were saying about a single arm trial,
everything that I\'ve heard here screams out that there are no reference
data for which you could do a single arm trial because every time I turn
around people are saying, \"Well, you can\'t do it if the tumor is close
to the skin. You can\'t do it if this, that and the other.\"

And so there are no reference data that one could fish out of a database
to serve as a proper reference group for a single arm trial.

DR. CHOTI: No, I think if you had local recurrence rates under five, six
percent at five, ten years, I think that may be sufficient pivotal data
to show that local control is effective. So I don\'t know.

The other thing, by the way, is that following ablation it may be that
local recurrence comes faster than local recurrence following margin
negative lumpectomy because failure following ablation may also be or
increased failure following ablation may be due to some persistence
rather than kind of this multi-focal or small focus that was missed in
the margin.

So it may be that if, indeed, the local recurrence rate is higher, some
of those may hit earlier and you\'ll know that quicker than that
ten-year duration, but who knows.

DR. BLUMENSTEIN: One more thing on this idea of doing the dual endpoint
type of trial is that the criterion for success for the local recurrence
doesn\'t have to be as strict as the criterion for success with respect
to survival. In fact, you have a lot of flexibility in how you set that
up.

You know, for example, from BO6 and so forth that local recurrences
don\'t matter that much, and so the criteria for inferiority can be
fairly loose because you think, well, it doesn\'t really make that much
difference, but the criterion for survival could be tighter and
ultimately assessed.

There\'s a lot of knobs one would have to turn in making that design,
but the real advantage is that ultimately you do get the survival
answer.

DR. HALBERG: Can I just make a comment? I think it\'s very important
that when we talk about surrogate endpoints and you talk about local
control, that not seeing failure, not seeing a local recurrence does not
equal success.

T1 tumors, they may sooner after ablation, but we don\'t know that. If
you look at T1 failures, they occur after five years. So if you don\'t
see follow-up at two years or five years, that really doesn\'t mean
anything.

So I think publishing data, if it is successful, I think it would be
important to know that there weren\'t local recurrences early, but I
think that\'s very different from saying something is successful, and so
I would really caution everyone on how that, you know, interim analysis
is done and what is generated from that.

And I just wanted to echo back to what Dean was saying about eliminating
node positive patients. If you take T1/N1 patients, it\'s not that they
will die before local recurrence. In that setting you see the local
recurrence goes faster. You don\'t actually see particularly more local
recurrences because combined with that modality therapy with
chemotherapy and radiation therapy after lumpectomy, it\'s actually
quite successful in terms of local control.

But those patients who fail the time course to failure is much earlier,
and that\'s why I was suggesting that might not be an unreasonable group
to include.

ACTING CHAIRPERSON McCAULEY: One final comment.

DR. KOPANS: I just want to make one comment on local recurrence, and
even though it may be scientifically innocuous for the individual woman
who has a local recurrence, it\'s psychologically very damaging. That
may not be, you know, the significant endpoint issue, but it\'s still
something to keep in mind.

ACTING CHAIRPERSON McCAULEY: The last final comment.

DR. BRENNER: Oh, I get it. And that\'s really the point here, is that
this is a treatment for local recurrence or for local control and that
what has come out here is that that\'s different from systemic control
of this disease, and whether you control locally using surgery or you
control locally using this modality, it\'s still a local control
measure, and the data to data, at least to my interpretation, do not
support the idea that local control does predict survival.

So you could very well end up with a negative survival outcome and yet a
positive local control outcome, and that might be sufficient for this
modality because what you\'re really looking at in a funny way is a
cosmesis endpoint, hence the need for a validated set of quality of life
as well as cosmesis data because that might be the indication for
approval here.

ACTING CHAIRPERSON McCAULEY: Dr. Witten, there has been extensive
discussion by the panel relative to Question No. 2. Has this information
been helpful such that we can move on to Question 3?

DR. WITTEN: Yes. Thank you.

ACTING CHAIRPERSON McCAULEY: Can we have the third question, please?

Radiation therapy and chemotherapy may be concomitantly used in patients
who receive tumor ablation or tumor thermal ablation in lieu of
lumpectomy. Thermal ablation of cancer may affect the radio or
chemosensitivity of the surrounding breast tissue. Please provide
recommendations regarding the best way that this concern may be
addressed in clinical trials aimed at the understanding, the safety, and
effectiveness of thermal ablation for the treatment of breast cancer.

We have two lead panelists for this particular question. We\'ll first
hear from Dr. Brenner and secondarily from Dr. Halberg.

DR. BRENNER: My response to this question was I don\'t know how to
answer it. The reason is that within a clinical design I don\'t know how
you can really get at this question definitively. I think you really
would need to go back to the rodent models and clear out cells, get them
into primary culture and test the question because this is really a
biological question.

And the question can really be divided into two areas. What\'s the
effect of thermal or cryo or approaches to cells at the molecular level?
And I don\'t know how you can do that in breast human samples, but you
can do it perhaps from rodent models, preferably rodent models with
carcinogenesis.

Secondarily, an equally important question is what are the effects on
the stroma, and the stroma would be both fat as well as fibrous stroma.

And, again, those questions I think are probably best answered
biologically in the rodent because I just don\'t know how I could really
answer those questions biologically in humans unless I pulled the tissue
out in the prove a principle trial that we responded to in Question 1
and then try to deal with those tissue samples by probing potential
mechanisms of thermal injury.

That begs the hypoxia question, which has been discussed in detail here,
and since I\'m not a radiation oncologist, hypoxia to me was not as
relevant because if you\'re thinking about cytotoxic events or, even
better, biological and targeted therapies that are likely to really deal
with signal transduction events, for example, UGFR targeters which are
on the market now actually; in other words, TK kinds of phosphorylation
inhibitors, that\'s where it\'s going.

And so, again, I\'d want to have the tissue samples prepared in both
frozen and fixed manners so that I could then probe those questions in
order to try to get such an answer, and then ask the question simply: is
there a proliferative effect? Is there an apoptotic effect? And then are
there specific phosphorylation or immediate effects from human samples
in order to really start to address?

So to me this was a biological question that really related to mechanism
of cellular death, so to speak, or cellular ablation or whether these
tools cause necrosis or apoptosis. I mean all of those kinds of
mechanistic questions that really an oncologist would think about that
one would have to test on human tissues.

So it really becomes a collection method and then probing those issues.

Will that affect cytotoxics? I haven\'t the faintest idea.

Will these affect targeted agents? I don\'t know.

Will they affect hormonal approaches? Again, I\'m not aware of any of
these data, and I probed back into the heat data that was published many
years ago. The only data really are about membrane fluidity and
dynamics, but not really about pathway mechanisms to the best of my
knowledge.

Perhaps people in the audience might have some more recent biological
information.

In terms of hypoxia, I\'ll leave that to the radiation oncologists.

ACTING CHAIRPERSON McCAULEY: Dr. Halberg.

DR. HALBERG: Again, many of the issues have already been brought up. I
thought what I might do is just read the first paragraph in the
editorial in last week\'s [International Journal of Radiation Oncology,
Biology and Physics]{.underline}, which is the main radiation oncology
journal, and there was an editorial by Arian Begg, who is one of the
preeminent hypoxia researchers, and it is actually looking at different
hypoxia markers.

And I think that if I just read what he writes, it basically summarizes
the issues quite eloquently.

\"It is now abundantly clear that tumor hypoxia is a strong prognostic
factor for outcome in many forms of cancer. High tumor hypoxia is
associated with a poor outcome after treatment with any of the major
treatment modalities: surgery, radiation therapy, and chemotherapy.

\"For radiotherapy, an obvious contributing factor will be intrinsic
radioresistance of hypoxic cells, a phenomenon known and well studied
since the first half of the last century.

\"For chemotherapy, contributing factors are reduced to drug delivery
hypoxic cells, and for psychodependent drugs, the reduced proliferation
rate of hypoxic cells.

\"In more recent years, hypoxia has also been shown to influence the
invasive and metastatic properties of tumor cells and to lead to the
selection of apoptotic resistance cells resulting in a more malignant
phenotype. This will affect outcome after all treatment forms, including
surgery.\"

And he goes on to say at the beginning of the next paragraph,
\"Eliminating hypoxic cells is, therefore, a very useful therapeutic
goal.\"

And we have just heard from the presenters that we\'re knowingly
generating a hypoxic zone around the tumor, around the area of
coagulative necrosis. It doesn\'t matter if it\'s laser or cryo or any
of the other forms of thermal ablation. You are cutting off blood supply
in the area of the tumor, and by definition you\'re perturbing the
environment right around that, and by definition you\'re creating
hypoxia, and it\'s well established that hypoxia increases radiation
resistance.

And so I think this is an issue that we have to keep in mind.

I just thought I would also read there is actually data emerging in the
animal models on hypoxia, and both chemo sensitivity and mutagenesis. I
thought I would \-- a group at Yale is very active in investigating this
in animal models, and I thought I\'d read the last sentence of a recent
article that they published as well.

\"The concept that the conditions of the tumor microenvironment can
inhibit DNA repair and consequently promote genetic instability provides
the basis for understanding the observation that very hypoxic tumors
follow a more aggressive clinical course.\"

So that sort of summarizes my main concerns around hypoxia. With that in
mind, I tried to investigate if there are ways that we can measure
hypoxia if you\'ve done ablation and you\'re not going to perform a
lumpectomy.

As I\'ve already mentioned, you can give patients pimonidazole, a low
dose of it, the day before lumpectomy and assess for hypoxia in the
resected tissue if you do a lumpectomy.

If you do not do a lumpectomy, I tried to see if there were any imaging
modalities that might be useful in terms of assessing hypoxia, and there
are none that are ready for prime time.

The group at M.D. Anderson has looked at a compound called copper ATSM
and are actively studying that with PET, and apparently that defines a
five millimeter rim of hypoxia quite well, and so one might in a very
limited way ask that investigators there be funded to look at the copper
ATSM plus PET in these patients who have undergone I guess M.D. Anderson
is radio frequency ablation.

ACTING CHAIRPERSON McCAULEY: Dr. Kopans.

DR. KOPANS: Two comments. One in support of what was just said. I think
you can look at the hypoxia, and the only way you\'re going to know what
its effect, I mean, we know that hypoxia does decrease radio
sensitivity, but you really don\'t know for sure until you do a human
study as to how significant that\'s going to be.

The other point about chemotherapy, I\'m not actually sure that
chemotherapy is that important in terms of local control, but in our
patients where we\'re doing neoadjuvant chemotherapy now, we\'re seeing
some very strange patterns of response.

One of the unusual patterns is that you have the diameter of the tumor
remains the same, but you have islands of residual tumor in this ghost
zone of the previous tumor, and you know, the question is: does this
have to do with the local vascularity of the tumor and that the
chemotherapeutic agents are not getting to those zones?

I mean it\'s open for speculation. So I\'m not sure it\'s completely
unimportant in terms of the benefits of chemotherapy to again have
vascular damage the consequences of which we don\'t really fully
understand.

ACTING CHAIRPERSON McCAULEY: Dr. Miller.

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

ACTING CHAIRPERSON McCAULEY: Ms. Brown.

MS. BROWN: I have nothing to add.

ACTING CHAIRPERSON McCAULEY: Dr. Doyle?

DR. DOYLE: Nor I.

ACTING CHAIRPERSON McCAULEY: Dr. Blumenstein?

DR. BLUMENSTEIN: Well, I think that the at least theoretical possibility
just screams out that ultimately you have to know something about
survival.

ACTING CHAIRPERSON McCAULEY: Dr. Choti.

DR. CHOTI: A couple of comments. First, it\'s not necessarily that clear
that ablation causes hypoxia. So I think that does have to be studied.
In fact, in liver tumors and other things, we don\'t know about hypoxia,
but certainly the rim is hyperemic and hypermetabolic on PET, and so it
may be that it\'s enhancing at least blood flow in the area of the zone
that\'s not totally necrotic.

So it\'s hard to know what exactly is happening in that microenvironment
immediately adjacent to the dead cells. Interesting to study in the
breast, and it may be different than the liver, for example.

I think ultimately though the best way to address it in a clinical
trial, address the impact on chemo and radiation therapy, will be the
same endpoints that we\'re looking at: local control and survival.

And I think if it\'s impacted in a deleterious way, then that will give
us some clues to that.

ACTING CHAIRPERSON McCAULEY: Dr. Leitch.

DR. LEITCH: I don\'t have too much to add other than to say we do need
to evaluate whether or not the hypoxia occurs and figure out some
techniques to do that, and the endpoints I think also ultimately are
going to be does it make a difference, and that\'s what you will see in
the outcomes.

ACTING CHAIRPERSON McCAULEY: Dr. Lanzafame, please.

DR. LANZAFAME: Being a somewhat simple surgeon, I would just suggest
that we handle these patients as we would handle a lumpectomy patient so
that if the patient would as standard of care receive radiation and/or
chemotherapy or both, that the same patient population do that. We may
have to control that a little bit in the trial because there\'s some
variations on the theme in terms of centers and parts of the country,
but I think nonetheless those are issues that could be nailed down.

The issue of local hypoxia duration, et cetera, again, very
scientifically interesting. I think we also have to understand that when
we physically remove a tumor with lumpectomy and then do radiation,
there\'s a specific time course over which the radiation therapist
doesn\'t deliver radiation therapy, which is really empiric based on
information in the really good old days about what people thought about
wounds and wound healing.

So I\'m not sure that we really have an adequate understanding of what
we\'re doing when we surgically excise wounds and how we sequence our
events, but just like we were starting to do with multi-nodal
chemotherapy, we\'re beginning to understand some of those things, and I
think some of the issues, the point have been raised. They\'re very
good, but I don\'t think they\'re an isolated event relative to these
technologies.

They really interface a lot of what we\'re handling clinically.

ACTING CHAIRPERSON McCAULEY: Dr. LoCicero.

DR. LoCICERO: Just to expand on that a little bit, lest we get hung up
only on hypoxia, the ablative therapy will produce a dense scar, and
this may alter the radiation physics locally.

Now radiation is sort of like horseshoes, only it\'s a large horseshoe.
So you only need to be close maybe, but I think the endpoints will
remain the same, but I don\'t know that the sponsor can address only the
hypoxia issue as a side study.

ACTING CHAIRPERSON McCAULEY: Dr. Solomon.

DR. SOLOMON: When one makes an ablation injury there\'s increased blood
flow to the area of the injury and pretty consistently you can see that
there\'s a rim of hyperemia around the lesion. We and others in the
literature have shown that there can be increased drug delivery to that
area, the margin. That happens to be the area where, you know, it\'s on
the margin, and that may be where the recurrence or the failed treatment
is.

So in some ways you might find that the increased blood flow enhances
chemotherapy or radiation therapy, for that matter, and so it\'s an
unknown. I think the endpoints that have been discussed will follow it.

The other issue that hasn\'t really been discussed right now is just
again for targeting the lesion, you need to have good imaging, a defined
lesion, and chemotherapy and radiation may alter the ability to \-- the
conspicuity of the lesion, and so that might be something to think about
avoiding prior to the procedure, as mentioned in several of the articles
provided.

ACTING CHAIRPERSON McCAULEY: Any other comments from the panel?

(No response.)

ACTING CHAIRPERSON McCAULEY: Dr. Witten, does that satisfy answers to
Question No. 3?

DR. WITTEN: Yes, thank you.

ACTING CHAIRPERSON McCAULEY: We\'ll move on to Question No. 4

Neoadjuvant and adjuvant chemotherapy or radiation therapy may affect
the ability to radiographically visualize the tumor margins either at
the time of thermal ablation or during follow-up for recurrence. Please
discuss how limitations of radiographic visualization will affect the
selection of candidates for these procedures and make recommendations
regarding appropriate follow-up of these patients.

Dr. Kopans will be the lead discusser for this question.

DR. KOPANS: Well, i think certainly at the beginning it probably would
not be advisable to enter patients into a trial unless you \-- it would
have to be a separate trial from what we\'ve already discussed
certainly. There\'s no question that neoadjuvant chemotherapy alters the
imaging appearance of tumors. As many as 30 percent of invasive cancers
may disappear completely on imaging, and the problem would be certainly
from a noninvasive ablative technique what to aim at.

We try to position radio opaque and ultrasound visible clips in the
tumor prior to neoadjuvant therapy. The accuracy of that placement can
be variable. With a surgical excision following neoadjuvant therapy
there is, I think, because of the volume of tissue that\'s removed the
likelihood of excising the tumor even if the clip hasn\'t been placed
precisely. It\'s probably okay. We don\'t know for sure.

I would be concerned with a precise targeting technique, such as the
ablative techniques that we\'ve been talking about, that the precision
may actually work against actually hitting where the tumor had been.

In addition, as I mentioned already, tumors respond to neoadjuvant
therapy in a multiplicity of ways. One of them is that they break up, as
I said, or the residual tumor is in scattered islands of tissue. So
targeting that may be difficult, again, for an ablative procedure.

So I think that we still are really at the beginning of understanding
the effects of neoadjuvant therapy. Again, imaging, as I\'ve said
repeatedly and others have also said, is not certainly microscopically
accurate in the pristine tumor. Once the tumor has had other effects on
it, it becomes even harder to image.

Ultrasound lesions can be very difficult to image once they\'ve been
treated with neoadjuvant chemotherapy, mammography, and magnetic
resonance. All of the imaging tests that are being looked at have a
variable effect from neoadjuvant, but certainly make it harder to see
them.

ACTING CHAIRPERSON McCAULEY: Any comments, Dr. Witten, at this point?

DR. WITTEN: No.

ACTING CHAIRPERSON McCAULEY: Okay. Dr. Halberg, any further comments?

DR. HALBERG: No.

ACTING CHAIRPERSON McCAULEY: Dr. Solomon?

DR. SOLOMON: No.

ACTING CHAIRPERSON McCAULEY: Dr. LoCicero?

DR. LoCICERO: No, no comments.

ACTING CHAIRPERSON McCAULEY: Dr. Lanzafame?

DR. LANZAFAME: No.

ACTING CHAIRPERSON McCAULEY: Dr. Leitch?

DR. LEITCH: No.

ACTING CHAIRPERSON McCAULEY: Dr. Choti?

DR. CHOTI: A couple of comments. One is one of my biggest concerns just
coming into this is what the postoperative imaging of these ablation
zones will be and whether the ability to detect a recurrence will be
diminished compared to lumpectomy.

Again, in ablation of other sites, this is a big problem. That is,
following an ablation zone to see whether recurrence occurs. In breast
it\'s different because actually the lumpectomy causes a big zone that
obscures the ability to detect recurrence, different than other sites.

So it may be very similar. You\'re just going to see this big area, and
you\'re just going to have to try to determine whether a recurrence is
occurring in that area. But this is a problem as far as imaging.

Regarding adjuvant therapy, clearly postoperative radiation therapy
impacts on the ability to detect recurrence, but again, it\'s similar to
lumpectomy. Certainly that\'s the way it\'s going to be done clinically.
So it\'s going to be an ablation plus radiation and recurrence
assessment has to be done in the face of adjuvant therapy.

ACTING CHAIRPERSON McCAULEY: Dr. Blumenstein.

DR. BLUMENSTEIN: No further comment.

ACTING CHAIRPERSON McCAULEY: Dr. Doyle.

DR. DOYLE: No comment.

ACTING CHAIRPERSON McCAULEY: Ms. Brown.

MS. BROWN: No comment.

ACTING CHAIRPERSON McCAULEY: Dr. Miller.

DR. MILLER: At M.D. Anderson in the trial of the radio frequency
ablation the only failure that was \-- in 20 patients, the only failure
was one who had preoperative chemotherapy in a lesion that was four
centimeters that was reduced to a centimeter and a half, and when they
did the ablation, it was complete ablation of the tumor, but there were
foci of tumor in that four centimeter original volume of tissue that was
not imaged after the neoadjuvant chemotherapy.

So I think that, you know, the patients who get neoadjuvant therapy
should be excluded from the trial and just emphasizes that patients
should be selected for these trials who have very discrete tumors, that
there\'s good confidence that the imaging is telling you exactly where
the tumor is.

ACTING CHAIRPERSON McCAULEY: Dr. Brenner.

DR. BRENNER: I have no comment.

ACTING CHAIRPERSON McCAULEY: Dr. Kopans, any comment relative to Dr.
Miller?

DR. KOPANS: Comments on my comment. I think the issue of recognizing
recurrences, the point were well taken. I would only point out that our
experience with recurrence following lumpectomy and radiation in the
modern era is incredibly small because we don\'t see a lot of
recurrences anymore.

So you know, I think these recurrences will probably look like an
increase in density on an X-ray and an increase in hypo code (phonetic)
tissue on an ultrasound, but we really don\'t know. That\'s a good
point.

But I do think that serial biopsies should be considered at least in the
pivotal trial, and I think exploring imaging modalities of PET, you
know, diffusion MR and other kinds f things, I think, looking at the
periphery extremely carefully to try to \-- of these ablation zones will
be important biologic endpoints that will be helpful.

ACTING CHAIRPERSON McCAULEY: Dr. Witten, you had a comment?

DR. WITTEN: I had a question of Dr. Choti, but it\'s been answered.

ACTING CHAIRPERSON McCAULEY: Any further discussion from panel members?

(No response.)

ACTING CHAIRPERSON McCAULEY: Have the comments been sufficient to answer
Question No. 4?

DR. WITTEN: Yes.

ACTING CHAIRPERSON McCAULEY: Are there any comments or concluding
remarks from any of the panel members?

MS. BROWN: I have one comment.

ACTING CHAIRPERSON McCAULEY: Ms. Brown.

MS. BROWN: As a member of industry when I hear the possibility that
studies might be thousands of patients and follow-up might be ten years
or five years, it\'s a signal that companies may not be able to develop
technologies like this because that\'s very expensive.

So there\'s a balancing act that\'s going on here with respect to will
these things come to market if that\'s what it takes.

ACTING CHAIRPERSON McCAULEY: Dr. Blumenstein?

DR. BLUMENSTEIN: Yeah, I\'ve been concerned about this as well, and I
think that one of the possible solutions is sort of an interagency
cooperation whereby in this case perhaps some of the National Cancer
Institute funded cooperative groups could be a basis of doing studies of
the nature that we\'re talking about here.

We\'ve already talked about NSABP and the American College of Surgeons\'
Oncology Group and Radiation Therapy Oncology Group and so forth like
that. These are well funded infrastructures that do trials quite
efficiently with respect to costs and so forth, and I think that we just
really haven\'t exploited these things.

I\'m a refugee of that system, and I think that it\'s a national
resource, and that national resource isn\'t being exploited to the
degree that it could by industry and the FDA and the NCI.

DR. KOPANS: There actually is a model for that with the DMIS study
that\'s going on now looking at digital mammography compared to film
screen mammography where FDA has approved digital mammography, but there
is now a post approval study going on.

Initially it was going to be mandated by FDA. Now it\'s just happening
because the money was earmarked, but it seems to me you could do I think
you mentioned or it was mentioned earlier an approval with the
requirement of maintaining follow-up studies over time.

ACTING CHAIRPERSON McCAULEY: Dr. Choti, you had a comment?

DR. CHOTI: No.

ACTING CHAIRPERSON McCAULEY: Dr. Leitch?

DR. LEITCH: I think for industry the other thing is identifying a big
problem that this can fix as opposed to a small problem where there\'s
less of a fix that it gives.

So like I said, the hard situations where you\'d like to do breast
preservation, but it prevents a difficult circumstance because of size
of the tumor, you know, lobular, whatever you want to say, all of the
things that make preservation difficult for those patients who really
desire it; if you had a technique that would facilitate preservation in
patients, then to me that\'s an easier thing to get through than this
kind of thing where, you know, you require these sort of dramatic, big
trials, you know, to get to the endpoint.

ACTING CHAIRPERSON McCAULEY: Dr. Brenner?

DR. BRENNER: I guess I\'d like to assure industry that, indeed, at least
I was very sensitive to that issue and tried to grapple with the issue
of a surrogate in order to avoid such a huge cohort. The problem you run
into here is the already high level success of the state of the art, and
then that forces an equivalence design on you.

And once you\'re there, then you\'re stuck. You\'re stuck with large
cohorts whether you like it or not because Brent won\'t let you prove it
otherwise.

(Laughter.)

DR. BRENNER: It\'s all his fault. You blame it on the biostatistician.

But I mean, getting at truth is really difficult in an area where you
already have outstanding result. And one possible work-around was what I
think we\'ve been alluding to, was to attempt a quality of life with a
cosmesis endpoint as a standard for an interim approval a la Brent\'s
design.

As a potential, quote, superiority endpoint, that might allow you
perhaps to write your trial with less size than you would need
otherwise, but I think we were certainly very sensitive to that, but
kind of boxed in with the state of the art, and that\'s unfortunate for
you, but it\'s great for the patients in that there is good local
control.

ACTING CHAIRPERSON McCAULEY: Any other comments?

DR. MILLER: Can I make one more? I hate to prolong this, but if I just
could make one more.

You know, there\'s some ways \-- and I may be naive about this. I
apologize if that\'s true \-- but in some ways this is like asking is it
better to use a Barr Parker scalpel or a scalpel from another company to
do a lumpectomy and designing a giant clinical trial which will
determine whether survival is superior using one of those two ways to
ablate the tumor.

I mean, the primary issue here, it\'s not a fundamental change in how
we\'re treating the breast. It\'s just a different way to ablate the
tumor, and I think if we focus on are we getting adequate tumor ablation
locally with this method, that answers the major question, and then all
of the other questions of survival I don\'t think we have to withhold
sort of endorsing this approach pending confirmation in ten to 15 years
whether it\'s equivalent survival unless we can really come up with a
real rational reason why we can suspect fundamentally change the way the
tumor behaves if we play it like this.

DR. HALBERG: Well, I think that when you lose margin assessment, I mean,
I\'m sure in the investigator\'s hands here that they will get, you
know, incredible local control. I\'m not so sure when a technology is
generalized that that can always be said.

It took a long time to establish that, you know, even a small degree of
positive margins increases local recurrence risk, and I feel like our
primary obligation is to our women with breast cancer, the majority of
whom get excellent cosmesis with a lumpectomy, and there are going to be
a large number of patients who have the potential to have residual tumor
that\'s not ablated.

I\'m playing a little bit of devil\'s advocate here, but I think it\'s
important to keep that in mind.

ACTING CHAIRPERSON McCAULEY: Dr. Doyle?

DR. DOYLE: I think listening with my consumer rep. hat on I\'ve heard a
great deal today about some of the possible risks, but I\'ve heard less
about the benefits, and cosmesis seeming to be the one.

And I was very impressed with something that Dr. Lanzafame said, that I
think it is different. When you ablate something and take it out, it\'s
different from killing it and leaving it in. I think there is a
difference in what you\'re talking about.

ACTING CHAIRPERSON McCAULEY: Other comments from panel members?

(No response.)

ACTING CHAIRPERSON McCAULEY: Well, I\'d like to thank the panel for
their very fruitful discussion, and I\'m sure it\'s very helpful to the
FDA. This meeting is now adjourned.

DR. KRAUSE: Just one quick comment. If anybody wants to keep the
materials from this meeting, they\'re certainly welcome to. There\'s
nothing confidential here. Anything you want to throw away just leave on
the table and it will get picked up.

Thank you.

(Whereupon, at 4:23 p.m., the meeting was concluded.)