U.S. FOOD AND DRUG ADMINISTRATION

CENTER FOR DEVICES AND RADIOLOGICAL HEALTH

MEDICAL DEVICES ADVISORY COMMITTEE

GENERAL AND PLASTIC SURGERY DEVICES PANEL

66^TH^ MEETING

TUESDAY,

APRIL 12, 2005

The Panel met at 8:00 a.m. in Salons A, B, and C of the Hilton
Washington DC North/Gaithersburg, 620 Perry Parkway, Gaithersburg,
Maryland, Dr. Michael Choti, Chairman, presiding.

[PRESENT]{.underline}:

MICHAEL A. CHOTI, M.D., Chairman

GRACE T. BARTOO, Ph.D., RAC, Industry Representative

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

LEIGH F. CALLAHAN, Ph.D., Temporary Voting Member

LEELEE DOYLE, Ph.D., Consumer Representative

CHERYL A. EWING, M.D., Voting Member

A. MARILYN LEITCH, M.D., Voting Member

STEPHEN LI, Ph.D., Temporary Voting Member

JOSEPH LoCICERO III, M.D., Voting Member

BARBARA R. MANNO, Ph.D., Temporary Voting Member

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

AMY E. NEWBURGER, M.D., Voting Member

DAVID KRAUSE, Ph.D., Executive Secretary

[FDA PARTICIPANTS]{.underline}:

CDR SAMIE ALLEN

SAM AREPALLI , Ph.D.

PABLO BONANGELINO, Ph.D.

SAHAR M. DAWISHA, M.D.

MIRIAM C. PROVOST, Ph.D.

[SPONSOR REPRESENTATIVES]{.underline}:

HAROLD J. BRANDON, D.Sc.

R. JAMES BRENNER, M.D., J.D., FACR, FCLM

MAGGI BECKSTRAND, M.P.H.

MICHAEL A. BROOK, Ph.D.

DAN COHEN

RONALD W. HELMS, Ph.D.

JoANN KUHNE, M.S.N., RAC

JAMES C. LAMB IV, Ph.D., DABT

JOSEPH McLAUGHLIN, Ph.D.

CARY REICH, Ph.D.

SCOTT SPEAR, M.D., FACS

MICHAEL TAYLOR

PATRICIA WALKER, M.D., Ph.D.

A-G-E-N-D-A

**CALL TO ORDER**

Executive Secretary Krause 6

**INTRODUCTION OF PANEL** 9

**APPLICANT PRESENTATION: INAMED CORPORATION, SILICONE BREAST IMPLANTS**

**Introduction**

Dan Cohen, 14

**Preclinical Studies Overview and Clinical**

**Studies Overview**

Dr. Patricia Walker 19

**Closing Remarks**

Dr. Scott Spear 47

**Panel Questions to Inamed Presenters** 62

**FDA PRESENTATION**

**Introduction, Device Description and**

**Preclinical Testing Overview**

CDR Samie Allen 143

**Rupture Overview**

Dr. Sahar M. Dawisha 154

**Long-Term Probability of Rupture**

Dr. Pablo Bonangelino 182

**Panel Questions to FDA Presenters** 192

**OPEN PANEL DISCUSSION** 217

**FDA QUESTIONS**

**Question 1** 279

**Question 2** 288

**Question 3** 297

**Question 4** 312

**Question 5** 332

**OPEN PUBLIC COMMENT**

Cynthia Pearson,

National Women\'s Health Network 346

Dr. Roberta Gartside 351

Dr. William E. Katzin 356

Dr. Joseph J. Disa 363

Dr. Sidney M. Wolfe,

Public Citizen\'s Health Research

Group 369

Dr. Michelle Lockwood 374

Statement of Dr. LaSalle D. Leffall

by Betsy Mullen 377

Vanessa Rose Ferrelli 381

Statement of Dr. Barbara L. Philipp

by Michelle Nawar 387

Statement of Dr. Arthur Caplan

by Dr. Jane Zones 391

Statement of Margaret Galloway

by Amber Fair 394

Dr. Diana Zuckerman

National Research Center for Women

and Families 397

Cynthia Russell 403

Statement of Dr. Harold Glick

by William Schultz 407

**OPEN PANEL DISCUSSION** 410

**SPONSOR SUMMATION** 424

**VOTE** 427

**PANEL RECOMMENDATIONS TO SPONSOR** 440

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

8:04 a.m.

EXECUTIVE SECRETARY KRAUSE: Good morning, everyone. We\'re ready to
continue the 66th Meeting of the General and Plastic Surgery Devices
Panel. My name is David Krause. I\'m the Executive Secretary of the
Panel. I\'m also a biologist and reviewer in the Plastic and
Reconstructive Surgery Devices Branch in the Division of General
Restorative, Restorative, and Neurological Devices.

I\'d like to remind everyone that you are requested to sign in on the
attendance sheets, which are available at the tables by the doors.

You may also pick up an agenda, panel member roster and information
about today\'s meeting at those tables. The information includes how to
find out about future meeting dates through the Advisory Panel phone
line and how to obtain meeting minutes or transcripts.

Before I turn the meeting over to Dr. Choti, I\'m required two
statements into the record; the deputization statement. There\'s
actually two of those today. And also the conflict of interest
statement. And then I have an additional addendum to last night\'s
meeting that I\'d also like to read. So if you could bear with me, I\'ll
get those out.

All right. This is the first appointment temporary voting status.
Pursuant to the authority granted under the Medical Devices Advisory
Committee Charter, dated October 27, 1990 and as amended August 18,
1999, I appoint Stephen Li and Barbara Manno as voting member of the
General and Plastic Surgery Devices Panel for this meeting on April 11th
through the 13th, 2005. For the record, these individuals are special
Government employees and consultants to this panel or other panels under
the Medical Device Advisory Committee. They have undergone the customary
conflict of interest review and have reviewed the material to be
considered at this meeting.

This appointment is signed by Dr. Daniel Schultz, who is the Director
for the Center for Devices and Radiological Health.

The second deputization memo goes as follows: \"Pursuant to the
authority granted

under the Medical Devices Advisory Committee Charter for the Center for
Devices and Radiological Health, dated October 27, 1990 and as amended
August 18, 1999, I appoint Leigh Callahan as a voting member of the
General and Plastic Surgery Devices Panel for the duration of the
meeting on April 11th through the 13th. For the record, Dr. Callahan is
a consultant to the Arthritis Advisory Committee of the Center for Drug
Evaluation and Research. She is a special government employee who has
undergone the customary conflict of interest review and has reviewed the
material to be considered at this meeting.\"

And this is signed by Sheila Dearybury, the Associate Commissioner for
External Relations of the Food and Drug Administration.

The Conflict of Interest Statement reads as follows:

\"The following announcement addresses conflict of interest issues
associated with this meeting and is made a part of the record to
preclude even the appearance of 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 interest. However, the Agency has
determined that 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.\"

We would like to note for the record that the Agency took into
consideration certain matters regarding Dr. Miller. Dr. Miller reporter
his institution\'s past and current involvement with firms at issue. In
the absence of personal financial interest, the Agency has determined
that he may participate fully in the Panel\'s deliberations.

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

As an addendum to last night\'s meeting, I would like to read the
following statement:

\"Several women who have been harmed by breast implants agreed to not
have their testimony read last night in order to allow last night\'s
session to end earlier. They thanked the Panel for their work and ask
that their testimony be entered into the record, which we will do.\"

Thank you very much.

Okay. At this point I\'d like to turn the meeting to Dr. Choti.

CHAIRMAN CHOTI: Thank you, Dr. Krause.

And good morning. My name is Michael Choti. I\'m a surgeon at Johns
Hopkins Hospital in the Division of Surgical Oncology. I\'m the Chair of
this Panel.

During this three meeting this Panel will be making recommendations to
the Food and Drug Administration on two pre-market approval
applications.

The next item of business is to reintroduce the Panel members who are
giving their time to help the FDA in these matters, and the FDA staff
here at the table.

I\'m going to ask each person to introduce him or herself, stating his
or her area of expertise, position title, institution and his or her
status on the Panel.

Let\'s begin on the left side.

DR. PROVOST: I\'m Miriam Provost, Acting Director of the Division of
General, Restorative and Neurological Devices, Office of Device
Evaluation, FDA.

DR. LEITCH: I\'m Marilyn Leitch. I\'m a surgical oncologist and
Professor of Surgery at the University of Texas Southwestern Medical
Center in Dallas. I deal a great deal with the patients who have breast
cancer and also patients with benign breast disease. I\'m a voting
member.

DR. MILLER: I\'m Michael Miller. I\'m a Professor and Deputy Chairman in
Plastic Surgery at the University of Texas M.D. Anderson Cancer Center.
My clinical work involves cancer-related reconstructive surgery. I also
have an appointment in the University of Texas Center for Bioengineering
and at Rice University. My work in these areas involves tissue
regeneration and trying to restore deformities with these kind of
techniques.

DR. CALLAHAN: I\'m Leigh Callahan. I\'m a health outcomes researcher and
epidemiologist at the University of North Carolina in Chapel Hill. I\'m
an Associate Professor in the Departments of Medicine, Orthopedics, and
Social Medicine and work at the Thurston Arthritis Research Center. I\'m
a voting member.

DR. LI: My name is Steve Li. I\'m the President of Medical Device
Testing and Innovations out of Sarasota, Florida. And my areas of
interest are biomaterials and biomechanics.

DR. MANNO: I\'m Barbara Manno. I am Professor in the Department of
Psychiatry at the LSU School of Medicine in Shreveport, Louisiana. My
area of expertise is toxicology. And I\'m a special voting member.

DR. LoCICERO: I\'m Joseph LoCicero. I\'m Professor and Chair of Surgery
at the University of South Alabama. My specialty is thoracic surgery,
general thoracic surgery and foregut surgery.

DR. NEWBURGER: I\'m Amy Newburger. I\'m a dermatologist in private
practice. Director of Dermatology Consultants of Westchester. This is a
large cosmetic and medical dermatology practice. I\'m a voting member.

DR. EWING: I\'m Cheryl Ewing. I\'m an Assistant Clinical Professor in
the Department of Surgery at the University of California at San
Francisco. I\'m a surgical oncologist with a special interest in breast
oncology. And I am a voting member.

DR. BLUMENSTEIN: I\'m Brent Blumenstein, a biostatistician working
independently out of Seattle, Washington. I\'m a voting member.

DR. DOYLE: I\'m LeeLee Doyle. I\'m a Professor Emeritus of obstetrics
and gynecology. And I\'m currently the Assistant Dean for Faculty
Development at the University of Arkansas for Medical Sciences. My Ph.D.
is in reproductive physiology, and my research revolved around
contraceptive development including the intrauterine contraceptive
device.

DR. BARTOO: My name is Grace Bartoo. I\'m the General Manager of Decus
Biomedical. I am a bioengineer by training and my expertise is in
clinical trials and medical device development. I\'m the Industry
Representative, which is a nonvoting member.

DR. DOYLE: I am the Consumer Representative, which is a nonvoting
member.

CHAIRMAN CHOTI: Thank you.

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

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

We\'re now ready to begin the applicant\'s presentation. The
presentation will be introduce by Dan Cohen, Inamed Corporation\'s Vice
President of Global Government and Corporate Affairs.

MR. COHEN: Mr. Chairman, distinguished Panelists, on behalf of all of my
colleagues at Inamed, I\'d like to thank you and the Food and Drug
Administration for all of your time and your effort in assessing the
safety and the efficacy of our product.

My name is Dan Cohen. I\'m the Vice President Global of Corporate and
Government Affairs.

Following my introduction this morning, you will hear from Dr. Patricia
Walker, M.D., Ph.D., our Executive Vice President and Chief Scientific
officer at Inamed. Dr. Walker will present the context for offering
silicone gel-filled breast implants and then will present a detailed
overview of the safety data, of the Inamed PMA, and the amendment.

Following Dr. Walker, Dr. Scott Spear, Chief of Plastic Surgery at the
Georgetown University Medical Center will provide a surgeon\'s
perspective. Dr. Spear is also the President of the American Society of
Plastic Surgery.

So what has brought us here this morning? In December 2002 Inamed
submitted its silicone gel-filled breast implant PMA seeking approval
for augmentation, reconstruction, and revision indications for several
implant styles.

In October 2003, FDA presented its PMA to the General and Plastic
Surgery Devices Advisory Panel. The Panel recommended in a 9 to 6 vote
that the PMA was approvable with conditions. The FDA subsequently
amended the revised draft guidance for product approval in January of
last year, and we received a nonapprovable letter.

We responded to the revised draft guidance in August last year by
amending our PMA and providing additional information and scientific
data.

The safety of any medical device is relative to its effectiveness. And
effectiveness is relative to its intended purpose. The safety and
effectiveness evaluation of a lifesaving device such as vascular stent
or silicone-encased pacemaker is relatively easy. But with silicone
gel-filled breast implants, determining that balance is more difficult.

If you believe that body image is a valuable and an important component
of the human quality of life, your tolerance for that risk evaluation
will be much higher than if you believe that breast reconstruction or
augmentation has little or no value. How each person evaluating silicone
breast implants \-- a patient, a physician, this Panel, the FDA staff
\-- defines safety and appropriate risk depends on how one values the
procedure itself. That individual choice put in the context of safety
becomes the center of the challenge that we, together, seek to resolve
today to determine the relative benefit and risk of silicone gel-filled
breast implants.

Are there risks in using silicone gel-filled breast implants? There are.
However, as with any implantable device, and as we have demonstrated in
our PMA and will demonstrate further today, the risks are largely
related to the surgical procedure and local complications, rather than
the nature of the device. In addition, those risks are known and are
quantifiable.

Our goal today is to provide you with clear, concise, and accurate
characterization of the relative risk a patient assumes when she chooses
to use our silicone gel-filled breast implant product. In addition, we
intend to provide you with sufficient data to support a recommendation
of approval for this device.

In order to address the key issues identified last year, we will present
additional safety data regarding the nature and frequency of ruptures
observed. We will provide for your consideration further safety data
that expands upon the vast body of peer-reviewed, published biomedical
research. This research provides a reasonable assurance of the safety of
silicone gel-fill in these implants and the product itself both in terms
of reliability and longer term use.

Whenever an issue of safety or substance has been identified, we have
studied, we have investigated, and we have supported the research of
those issues with rigorous scientific methods.

Despite the current controversy surrounding their availability in the
United States, silicone breast implants were widely available to women
here from the early 1970s through 1991. Since that time, they have been
provided to tens of thousand of women throughout the United States
through the vehicle of clinical studies.

Since the 1992 moratorium, Inamed has provided nearly 100,000 silicone
gel-filled breast implants to the U.S. market for over 50,000 women. In
addition, silicone gel-filled breast implants have been available
without restriction for the past 30 years throughout most of Europe and
in many other developed countries around the world.

When we were before the predecessor to this Panel in October of 2003, we
made several commitments that that Panel adopted as post-approval
recommendations. Even though we have not yet reached that post-approval
stage, every one of those commitments that could be implemented has been
implemented. Today, we seek your endorsement to lift the remaining
restrictions on the sale of our silicone gel-filled breast implants in
the United States because we believe in our product, because we believe
the risks are acceptably low, because those risks can accurately,
clearly and reasonably be communicated in a robust, informed consent
process, and because our belief is founded in the safety data that this
generation of implants data generated by our studies and that reported
in the peer-reviewed literature.

Finally, we are unwavering in our commitment to improve each succeeding
generation of this product. We will continue the clinical studies and
laboratory studies of the implants in the post-market phase in order to
provide an even more complete knowledge base to surgeons and to women so
they can make a most informed decision.

Let me know ask Dr. Walker to present the information we have developed
in response to the nonapprovable letter and the modified draft guidance
of January 2004.

DR. WALKER: Thank you, Dan.

Good morning. I\'m Dr. Patricia Walker, and on behalf of Inamed I want
to thank you for the opportunity to present our scientific data on the
safety and effectiveness of silicone-filled breast implants.

We recognize that breast implantation remains controversial. But we are
not here to attempt to resolve this controversy. We are here to ask you
for your recommendation to include in the Inamed silicone breast
implants as an implant choice. Let\'s put this choice into context.

The value of breast implantation with a silicone breast implant is
readily apparent in the context of a mastectomy. It is of particular
importance that these women have the choice to restore their body image
and therefore their ability not only to overcome the cancer itself, but
also its effect on her appearance. Because they are more natural looking
and feeling, silicone breast implants should be an option for
reconstruction patients as well as women who choose breast augmentation.

While it might be tempting to dismiss the value of cosmetic surgery in a
healthy individual such as this, some women choose this procedure. If,
in consultation with her doctor, she decides that augmentation is right
for her, as thousands of women do, she should have the access to the
best available implant options.

Silicone gels do offer patients with advantages over saline. The
advantages are numerous. Silicone filled implants have a natural
appearance. They have a more natural feel. They provide more choice to
match a patient\'s needs, and they\'re ideal for reconstruction. Because
of these advantages, women consistently prefer silicone over saline.

In European countries and other countries where patients have a free
choice, they choose silicone 9 to 1 over saline implants.

One of the reasons for this preference is the wider range of options
available that silicone offers these patients and their doctors so that
they\'re able to select the implant which most closely matches their
aesthetic needs. These options vary in size, surface and profile.

To help illustrate the variations you all have a plexiglass box, at
least in front of every two to three Panel members. And for the initial
comparison, if you look on the bottom shelf of those boxes, you have a
saline implant. So you can pick up, I think you can just open those
boxes.

If you pick up the saline implants, you can get an idea for how a saline
implant feels relative to a silicone implant.

On the top shelf are two forms of our silicone gel implants. These are
our third generation implants. There\'s a smooth implant or a textured
implant. The texture some surgeons feel is better than the smooth
because it does provide a mild adherence and can help in placement of
that implant in the breast cavity.

Also note there the textured implant that you have is a shaped implant.
The implants come in a round or shaped form. The shaped implant that you
have there is the only shaped implant that is part of our PMA, and it\'s
what we refer to the Style 153. I will refer to this style over and over
again in this presentation. That shaped implant is unique in that it has
a lumen within the lumen, both filled with silicone.

These implants vary according to their size, so they\'re round or
shaped. The size varies by width and height for the rounds; width,
height and projection for both the rounds and the shaped. And as you can
see on the slide, the Style 153, the shaped implant, does have the lumen
within the lumen.

There are as many as nine different styles of the implants, and each one
comes in as many as 20 different sizes. The rounds come with three basic
projections. They have a moderate projection, a mid-range projection and
a high projection or profile.

The effectiveness of Inamed silicone gel implants have been demonstrated
in several prospective multicenter clinical trials. The two primary
trials I\'m going to discuss today are our core and our adjunct studies.
The aore study is a ten year ongoing study that assesses both the safety
and effectiveness in a total of over 900 patients. The Adjunct Study is
a five year study which is also ongoing. It\'s a large scale study with
over 46,000 patients who have received either reconstruction or
revision.

The AR90 was a small study in augmentation reconstruction patients that
we completed. It looked at both safety and effectiveness.

In these trials, the median age of the typical women in the Core Study
ranged from 34 to 50 years of age. These patients were primarily
Caucasian, they were married, college-educated and had professional
occupations. They also had an above-average self-esteem and quality of
life.

The study showed that the most common reason for implantation in this
population was a choice that the woman made for herself. Over 70 percent
of the patients chose to have implants to make themselves feel better
about their physical appearance, less than 20 percent to please their
partner, and less than 15 percent to improve their sex life.

At three years, post-surgery patients expressed satisfaction with their
implants. Looking across all three populations: those receiving implants
for reconstruction, augmentation revision, there was an overall high
rate of self-satisfaction. It was 88 percent in the revision group, 92
percent in the reconstruction group, 96 percent in the augmentation
group.

Quality of life instruments also demonstrated that their body image
improved after implantation. They had statistically significant
increases in their self-image, their physical self-concept and their
body self-esteem related to sexual attractiveness.

We are here, though, primarily to offer to you that our silicone gel
safety results, they\'re here for you to assess. The key question in
this assessment is whether the implant has an acceptable safety profile.
The results of our overall safety program provide reasonable assurance
of our implant safety.

Furthermore, we are continuously gathering new data, new information,
which will improve the safety and reliability of Inamed\'s implants. The
combined results of our nonclinical and clinical programs have already
helped us advance the quality of our implants. These third generation
implants incorporate several technological improvements, which enhance
the integrity of the implants.

The device in quality improvements include improvements to the implant
shell, the composition of the shell, as well as quality improvements in
our manufacturing. Our implant shells have an increased thickness over
the second generation product of over 50 percent. In addition, we\'ve
added a barrier layer in both the shell and the patch to reduce gel
bleed.

The composition of our gel is more cohesive due to an increased
crosslinking.

Our tighter manufacturing specifications have improved the quality of
our products. Each of these products is handmade and has multiple
quality assurance steps.

The third generation implants have undergone rigorous mechanical testing
and can withstand extreme stresses beyond what the human would normally
endure.

These implants are evaluated through static rupture testing as well as
fatigue rupture testing. The static rupture testing is shown in the
photograph on the right hand side of the screen there. That is the
ability of the implant to withstand pressures from both sides. These
implants are able to withstand pressures greater than 1,000 pounds of
force. To put this into perspective, a mammogram is approximately 32
pounds of force.

Using the same machine, we test the implants for their ability to
withstand fatigue rupture testing. And this is a cyclic fatigue testing.
These implants are able to withstand 30 pounds of force or 6.5 million
cycles. To try to put this into context: If you took a world class
runner, gave her an 800 cc implant and she ran continuously 24 hours a
day for one year, she would not fatigue her implant.

Another way that we have accessed the integrity of our implants is
through analysis of the potential for the silicone gel constituents to
bleed through the shell. Using hydrocarbon-coated disks which mimic the
lipid-rich environment breast we have demonstrated that there\'s a very
low rate of gel bleed, and that this rate decreases with time. Looking
at low molecular weight constituents under 1500 Daltons, we find that
that bleed compromises less than 0.3 percent of the bleed. We also have
demonstrated that there is no evidence of platinum in this bleed.

To assess the exposure of silicone as well as its safety and
biocompatability, we did a series of tests. We\'ve looked at in vivo
animal studies where we take the gel without the shell, radiolabeled
that gel so it\'s an unrestrained gel, implanted it into animals and
looked at where it went. What we found was that 99.4 percent of that
unstrained gel remained in place.

We have also done a series of standard toxicological studies which
demonstrate that the implant materials are biocompatible and safe.

We have analyzed the potential exposure to specific constituents of gel
also. We have done this through physiological-based pharamacokinetic
modeling, which is referred to as PBPK on the slide. These studies
demonstrate that the constituents, the low-molecular constituents, are
quickly cleared from the body. They\'re cleared primarily through
exhalation and the constituent D~4~, which is a measurable small
molecular weight silicone constituent, is predicted to be clear from the
body to levels below 1 part per million in less than 30 days.

Another question that we have addressed relates to the potential
presence of platinum. Platinum is used as a catalyst in the
manufacturing process of the gel. Just to put this into perspective,
platinum at levels that you would find in the gel is an approved use in
in vivo devices. The most common use is in pacemaker leads.

Also, levels that you would expect in the gel have been demonstrated in
the literature to be of no medical concern.

And finally, the platinum used in our implant materials is in the zero
oxidative state, and it is biologically inactive.

The safety and biocompatability of our of our silicone gel provides us
confidence about the safety of Inamed silicone implants. The integrity
of the shell is also important. The third generation implants have an
acceptably low rate of rupture. The ruptures can be either clinically
evident or silent.

Clinically evident ruptures are those which are detected by physical
examine or by symptoms, such as palpability, asymmetry, or pain. These
may be symptomatic or asymptomatic. But they have to be able to be
detected clinically.

Silent ruptures are detected only by a diagnostic screening such as an
MRI, mammography or ultrasound. And these are, by definition,
asymptomatic.

The rupture data I\'m going to discuss today has been derived from
several studies. The primary study is the Core Study. Remember, this is
our safety and efficacy study. There were 940 patients in this trial.
The patients had annual follow-up, and they had biannual serial MRIs.
And that was in one-third patients. It is the MRI screening in that
one-third of the patients where we have determined our silent rupture
rate. And in all graphs I\'m going to show you, that silent rupture rate
is extrapolated across that entire population.

Our Adjunct Study is the large safety trial that was over 46,000
patients. These patients also had biannual follow-up, but they did not
have serial MRI screening for silent ruptures.

We also did a retrieval study. This study was an analysis of all
explanted core and adjunct Study devices.

I\'m also going to share with your surveillance data, which is data
based on complaints for the devices that we received for the Core Study,
the Adjunct Study and an Urgent Need Program.

The Urgent Need Program was a program in place from 1992 to 1997, and
that was for the Style 153 only. That\'s the implant, the shaped implant
that you have in the boxes in front of you. That Style 153 was created
specifically for the reconstruction patient. Because of the shape, it
allows the physician to recreate a breast, the remaining breast in the
case of a single mastectomy because it allows for slope and shape and
changes that a breast would have over time.

To identify our ruptures, we include clinically evident ruptures as well
as the silent ruptures. As a reminder, the silent ruptures were those in
the MRI and we included any MRI reading which was read as positive or
indeterminate. So this is a very conservative measure of silent
ruptures.

Our rupture rate calculations that I\'m going to share with you are all
extrapolated. The estimates are extrapolated to include the silent
rupture across the entire population, and they\'re based on that MRI
cohort.

Of note, 86 percent of the ruptures were silent.

Using these calculations we include a predictive silent rupture rate at
three years from our Core Study to be 2.5 percent as shown on this
slide. This is a Kaplan-Meier rate. And, again, it\'s an extrapolation
with the silent rupture rate.

To extend this picture of the rupture rate, we have extrapolated the
current results from the Core Study out ten years.

The dotted lines are the actual rupture experience, and we\'ve used data
out to four years, which is now available. The hash line is the
projected rupture rate at ten years. This gives us a constant linear
failure rate, which gives you a ten year projection of 13.9 percent.
This rate, again, is based on silent as well as clinical evident
ruptures.

Those graphs that I just showed you were implant rupture rate by
implant. If we look at what is the rupture rate by patient, I have that
outlined here. And what you can notice right off is that the
reconstruction group has a higher rupture rate of 10.6 versus the saline
at 6.2.

We asked ourselves, is there something unique about the reconstruction
patients that they have a higher rupture rate? And what we\'ve
discovered through this study as well as our retrieval study, is that
it\'s not the reconstruction patients, but rather the preponderance of
one implant style, which is the Style 153. Again, that\'s the double
lumen, shaped implant. Sixty-four percent of the patients in this group
used the Style 153 implant. In subsequent slides I\'ll show you that
these differences are relevant to the Style 153, which does have a
different rupture rate relative to the rounds and does have a unique
rupture mode.

If you look at this slide here, you can see the breakdown of Style 153
in comparison to the round implants. The Style 153 had a three year
rupture rate. This is derived empirically and includes silent ruptures
of 8.3 percent. The green line are the rounds, which have a very low
rupture rate of less than one percent at three years.

When you look at the rupture rates together, combining the 153 and the
round styles, you get the yellow line again which I\'ve shown you
previously, which is the 2.5 percent overall rupture rate for this PMA.

We also looked at the Core Study slides, where I just showed you the 2.5
percent, and compared that with the Core Study in saline implants. The
implant shell is essentially the same on these products. How do they
compare?

You can see at three years the 2.5 percent compares very favorably to
the same time point in the saline study. The saline does have empirical
data out to eight years with an overall rupture rate of 7.3 percent.

The other thing that\'s important to notice on this graph is that the
saline rupture rate is a constant rupture rate over time. It\'s not a
quadratic rupture rate, but it\'s constant, has an increased number each
year.

Now I\'m showing you the data from the surveillance. The surveillance
data is an underprediction because it, of course, does not include
silent rupture rates but there are some important things I think to
notice on this.

First notice the five year rupture rate at the green line, and that\'s
the lowest line or the bottom line on your graph. Those are the rupture
rates for the round implants that are part of this PMA submission. Very
low rupture rate, less than one percent.

Now look at the Style 153, that\'s the pink line. As you recall from my
earlier presentation, the Style 153 was used in the Urgent Need Program
for five years, so we do have a real data out ten years on the Style
153. And it a surveillance rupture rate of 5.4 percent. This is in
comparison with saline rupture rates, which is the orange line, which
gives a rupture rate of 4.4 percent.

I really don\'t want you to focus so much on the rates, because this is
surveillance data, but rather on the shape of the curve. All of these
curves show a constant rupture rate over time. They\'re not a quadratic
hazard.

When you take all curves together, this is a busy slide, but it shows
the rounds, the Style 153, the saline, the Style 153 surveillance, and
then our predicted line, which is the yellow hash line, for all models
of this PMA. And what you can see is the shape of the curve is
essentially the same in all manifestations of this data. And it\'s a
constant curve.

Now I\'d like to take this projection and show it with what the FDA has
projected in their briefing package, which is shown here. The FDA\'s
lines are the gray dotted lines. I also changed the y-axis here. It\'s
now 100 percent.

I focus you on the yellow line and below, those are the Inamed curves.

The first hash line of the FDA curve is very similar. What they\'ve
predicted there is a constant rupture rate. Our prediction, that
prediction are very similar. I would argue that our data does not
support the other curves, the quadratic hazard curves as there\'s
nothing to suggest either in the saline or the gel data that they\'re
anything but a constant rate of rupture over time. That these graphs are
highly speculative and really inconsistent with our observed data.

We\'ve also looked at explanted implants. In the Core Study of the 1,782
implants which were placed, 248 of those were explanted for various
reasons. Twenty-five of those were confirmed ruptures. Of the confirmed
ruptures, 24 were intracapsular, one was extracapsular, and there were
no cases of gel migration in this study.

The Adjunct Study has a higher number of patients and also includes an
analysis of all ruptured patients. Here we have over 83,000 implants,
118 which were ruptured, 114 of those were intracapsular ruptures, four
were extracapsular ruptures such that the extracapsular rupture rate was
1 in 20,000.

There were two cases of gel migration noted in this study. One in 40,000
gel migration, 1 in 20,000 extracapsular ruptures.

Most importantly, none of the patients in either the Core Study or the
Adjunct Study who had a rupture had any serious or lasting consequences
related to this.

Our retrieval study has enabled us to determine the modes and causes of
rupture. We have looked at the devices and we have identified the device
failure for 91 percent of those analyzed implants. We\'ve identified
that surgical damage is the leading cause of device failure. And this is
due to sharp instrumentation such as the suture needle or a scalpel.

The results of this retrieval study have already begun to guide us to
minimize the specific factors contributing to rupture. We are working
with surgeons to develop techniques to minimize the surgical damage.

As already discussed, the Style 153 has a higher rupture rate. This is
consistent with our retrieval study, which has identified a posterior,
sharp-edge opening which is unique to the Style 153. Our design team has
proposed modifications, which are being reviewed by the FDA now, for the
Style 153.

The retrieval study has also provided us with insights into the
durability of the explanted devices. We have analyzed explanted devices
out three years in the Core Study as well as out 20 years in our
surveillance programs worldwide, and what we\'ve discovered is that the
mechanical properties of these explanted devices have not changed over
time. They don\'t change in terms of properties of ultimate break force,
ultimate elongation, tensile strength, and stress at 200 percent strain.

The most obvious consequences of rupture in our trials were aesthetic,
such as asymmetry, malposition, implant palpability and visibility. The
primary clinical effect of rupture is that the patient needs an
additional surgery.

The complications associated with breast implant patients is
well-characterized. We have looked closely at the complications of those
patients who had a rupture both before and after removal.

In this graph, we\'re looking at or this table we\'re looking at
patients from the Core Study who had a confirmed rupture. And what were
their symptoms before the rupture and how did that compare to the cohort
in the same group who did not have a rupture. And what we see most
importantly is that there are no unique or unexpected adverse events in
this table. Regardless of the rupture status, the most common reason for
explanation was a capsular contracture.

All of these patients underwent explanation., and 90 percent of these
patients chose to be replanted. We have follow-up data on most of them.
Now, this is looking at those patients with reimplantation with a
confirmed rupture compared to the cohort who had a confirmed nonrupture.
And, again, you see that there are no unexpected or unique adverse
events observed in the patients who had had a rupture. Although you can
also note that the infection rate is higher, and this is what\'s pointed
out in the FDA briefing package and is statistically significant, we
acknowledge that, it is only three patients, and may reflect something
that would go away with more patients or may in fact be real.

The data in the Adjunct Study is also similar. Here we have more
patients. There are 99 patients with a confirmed rupture. And then these
tables I\'m comparing confirmed ruptures with all patients, and there
were greater than 25,000 in the other group.

Again, capsular contracture was the most common reason, and there are no
new adverse events identifiable or distinguishable between groups.

After explantation, the complications observed were at rates similar to
all other patients.

This table is looking at the same thing. Patients with confirmed rupture
versus other patients after reimplantation. The average follow-up time
here was 1.8 years. Again, no new or unexpected adverse events.

More importantly, three year follow-up data from the Core Study have
shown that there are no lasting or serious health consequences in the
rupture population. We had no unanticipated adverse events, no reports
of connective tissue disease, no breast cancer, and a 100 percent of
these patients were satisfied with their implants.

Data suggests that implant rupture does not pose a serious health risk
to these patients.

Yesterday, we heard from several women who described very real and
serious medical illnesses. As horrible and heartbreaking as these
testimonials are, we must rely on science to establish if there is a
causal relationship between systemic illness and silicone breast
implants. The field\'s most respected researchers have continued to
confirmed the safety of silicone breast implants. The following reviews
reflect the most respected independent sources on silicone implant
safety.

The United Kingdom Review Group published a paper in 1998. The Federal
Judiciary National Science Panel in 1998. The International Agency for
Research on Cancer, the Institute of Medicine, and the U.S. National
Institutes of Health. Each one of the comprehensive reviews has
concluded that there is no risk of breast cancer or connective tissue
disease linked to silicone breast implants.

In addition, there\'s been no risk of silicone breast implants to
offspring that\'s been reported.

In vivo animal studies done by Inamed have demonstrated that there are
no problems with reproduction or birth defects with animals implanted
with silicone.

Silicone levels in breast milk of women with implants are the same as
those without implants. Furthermore, if you look at silicone levels in
the breast milk of women, you\'ll find that they\'re lower than in
formula or cow\'s milk.

The weight of this evidence demonstrate that Inamed silicone breast
implants can be assessed as reliable and safe.

We have ten year projected rupture rate of 14 percent. The causes of
rupture have been determined for 91 percent of the analyzed devices.
Surgical damage is the leading cause of rupture. We\'ve demonstrated no
systemic health consequences of rupture. The literature supports that
there is no increase in breast cancer with silicone breast implants. No
increased risk of connective tissue disease, and no risk to the
offspring. Based on the sum of our safety data, we make the following
recommendations to patients and physicians:

We recommend that patients should contact their surgeon if they have
symptoms such as asymmetry, pain, swelling, redness, or other changes
with their implants. These patients should have annual breast exams with
a physician familiar with breast implants. Further diagnostic imaging as
recommended by their physician. And in the case of a suspected rupture,
their implants should be removed.

Inamed is committed to the physicians and patients who use our implants.
We will provide the most current information to physician on surgical
techniques to prevent rupture. We will fully inform our patients of the
risks and benefits of silicone filled breast implants. We will continue
ongoing studies to increase the knowledge base.

We will continue to make product improvements based upon this knowledge.
We will continue to work to reduce the possibility of rupture. And we
are committed to assuring the safety and quality of our breast implants.

We will do this by continuing to evaluate all retrieved explants to
further characterize the origins of rupture and the long term
durability. We will continue our large scale, ten year Core Study
including the MRI cohort. We are committed to establishing a registry
which is linked with our warranty program to provide a mechanism for
additional data capture.

We will actively work with surgeons and surgical groups to develop
practices that reduce the risk of rupture. We will do this through
Inamed\'s continuing medical education publications as well as the
Inamed Academy seminars.

We will actively educate patients about the risk of breast implants. We
will do this by providing information that patients can make an informed
decision. This information will explain the surgery and possible risks.
The patients and the surgeons will document that the information was
reviewed and that questions were addressed by the physician. We will
conduct focus groups to ensure that this information is clear.

These commitments and the evidence we presented today provide the
foundation for our risk benefit assessment.

The risks are those of surgery, of local complications, and the
potential for an additional surgery. The benefits are numerous. These
silicone breast implants have a more natural appearance, a more natural
feel. They have a wide range of options for patients and physicians, a
greater ability to meet the patient\'s needs and an improved choice with
no increased risk over saline.

We propose to you that the benefits of silicone breast implants outweigh
the risks, making them a reasonable alternative for patients and
physicians.

Our implants are well-characterized, and they have a well-characterized
safety profile. We have experience in over 50,000 patients in the United
States for up to ten years. The materials are biocompatible, and
they\'re safe and nontoxic. We have a low rupture rate. The primary
causes of rupture have been and can be identified and, most importantly,
there are no serious or systemic complications associated with these
ruptures.

In the United States women and their physicians should be able to choose
the implant that best suits their needs.

I\'d now like to turn the podium over to Dr. Scott Spear who will close
this presentation.

DR. SPEAR: Thank you, Dr. Walker.

Good morning. My name is Scott Spear, and I\'m here to give you the
surgeon\'s perspective.

I was born and raised on the campus of the University of Chicago,
educated as an undergraduate at the University of Michigan and as a
doctor back at the University of Chicago. I trained in general surgery
with Bill Silon and Ron Weintraub at the Beth Israel Hospital in Boston
and at Harvard Medical School, and with Bill Blaisdell at the University
of California in San Francisco.

Like some of the Panel, I am first and foremost a university surgeon
with my primary responsibilities to my patients, my profession and to
intellectual honesty, which is critical to our role as surgeons.

I\'m also Chairman of Plastic Surgery at Georgetown University Hospital,
President of the American Society of Plastic Surgeons. And, yes, Medical
Monitor of Inamed\'s clinical studies for the last 16 years.

As a plastic surgeon at the Lombardi Cancer Center who has operated on
well over 10,000 women, I take this subject very seriously. Like my many
of colleagues, I deal with these issues on a daily basis. For us, this
is not an abstract debate. The decision that we reach here today effects
the options available to thousands of surgeons and to millions of women.

Eighteen months ago it was my privilege to deliver the closing to
Inamed\'s earlier presentation in October of 2003 in front of the very
same Panel. And that privilege is mine again today.

Let me begin by emphasizing several of Dr. Walker\'s critical points.
Inamed has, in fact, lived up to the commitments that it gave at the
2003 Panel, including continuing the Core Study out to ten years and
improved retrieval analysis, collecting additional long term evidence
for failure rates, enhancing surgeon education, improving patient
education and establishing a post-market registry.

Dr. Walker has shown you consistent evidence from multiple studies and
multiple independent sources that predict with a high degree of medical
certainty what the failure rate of these devices is out to ten years.
There is nothing here, absolutely nothing here to even suggest an
exponential shape to that failure rate curve.

Let me address the three most important questions that you have been
asked to answer by the FDA.

Can we characterize the rupture rate? My answer is yes. For all PMA
devices, the rupture rate of ten years is 14 percent. It\'s a constant
rate of 1.4 percent per year. For the single-lumen devices, not the
Style 153, but for the single-lumen devices the rupture rate is lower, 3
percent at ten years, 0.3 percent per year. And yes, these rates are
reasonably constant out to ten years.

Can we characterize the consequences of rupture? My answer again is yes.

What percent of the ruptures are extracapsular? If you read the
literature, the worst case scenario is 20 percent. In the Inamed Core
Study only 1 out of 1782 implants was extracapsular rupture. And in
Inamed\'s Adjunct Study, 1 in 20,000 implants was extracapsular and 1 in
40,000 actually had gel migration. That\'s the data. That\'s Inamed\'s
data. That\'s the literature data.

And what are the health consequences of rupture? The local health
consequences are those associated with reoperation.

Are the recommendations for screening and management supportable? My
answer again is yes. And we have collateral evidence from the plastic
surgeon\'s survey. We recommend screening every one to two years by
knowledgeable doctors with radiological studies as recommended by a
physician. We recommend replacement and removal for ruptured devices.
And we recommend MRI screening based upon physician recommendations.

So where are we today? Why do surgeons and patients around the world
prefer silicone gel over saline? What is different today about our
situation as compared to October 2003 or January 1992? And what is
unique about this situation we are facing with silicone breast implants?

Why do patients and doctors around the world prefer silicone gel
implants by a factor of 9 to 1 despite all the noise? The answer is they
have an improved shape and a better feel. They\'re more comfortable. A
better appearance. More options. And surgeons consider them more
durable, based upon the data.

Let me share with you the comparative data of silicone versus saline in
the PMA\'s for both devices at three years. If you look at the numbers
in yellow, silicone actually has a better safety record than saline, and
we\'ve already approved saline implants. The rate of malposition is
lower. The rate of asymmetry is lower. The rate of loss of sensation is
lower. The rate of wrinkling is lower. The rate of visibility and
palpability is lower. Silicone outperforms saline.

Let me show you some photographs of patients with silicone breast
implants. This first example is a straightforward example of silicone
breast implants used for reconstruction. Going from left to right we see
the patient pre-mastectomy. The middle row is the patient with tissue
expanders. And patients and doctors often ask, why do we use tissue
expanders. And the reason is, in part, because during this era of
controversy it gives patients six months to decide whether they want to
have a silicone or a saline implant. They don\'t have to make that
decision at the same time as whether they\'re going to have radiation,
chemotherapy, or a mastectomy.

This patient elected to have a silicone implant in her second stage. The
far right is the patient after her reconstruction has been completed,
including a silicone gel implant, the nipple reconstruction, and even
tattooing.

Now let me show you a comparison. The top row is a patient of mine who
had a reconstruction with saline implants. The far left, preoperative.
The middle picture is after a subcutaneous mastectomy. This is a
prophylactic mastectomy for a women who is gene-positive for breast
cancer. And in the far right the tissue expander has been removed and
she has been reconstructed with a saline implant. And this is a good
result, but it\'s not a natural result.

The bottom row is a very similar patient, also gene-positive. In fact, a
doctor who works at NIH. And this patient chose, after her expander had
been placed to have a silicone implant. And this is an NIH physician,
Ph.D. researcher who made that decision. She has access to the same data
that you have.

You\'ve heard about rippling statistically, but this is rippling in a
photograph. The top row is a patient with a reconstruction where we
demonstrate rippling. This is what the patients don\'t like because it
shows in clothing. The bottom row is a similar patient who had a
reconstruction with silicone gel implants where rippling is much less
common.

There\'s a big misunderstanding about the uses of breast implants, and
this patient typifies one of the unusual examples. She had a partial
mastectomy for breast conservation therapy. She\'s lost the bottom half
of her right breast. The solution here was a silicone implant to
reconstruct half of the right breast, but also to augment the left
breast.

Silicone breast implants also work best in patients who have lost tissue
not from cancer, but from pregnancy and nursing. This patient has been
reconstructed with a silicone implant as well as the procedural we call
a mastopexy to deal with postpartum atrophy.

In a dramatic example of why some patients prefer silicone gel implants,
on the left we have a patient who has an augmentation with a saline
implant. These do not look natural. And while some saline implants do,
these don\'t. She\'s been repaired by replacing these with silicone
implants. You can see why she would prefer them.

There is a continuum of uses for silicone breast implants. It isn\'t
simply about breast reconstruction and breast augmentation. The uses
include reconstruction after mastectomies, but also to help women who
have pre-malignant dispositions or for partial mastectomy defects or for
congenital deformities, or acquire deformities not from breast cancer,
but from other surgery or from trauma. Some women have lost breasts not
to disease, but to just aging. Some women are born very disproportionate
with large other parts of their body and very small breasts and are
self-conscious about it. And some women just want to have the right to
choose to change the size of their breasts to make them smaller with a
breast reduction, to make them larger with a breast implant.

What is different about today than October 2003 or January 2002? First,
these are not the same implants that preceded the 1992 moratorium. Let
me make that clear. These are not the same implants. These are the third
generation implants that dominated the U.S. market by 1998. It was
transitioned from second generation in the \'70s and early \'80s to the
third generation in the late \'80s and early \'90s.

Prior to 1991, there were several claims of injury from silicone gel
implants, much as you heard yesterday. In 1991 the American Society of
Plastic Surgeons invited several scientists who authored some of those
claims to present their data at our annual scientific meeting in
Seattle, Washington. Only one of those scientists, Frank Vassey, to his
credit, showed up. At that time, although Vassey\'s and others? claims
seem unlikely, we did not have sufficient scientific evidence to answer
them.

Meanwhile, by 1991 the technology had moved definitively on to third
generation implants, which is, as we have heard today are more durable
with more cohesive silicone gel.

We\'ve also heard from plastic surgeons who have several years of
experience with these newer devices that surgical techniques, too, have
changed. For example, 98 percent of American plastic surgeons no longer
do closed capsulotomies, which in retrospect were risky and often lead
to extracapsular gel migration.

By 2003, women and surgeons could be reassured by the emerging
epidemiological data. Looking at the possible health risks from the
earlier generation silicone gel implants, there was good news \-- good
news. The fact that diseases don\'t happen is good news. It\'s not bad
news. This news is from the Institute of Medicine from Judge Pointer\'s
Federal Judiciary National Science Panel, from the United Kingdom, and
from hundreds of peer reviewed papers. And please bear in mind that
these reports were from experts \-- experts in their selected fields who
had ample time, sometimes years, to review and discuss the data and the
evidence.

In 2003 we also had data specific to these new third generation, more
durable, more cohesive silicone gel implants. We had information and
data from Inamed\'s 1,000 patient Core Study that Dr. Walker discussed
with you before me, from patients in Europe where they\'d been in use
since 1992, from Inamed\'s Adjunct Study with 50,000 patients, from
thousands of U.S. patients with third generation silicone gel implants.
There were no documented systematic health consequences from silicone
gel and far fewer local problems from rupture or from silicone gel
itself as compared with the older devices.

In 2003, this very same Panel voted 9 to 6 to approve Inamed\'s PMA for
these devices. As you know, the FDA held off approval and asked for
additional information. So now, in 2005, we have two year\'s more data.
And what does it tell us?

We now have saline data out past eight years. And Dr. Walker showed you
the failure rate. No silent ruptures with saline, 7.9 percent. A stable,
constant curve.

We have the Core Study data out past four years. We have the Adjunct
Study information out to five years. And we have 15 years experience in
the U.S. and in Europe. We have the NCI study authored by Louise Brinton
funded by the Government which looked at over 13,000 women. And I am
proud to say that the American Society of Plastic Surgeons supported
that study. And I\'m also proud to say that it included my patients.

And this week, we have survey data from hundreds of American plastic
surgeons who have actually been using these devices over the last
several years.

What is unique about today? Silicone gel implants have been available
around the world since 1992. In fact, since before 1992. They are still
available in the United States today to many selected women. Only
certain women are excluded from having silicone gel implants. And unlike
any other medical device, before approval, we already have 30 years of
safety data about these devices.

Although we do not have one all encompassing perfect study to share with
you, we do have the overwhelming weight of evidence that supports their
safety and efficacy.

Let me introduce one of my patients who came in last week and who
typifies my practice at Georgetown University. I want to share her exact
words from a conversation when I spoke to her yesterday asking her, why
did you choose a silicone gel implants. These are her pictures, and
these are her words. \"I could have gotten saline and gone to Bethesda
Naval Hospital, but I came to Georgetown so that I could have silicone.
Saline is stiffer and gets colder in cold weather. My implants are
working great, and I don\'t even know that they are.\" This is a woman
who had a bilateral prophylactic mastectomy for breast cancer genes.

I think women should have the right to choose whether for reconstruction
or cosmetic purposes for themselves.

This woman is a very intelligent and informed person. She\'s an engineer
with a master\'s in public health. She works for the Federal Government
as a scientist.

As surgeons whose responsibility it is to provide the very highest
quality and care available, we are comforted more and more with an
increasingly uncomfortable dilemma. And that is that we are knowingly
using implants in some patients that are clearly less effective and no
more safe than devices that we would otherwise recommend and that are
widely available and preferred in 60 other developed countries.

Thirteen years ago, in 1992 the FDA restricted the use of silicone
gel-filled breast implants because of insufficient evidence as to their
safety. In 2005 we clearly \-- let me emphasize, we clearly have far
better implants and a lot more comprehensive, independent, scientific
information to reassure about their safety. Surgeons and patients
deserve the right to make medical decisions based upon the legitimate
medical evidence, not claims without substantiation.

Now in closing, on a more personal note, I want to thank each and
everyone of the panelists for your time, attention and personal
sacrifice in this Panel proceeding. I can only guess how difficult your
task must be.

And at this point let me ask Dr. Walker to come back and open the floor
to questions.

Thank you.

DR. WALKER: Thank you very much.

We have many people available today to answer questions. We have the
Inamed employees, as on this slide, as well as several consultants who
are specialists in different fields.

Inamed has provided you with a little bio on our consultants so that you
can, if you\'d like, specifically ask them questions in their area of
expertise.

CHAIRMAN CHOTI: So the discussion is open to the Panel to ask questions
of the sponsor regarding the presentation. Yes, Dr. Leitch?

DR. LEITCH: I have some concerns about the 153 style. And you mentioned
that there were some ongoing changes to be made in that device. Could
you tell me a little bit more about that and what the plans are and the
expectation of that?

DR. WALKER: Yes, I will.

This is a schematic on the slide of the Style 153. The original design
is on your left if you\'re looking at the screen. And it\'s a more round
lumen within the shaped implant.

What has happened, as you see, that there\'s a patch where that inner
lumen is attached to the posterior wall as well as the patch where the
gel is filled. And what that resulted in are two stiffer areas of the
patch with the normal shell between them. And with movement that\'s
where the posterior tear occurred.

So our engineers have redesigned the implant. It\'s now a more
tear-shaped interior lumen with one patch on one site where they adhere
to the wall.

Those design changes are sitting with the FDA, and we\'re in discussions
with them.

CHAIRMAN CHOTI: Yes. Dr. Miller?

DR. MILLER: Yes. I wonder if you could be more specific about the gel
migration studies? How exactly where they performed and where did you
look for the presence of gel outside the capsule and that sort of thing?

DR. WALKER: The gel migration clinical data that I showed you was
looking just in the clinical picture in terms of the migration. The
animal work, the preclinical work I\'m going to turn to Dr. Cary Reich
and have him share that data with you.

DR. REICH: I\'m Cary Reich, Senior Vice President of R&D with Inamed.

In our animal study, we implanted radiolabeled gel in a rat. This is gel
without a shell. And then looked at the migration of the radiolabel. And
99.94 percent of that material remained in place. Of the remaining 0.06
percent, a third of it was excreted in the feces or urine or exhaled,
and the remaining amount of material was found, a small amount in the
liver, an every smaller amount in the muscles and the remaining less
than .02 percent distributed randomly throughout the rest of the
carcass.

DR. MILLER: How about the clinical determination? I mean, were tissue
specimens taken and that sort of thing?

DR. WALKER: In the clinical determinations of the two patients, I\'d
like Ms. JoAnn Kuhne tell you what we saw in those two patients
specifically. But I will note that we didn\'t do routine biopsies of
sites outside on patients. You know, we didn\'t biopsy their skin, liver
or other organs routinely.

JoAnne?

MS. KUHNE: JoAnne Kuhne, Senior Director of Global Regulatory Affairs.

The two patients that we had in our study with gel migration, both of
the gel was in to the left axilla. One patient was a bilateral revision
patient, had capsular contracture, and there was no specific reason for
why the gel was in the left axilla.

The second patient had multiple needle procedures, and it was the
physician\'s opinion that the gel had actually been aspirated from the
implant and placed in other areas, for instance in the left axilla from
the needle.

DR. MILLER: Just ask one more patients. Did the patients, I know there
are only two, but did these patients manifest any symptoms related to
the presence of the gel outside the capsule?

MS. KUHNE: There were neither any local complications or systemic types
of complications that reported in these two patients that were not
reported in other types in other patients who did not have either
extracapsular ruptures or ruptures at all. In fact, patients who had
intact implants, they had similar types of complications as well as
rates of complications.

DR. MILLER: Thank you.

CHAIRMAN CHOTI: Let me ask Dr. Walker. Regarding the silent rupture you
said a third of the patients in the Core Study had MRI. How was that
group decided? Which patients got the MRIs and which didn\'t, and were
there any differences in the group that got MRI versus those that did
not?

DR. WALKER: JoAnn Kuhne.

MS. KUHNE: A third of the overall cohort was determined to receive MRIs.
And the way those patients, actually it was the sites that were picked
were sites that had radiological facilities nearby that had a breast
coil and could perform the proper MRI procedures. And then the patients
were then selected randomly from those sites to be entered into the MRI
cohort.

CHAIRMAN CHOTI: So your assumption that the silent rates based on MRI
extrapolated to the entire group isn\'t hard to make. Only certain sites
that had the MRI facilities were the ones that actually were studied for
silent rupture, is that fair to say?

DR. WALKER: They were specific sites, but all patients at a specific
site has the ruptures.

CHAIRMAN CHOTI: And along those lines, a little bit of confusion between
a silent rupture and a reported rupture in the numbers that you quoted.
And you\'re showing a linear rupture rate that I think if I recall the
curves went to five or six percent at ten years, and yet the numbers
were 14 percent at ten years. And you suggested that the silent rupture
rate makes up 80 percent \-- 86 percent, I think, of the ruptures. So
we\'re a little bit confused here as to what numbers you\'re using. What
is the true silent rupture rate?

DR. WALKER: Okay. The true silent rupture rate, and I can show you that
data in a moment, is 86 percent. The surveillance is better than just
symptomatic ruptures because we have a warranty program that if the
patient has an explanted device and that explanted device is ruptured,
the patient returns that. So we actually have more data that you would
have if the patients were just walking around asymptomatic.

Many patients change their implants for multiple reasons; for size
changes, malposition, capsular contracture. So we get more information
because these patients are in the study program. We have a warranty
program. That warranty program gives them financial compensation to
offset the surgery such that the silent ruptures are captured at a
higher rate than a symptomatic rupture would be captured.

If I were to show you the European data, you\'d probably see a more
accurate reflection, and I can do that, of what the real symptomatic
rupture rate is.

So our surveillance data is more than just symptomatic ruptures. It\'s
symptomatic ruptures as well as identified ruptures.

Does that help?

CHAIRMAN CHOTI: It\'s still confusing. I mean we\'re interested in
knowing what the rupture rate is. And if 86 percent of the ruptures are
silent, then it\'s really the total rupture rate I think that is the
important figure. But \--

DR. WALKER: Which would be the 13.9 percent predicted rate at ten years
or 2.5 percent at three years. Because that silent as well as
symptomatic ruptures.

CHAIRMAN CHOTI: All right.

Yes, Dr. Li?

DR. LI: I had a follow-up question to Dr. Miller\'s question on the
animal model that you used to assess gel migration. Could you give some
details about that? Did you simply inject the gel subcutaneously or did
you create an air pouch and put the gel in the air pouch? Could you give
some details about how that was done?

While you\'re wondering about that, the reason I asked the question is
in orthopedics there\'s an air pouch model where they introduce things
like metal particulate or polyethylene particulate into the air pouch
that\'s created under the back of a mouse. And they use that then to
assess the biological interaction with those particles. However, in that
particular model there\'s no migration of those particles, as you would
find in a human. So my question is how do you know your model is
actually capable of predicting migration because there are some animal
models where we know it doesn\'t actually migrate, even though we know
it does in a human?

DR. WALKER: Yes. Dr. Cary Reich is going to answer that question for
you.

DR. REICH: I have to apologize. I don\'t know the details of how that
implantation was done. I believe it was basically a subcutaneous
insertion of the gel into the animal model. But we will get that
information to you.

DR. LI: And the real question there is, however you did it, does that
particular methodology have some literature or some validation that if
you put something in that you know migrates, that it actually migrates?

DR. REICH: Well, actually, we do have the gel was subcutaneously
implanted. I\'ll get to the answer to your question, I think, in a
minute.

DR. LI: All right. And the reason for my confusion is the air pouch
model is also described as a subcutaneous injection. So that in itself
might not be \-- it\'s a little ambiguous, I guess, in the description.

DR. REICH: Right. This is not an injection, it\'s an implantation
because this material really doesn\'t lend itself very well to injection
because of the physical nature of it.

DR. LI: Okay. So it\'s not an injection. So you\'re actually making an
incision and laying the gel in there?

DR. REICH: Right. Right. I guess you do have a shell \--

DR. WALKER: If you were to lift up the shell on the samples that you
have, you can feel the implant there. You can strip the shell away, and
that silicone gel stays in the shape that it\'s in. It doesn\'t run or
move.

DR. LI: Oh, I understand that.

DR. WALKER: They took basically an implant without a shell and made a
subcutaneous pocket where they put the gel.

DR. LI: Okay. And I guess my question is, if you did that with something
that you know migrates, maybe from some other device or from the
literature, would it actually show migration?

DR. WALKER: Based on the physiologically- based, pharmcokinetic modeling
you can see other control things move throughout the body. So assuming
that model is valid, you would assume this model is valid.

DR. LI: Yes, but maybe not specifically for this one then? For this
model?

DR. WALKER: Yes.

DR. REICH: This model actually is consistent with other animal models
that have been used. And again, I\'ll try to bring this bad to the
clinical picture in just a second. But there are several other studies
in the literature using a very similar model which have demonstrated
that the gel remains in place in these animal models.

This actually is consistent with literature looking at silicon as a
surrogate to silicone clinically, in which it was found that the silicon
levels in capsular tissue directly adjacent to the implant was higher
than in breast tissue in controls.

As we can see in this slide, the top line basically are silicon levels
as determined in cadaveric tissue. The second to the bottom line is the
silicon level in capsules directly adjacent to silicone gel implants.
And when these patients were actually sampled at distant sites, they
found that the silicon level was no different from the silicon level in
nonimplanted cadaveric tissue.

So, you know, it\'s a little bit of a roundabout way to answer your
question. The animal model that we use appears to be correlated and at
least consistent with clinical data that\'s been developed.

DR. LI: And what specifically was the radiolabel? How did you label the
silicone?

DR. REICH: It was labeled \-- it was a C-14 label silicone. I don\'t
know the details of it.

DR. LI: Okay. But it was the carbon that was labeled?

DR. REICH: Right. Right.

DR. LI: Okay.

CHAIRMAN CHOTI: Yes. Dr. Newburger?

DR. NEWBURGER: I see in the guidance document of January 2004 that one
of the things the FDA had recommended was the sponsor provide tissue
sampling data on surrounding breast tissue and capsule to confirm
whether or not gel implant constituents are present. You did that in two
only. And I\'m sure that more than two were available. And I\'m
wondering what the difficulty was?

There\'s an article that was published just a couple of weeks ago in the
American Journal of Surgical Pathology by Katzin, Centeno, Feng et al
that shows that when nodes were sampled from 96 patients with breast
implants, half of whom had ruptured and half had intact implants, that
using laser-Raman spectroscopy and Fourier microanalysis that they were
able to confirm not only the presence of silicone in the regional axilla
nodes, all of these patients had nodes sampled, but also that there was
alternation in the nodal pathology. Of course, we have no information
whether or not this is clinically significant. But I\'m interested
since, obviously, a substantial number of these people had intact
implants why don\'t we have a little bit more data on this with your
improved versions?

DR. WALKER: The reason we didn\'t do it is that there are no controls
and there is no way to evaluate or put that data into context.

We know from the literature that if you biopsy the area surrounding an
implant, you will have silicone levels. We know that if you biopsy a
woman without an implant, there will be silicone levels. We know if you
look at lymph nodes of women with or without implants, there may be
silicone in those. If you look at the liver of cadavers, there will or
will not be silicone in there. There is silicone in multiple products
that we use: toothpaste, deodorants, it\'s in the environments, it\'s in
nipples, other plastic products that it becomes impossible to put that
data into context.

Patients and surgeons aren\'t very enthusiastic about making a biopsy of
an area that you would gather data that you would not really be able to
use or would be of value. So we chose not to do it without having
appropriate controls.

DR. NEWBURGER: This, by the way, was a controlled study. And the
controls showed no evidence of this, and the controls were people with
breast cancer.

DR. WALKER: That is one paper, and I appreciate that that paper exists.
But there is a lot of literature in this area that shows that there are
silicone in many different places.

If you do have silicone bleed around the gel capsule, it\'s not a
surprise that you would have some microscopic silicone in the lymph
nodes with migration, macrophage migration.

I think what\'s most important to remember is to put this in context, is
that none of these patients with 30 years of experience with silicone
implants have had systemic illness associated with that. Only one
percent or less of our patients in the Core Study or the Adjunct Study
had associated lymphadenopathy.

Dr. Spear would like to add something to this.

DR. SPEAR: A couple of things. I\'m familiar with that paper which just
came out. And, first of all, it was published out of a center which is
specifically a center for patients who have breast implant problems. I
mean, that surgeon and that pathologist have been a magnet for patients
with problems. So you don\'t know the denominator. We\'re just getting
the numerator.

Second thing. Not these devices. That\'s all product of second
generation implants and that\'s data based upon \-- you know, we only
had so many patients in this study who have implant problems not
relevant to this device.

Regarding the biopsy thing, the American Society of Plastic Surgeons
specifically addressed that guidance document and responded to the FDA
that to ask to get tissue sampling from patients without approval or
without IRB approval is inappropriate and also would not lead to any
useful scientific information. So all the appropriate bodies responded
to the FDA that that was not an appropriate request for the sponsor. And
I think, basically, the FDA has realized that that was not a request
that could be followed up on.

DR. NEWBURGER: Thank you.

CHAIRMAN CHOTI: Yes. Dr. LoCicero?

DR. LoCICERO: Yes. I\'m really quite intrigued by your curve fitting.
And I\'d like to know something about your methodology for linear fit,
what your regression analysis was, why this one was better than other
curve fits?

DR. WALKER: We chose a constant failure rate. And I\'m going to have my
statistician Maggi Beckstrand explain to you how they chose that. I\'m
actually going to have an outside consultant, I think, who can give you
an outside view who has looked at the data, Dr. Ron Helms.

DR. HELMS: Good morning. I\'m Ron Helms, Professor Emeritus University
of North Carolina.

Let\'s put this up, if we could.

To some extent this slide isn\'t totally appropriate because the curves
we\'re interested in are all at the bottom. But this isn\'t an
appropriate situation for regression. The curves, the lines where we
have the solid ones at the bottom are Kaplan-Meier curves. In this case,
coming up from the bottom, we often see them coming down from the top;
these are Kaplan-Meier curves.

And there is no assumption underlying those curves where the data are.
The assumption comes in after the point where you have data to project
out to ten years.

There are several possible assumptions, and FDA explored several of
those. But as you can appreciate from the curves there at the bottom,
they\'re practically straight lines. That\'s consistent with a constant
hazard assumption. That is, that the risk remains the same throughout
for any particular interval throughout the time period. So a constant
hazard assumption gives a straight line, as in FDA\'s projection, as in
Inamed\'s projection and so on.

Where there is data, and there is actually a number of studies with
different types of data, but in all of these studies, as you can see
from the lines, it\'s basically a straight line.

Now, there\'s some exceptions and if you\'d like, we can go into those.
But given that it\'s basically a straight line which corresponds to the
constant hazard assumption, you take the end point, the estimate at the
end of the Kaplan-Meier data, as the best estimate of that hazard, of
the rate, and then simply project that as a straight line out to the
end.

DR. LoCICERO: If this were a Kaplan-Meier curve, then your rate would be
4 percent at ten years?

DR. HELMS: Depending on where you start. It was 2? percent at three
years roughly and so it projects to 14 percent at ten.

DR. LoCICERO: How can you follow up 14 percent? There\'s no data. It
ends at that point and then it\'s continuous from that point.

DR. HELMS: Correct. But if you take the estimate at 3? years being 2?
percent, then you\'re basically just projecting a straight line from
zero through the appropriate multiple of 2? percent to get out to ten
years.

CHAIRMAN CHOTI: And is this silent rupture, all ruptures, or just
clinical ruptures that you used these calculations for?

DR. HELMS: It\'s all-inclusive. All models, silent, asymptomatic, and
symptomatic as well.

DR. WALKER: And it\'s weighted to include that you take the one-third
population that we calculate the rate of silent rupture, and that\'s
weighted to include all patients.

So I don\'t know if I made it clear before. Of all ruptures, 86 percent
of those ruptures are silent. Not that there\'s 86 percent \--

CHAIRMAN CHOTI: Five out of six ruptures are silent. And yet that curve
for the Adjunct Study is not silent, right? That pink line or whatever.

DR. WALKER: No. The Adjunct Study are only ruptures that were noted
after explant \--

CHAIRMAN CHOTI: Right.

DR. WALKER: \-- or were symptomatic.

CHAIRMAN CHOTI: So what would the projects curves be for all ruptures
including five times as many that would be silent?

DR. WALKER: Well, that would be your Core Study. Because your Core Study
includes silent ruptures and total ruptures. So the Core Study is your
best predicated rate of rupture, and it\'s 2.5 percent at three years
and then predicted to be 13.9 percent at ten years.

The Core Study is really the only study that has a measure of
symptomatic as well as silent ruptures.

DR. LoCICERO: Could we see you redraw this with a Kaplan-Meier curve?
Because you say this is device survival rate.

DR. HELMS: You mean having it come down from one as opposed \--

DR. LoCICERO: No. Show us a regular Kaplan-Meier curve.

DR. HELMS: I don\'t know that we have that here. This is the one that\'s
traditionally been used.

DR. LoCICERO: I don\'t know. It\'s not traditionally used for cancer
patients.

DR. HELMS: No, no. That\'s a different arena. And I\'m used to seeing
them the other way as well.

DR. LoCICERO: You have time before this afternoon. Show it to us.

DR. HELMS: Okay.

CHAIRMAN CHOTI: Dr. Callahan, question?

DR. CALLAHAN: Could you explain a little more about the Style 153
surveillance study? Do you have ten years on all 20,000 individuals? And
what other things were collected in that surveillance?

DR. WALKER: The Style 153 surveillance data, that study had an Urgent
Need Program. So there weren\'t, you know, 20,000 patients in the Urgent
Need Program. There were 1200.

So if you would put the Style 153 surveillance graph up for me.

This has a lot of the graphs on there, but the Style 153 is the pink
line. So if you look at year five to year ten, there are 1200 patients
in that group. So the numbers are lower because those were patients who
had reconstruction who were part of the Urgent Need Program and got
Style 153.

DR. CALLAHAN: So what are these 20,000 implants on the other slide? It
says N equals 20,000.

DR. WALKER: Those are overall. That includes \-- The first five years,
the bulk of those patients are only in the first five years, they\'re
part of the Adjunct Study. The ten year data, the years five through
ten, are only 1200 patients that go out with time. Because it
accumulation of the addition of the data from the Adjunct Study which
were the 20,000 as well as patients who had the device out now between
five and ten years, which were only part of an Urgent Need Program. The
Adjunct Study is in year five, and we have taken all the 153 data that
we have, which is Urgent Need Program plus Adjunct Study.

Does that help?

Dr. Spear would like to add something.

DR. SPEAR: Dr. Choti, I\'m trying to help resolve that question you
asked. I get the point, and I think I can explain it.

And it has to do with the composition of the implant types of the
studies. So in the Core Study with the MRI study, you have a large
number of these 153 devices. So you actually have picked up a fairly
high number of silent ruptures. In the surveillance studies, it\'s a
much smaller proportion of the total device population.

I think that will explain the discongruity that if you multiple times
five with the silent rupture, you get a bigger number than you would
expect in looking at our projected numbers. Because one-third or so of
our population is reconstruction, and I think 60 percent of the implants
were 153s. We\'ve learned they had a higher failure rate. But if you
extrapolated that failure rate over the whole population, it would give
you a wrong number.

So the reason why the whole population of implants seems to have a lower
number then you\'d get from the MRI study is because there\'s a higher
proportion of 153s in the MRI study.

Does that explain it?

DR. DOYLE: Yes.

Dr. Manno?

DR. MANNO: I have a question of Dr. Spear. Sorry that you \-- I didn\'t
catch you before you sat down.

I\'m confused about something, and I just need to be straightened out.
You talked about the use of the expander. And the reason you gave for
using the expander is to give six months to decide what they\'re going
to do. But yesterday we heard from other physicians that you used the
expander in the, I believe, it was the reconstruction patient in order
to expand the skin, if you will, so you have enough covering material.
Which is it?

DR. SPEAR: Well, it\'s actually both things and several others, too. I
only got ten minutes. But I will tell you that there are a lot of
reasons for using tissue expanders. But over the last 15 years, one of
the sort of side benefits of using tissue expanders so that women who
have got breast cancer and have to make so many decisions, the idea that
they\'re going to choose whether to get a silicone or saline device is
just more than I know my wife could handle.

So in addition to the fact that it allows us to begin the process, make
the space, maybe stretch out the skin, begin to get a \-- I call it a
\"rough draft\" part of the reconstruction. But also as a side benefit,
that a woman isn\'t forced to choose a silicone or saline implant at
that moment. And, frankly, women make the choice depending upon how they
weigh the risk benefit analysis. But it\'s not the specific reason to do
a tissue expander, it just turns out to be one of the dividends of
having an expander in there for four to six months because, of course,
women are afraid of all kinds of things. But at that point they can make
a more thoughtful reflective decision is silicone what I want to do or
saline.

And it turns out for my patients, at least, from my practice that
that\'s a good thing. I want them to feel like they\'ve had lots of time
to make the right decision.

DR. MANNO: I just was trying to get a perspective from your side.

DR. SPEAR: Yes.

DR. MANNO: So that\'s I asked. Thank you.

DR. SPEAR: Yes. It\'s primary purpose is to start the reconstruction.
It\'s just that one of its unexpected dividends is that it gives people
time to make all the decisions.

DR. MANNO: Thank you.

CHAIRMAN CHOTI: Dr. Ewing, question?

DR. EWING: Dr. Walker, I have two questions. One, could you elaborate on
more how the offspring studies were conducted, what animal models were
used for evaluating birth defects? And also, how was the breast milk
evaluated?

DR. WALKER: I\'m sorry. The second part is?

DR. EWING: The breast milk evaluation.

DR. WALKER: Okay.

DR. WALKER: And the second question is that you discussed in part of
your presentation the importance of patient education and also the
surgeon\'s education because the most common reason for rupture of the
implant was during implantation. And also, what kind of education tools
have you developed to address these problems?

DR. WALKER: All right. I\'m going to answer your second question first
because afterwards I\'m going to ask Dr. Lamb to come up to the podium.

So patient education, what we\'ve developed are multiple tools. We have
written materials, DVDs, we have interactive website materials, all to
educate the patients. That material is being tested with focus groups to
assure that patients of different ethnic backgrounds, different age,
different educational backgrounds, can understand that material. So the
materials is multifaceted; hearing, seeing, interacting because
everybody learns differently.

As far as the physicians, we have identified surgical practices being
the number one or surgical damage being the number one cause.

We then are now going into the data and we\'re looking at different
practices used by different surgeons to see if we can identify unique
causes. Is it the size of the pocket that\'s made, is it the size of the
incision, is it the location of the incision, so that we can identify
things that put that at risk. And we\'re working very closely with the
plastic surgery physician groups to do that.

We\'ll then work with the plastic surgery groups to identify what those
are and actually have them as part of our labeling, physician education,
and continuing medical education things of what you do uniquely or
differently with a silicone implant to protect and ensure its integrity.

At the same time, we\'re always working with our engineers are there
design things that we can do which will minimize and decrease damage
during the surgical process.

So if I\'ve answered that question, I\'m now going to turn it over to
Dr. Lamb who will tell you how we looked at the toxicity in our
preclinical animal models.

DR. LAMB: Hi. I?m James Lamb. I\'m a toxicologist and Senior Vice
President of The Weinberg Group.

We did a collection of studies of fairly conventional design but
unconventional exposures because we were treating with subcutaneous
implantation of either pulverized shell or the gel. And so studies were
done showing no developmental toxicity in, for example, a rat
multigeneration reproduction toxicity study on the shell. Developmental
toxicity studies where animals were exposed during pregnancy and their
offspring were evaluated. All showing very consistently a lack of
developmental toxicity.

DR. EWING: And the breast milk?

DR. WALKER: The breast milk we relied on the literature review, which
has looked at patients with silicone implants and measured the silicon
levels in milk as well as in patients with and without implants. And
there is support by the American Society of Pediatrics which state that
they see no contraindication of breast feeding for women with silicone
breast implants.

CHAIRMAN CHOTI: Dr. Blumenstein?

DR. BLUMENSTEIN: In your presentation, you didn\'t mention the analysis
of the connective tissue disease signs and symptoms or the quality of
life data. Would you care to say something at this point about that?

DR. WALKER: Yes. I think you\'re referring specifically to a collection
of signs and symptoms that we looked at. And I\'m going to show you this
on a slide here. This is a little bit, for me, when I first looked at
these, complicated. These are collections of symptoms in groupings for
either gastrointestinal, joint, muscular, neurological, skin, urinary.
These aren\'t diagnostic criteria associated with connective tissue
disease but rather constellations of symptoms. They were identify
patients who may need and require further evaluation for connective
tissue disease.

The only that showed any remote statistical significance was the group
of muscle. This isn\'t surprising because women who get implants,
especially if they?ve had small breast previously, will often have a
little bit of upper back or trapezius paint until they adjust to their
implants. But what\'s important is that when we looked at these groups,
these patients were all evaluated if they had a constellation of
symptoms, and some who never were identified as this constellation of
symptoms were evaluated for connective disease.

And what we found was if we looked at the number of patients who had
connective tissue disease, and we look at the Kaplan-Meier risk. So
these were patients who were identified as having connective tissue
disease in the Core Study. There were two with the augmentation cohort,
one in the reconstruction cohort and one with the revision cohort. They
all had a Kaplan-Meier risk of 0.5 percent. This is consistent with what
you would see in the general background.

DR. CALLAHAN: Who were the 88 patients? They weren\'t the entire Core
Study? This previous slide where you had the 11 and 72?

DR. WALKER: The first slide I showed you?

DR. CALLAHAN: Yes. Were they a subset of the \--

DR. WALKER: Now, which 11 patients?

DR. CALLAHAN: Well, it says N equal 11 and N equals 72.

DR. WALKER: Oh, these were patients with confirmed ruptures versus
patients with intact ruptures. This looks specifically also this table
to see were there different symptom groups that you could identify in
patients who had ruptures versus patients who had intact. That was
confirmed on explanation. So we can look at all, you know, group of
patients who were explanted for whatever reason in the Core Study.

DR. CALLAHAN: Do you have the signs and symptoms in the entire Core
Study?

DR. WALKER: Oh, sure of all \-- we have signs and symptoms or any
adverse event reported in the Core Study for any patient. I showed you
in main presentation how the signs and symptoms varied, whether they
were ruptured or not ruptured. But we have the whole population together
also.

DR. BLUMENSTEIN: That was actually my question was that plus the quality
of life data for the whole population?

DR. WALKER: Would you like to see the adverse event tables from the Core
Study?

DR. BLUMENSTEIN: There was data presented at the last Panel on the
changes in signs and symptoms related to connective tissue disease over
time. And I would like to \-- and this is a big part of the material
that we have here and we didn\'t hear you say anything about that in
your presentation and the presentations earlier. So I was curious about
what you had to say about it, if you wanted to say anything about it at
all now.

DR. WALKER: I can show you the signs and symptoms. We focused the
presentation on Amendment 7.

To discuss the signs and symptoms, I\'m going to have Maggi Beckstrand
from our statistics department to come up and we are prepared to show
you that data.

MS. BECKSTRAND: My name is Maggie Beckstrand. I\'m a senior statistician
at Inamed.

And for this presentation, we have focused really around the rupture
issue and its signs and symptoms of CTD increase in rupture. We see an
increase after a patient ruptures versus explanting an intact implant.

WE have performed the CTD analysis in the past. And we can certainly
provide it, but we did not bring it to this presentation right now.

DR. BLUMENSTEIN: What about the quality of life data?

CHAIRMAN CHOTI: Yes, this is \--

MS. BECKSTRAND: Actually, we do have the quality of life data for the
whole entire population.

DR. WALKER: That was vast. I mean, we have many different measures. Is
there one particular measure that you would like to see first or focus
on, because I have several slides on that.

DR. BLUMENSTEIN: You don\'t have to say anything about it at all, but
it\'s in these materials that were sent to me.

DR. WALKER: Right.

DR. BLUMENSTEIN: And I just wondered if you had anything to say about it
here.

DR. WALKER: Well, the quality of life of the patients overall improved
relative to their body imagine and how they felt about their breasts and
their sexual attractiveness. Actually, that data has been very
extensively reviewed by Dr. David Sarwer, who is a consultant here. And
I\'d like to turn the podium to him and he can make some comments on his
review and assessment of that data.

DR. SARWER: I\'m Dr. David Sarwer. I\'m Associate Professor of
Psychology with appointments in the Department of Psychiatry and Surgery
at the University of Pennsylvania School of Medicine. And my research
expertise is in the area of the psychological aspects of cosmetic
surgery.

I think what\'s particularly remarkable about the Inamed data in many
respects regarding the quality of life measures is the high level of
quality of life of women as they enter into these studies, that looking
at the scores on the SF-35 measures, they are anywhere from 10 to 15
points higher than what we typically find in the baseline populations.

DR. BLUMENSTEIN: And what is that supposed to mean? I mean, what are the
changes in people\'s quality of life after they have an implant?

DR. SARWER: I can show you some of this data here. Looking at data from
the Core Study, looking at the breast augmentation patients, what we see
in fact is a baseline as I alluded to a moment ago that are on all eight
subscales of the SF-36. Their scores are very high. The scale ranges, as
you can see, from zero to 100 with higher scores reflecting greater
quality of life. The scores are very high at baseline and much greater
than what we see in the general population of individuals who complete
this instrument.

DR. CALLAHAN: But do your general population \-- oh.

CHAIRMAN CHOTI: Hold on. You had a follow-up on that?

DR. BLUMENSTEIN: Yes. But what happens to them on follow-up? Is this a
difficult question? I mean, there\'s data in here but you\'re choosing
not to present it to us in this public forum. Okay. Thank you.

DR. WALKER: No. Yes, we\'re happy to present it. There\'s just many
different sides.

Okay. This one looks at the SF-36, which is a general study on quality
of life looking specifically at the augmentation of cohort.

You wouldn\'t expect a general quality of life to maybe be picked up
with this. And what you see, in fact, is you don\'t see an overall
improvement in their general quality of life: their pain, social
functioning, physical functioning. Interestingly, you actually see some
decreases, but the decreases are slight and really not clinically
significant as they all stay above the population norm.

If you look at specific ones, which look at self-concept, self-esteem,
and a Rowland Expectation, which is shown on this slide, you actually
begin to pick up the improvements.

So you have an improvement in physical self-concept. There\'s an
improvement in self-image and social relations and improved daily
living. So when you go to a more specific quality of life measures,
you\'re actually able to pick up the changes.

The SF-36 is a very general quality of life measure.

If you now look at satisfaction, you see that there\'s improvements in
the satisfaction with their breasts: how the breasts matched, the breast
shape, the breast size and satisfaction of the breast feel or touch.
Those were all improved in the study at one year.

CHAIRMAN CHOTI: Okay. Dr. LoCicero, question?

DR. LoCICERO: Yes. Concerning the company\'s commitment to further
study, I have a couple of questions.

First of all, if this were to be approved for general use, what is your
estimate of the yearly implantation rate?

DR. WALKER: Well, that\'s more of a marketing estimate. And to be honest
with you, I don\'t know what is a predicted estimate.

DR. LoCICERO: Two times? Five times? Ten times what you\'ve done? Twenty
times?

MR. COHEN: Our estimation is that the market, which has been growing at
an annual rate in the low to mid-double digits, would maintain its rate.
The change would be a change from silicone to saline or saline to
silicone products over time. We don\'t have an estimation of what that
rate would be. The surveys have suggested that the conversion would be
somewhere initially in the 30 to 50 percent of the market based on
literature that we?ve seen.

DR. LoCICERO: So that would be about how many? Just rough.

MR. COHEN: Roughly the American Society for Plastic Surgeons has
suggested that there were approximately 250,000 procedures last calendar
year.

DR. LoCICERO: Okay. Now, how many clinical research associates do you
have for your Core Study?

DR. WALKER: We have 21 clinical research associates at Inamed. But as
numbers go up, and if we need numbers to go up, say with the Adjunct
Study, we hire more and we also use outside contractors and monitors to
expand as needed for our trials.

DR. LoCICERO: So that\'s 21 for a 1,000 patients?

DR. WALKER: That is part of a study. Are you saying what if we made this
in a general population? Well, then it would be a different sort of
study.

DR. LoCICERO: If there were to be a post-market study the same as the
Core Study?

DR. WALKER: If there were to be a post-market study the same as the Core
Study where every patient were enrolled, we would have to evaluate how
to handle that sort of data. And that would be more patients. I think
that would depend on what the numbers we were asked to do, and then we
would have to determine, as we always do, planning for how many sites
and how many patients individual clinical coordinators can handle.

CHAIRMAN CHOTI: Dr. Doyle?

DR. DOYLE: You may have said and I may have missed it. What do you
estimate to be the accuracy of your diagnoses of silent rupture by MRI,
and did you determine that accuracy level?

DR. WALKER: We determined that there is actually around a 30 to 36
percent false positive rate in our MRI cohort of silent ruptures. And
that number is based on having done serial MRIs on patients through
explantation of those patients as well as using other modalities such as
mammography or ultrasound.

So the numbers and the estimates I\'ve given you of rupture, they\'re a
very conservative number, and include false positives. I can show you
that data here.

We had 38 patients who on MRI have a suspected rupture. Fourteen of
those were unconfirmed. We confirmed 24 of those and they were confirmed
by demonstrating a rupture at explant in 15 patients, two were
nonruptured at explant. And some of the confirmed nonruptures, there
were 7 of those. One was just simply mislabeled initially and misquoted
on our CRF. Other ones were given second and third MRIs and demonstrated
to be nonruptured or mammography or ultrasound.

CHAIRMAN CHOTI: Dr. Newburger, yes?

DR. NEWBURGER: In your risk of implant rupture graphs, this is by
implant. Could you tell us the by patient rupture rate?

DR. WALKER: Yes, I can. It\'ll bring the slide up for me in a moment.

I did show you the core presentation one slide. Here, this is three year
and four year risk of overall rupture by patient. Now, not every patient
has two implants, so that\'s why it\'s not exactly a one-to-one.

In the augmentation group, this is from the Core Study. Remember, this
is silent as well as symptomatic ruptures, so it\'s all ruptures. 2.2
percent in the augmentation group at year three, 2.7 in year four. The
reconstruction group was higher. 8.6 and then 22 percent at year four.
Revision 7, 11 percent at year four.

It\'s worth nothing here that almost 65 percent of the reconstruction
patients were Style 153, approximately 30 percent in the revision cohort
and 7 percent in the augmentation. And the difference in rupture rates
when you normalize for rounds is essentially the same between the three
groups.

DR. NEWBURGER: And in which classification do patients who have
mastopexy as well augmentation go?

DR. WALKER: Mastopexy and augmentation, I don\'t have \-- I mean, some
of the patients with augmentation also have mastopexy but we didn\'t
make that cut. If they had it not for reconstruction or not for total
revision, they were counted in the augmentation group. So if they had
\-- you know, wanted larger breasts and they had ptosis and they had
mastopexy, they would have been considered just an augmentation patient.

CHAIRMAN CHOTI: Dr. Miller, a question?

DR. MILLER: Yes. I recall from the last hearing that some questions were
raised about the in vitro studies \-- mechanical studies on the
implants. And that the typical ways of studying these devices don\'t
really mimic the in vivo environment, and I wonder if you could review
for us some of the things that you\'ve been doing in response to those
criticisms about the mechanical studies?

DR. WALKER: We learn a lot from \-- I\'m going to turn this over to Dr.
Harold Brandon who does a lot of those and is an expert in this area.

But I will say that the retrieval study has been great in that it has
identified ruptures, which have then helped us modify how we do our in
vitro testing so that we\'re able to improve and to be able to predict
ruptures or ways to improve the designs.

Dr. Harold Brandon, would you like to address this question?

DR. BRANDON: I\'m Harry Brandon from Washington University. And one of
my specialties is retrieval analysis of plastic surgery devices, in
particular, breast implants.

During the last year and a half, a major emphasis has been directed
toward determining what the modes and causes of failure is. And we
accomplished that by analyzing retrieved failed devices. We were able to
categorize the modes of failure, which included surgical damage,
posterior, sharp-edge openings associated with the Style 153, a few
manufacturing defects, some fold flaw failures, and a few failures
associated with unknown mechanisms.

Based on those failure modes, the object of the retrieval and analysis
study was not to determine what the rupture rate is. The object of the
retrieval and analysis study was to determine the modes of failure. With
this background we\'re now in a position to bone up and improve the
mechanical testing laboratory techniques to try to reproduce these
failures as a function of time in vivo.

DR. MILLER: Thank you.

CHAIRMAN CHOTI: A follow-up to that question: the data you showed, I
think, was about 47 percent of the mode of failure was surgically
related, is that right?

DR. BRANDON: Yes, roughly.

CHAIRMAN CHOTI: Was there a difference in the \-- granted, I think the
retrieval is mainly based on the Core Study, I assume. But based on \--

DR. BRANDON: Core and the Adjunct Study.

CHAIRMAN CHOTI: But based on longer term data, would you speculate as to
whether there are differences in the mode of failure based on the time
at which it ruptures, number one, that is one that rupture at ten years,
is that still half of those were due to surgical technique?

And second, is there a difference in the mode of failure between the
silent ruptures and the clinical ruptures?

DR. BRANDON: The answer to the first question is that the time that the
implant fails because of a surgical flaw is a function of the type of
flaw induced in the implant as well as the location of the of the flaw
in the implant and the associated loads associated with that implant
position.

For example, a deep surgical cut may induce a failure interoperatively
or it could cause the implant to fail in a few months. If it\'s a very
tiny flaw induced in the shell, it\'s certainly possible, we\'ve seen
this that the implant may last for maybe up to ten years without
failure. So that\'s the surgical-induced failure mode.

With respect to say a fold flaw, again it\'s the function of the degree
of the fold flaw failure, and it could last \-- or an implant could fail
due to a fold flaw within a few years or the implant could potentially
last for decades before a failure would be induced.

CHAIRMAN CHOTI: So, again, would you speculate on \-- so you\'re saying
that still about half the delayed ruptures, ten years or so, are still
\--

DR. BRANDON: Well, with respect to silent ruptures, I don\'t know.

CHAIRMAN CHOTI: No. I meant first would you expect that the delayed
ruptures are still about half due to surgical technique or is that
number less?

DR. BRANDON: I would suspect that the delayed flaws would be less due to
surgical damage than those that failed initially. My gut feeling is
that, and based on the data that we\'ve seen, that the full flaw failure
\-- the surgically-induced failure is going to cause the implant to fail
pretty quickly.

On the other hand, a surgical instrument can induce a very, very small
microflaw in the device. For example, we can see an implant that failed
with a flaw maybe 80 microns, about the size of one of my gray hairs,
for example. And that type of flaw may take several years to propagate
into a large tear.

CHAIRMAN CHOTI: And again, the question of silent versus clinical mode
of failure, can you predict?

DR. BRANDON: The only way to determine what the mode of failure is is to
run through a detailed analysis of the implant after it has been
explanted. That\'s the only way to really determine what the mode of
failure is.

DR. WALKER: In the Core Study, we do that because any implant that is
suspected as being failed, we recommend removal of that implant. But
nothing unique was identified.

I\'d like to just make one clarification that I\'m not sure was fully
understood. And that is on the curves that I have presented to you, the
2.5 percent, that that is an estimate of failure rate. The 2.5 and then
out to the 14 percent from the Core Study. And that all the other
studies really support that estimate rate, that estimate out to ten
years, and it is a constant rate of failure. Just to make sure that
I\'ve clarified that.

CHAIRMAN CHOTI: Yes, Dr. Bartoo?

DR. BARTOO: Regarding your rupture rate curves. You have a lot of data
saline surveillance, over a million implants out to ten years. And I
just have two questions.

One is, is the barrier on the saline implant the same as on the gel
implant?

And second, I assume there\'s no silent ruptures in those cases, right?

DR. WALKER: There are no silent ruptures in saline, and the barrier in
the gel shell are essentially the same but not totally identical.

CHAIRMAN CHOTI: Dr. Doyle?

DR. DOYLE: I\'m still confused about the rupture rate. On slide 43,
where you do the explants, you have 248 implants that have been
explanted. And of those 25 are confirmed ruptures which would seem to be
a ten percent rupture rate. But on slide 38, the risk of implant rupture
is from that same cohort number of 1782, seems to be 2.5 I guess I
don\'t understand the difference.

DR. WALKER: I\'m not sure I understand the question.

DR. DOYLE: Well, on slide 38.

DR. WALKER: Okay. This is slide 38.

DR. DOYLE: You show the all style, three year rate of 2.5 risk of
rupture.

DR. WALKER: Okay.

DR. DOYLE: And on the slide where you counted the actual ruptures from
explanted, it looks like there\'s a ten percent actual rupture rate.

DR. WALKER: No. It\'s a difference between an estimate \-- we\'ve
weighted the estimate on these to assume silent rupture rate. But would
you like to answer that? Dr. Helms would like to add to that. DR. HELMS:
I\'d like to take a try, but I didn\'t quite hear all of it. Could you
help me out again?

DR. DOYLE: Okay. Where you\'ve explanted and you have the actual number
of ruptures, the percentage would seem to be 10 percent, which would
seem to be the best measure of all on an explant because you\'re
counting the ones that you can visually see as opposed to the ones
you\'ve estimated, where you seem to have a much lower 2.5.

DR. HELMS: The explanted ones were explanted for a reason. They were
suspected of being ruptured. So that\'s not a sample of the whole
population; it\'s of those that are explanted. So you would expect a
higher proportion of those you thought to be ruptured, actually to be
ruptured.

DR. DOYLE: So there weren\'t any explants that were not done for \--

DR. HELMS: That includes false positives as well.

CHAIRMAN CHOTI: Dr. Li?

DR. LI: Perhaps a question for Dr. Brandon.

Could you explain or better yet show me exactly how you determined that
these failures were due to a scalpel? Because quite frankly, I looked
through your micrographs, and it was not obvious to me that the scalpel
was really the culprit.

DR. BRANDON: We inadvertently did not send you some of the SEM
micrographs we probably should have sent you.

But basically, in order to determine a failure is caused by a surgical
device, it\'s pretty much necessary to know what the flaw looks like
before you try to search for it. And so what we did was surgically
artificially induce failures into actual implant shells. So we
characterized what the failure looked like. So we had a reference for
comparison of the explant damage.

And using that technique, we were able to determine it was a surgical
failure.

DR. LI: Could you dig those up, because that\'s actually crucial because
in my view of the micrographs, there was really \-- well, one of the
features that I would look for, for instance, if it was scalpel-caused,
that there would be some feature there the dimension of a scalpel or the
geometry of a scalpel. And I think I only saw evidence of one micrograph
that had that.

DR. BRANDON: Sometimes you may see, for example, if the flaw is induced
with a suture needle, you can see a triangular cut in the implant, if
it\'s a small tear.

DR. LI: I didn\'t see one of those in your micrographs, though.

DR. BRANDON: Right. On the other hand, you can often see striations in
the cut portion of the implant, which are induced by the machining lines
of the actual surgical device. And you should have examples of those,
where you can see striations along the cut.

DR. LI: Right. Well, again, perhaps \-- and I think the thing that\'s
missing is your control samples where you cut the \-- I mean, because in
the absence of that there\'s really no good \--

DR. BRANDON: Right. We can get those for you.

DR. LI: Okay. Good.

DR. BRANDON: But that\'s how it was done. And that\'s really the only
way to do it.

DR. LI: I hear your words. I just don\'t see the evidence.

DR. BRANDON: He?s asking for a control. We?ll have the \--

DR. LI: Well, actually, as you raised this up, this is my point. I
presume you mean that this area here is the cut?

DR. BRANDON: Yes.

DR. LI: Well, and which is the inside and which is the outside?

DR. BRANDON: We\'re looking at a surface. That\'s a cut through the
shell of the material.

DR. LI: So the top is the surface and the bottom is the inside?

DR. BRANDON: It depends. It\'s hard for me to tell because the specimen
is actually bent.

DR. LI: Well, you see my issue here.

DR. BRANDON: Yes.

DR. LI: If the top turns out to be the inside, then you have a cut going
from the inside out, so it can\'t be a scalpel.

DR. BRANDON: Right. Right. I understand what you\'re saying.

DR. LI: Right. S in the absence of these labels, there\'s really no way
to tell if it\'s a scalpel or not.

DR. BRANDON: You need to have a relative comparison.

DR. LI: Right. I really saw none of that. The labels, I mean they\'re
nice pictures but they\'re kind of unlabeled, and I can\'t really make
heads nor tails of it.

The other feature is \--

DR. BRANDON: We can get those.

DR. LI: \-- these little lines here. This thickness is probably about 13
or 15 mil something like that, .013 105 inches, so these vertical lines,
are these the striations that you\'re referring to so that I know that
we\'re talking about the same thing?

DR. BRANDON: Probably so.

DR. LI: Well, the feature there is, if this is .013 inches these are
thousandths of an inch part, and that\'s way smaller than the dimension
of a razor blade. In other words, if I tried to make little striations
and move the razor blade at that small length, it would be impossible.

DR. BRANDON: It\'s the striations associated with the machine lines on
the surgical device itself.

DR. LI: So we\'re using brand new razor blades or used razor blades?
Because I do this all the time, and we typically we don\'t make more
than one cut with one scalpel or one razor blade because it does create
those artifacts. So if you\'d go in with a new blade, we\'d never see
this type of striation.

DR. BRANDON: Right. A lot of times you don\'t see striations associated
with a surgical cut. With a needle, for example.

DR. LI: Right. Well, my bottom line here is, from the micrograph and the
labeling that I have, it is not at all obvious to me that the scalpel
was even involved.

DR. BRANDON: We can get those for you.

DR. WALKER: Okay. I think that\'s a point made. We can label for those
photographs for you.

The important thing is that the retrieval study is certainly increasing
our knowledge, although possibly not perfect in terms of identifying
modes of rupture. We identified the mode of rupture in the 153, which
was very important for us in terms of improving our designs. So the
studies, I think, are very helpful. And importantly, the silent ruptures
and the ruptures really aren\'t related to any significant medical
consequence.

Our goal is a zero rupture rate, but most importantly the data
demonstrates that these implants, as they exist now, are safe.

DR. LI: And kind of a mechanistic question. This relates to the rate of
rupture. It seems very peculiar to me if a surgeon for whatever reason
nicks an implant at the time of surgery. That it is almost remarkable
then that the rate of rupture due to that is linear for ten years.

Typically, when there\'s a feature caused by the surgeon at the time of
surgery, you have a lot of early breaks and then those disappear as a
function of time. The idea that you can kind of \-- I mean, I guess
it\'s possible, but the odds of creating a series of nicks and cuts in
locations and depths, and it just so happens that the same number of
them break every year, it\'s almost fantastic that that would appear.

DR. WALKER: I think you\'re absolutely right. And the distribution of
surgical damage as we\'ve identified is not linear over time. We\'ve
identified more in the first year, and they decrease with time.

DR. LI: I\'m sorry, but these are \-- How was this curve generated? I
don\'t recall seeing this in our package.

DR. WALKER: I\'m going to ask Mr. Michael Taylor who has done the
retrieval study to come up and explain that to you.

DR. LI: Okay.

MR. TAYLOR: I\'m Michael Taylor, Manager of the Quality Technology
Group. I\'m responsible for the Retrieval Analysis Program.

This chart, this was developed from the retrieval devices that we\'ve
analyzed in the last few years. It goes beyond the study provided in our
presentation. So it looks at older devices as well as those in the Core
and Adjunct Studies.

DR. LI: Okay.

MR. TAYLOR: We took those devices where we did see those indications of
striations, we plotted them versus time in vivo. So it does agree with
what you were speculating, that we \--

DR. LI: I\'m sorry. These are actual implants that were retrieved that
were ruptured?

MR. TAYLOR: Correct.

DR. LI: And so the number \-- I\'m not really sure what to do with this
without knowing the denominator. So I mean this was out of how many
and\-- you know, I guess it\'s a little hard to interpret this without
knowing what the whole set looks like. You know, were these different
ages, different times, same design?

MR. TAYLOR: The study was done last year.

DR. LI: Right. But what was the \--

MR. TAYLOR: The devices were \--

DR. LI: Well, let\'s start with the easy question. How many implants
were there that are included in here that you looked at?

MR. TAYLOR: We had 630 devices. Of those that we had ruptures and that
we have in vivo times, that\'s what\'s presented. There\'s about 130.

DR. LI: Okay. And you\'re looking at, if I get it right, you\'re saying
that if you have a ruptured implant and you look at the microscopic view
of the rupture and you see a striation, that you\'re using the striation
as the criteria that it was scalpel mark?

MR. TAYLOR: If striations are the only characteristic we find along the
failure plane, we categorize it as surgical damage. Because we\'ve done
a study where \--

DR. LI: So if you have tear and there are no striations, that\'s not on
this curve?

MR. TAYLOR: That\'s correct.

DR. LI: And how many of those were there?

MR. TAYLOR: On the original study there was \--

DR. LI: No, how many \--

MR. TAYLOR: \-- those represents our unknowns or unless there was a
manufacturing defect or a fold flaw. So this is only those that had
striations that we categorized as surgical damage.

DR. LI: Okay. I\'m not quite sure what to do with this.

The other question I have is in your retrievals where most of them are
unruptured that you\'re getting, apparently?

MR. TAYLOR: That\'s correct.

DR. LI: Do you look at those for signs of scalpel marks or any kinds of
puncture type of things? In other words, I would feel a little more
comforted if not every scalpel mark resulted in a failure. In other
words, if this is a common practice that for whatever reason they\'re
using the scalpel to position or move the implant in place, then I would
expect both ruptured and unruptured components to have these marks. So
the question is, do you ever \-- first of all, do you look at the
unruptured components for signs of scalpel marks? And if so, what
portion of those are there?

MR. TAYLOR: Well, we did do a leak test on the \--

DR. LI: No, I\'m not looking for leak test.

MR. TAYLOR: Right.

DR. LI: I\'m looking for signs of a scalpel.

MR. TAYLOR: We look for any nicks or tears that may indicate that. If we
just see them, we\'ll \--

DR. LI: So this is in \--

MR. TAYLOR: \-- looking for suture marks.

DR. LI: In the unruptured group, I\'m talking about now. The implant
comes back unruptured, do you look at those for the presence of any kind
of \-- and the answer is how of those have any kind of surgical evidence
that something happened to it?

MR. TAYLOR: We\'ve found practically zero.

DR. LI: So you\'re telling me that every time a scalpel mark \-- every
time an implant is nicked by a scalpel, that\'ll eventually go to a
rupture?

MR. TAYLOR: No. No. There may be nicks there that we have not detected.

DR. LI: That\'s what I wanted to hear. Thank you.

CHAIRMAN CHOTI: Dr. Callahan \--

DR. WALKER: Dr. Spear would like to just add something further to this
discussion.

DR. SPEAR: Dr. Li, you will be reassured to know that very few plastic
surgeons use scalpels around implants.

DR. LI: I\'m pleased to hear that.

DR. SPEAR: So, number one. So, you know, scalpels are probably in the
minds of other people other than surgeons who are operating on people.

In fact, the injuries are probably \-- what I\'ve learned from this
process over the last two years is that, although the implants are not
necessarily broken at the time of insertion, that excess trauma to the
device may predispose it to fail later. And that is not specifically
cutting it with the scalpel, since surgeons don\'t use scalpels around
implants, but it can be primarily by scratching it excessively, by the
insertion of it, by damaging it by running it against a surgical
retractor, by actually hitting it with the electrocautery device which,
although it doesn\'t cut it, can abrade it.

I think what\'s interesting, I think your question is exactly right. You
know, we can\'t expect for the lifetime of the device for everything to
be surgical damage. It probably does predispose to damage over the
lifetime of the device even though it may not happen the first year or
two. And I think what\'s interesting for me, again, being a scientist
looking at this stuff objectively, is that if anything we would expect
the rupture maybe even to fall over time. That\'s why the number that
you\'ve been given at 13.9 percent includes what probably a heavily
laden early rupture or failure mode based upon the fact that some of
these are predisposed to damage later because of the surgery at the
time. But it\'s not from scalpels. And let me explain why it doesn\'t
fit your model of what the size should be.

DR. LI: Well, I was just going to \-- making, perhaps maybe a larger
point than it is, but it seems as if in the application that certainly
the implication I read is that the majority of these ruptures, or at
least a very large portion of these ruptures were due to a scalpel. And
it just struck me is there was very actually little evidence to actually
support that.

I mean, it\'s an interesting hypothesis, but there\'s not much support
for that.

DR. WALKER: One just final comment is that looking at the rounds, less
than one percent are ruptured. So we\'re looking at a small percentage
of a small percentage. So this isn\'t a common occurrence. Just to leave
you with that thought.

CHAIRMAN CHOTI: Dr. Callahan?

DR. CALLAHAN: I just have one quick question. I\'d like you to comment
on the demographics of the Core population and how you think that\'s
generalizable.

DR. WALKER: All right. I\'ll have a slide up for you in a moment here.

All right. I did share with you what the predominance was of the
demographics. The median age for the augmentation group is younger than
the reconstruction or revision. That\'s as you would expect. Cancer
patients tend to be a little older.

They were primarily Caucasian with lower percentages of Hispanic, Asian,
and African-Americans. This is consistent with what is published for the
plastic surgery literature in terms of who comes in for plastic surgery
and who comes in for these procedures.

The demographics for race was certainly not, you know, the demographics
of the United States population. Similarly, the marital status is,
again, I think consistent for patients who get breast surgery, whether
it\'s augmentation or reconstruction. So our data is consistent with
plastic surgery demographics, although not necessarily consistent with
the United States population.

CHAIRMAN CHOTI: Okay. We\'re running a little late, but I\'d like to get
all the questions answered.

Dr. Miller?

DR. MILLER: Thank you. I don\'t mean to drag this on, but I just want to
make sure I understand this clearly because it\'s one of the questions
that we have to answer later. And that\'s how exactly these rupture
rates were calculated. Because I thought I understood when you went
through, and then there\'s questions. I\'m a little confused now.

So the graph on page 35 and the number that you come up of the three
year rupture rate of 2.5 percent, that number comes from a combination
of the subset that you did MRIs on to determine the silent rupture rate.
And you assumed that that number is missed in the actual rupture rate.
So you combine \--

DR. WALKER: We extrapolated.

DR. MILLER: You extrapolate from the actual rupture rate in the Core
Study. You add 86 percent, assuming that there\'s going to be a number
of silent ruptures. And so you come to the 2.5 percent?

DR. WALKER: Well, it\'s not 86 percent. But I\'m going to have the
statistician explain it to make sure it\'s clear. I\'m a clinician by
training, too.

But the number is weighted to include a predicted silent rupture rate
across the entire population. But there she is, Maggie Beckstrand from
Inamed.

MS. BECKSTRAND: Our 2.5 percent rupture rate at three years is a
Kaplan-Meier rupture rate using the entire population, not just the MRI
cohort.

We saw symptomatic ruptures in both populations, MRI cohort and the
non-MRI cohort. But in the MRI cohort we did screen more with MRIs for
silent ruptures. So that would provide a more robust estimate of our
silent rupture rate in the whole population.

So what we did is, if you can see, the first column of numbers shows for
the augmentation population there was 331 patients enrolled in the MRI
cohort. We saw five silent ruptures in the MRI cohort, which gives us a
straight proportion of ruptures in that cohort of 1? percent.

In the non MRI cohort there were 656 implants enrolled. And so when you
take 1.5 percent and multiple it by 656 you get ten \-- your expected
number of silent ruptures you would see in that population had they
undergone the same MRs as the MRI cohort.

DR. DOYLE: That\'s assuming 100 percent accuracy of the MRI ability to
diagnose silent rupture?

MS. BECKSTRAND: That\'s assuming \-- those five were diagnosed via MRI,
not necessarily explanted.

DR. DOYLE: But that\'s what I asked earlier.

DR. WALKER: Excuse me. You\'re asking if there are false negatives,
correct?

DR. DOYLE: Right.

DR. WALKER: If anything, we\'ve shown that we have a false positive rate
\--

DR. DOYLE: But I\'m asking do you have anything \--

DR. WALKER: Yes. It\'s impossible in our study to give you a false
negative rate because we have explanted all the patients who have an MRI
which was positive. As we go out in time, if you find people who are
positive with an MRI later, it\'s really not possible to know are those
new ruptures or were they falsely negative in the past. So this study is
not designed to give you a false negative rate. You would have to have
explanted, you know, you have to look at all people that are explanted
and say did they have a negative MRI and then have a positive rupture.
And we haven\'t seen any of those. So our data doesn\'t show any.

DR. DOYLE: But when I asked about the ten percent from the explanted, I
was told that all of those explants was because they were suspected
rupture. That\'s what you said.

DR. WALKER: Well, maybe I misspoke.

DR. DOYLE: Which doesn\'t make sense because then have 223 that are
confirmed intact. So they couldn\'t have all been taken about because
they were suspected.

DR. WALKER: No, no.

DR. DOYLE: That\'s what you said.

DR. WALKER: All suspected \-- I probably misspoke, so I apologize. It\'s
complicated, and I\'m nervous.

All suspected ruptures, those patients, unless they had a separate test
that confirmed that they didn\'t have a rupture, you know through serial
MRIs, if a patient had a suspected rupture, we recommended that they
have explanation. Those were removed.

All explanted patients were not, by definition, patients who we expected
silent ruptures. The most common reason for explanation is a change in
size or contractures or a cosmetic problem.

DR. DOYLE: That\'s not what I was told the first time I asked this
question.

DR. WALKER: Well, I\'m sorry. I think I must have misspoke.

DR. DOYLE: I still can\'t figure out then the correlation between the
two figures. And maybe I\'m just missing something.

MS. BECKSTRAND: Can we see the slide, let me go through it with you, the
tree. The tree with the 25 confirmed ruptures that we\'re looking at.

In our Core Study, we explanted, totally explanted for all different
reasons 480.

DR. DOYLE: That makes sense. They said the first time \--

MS. BECKSTRAND: Okay. I mean there were 248 implants. Twenty-five of
those were confirmed ruptured when we looked at the devices.

So when you take 25 divided by 248, which is your ten percent, what
you\'re saying is, out of all explanted devices, 25 percent of them are
ruptured.

DR. DOYLE: Ten percent.

MS. BECKSTRAND: Ten percent. I\'m sorry. Ten percent are ruptured. I\'m
sorry. So, which is clear from the picture.

What we\'re saying with our 2.5 percent is, out of all implanted women,
how many of them are ruptured through three years, silent and
symptomatic. So that\'s the difference between the 2.5 percent and the
10 percent you\'re taking with the explanted denominator.

CHAIRMAN CHOTI: Oh, perfectly clear now. Thank you.

MS. BECKSTRAND: Okay.

CHAIRMAN CHOTI: Dr. Newburger question?

DR. NEWBURGER: No.

CHAIRMAN CHOTI: Any other questions? Dr. Leitch?

DR. LEITCH: Just \--

CHAIRMAN CHOTI: Use the microphone, please.

DR. LEITCH: Just back a little bit go the extracapsular rupture and how
that was identified. Was that by MRI, mammogram, sono, the surgeon\'s
interpretation at the time of surgery? How was that\--

DR. WALKER: Those extracapsular ruptures on the explant curve were
diagnosed at surgery. But you can also diagnose extracapsular rupture by
MRI. But those in that flow chart I showed you were identified at
surgery. You can feel the sticky gel on the \--

DR. LEITCH: So none of the \-- of course, I guess we can\'t know if
those \-- were those two with extracapsular relayed in the MRI cohort
\--

DR. WALKER: The extracapsular ruptures that I showed you were from the
Adjunct Study. And the Adjunct Study population did have MRI.

DR. LEITCH: And your false positive rate for the MRI to detect rupture.
I don\'t know if Dr. Brenner might answer that question of what he
thinks of that number compared to other studies.

DR. BRENNER: I\'m Jim Brenner. I\'m a clinical Professor at UCLA and
Director of Breast Imaging at the John Wayne Cancer Institute at the St.
Johns Health Center in Santa Monica. I have no equity interest in
Inamed.

Perhaps to the dismay of the company, I maintained a threshold as a
central reader for the studies in that I would not read a study as
negative if, for any reason, the imagines were insufficient. One example
might be if a particular institution, for whatever reason, sent only one
projection, a sagittal projection or a coronal or an axial. The protocol
really required two orthogonal projections with certain criteria that
have already been referenced by Dr. Walker. For example, breast coil. So
that, for example, when you read a lot of the references from the FDA
statement with such varying sensitivities and specificities, they are
very technical dependent. And unlike the obtaining of an x-ray, MRI
acquisition information is highly technical, dependent, and variable.

So for example there were seven cases that were originally read as
positive. As Dr. Walker indicated, one of them was simply a data error.
So what do we do with the other six?

A subsequent MRI confirmed that by central reading those MRIs were
intact by adequate studies.

Obviously, a ruptured implant will not repair itself. So when we looked
at that data, five of those six cases were read by me as indeterminate.
In order not to underestimate the sensitivity or the implant failure
rate, there was an attempt made at being very critical. So that if a
study was simply insufficient, it was read at as interdeterminate and it
was counted as positive.

When a subsequent MRI was performed two or three years that was adequate
and negative, then retrospectively one could conclude that the first
study that was read as indeterminate or counted as a positive was, in
fact, false positive. And the only reason it was counted that way is
because I declined to call an MRI study negate if the image quality was
insufficient.

Some of the other positives may have been counted by reference readers.
And I\'ll defer to Maggie with respect to how they count those
positives. There were reference readers, and there were central readers.
And the only conversations that I\'ve had with some of the reference
readers over the last couple of years in an attempt to resolve
discrepancies where two instances where I had called it positive, the
reference reader considered it negative. It was explanted, it was
positive. And there was one case where I considered it negative, the
reference reader thought it was positive. And it in fact negative.

So many of these discrepancies fell out because of the criteria, the
threshold use to cause a negative study, in my opinion, was considered
very high and I would rather read those as indeterminate and then
considered them negative, running the risk of false negatives.

DR. BARTOO: Can I have a follow-on question to that? We\'ve talked a lot
about the false positives. Obviously, we cannot know the true
sensitivity of the MRI in this case, but are there other studies that
have validated the MRI in terms of sensitivity?

DR. BRENNER: There have been a number of studies. And one of the
problems, there was a meta-analysis performed in the plastic surgery
literature, trying to collate all the different reported sensitivities
and specificities. And when you look at that paper one of the real
problems was that the author has declared in the methods and materials
that they did not try and compare techniques. So, for example, in one of
the references that the FDA submitted, a study from San Paolo by very
good investigators, they used an adequate magnet with strengths of 1.5
Tesla, but they didn\'t use a breast coil. And that\'s like trying to
hear a radio from a long distance. You simply cannot pick up the signal
sufficiently. And that same study where they did use a breast coil, they
used an insufficiently strong magnet.

In general, statistics for sensitivities and specificities are quite
variable. And I think most of us, under preferred circumstances of image
acquisition, consider the sensitivity in the order of 97 percent,
specificity similar.

CHAIRMAN CHOTI: Dr. Newburger?

DR. NEWBURGER: This is a quick question which relates to your patient
information. Under the section \"Other Events\" under \"Biopsy
Procedure\" three percent malignant breast cancer less than one percent.
And then there\'s a categorization \"Benign Breast Cancer.\" I\'m not
familiar with this diagnosis. What is that?

DR. WALKER: I\'m not sure. Are you referring to a table from \--

DR. NEWBURGER: From your labeling. Your patient information labeling.

DR. WALKER: A benign breast cancer?

DR. NEWBURGER: That\'s what it says.

DR. WALKER: JoAnn Kuhne from our Regulatory Affairs is going to address
that question.

MS. KUHNE: If it says benign breast cancer, then that\'s an error
because it should say benign breast disease such a fibocystic disease.
That\'s the intent of that.

DR. NEWBURGER: Yes. And so then the category underneath that unknown
breast cancer would be unknown breast disease as well.

MS. KUHNE: Yes.

DR. NEWBURGER: Thank you.

CHAIRMAN CHOTI: Dr. Manno?

DR. MANNO: I\'d like to ask \--

CHAIRMAN CHOTI: Use the microphone, please.

DR. MANNO: I\'m sorry.

I\'d like to go back and have you discuss a little bit about the
platinum assay. You said that you did not find any platinum in the
bleed.

DR. WALKER: Correct.

DR. MANNO: Okay. What technology was used to make that determination?

DR. WALKER: All right. I\'m going to bring up an expert in platinum to
answer that question. Dr. Michael Brook.

DR. BROOK: My name is Michael Brook. I\'m a Professor of Chemistry at
McMasters University in Hamilton, Canada.

Platinum is assayed in a variety of ways, and this was done with x-ray
fluorescence, actually absorption. Excuse me.

DR. MANNO: What was your lower limit of detection for that technology?

DR. BROOK: The technology is about ten parts per billion.

DR. MANNO: Okay.

CHAIRMAN CHOTI: Okay. A quick follow-up question, Dr. Li?

DR. LI: Yes. Could you tell me \-- The x-ray absorption doesn\'t tell
you the valent state of the platinum. So what is the valent state of the
platinum, and how did you determine it?

DR. BROOK: We didn\'t specifically determine the valent state of the
platinum. We didn\'t see any in the bleed, and so there was nothing to
detect. But there are many, many studies in the literature that
demonstrate that platinum is in the zero valent state.

DR. LI: But is that in a compound, though, so it\'s a compound with a
zero valent state or are you saying it\'s platinum metal?

DR. BROOK: Well, there\'s a distinction. Platinum metal is in the zero
valent state, but there can be other platinum species also in the zero
valent state.

DR. LI: Correct. So which is it in this particular case? Particular to
platinum \-- just correct me if I\'m wrong. My understanding is the
platinum is what\'s left over after you do the curing because it\'s the
catalyst for curing, is that correct?

DR. BROOK: That\'s correct.

DR. LI: So what is the chemistry of the platinum after the curing?
What\'s the compound that\'s left.

DR. BROOK: It\'s actually platinum metal, but it\'s colloidal metal,
small particles. Typically a couple nanometers in size.

DR. LI: A couple of nanometers in size? Okay. So that\'s small enough to
go through, like, blood vessel walls and easily \--

DR. BROOK: I don\'t know about permeation through blood vessel walls.

DR. LI: Okay.

DR. BROOK: But it\'s a couple of nanometers.

DR. LI: Okay. Thank you.

CHAIRMAN CHOTI: Dr. Miller?

DR. MILLER: No questions.

CHAIRMAN CHOTI: Okay. If there are no further questions, why don\'t we
take a break here. And following that will be the FDA presentation.

A ten minute break. Thank you.

(Whereupon, at 10:37 a.m. a recess until 11:02 a.m.)

EXECUTIVE SECRETARY KRAUSE: All the technology has been set up and
prodded and apparently is now in working order. So I think we can start
the FDA presentation. The faster everybody sits down, the faster they
can start, the faster we can eat lunch.

Okay. Back to Dr. Choti. Thank you.

CHAIRMAN CHOTI: As Dr. Krause, we\'re now ready for the FDA
presentation. Dr. Samie Allen.

CDR. ALLEN: Good morning. I\'m Samie Allen, the lead reviewer for this
PMA. FDA will now provide an overview of Inamed\'s silicone filled
breast implant PMA. For your convenience, we provided you a copy of
FDA\'s slides.

FDA\'s review team was comprised of many reviewers from across the
agency. However, this slide shows only those FDA reviewers who are
presenting today.

I will now present background information for this PMA followed by an
overview of the device description and preclinical testing submitted
since the October 2003 Panel meeting.

In December 2002 Inamed submitted this PMA. October 2003 this PMA was
presented at Panel. In terms of the clinical data at that Panel meeting
the Core Study consisted of complete two year and partial three year
physician follow-up data as well as MRI data at year one with some
patients at year three. The Panel recommended in a 9 to 6 vote that the
PMA was approvable with conditions.

In January 2004 FDA determined that the PMA was not approvable because
the data did not provide a reasonable assurance of the safety of the
device. The three primary safety issues were: The lack of information
regarding rupture rate over the expected lifetime of the device; health
consequences of implant rupture, and; modes and causes of rupture.

In August 2004 Inamed submitted a response to their not approvable
letter. The PMA data being presented today now includes Core Study data
with complete three year and partial four year position follow-up data
as well as MRI data at year one and additional patients at year three.
The new clinical data will be presented by Dr. Sahar Dawisha later in
FDA\'s presentation.

Inamed\'s August 2004 response also included information to characterize
the modes and causes of rupture. FDA\'s Panel presentation focuses on
the information provided at Inamed\'s August 2004 response.

With regard to the device description, since the August 2003 Panel
meeting Inamed added two new styles, 15 and 115. There are now nine
styles under PMA review for the indications of primary augmentation,
primary reconstruction and revision. The styles are available in
different combinations of shapes, profiles, surfaces and volumes. All
styles are single lumen, but Style 153. Style 153 is a double lumen
device with inner and outer lumens filled with silicone gel. The inner
lumen is located at the lower pole of the implant and its function is to
maintain its curved profile.

All styles are comprised of the same basic components; a shell, a patch,
silicone gel filler and silicone adhesive to seal the fill hole.

These are the preclinical tests I will cover. As a note, fatigue testing
and gel cohesion were previously discussed at the October 2003 Panel
meeting. No additional information regarding those two tests were
provided in Inamed\'s August 2004 response.

Inamed provided numerous test reports and other information to
characterize the modes and causes of rupture of their device such as
failure analyses of retrieved devices, physical property testing,
assessment of manufacturing processes and surgical techniques that may
impact rupture and a review of the explant literature. My focus will be
the primary set of retrieval study data. A summary of the other
information was provided in FDA\'s panel memo.

The purpose of their retrieval study was to identify failure modes of
all Core and Adjunct Study devices that are part of Inamed\'s retrieval
program. This study involved 442 devices of which 287 were found to be
intact, and 20 were excluded because they were unable to be analyzed
based on their condition. This leaves 135 devices available for
analysis.

This table shows the failure modes for the 135 failed devices. A
description of these failure modes was provided in FDA\'s Panel memo.
Inamed determined that the modes and causes of rupture for 123 or 91
percent of the 135 failed devices. There were 12 devices with sharp edge
opening for which Inamed could not determine the cause of rupture. Two
of the failure modes involved a specific failure region of Style 153.
For all other failure modes there was no evident correlation to a
specific failure region such as the radius.

As a supplemental analysis Inamed then combined the data from this
retrieval study with the findings from an independent reassessment of
the failure modes for their original retrieval study of 339 devices
presented at the October 2003 Panel meeting. All duplicate devices were
removed.

Inamed also focused on those implants with recorded in vivo times for a
total of 184 retrieved failed devices.

It should be noted that these retrieval data cannot determine the time
at which a given failure mode will occur because the data are based on
only a small collection of retrieved implants that were available for
analysis. The data can, however, be used to present the distribution of
device failure types observed in this sample at particular time frames.
Accordingly, this table reflects this for the 184 retrieved failed
devices.

The retrieval study sample showed that the observed failures at the
earlier time points were due primarily to surgical instrument damage.
Inamed stated that the longer term failures attributed to surgical
damage could have been due to delayed interoperative damage, explanation
instruments or instruments used during in situ procedures such as a cyst
biopsy. Inamed also clarified, though, that although a retrieval study
analysis can determine whether an implant was damaged by a surgical
instrument, it cannot determine with certainty when the damage occurred.

There were also a large percentage of the sample that involved posterior
openings in Style 153 that originated near the lower patch typically
above the bladder shell interface. With regard to sharp edge openings as
noted above, Inamed could not determine the casue of these. These
devices showed no sign of fold, abrasion, flex fatigue, manufacturing
defect or instrument damage at the opening. And there were no samples
observed to have failed from pure cyclic fatigue.

The following bar graphs reflect a percentage or distribution of the
failure modes based on the data shown in the previous table. Here is the
distribution of failure modes for devices that failed from zero to five
years, from six to ten years, and after ten years.

Based on their findings with regards to modes and causes of rupture,
Inamed is proposing the following:

They will investigate sharp edge openings which is the failure mode for
which the cause remains unknown;

They will modify Style 153 to reenforce the patch area to address one of
the primary failure modes identified in the retrieval sample;

They will research whether they can find any correlation between device
rupture and surgical factors such as incision size, incision location
and implant placement. This should help to address failure modes related
to surgical procedures such as instrument damage, surgical impact and
fold flaw;

Inamed will revise their labeling to reflect the findings of their
retrieval studies, and;

Inamed will include the findings as part of their training program.
However, the specifics for this was not provided in their PMA.

Gel bleed testing. Silicone gel bleed is the diffusion of gel
constituents through an intact shell. Although current designs of breast
implants should minimize gel bleed, it appears to occur continuously for
silicon gel-filled breast implant. The purpose of Inamed\'s gel bleed
study was to mimic in vivo conditions and identify gel bleed
constituents, the rate that the gel constituents bleed out and how that
rate changes over time.

A description of the test methodology was provided in FDA\'s Panel memo.
It involved a modified ASTM F703 method in which the implants were
placed on 3M silica disks and incubated for eight weeks at 110 degrees.
Weights of the disks were measured at weekly intervals.

As a note, ASTM F703 is the testing standard for implantable breast
implants for which one of the elements is gel bleed testing. The ASTM
F703 test methodology was not established to mimic physiological
conditions, but instead to accelerate the bleed diffusion process to
compare various smooth implant designs.

Using the modified ASTM F703 test methodology, Inamed quantified the
bleed amounts for cyclic species D8 to D21 in one year species, MD6M to
MD18M at eight weeks. The average cumulative release rate at eight weeks
was .0003 grams per centimeter squared per week.

Inamed stated that the results for species below DA and MD6M were
unreliable because control disks became saturated with silicones
absorbed from the gas phase.

Tin and platinum were below the detection levels of this test.

This slide also shows the outstanding issues with Inamed\'s gel bleed
testing that FDA believes are significant issues that may make the
testing, current testing of limited value.

Since the October 2003 panel meeting Inamed continued their shelf life
studies which consist of device and package testing. Inamed provided a
combination of real time and accelerated testing to now support a three
year shelf life on their packaged label. Inamed\'s goal is a five year
shelf life, thus they plan to continue with their self life studies.

This slide summarizes some of the key findings from each of the
preclinical tests that I covered. Inamed provided ample testing and
other information to characterize the modes and causes of rupture of
their device through approximate ten years. However, this information is
not predictive of the lifetime rupture rate of the device because the
tests were set up to test hypothesis about failure modes, to force
failures and/or to perform device characterizations of a subset of
explanted devices returned to Inamed for analyses.

Although Inamed stated that they will research whether they can find any
correlation between surgical factors and device rupture, they are
primarily focusing on labeling and physician training to address the
observed failures related to surgical technique.

Inamed has proposed a design change for Style 153 to address one of the
primary failure modes of the retrieval sample. Inamed also plans to
continue to investigate the cause of sharp edge openings.

With regard to the gel bleed testing FDA believes that there are
fundamental issues with the test methodology that may warrant new
testing in order to identify and quantify the gel bleed constituents and
the rate of bleed of those constituents.

And finally, FDA believes that the shelf life testing is adequate, but
should be continued to support their desired five year shelf life.

The Panel should consider this preclinical testing and its safety
assessment of the breast implant.

Thank you.

Dr. Dawisha will now present the new clinical data.

DR. DAWISHA: I had to check my watch to make sure it was still morning.
Good morning, everybody.

I\'m Dr. Sahar Dawisha, a medical officer in the division. I reviewed
the clinical data for this PMA as well as the clinical data that was
presented at the October 2003 Advisory Panel meeting.

My presentation today will focus on the new information that the sponsor
submitted regarding the rupture rate and the health consequences of
rupture. I will also be discussing the sponsor\'s proposed labeling and
proposed post-approval plans as they relate to rupture.

When a silicone gel-filled breast implant ruptures, the patient and
physician are often unaware of it. The body does not have a mechanism to
eliminate the silicone and the gel can migrate outside of the fibrous
capsule into the breast area, lymph nodes and to distant locations. This
is referred to as a silent rupture.

MRI is currently the diagnostic method with the greatest sensitivity and
specificity compared to other radiographic methods to detect silicone
breast implant rupture with the sensitivity reported about 80 to 90
percent and a specificity reported of about 90 to 100 percent.

The specificity of 80 to 90 percent means that you will miss 10 to 20
percent of ruptures with this modality, but of the other modalities it
does have the highest reported sensitivity.

In contract, symptomatic rupture is associated with symptoms such as
flattening of the implant, lumps around the implant or silicone
extrusion through the incision site. When a silicone breast implant
ruptures the gel usually remains confined with the capsule. This is
called intracapsular rupture. The gel may sometimes be found outside of
the capsule, which is referred to extracapsular rupture. Intra and
extracapsular ruptures can be either silent or symptomatic. But as you
will see in my discussion the majority of silicone breast implant
ruptures are silent. This is true both for Inamed\'s data and the MRI
studies reported in the literature.

There are several questions related to implant rupture which the sponsor
was asked to address with the main questions shown on this slide. And I
should point out that if you review the Panel transcripts from the 1991
and 1992 Advisory Panel meetings, these were the same questions that
were asked at that time.

What is the implant rupture rate over the expected lifetime of the
device?

How often and when do intra versus extracapsular ruptures occur?

How often and when did intracapsular ruptures become extracapsular?

And what are the health consequences to the patient as a result of
implant rupture?

FDA believes that the answers to these questions are crucial for
determining the safety of the device with respect to rupture, and for
providing adequate information to patients making an informed decision
on whether or not to get implants.

To address these questions the sponsor relied primarily on their Core
Study data, their Adjunct Study data as well as the published
literature, which I\'ll be discussing next.

Before I discuss each rupture question specifically, I would like to
refresh your memory on the MRI substudy of the Core Study which contains
most of the rupture information for Inamed\'s product. This is a subset
of approximately one-third of the Core Study patients who are scheduled
to undergo MRI, screening for silent rupture at year one, three, five,
seven and nine following implantation. I will refer to this as the MRI
cohort.

I should mention that the follow-up compliance in the MRI cohort is
about 90 percent at the first screening and about 85 percent at the
second MRI screening for all three patient groups.

Note that because MRI screening for the reconstruction and revision
patients was started later than for augmentation, the MRI data at the
second MRI is partial for these two groups of patients and it is
complete for the augmentation patients.

The sample size of the MRI cohort was based on the IDE study as
estimating a hypothesized rupture rate of five percent at ten years. We
will come back to this five percent rupture rate at ten years later.

The non-MRI cohort is the remaining two-thirds of patients from the Core
Study who did not undergo MRI screening for silent rupture. Silent
rupture is underascertained in the non-MRI cohort. Because of this
difference in determining silent ruptures, I will present the rupture
rate for these two cohorts separately. The Kaplan-Meier implant rupture
rate are shown here on a by patient basis separately for the MRI, which
is in the left column, and the non-MRI groups through four years. This
table includes both silent and symptomatic implant ruptures.

The rupture rate in the MRI group is higher than in the non-MRI group
for all three patient indications. The sponsor attributed the higher
rupture rate in the MRI group to what they believe is about a 36 percent
overdiagnoses of MRI, which is erroneously based on implant which have
yet been explanted. Note that if explant is used as the method to
confirm rupture, which is also the standard which is used in the
literature, then their false positive rate is 12 percent.

Inamed also attributed the high rupture rate for reconstruction patients
to be the greater use of Style 153 double lumen implants in these
patients. This may well be the case. Of all the implant ruptures
confirmed via explant in reconstruction patients, all were Style 153
implants.

Note that the sponsor is asking for approval of Style 153 implants
proposing to address issues with the rupture through animal studies and
physician training.

This table breaks out the silent versus symptomatic implant ruptures for
the MRI and non-MRI cohorts separately on a by-implant basis through
four years. There were a few silent ruptures reported in the non-MRI
group when, for example, the patient\'s implant was being replaced for
some other reason like capsular contracture and was unexpectedly found
to be ruptured at the time of explant. The proportion of silent ruptures
in the MRI group is higher than in the non-MRI group.

Note that not all of these implant ruptures shown in this table have
been confirmed with explant. For example, of the 30 total silent
ruptures in the MRI group; the five in augmentation, the 17 in
reconstruction and the 8 in revision 16 have been confirmed as ruptured
via explant.

What about the frequency of intra versus extracapsular ruptures? In the
Core Study 25 implants in 25 patients were reported by the sponsor to
have been found ruptured at the time explant. Sixteen of these confirmed
25 ruptures were silent from the MRI group, and seven were silent from
the non-MRI group. Therefore, 92 percent of the confirmed ruptures in
the Core Study were silent.

Of these 25 confirmed implant ruptures 23 were reported as
intracapsular, 1 was reported as extracapsular. This was an augmentation
patient from the MRI cohort. And one was a double lumen Style 153
implant in which there was detachment of the inner and outer lumens.

The sponsor reports no obvious cases of migrated gel in the Core Study.
However, because surgeons do not routinely sample local lymph nodes and
surrounding breast tissue for migrated silicone, this biases against
finding migrated silicone.

The sponsor also reports that there were no cases of intracapsular
rupture which progressed to extracapsular rupture. They acknowledged
that, however, that because it is routine clinical practice to remove
ruptured implants their ability to determine this progression is
limited.

The sponsor, recognizing that three to four year data is insufficient to
describe the rate of rupture over the expected lifetime of the device,
attempted to estimate the ten year rupture rate from their existing Core
Study data. To do this, they made several assumptions.

First, they used the proportion of silent ruptures observed in the MRI
cohort by indication to estimate the number of silent ruptures in the
non-MRI cohort.

Next, because they believed that the false positive rate of MRI in the
Core Study is about 36 percent, they reduced the estimated number of
silent ruptures in the non-MRI cohort by this proportion. Because there
were a few silent ruptures reported in the non-MRI cohort, they
additionally reduced these from the estimated silent ruptures in the
non-MRI cohort to avoid double counting.

Finally, they assumed that the rupture rate would remain constant
yielding a straight line for the shape of the rupture curve, which
results in a ten year by-implant rupture rate of 14 percent across all
indications.

Note that this estimated ten year rate of 14 percent is higher than
their hypothesized rate of five percent which I showed a few slides ago.

FDA has questions about these assumptions. And as the FDA statistician
will demonstrate following my presentation, there are other models which
could be selected which would lead to higher rupture estimates.

In addition to the Core Study Inamed used other sources of their data to
describe and estimate a long term rupture rate: their Adjunct Study,
their saline-filled breast implants and their product complaint
database, and the Danish implant registry.

Because there is no screening for silent rupture in the Adjunct Study
and because the follow-up rate at five years is about 30 percent, the
Adjunct Study data are of minimal utility in describing the rupture
rate.

Because saline breast implant deflation is almost always symptomatic,
while silicone breast implant rupture is most often silent.

Because of significant differences in design and materials. For example,
gel implants are prefilled and saline implants are inflated, and because
of significant differences in operative techniques such as incision size
and degree of implant handling, saline implants cannot be compared to
gel implants to estimate rupture.

Because Inamed\'s product complaint database, which they refer to as
their surveillance study, is voluntary there may be under reporting of
rupture.

Because the denominator is based on the number of implants sold, which
is larger than the number actually implanted, the denominator is
overstated. Both of these factors will under estimate the rupture rate.

Of the 1,472 patients in the Danish registry, there are 263 Inamed
devices with a median rate of implantation of about four years. Although
the sponsor reports that done of these implants have ruptured, there is
also no MRI screening for silent rupture in this group of patients.

What about the frequency of intra versus extracapsular study in the
Adjunct Study? Recall that there is no screening for silent rupture of
the Adjunct Study and the follow-up rate of five years is about 30
percent.

There have been 99 implant ruptures confirmed via explant in the Adjunct
Study patients. Of these 99 confirmed ruptures, the sponsor reported 95
as intracapsular, 1 as extracapsular with resulting migrated gel into
the axilla, and 3 implants in three patients with silicone gel leaking
from their wounds.

Upon my review of individual patient histories which were provided by
the sponsor, there were 2 patients reported with intracapsular rupture
who also had free silicone in the axilla. These should be reported as
extracapsular rupture as a worse case analysis. Therefore, of the 99
confirmed implant ruptures, 93 were intracapsular and 6 were
extracapsular.

Note that for the 3 patients with silicone gel which migrated to the
axilla, all occurred after three years of implantation. One was a
revision augmentation patient, one was a contralateral augmentation and
one was a reconstruction patient.

Now that we\'ve reviewed Inamed\'s data to determine rupture rate and
frequency of intracapsular and extracapsular gel, let\'s focus on the
published literature for these topics. Keep in mind that because this
literature is not specific to Inamed implants, it serves as supportive
information.

Serial MRI studies have been performed in Scandinavian women which
report the prevalence and incidence of silent implant rupture published
by Dr. Holmich and colleagues. These studies report rupture rate only
for augmentation patients and only for patients who did not have their
implants removed within the first three years of implantation. With a
median duration of implantation of 12 years the point prevalence of
rupture was reported to be 32 percent of implants if definite and
possible rupture via MRI is considered. About one-fourth of these
implant ruptures were extracapsular.

After performing two serial MRI examinations these authors report an
incidence of 8.9 definite or possible implant ruptures per 100 implants
per year. I will discuss the potential implications of this incidence
later.

Note that most of the implant ruptures were silent, most often diagnosed
via MRI, 48 out of the 56 ruptures, rather than at a reoperation 8 of
the 56 ruptures.

I would like to turn your attention to two other MRI studies published
in the literature regarding silent rupture. Again, these studies report
silent ruptures via MRI in patients with breast implants from a variety
of a manufacturers and are not specific to Inamed implants serving as
supportive information.

The first study reported by Dr. Brown of FDA and colleagues studied a
cohort of augmentation patients with a median duration of implantation
of 16 years finding a prevalence of 55 percent of definite implant
rupture with extracapsular gel found in 12 percent of these cases.

The second study reported by Dr. Gaubitz and colleagues included women
with a mean duration of implantation of nine years. Approximately
three-fourths of these woman had implants for reconstructive purposes
and one-fourth had them for augmentation. The prevalence of rupture in
this cohort was 24 percent of women with 12 percent of these women
having extracapsular rupture.

To assess the health consequences of breast implant rupture the sponsor
compared the local complications, connective tissue disease signs and
symptoms and patient satisfaction results for women with confirmed
implant rupture to those with confirmed intact implants in the Core
Study with confirmation occurring at explant.

While this is a reasonable approach, recall that there only have been 25
patients with ruptured implants confirmed via explant in the Core Study.
The data from these 25 patients were compared to 131 patients with
confirmed intact implants. Because several patients had not yet had a
follow-up visit after explant; this was the case for 30 percent for
local complications, 60 percent for patient satisfaction and 50 percent
for connective tissue disease signs and symptoms, the numbers compared
were very small. This limits the utility of these data to address the
health consequences of rupture for Inamed\'s product.

To evaluate the health consequences of rupture in the Adjunct Study the
sponsor reported the local complication result at the time of rupture
confirmation and after rupture for those patients who came back for a
follow-up visit. No attempt was made to compare these data to patients
having confirmed intact implants.

At the time of explant when rupture was noted, the three most frequent
complications reported were capsular contracture, asymmetry and implant
palpability. Seventy-seven of these patients had their implants replaced
and follow-up was obtained for 63 of these with 21 reporting a
complication or a reoperation.

Following implant replacement due to rupture, reoperation was the most
frequently reported event with the most common reoperation reported as
implant replacement followed by a capsule procedure.

So what\'s in the published literature regarding the health consequences
of implant rupture? There are case reports of silicone granulomas found
in axillary lymph nodes and in the chest area, as well as in distant
areas such as the eyelid and the abdomen. The reference by Dr. Gaubitz
and others I mentioned a few slides ago, describes the presence of
silicone in the liver of asymptomatic women using magnetic resonance
spectroscopy, a finding which was statistically significantly higher in
women with ruptured implants.

Turning to the literature of Danish women in comparing the self-reported
signs and symptoms collected one year before MRI as well as autoantibody
levels in 146 women with intact implants versus 92 women with ruptured
implants there were no statistically significant findings. However, the
self-reported symptoms were collected about one year prior to the MRI
which diagnosed rupture.

Women with extracapsular rupture were six times more likely to report
breast hardness than women with intact implants in the study. Whether
these patients had capsular contracture, which is also associated with
breast hardness, was not specified in the report.

The only published study to report on local symptoms over time following
rupture, which is Holmich 2004, reported that women with ruptured
implants were two times more likely to report pain in the breast or
change in breast shape compared to women with intact implants. Of the
intracapsular ruptures from the first MRI, ten percent had progressed
within the two year period of the second MRI with 9 percent of these
converting from intra to extracapsular rupture.

Note that about half of these conversions were spontaneous, not
associated with trauma, closed capsulatomy or mammography.

Of the implants with extracapsular rupture noted on the first MRI, there
was progressive silicone seepage, diffusion in 14 percent, none of which
were associated with trauma or any symptoms.

I would now like to summarize what is known regarding rupture rate
information from both Inamed\'s data and the published literature.

There is full three years of comprehensive rupture information from
Inamed\'s data. The majority of silicone breast implant ruptures are
silent, diagnosed only via MRI.

For Inamed\'s data, most ruptures are intracapsular based on explant.
Four percent of the implant ruptures in the Core Study and 6 percent in
the Adjunct Study were extracapsular with 3 percent of ruptures having
migrated gel in the Adjunct Study.

Three to four year Inamed rupture data are limited to characterize the
expected lifetime rupture rate. Because ruptured implants are routinely
removed, Inamed\'s data is insufficient to address how often and when an
intracapsular rupture progresses to extracapsular, as well as how often
and when a silent rupture becomes symptomatic.

To evaluate the health consequences of rupture, Inamed relied on their
Core Study and Adjunct Studies to determine if there were differences in
local complications, patient satisfaction and connective tissue disease
signs and symptoms between women with ruptured and intact implants,
which is a reasonable approach. The problem with this approach is that
because the numbers were small and follow-up after rupture had not yet
occurred for several patients, lack of significance could be due to lack
of statistical power rather than a lack of an association.

What about the rupture information in the literature? Keep in mind the
caveat that the literature is not specific to Inamed\'s breast implants,
and for the most part is pertinent to augmentation patients.

Although there have been numerous publications regarding the health
effects, like connective tissue disease in breast implants, only one
publication, the Holmich 2004 reference, describes the health
consequences of women with ruptured implants followed over time. This
reference describes local breast symptoms and is over a two year
follow-up period.

In the literature serial MRI data are available from one study, again
from the Danish cohort, and is over a two year period. Like the Core
Study in these studies of Danish women the majority of ruptures are
silent diagnosed via MRI. Most ruptures are intracapsular with 25
percent of ruptures as extracapsular. About 9 percent of intracapsular
ruptures progressed to extracapsular within two years, with about half
of these associated with trauma and half occurring spontaneously.

Fourteen percent of extracapsular ruptures had progressive silicone
seepage over two years no case of which was associated with trauma or
any symptoms.

Women with ruptured implants were more likely to report breast pain and
breast hardness. Whether this was associated with capsular contracture
or not was not reported in these references. And there is evidence of
the presence of silicone outside of the breast area.

The incidents of rupture, again, for augmentation implants with a median
duration of implantation of 12 years is about nine ruptures per 100
implants per year. According to the American Society of Plastic Surgery
website for year 2004, that would be about 22,500 implant ruptures per
year in the U.S. augmentation population alone assuming that only half
of women who get augmentation implants in the U.S. would get silicone
implants.

Although extracapsular rupture occurs less frequently than intracapsular
rupture, I would like to share with you the case history of the patient
who had extracapsular rupture in the Core Study because it did occur at
three years for this patient.

This patient is a 36 year old who entered Inamed\'s Core Study as a
primary bilateral breast augmentation patient. Six months later she
developed Baker grade III capsular contracture on the right which
progressed to Baker grade capsular contracture IV four months later.

Capsulectomy was done on the right at ten months. Her first MRI as part
of the MRI cohort was done four months later showing no evidence of
rupture.

Two weeks later an exploratory surgery with capsulotomy was done and
free gel was noted in the pocket. Two months later the patient returned
to her surgeon because her incision site had opened and silicone was
extruding through her incision causing an inflammatory reaction. Four
days later the implant shell and residual shell were removed as well at
the contralateral implant. Neither implant was replaced in this patient.

Note that the patient reported no complications or symptoms with her
ruptured implant. And her plastic surgeon, who was evaluating her
annually, also did not report any changes with her implant suggestive of
rupture.

As you will see later when we discuss the questions to you, the Panel,
half of the panel questions deal with implant rupture. In considering
the safety of this device we would like you to consider whether the
sponsor\'s data are adequate to characterize the rupture rate over time
and the health consequences of rupture, as well as whether the existing
data for rupture provide a reasonable assurance of safety. Because most
silicone gel-filled breast implant ruptures are silent if you are
considering recommending approval, you will need to carefully consider
your recommendations for the screening method and screening frequency
for silent rupture.

If you believe the sponsor\'s data provide a reasonable assurance of
safety and effectiveness, then you will need to comment on the adequacy
of their proposed labeling recommendations and their proposed
post-approval plans.

In one of our Panel questions we asked three labeling issues: The method
and frequency of screening for silent rupture; the clinical management
of suspicious and silent ruptures, and; the potential health
consequences of extracapsular and migrated gel.

To address the first issue, Inamed refers to one literature reference
citing a sensitivity of 64 percent and a specificity of 77 percent for
MRI despite numerous other articles indicating a higher sensitivity of
80 percent as well as in the Danish studies and a higher specificity of
95 percent.

Inamed recommends MRI screening every one to two years or at a frequency
recommended by the plastic surgeon. As an example of what the plastic
surgery community recommends on this topic, the American Society of
Plastic Surgery\'s current training recommends the first MRI screening
for silent rupture be done at ten years, which is clearly inconsistent
with those of Inamed.

The proposed labeling fails to point out that most silicone breast
implant ruptures are silent. The recommendation on whether to remove a
ruptured implant is not clear. The proposed labeling indicates that the
decision to remove a silent ruptured implant is left to the patient and
her surgeon. That the implant might be removed particularly if there is
extracapsular gel.

The labeling also implies that because the accuracy of MRI is
questionable, it may be acceptable to leave in a ruptured implant.

And finally, the label states that there is no evidence of extracapsular
gel causes any symptoms.

At the October 2003 Advisory Panel meeting the Panel recommended to
approve this product with multiple post-approval recommendations to
address long term rupture rate, to address health consequences of
rupture, to address data on women with breast implants, and to address
connective tissue disease.

To address primarily rupture issues, Inamed proposes to continue the
Core Study with yearly physician follow-up and MRI to continue in the
MRI cohort at years five, seven and nine.

Although the patient follow-up in the Core Study is relatively good, as
patients have their implants removed or have other contraindications to
MRI, they are no longer in the MRI cohort of primary rupture data.

For example, in the augmentation MRI cohort, ten percent of the patients
were discontinued from the MRI cohort between years one and three for
primary rupture determination. As more patients from the MRI cohort have
their implants removed, their MRI data would not be used for determining
the rupture rate.

The sponsor also proposes to link their voluntary product registry which
collects only baseline demographic information to their rupture warranty
program which provides financial incentives to patients for implant
replacement.

Note that there is no post-operative clinical data collected with either
of these programs.

To address issues other than rupture, the sponsor proposes to collect
data from the Danish registry or from some other third party. Neither
the third party data source nor the types of analyses have been
specified.

And finally, they\'ve proposed a physician education training program.
However, there is no acquirement for certification to have access to the
product, there is no information regarding silent rupture screening
method or frequency, nor are there recommendations to remove ruptured
implants.

You\'ll be asked in the Panel questions to determine whether there is
adequate data to demonstrate a reasonable assurance of safety and
effectiveness for Inamed\'s product. In considering the safety and
effectiveness you will need to consider complications other than rupture
as well as the benefit for Inamed\'s products. Included in your Panel
pack in Tab 5 are the FDA Panel memorandums from the October 2003 Panel
meeting which contains this information with a date of database closure
approximately one year before that for rupture.

Although the data is often presented with augmentation and
reconstruction shown side-by-side the risks and benefits from these two
patient groups should not be compared. For example, the reoperation rate
for reconstruction patients appears higher than for augmentation
patients. But this rate should be considered in the context that
reconstruction women are already having breast surgery.

And finally, because revision patients start out as either initially
primary augmentation or primary reconstruction, consider the risks of
revision patients as a continuum to those of augmentation and
reconstruction.

Thank you.

I now introduce Dr. Pablo Bonangelino, the FDA statistician who reviewed
this PMA.

DR. BONANGELINO: Good morning. I am Dr. Pablo Bonangelino, the
statistical reviewer for the Inamed silicone gel-filled breast implant
study.

Before I begin, I would like to clarify that there have been several
speakers yesterday and even newspaper articles that have referred to the
numbers in this talk as FDA estimates of the rupture rate. It is
important to remember that these numbers were not meant to be estimates
of the rupture rate; rather, they were simply meant to illustrate the
difficulty and variability in predicting the long term rupture rate with
short term data.

In this presentation, as I have just mentioned, I will comment on the
difficulty in predicting long term probability of rupture with limited
short term data. Specifically, I will try to show the difficulty in
predicting the probability of rupture by year ten having complete data
only through year three.

The sponsor has attempted to address the issue of long term probability
of rupture by extrapolating an average percentage of ruptures per year
of 1.4 percent. They have calculated that 1.4 percent ruptures per year
for ten years would yield a probability of rupture by year ten of
approximately 14 percent.

The sponsor\'s estimate of 1.4 percent ruptures per year can be
questioned. In particular, the sponsor is assuming that the average
percentage of ruptures per year which was observed through year three
will hold through year ten. That is, they\'re assuming a constant
percentage of ruptures per year. The problem with this is that the
percentage of ruptures per year may not be constant and in particular,
may increase with increasing age of the implant. That is, there could be
an increasing percentage of ruptures per year in later years due to the
implant wearing out.

The difficulty in predicting the long term probability of rupture can be
illustrated by considering various models for the rate of rupture or the
percentage of ruptures per year of the breast implants. Specifically, we
consider three simplified models out of a large number of plausible
models.

In the first model, like the sponsor, we considered that the percentage
of ruptures per year is constant. This type of constant model is
commonly used to describe the rate of failure of electronic equipment,
such as stereos or televisions, after a suitable \"burn in\" period
because they do not appreciably wear out over time.

In the second and third models, we consider that the percentage of
ruptures per year increases with time. In the second model, we assume
that this increase is a linear function of time, and in the third model,
a quadratic function of time. These types of models with increasing
hazard could be used to describe automobiles or perhaps also rubber
components which could dry out and crack over time.

It must be emphasized that these three models were chosen to illustrate
the possible variation in the behavior of the percentage of ruptures per
year and not because the models were judged to be likely to be correct.
In fact, we really don\'t know.

The three models for the percentage of ruptures per year which we have
chosen to illustrate correspond to three survival models which can be
used to calculate the cumulative probability of rupture by a given time.

It must again be noted that our three models are not meant to be an
attempt to present the true model. In particular, different modes of
rupture could correspond to different models for the percentage of
ruptures per year yielding a complex composite model as being closest to
the true situation.

In addition, it should be remembered that the three models are a small
subset from a much larger collection of possible simplified models. In
spite of these deficiencies, these three models are still useful to
represent our uncertainty about the behavior of the percentage of
ruptures per year.

Although the three models are theoretical, we attempted to find our
closest fit to the available data. In order to do so, we needed
estimates of the percentage of rupture per year for each year for which
we had data. More specifically, we used the following data: Kaplan-Meier
risk of symptomatic rupture through year three and Kaplan-Meier risk of
silent rupture based on MRI data from year one and year three.

Note that although partial year four data was available, we did not use
it in what follows because it consisted of few observations and did not
include any additional information on silent rupture.

Note that we only fit models for the MRI cohorts since these were the
only patients with active ascertainment of rupture. That is, we felt it
was necessary to use data from patients who had had MRIs to detect
possible silent rupture. However, note that for the silent rupture in
the MRI cohort we really only have two data points; at the year one and
year three MRI. That is, the year two and year three percentages were
not known individually. Only their sum was known at year three. To solve
this problem we calculated an average percentage of rupture over years
two and three and estimated this percentage as occurring on the average
at year 2.5. Thus, in the graphs which follow we only show two data
points, at year 1 and at year 2.5.

Note that the approach just mentioned for estimating the percentage of
ruptures per year differs slightly from the approach described in the
Panel memo. Although both approaches are reasonable, the current method
yields a more clear graphical representation of the data.

Other details of how we went about fitting the three models are given in
the FDA Panel memo.

In the next slides we present an example of fitting our models for the
percentage of ruptures per year to the existing data. The data is from
the augmentation MRI cohort.

This slide shows the data and the fitted model. The points on the graph
represent the observed data for the percentage of ruptures per year for
each of years 1 and 2.5. These percentages for the augmentation cohort
were found to be 0.3 and 0.6 percent respectively. Note that the points
are the percentages of ruptures at each year. They do not represent the
cumulative probability of rupture.

The line represents the model with a constant percentage of ruptures per
year. In this case, the constant percentage of ruptures per year was
estimated to be approximately 0.5 percent.

This second slide has the same two data points with values of 0.3 and
0.6 percent. However, the line now represents the model with a linearly
increasing percentage of ruptures per year. According to the model, the
percentage of ruptures per year at year one would be approximately 0.25
percent. At year 2.5, the percentage would be approximately 0.63
percent. And at ten years, it would be approximately 2.5 percent.

Finally, this third slide shows the same data and a curve which
represents a model with a quadratically increasing percentage of
ruptures per year. According to this model, the percentage of ruptures
per year at year one would be approximately 0.1 percent; at year 2.5 the
percentage would be again approximately 0.63 percent; and at year ten it
would be approximately 10 percent.

These graphs show that all of our three models are plausible. In fact,
with so few data points a large number of models could approximately
fit. This is one of the difficulties in making long term predictions
from a few early data points.

The graphs I have just showed you were representations of models for the
percentage of ruptures per year. Obtaining the cumulative probability of
rupture requires use of the corresponding models for the survival
function. The process of fitting models for the percentage of ruptures
per year was carried out for the MRI augmentation cohort just as shown,
and also for the reconstruction and revision MRI cohorts and all
indications combined. We then used the corresponding survival models to
calculate the cumulative probability of implant rupture by year ten.

In this slide, we show our results for the MRI augmentation,
reconstruction and revision cohorts in all indications combined. The
confidence intervals were derived from the corresponding 95 percent
confidence intervals for the Kaplan-Meier risks of rupture.

Once again, these results are not meant to be true estimates of the
probability of rupture. They are simply meant to illustrate the large
uncertainty in attempting to make those predictions.

I will now take a moment to describe the table. The rows of the table
represent the various cohorts for which predictions were made and the
columns represent the different models which were used to make those
predictions.

For example, the top row of the table represents the augmentation MRI
cohort for which we saw the graphs.

This is saying that using the model which assumes a constant percentage
of ruptures per year, we predict a 5 percent probability of rupture by
year ten for the augmentation cohort. Using the model with linearly
increasing risk, the prediction is for a 12 percent probability of
rupture by year ten.

Finally, the model with quadratically increasing percentage of ruptures
per year yields a probability of 29 percent of rupture by year ten.

Note that large differences are seen for each of augmentation,
reconstruction, revision and all indications combined depending on which
model is used to predict the ten year results.

In the next slide I will show a graphical representation of the
predictions for all indications combined, which is the bottom row of
this table.

This slide shows graphically the probability of being rupture-free for
the combined MRI cohort. The line labeled one corresponds to an
assumption of a constant percentage of ruptures per year. The line
labeled two corresponds to an assumption of linearly increasingly
percentages of ruptures per year. Finally, the line labeled three
corresponds to an assumption of a quadratically increasingly percentage
of ruptures per year.

It can be seen that the predicted probability of being rupture-free has
large variability at ten years.

In summary, by fitting three simplified but plausible models, we have
observed a large range of predictions to the long term probability of
rupture. Thus, it can be seen that it is difficult to reasonably predict
the probability of rupture by year ten with the available data.

This concludes FDA\'s presentation. Thank you for your attention.

I will turn now turn it over to the Panel for discussion.

CHAIRMAN CHOTI: Thank you.

I now open for the Panel to discuss, ask questions of the FDA group. Dr.
Miller?

DR. MILLER: I have a question. You seem to not prefer the Inamed\'s
approach to doing their calculations where they try to take the known
ruptures in the whole group and estimate the number of silent ruptures
based upon the MRI cohort and develop some projections based on that.
You seem to think that\'s not a valid approach because you\'re being
very stringent here looking only at the MRI cohort, I think.

I would have liked to have seen \-- if you don\'t like the Inamed
assumptions in terms of the numbers or how they projected the rupture
rates based upon a combination of the known ruptures in the MRI cohorts,
you seem to have had a problem with their estimates of the MRI results,
to use their same approach but recalculate them with what you think are
a more reasonable set of conclusions from the MRI data. Do you
understand what I\'m saying? Am I expressing myself properly?

You seem to have rejected the method where ten year projections were
calculated that Inamed used. And rather than taking the sort of
Kaplan-Meier data that, if I understand it correctly, is a combination
of actual confirmed ruptures modified by what ruptures would be
anticipated to be based upon the MRI cohort. They developed a number \--
a series of calculations which spanned over the years. You seem to not
think that\'s a valid approach because you haven\'t used it.

Dr. Blumenstein, can you help me here? I don\'t feel like I\'m
communicating here, but I \--

DR. DAWISHA: Well, I guess I should comment and say that we chose to use
the data that were available rather than trying to extrapolate, which is
based on assumptions. We decided to take the approach, okay, what data
do we have and what can you say about the existing data? And for that
reason we focused on the MRI cohort because we recognized that this
group had ascertainment of silent rupture. And as I said earlier, the
sensitivity of MRIs is 80 to 90 percent. So you\'re already missing 10
to 20 percent of ruptures in this group. But our focus was to focus on
the data that they had and not make assumptions about what the silent
rupture rate would be in the non-MRI cohort. And that was our approach.

DR. MILLER: Well, I \--

DR. DAWISHA: We\'re not necessarily saying we reject or accept a
particular approach, but our approach was to focus on the data that we
had. And we were already making \-- fitting models to data and we
thought it would be more appropriate to fit models to actual data.

DR. MILLER: It seems difficult to fit any model to two data points. I
mean, you know, anything could fit that model. So clearly if you are
assuming that the only valid data that we have to consider is the MRI
cohort with two data points, we know nothing about rupture rates if
that\'s the only data that we have. I mean, you can\'t project anything
\--

DR. DAWISHA: Well, the MRI is done at one and three years following
implantation. And those MRIs are not all done at year one and year three
because patients don\'t get their implants all at the same time. So we
included all of the data through three years. It was the most complete
data set and it included ascertainment of silent rupture.

DR. BONANGELINO: I believe in Inamed?s presentation they stated that
silent ruptures accounted for 86 percent of all ruptures. Is that
correct?

DR. MILLER: That\'s what I read, yes.

DR. DAWISHA: Yes.

DR. BONANGELINO: So therefore it would be incorrect to fit data that
didn\'t include the silent ruptures.

DR. MILLER: No, I appreciate that. And, again, bear with me here because
I\'m just trying to understand this.

It appears to me that you have taken an approach as \-- it can\'t be
criticized, but it is extremely rigorous and gives us very little data
to go on. And if it\'s the best approach, then we basically \-- there\'s
not much we can say about the ten year projection because with two data
points you really can\'t project anything.

Now, what I saw from the Inamed presentation was that they did not take
this approach. But their approach seemed reasonable to me, and there was
certainly a lot more data to analyze with that approach.

Now the thing I\'m curious about is do you feel that approach is not
appropriate to use, because you haven\'t used it?

DR. BONANGELINO: Well, Inamed\'s approach was one of the approaches that
we took in the presentation. And the difference might be in the estimate
of the average percentage of ruptures per year, how that was calculated.
Inamed came up with numbers that stated that the average rupture rate
was 1.4 percent. We came up with slightly different numbers.

DR. MILLER: Okay.

DR. BONANGELINO: But it is one of the approaches that we examined in my
presentation.

DR. MILLER: It would have been helpful to me if rather than not \-- you
disagree with some of the assumptions that Inamed made, which I can
accept that.

DR. BONANGELINO: Let me just clarify. When you extrapolate \-- let\'s
say you have 20 patients, 10 of them are in the MRI group and you
observe, let\'s say, 30 percent of them ruptured. And then you go on and
say, well, in the overall group, in the other group, there should be the
same amount of rupture, so that\'s 30 percent. It doesn\'t change the
result because in the overall group it\'s still going to be 30 percent.
Thirty percent of ten plus 30 percent of ten is 30 percent of 20.

DR. MILLER: I understand. If there is \-- I mean, I saw in your
presentation that you felt that some of the assumptions that Inamed made
underestimated certain \-- let\'s see if I can find that.

Well, the sense I got from your presentation was that you disagreed with
the calculated annual rupture rate. Is that accurate to say?

DR. BONANGELINO: As I said, there could be considerable debate as to
what the average \--

DR. MILLER: Sure. But it would have been helpful to me if you had taken
the range of possibilities and done a similar calculation that Inamed
had done with a range of possibilities rather than just abandoning it,
which it seems to me I see nothing that you\'ve done which helps me
compare what you\'re saying and what Inamed said. So I have just two
separate groups of data, so I don\'t know what to say.

DR. BONANGELINO: What I\'m saying is slightly different numerically from
what Inamed did, but it is one of the approaches that we described. It
is exactly the approach that was taken by Inamed.

DR. MILLER: Is it possible to present?

DR. BONANGELINO: The constant probability of rupture.

DR. MILLER: I would like to see a Kaplan-Meier curve based on that doing
a similar type of analysis, which I don\'t see any data \-- I don\'t see
any comparable presentation, which would help me tremendously to know
how to put in perspective what you\'re saying and what Inamed is saying.

DR. BONANGELINO: I understand.

CHAIRMAN CHOTI: I think there are two separate questions. One is the
projection and the other is the different assumptions about what is a
rupture. I think that Inamed used the, I think it was the over 30
percent false positive rate and eliminated that because it found that in
some patients where they called a leak was not a leak on the actual
explant. So there are factors regarding the definition of what is a
silent rupture, and then the differences in the projection. I may be
wrong about that.

DR. DAWISHA: Yes. That may have accounted for \-- I mean, I think what
you\'re doing is you\'re looking at the final table in Dr.
Bonangelino\'s slides and comparing that number to what Inamed got at
ten years. And part of the problem is that, again, there were a couple
of things that the sponsor did.

First of all, they eliminated the 36 percent false positive MRIs. Then
they also eliminated silent MRIs which were observed in the non-MRI
cohort. And then they also weighted \-- rather than actually taking the
data for the augmentation, the reconstruction and the revision patients,
they weighted the number of ruptures based on the proportion of patients
that were in those three cohorts.

So there are some slight differences in Inamed\'s approach versus our
approach. And, again, our approach was to say, let\'s not make any
assumptions. Let\'s just look at the data that we have and then try to
model the data based on what we have.

CHAIRMAN CHOTI: Dr. Leitch?

DR. LEITCH: So why is not appropriate to weight them based on the groups
that they\'re in?

DR. BONANGELINO: It\'s not that it\'s not appropriate. It\'s just that
there\'s no new information. When you weight, the information is the
same. It\'s still going to be 30 percent ruptures whether you weight the
observations that weren\'t included, you\'re going to take 30 percent of
those and 30 percent of the previous ones and it\'s going to be 30
percent of the total.

DR. LEITCH: But if most of your ruptures\--

CHAIRMAN CHOTI: Would you use the microphone?

DR. LEITCH: If most of your ruptures occur in the group that\'s the
smallest, which is the reconstruction group.

DR. BONANGELINO: Oh, correct. It would be incorrect to use just the
symptomatic data and ignore the silent rupture. But the actual
extrapolation to the non-MRI cohort doesn\'t add information.

DR. LEITCH: Okay. Let me ask one other question. You know, for me in
looking at which line looks like it would be the most likely one that we
would pick, you said that using the saline data which goes out to eight
years and looks more like the line that Inamed has shown, you say it\'s
not appropriate to use that, I think one of the ideas being that the
insertion technique is different so the methods of injury to the implant
might be different.

So if you say that\'s the case, they also showed that the gel implants
that were thought to be injured related to surgery, those occurred
earlier on in the series. You know, they were more likely to be early as
opposed to late. So it seems to me that using that saline curve where
the materials of the device are similar in terms of the shell would make
sense to assume that that appearance of the curve could be used?

DR. DAWISHA: Well, as I pointed out, when you\'re looking at saline
ruptures, you\'re looking at ruptures that are clearly evident. They\'re
symptomatic, they happen quickly. And when you\'re looking at silicone
gel ruptures, you\'re looking at ruptures that are silent, that the
patients are not aware of.

And, yes, the same basic material is silicone, but the two products are
very different in terms of the way they\'re implanted, in terms of the
fact that one is pre-filled, one is inflated. The degree of handling is
different. So, you know, for all of those reasons we don\'t think that
it\'s appropriate to extrapolate from saline data, particularly for
rupture, to the silicone gel data.

DR. BARTOO: Excuse me. But in their presentation they also had a ten
year shape of the rupture rate curve for the 153. So that would be a gel
and it does have a similar shape to the saline.

DR. DAWISHA: That was also extrapolated. All of those curves to ten
years are extrapolated curves.

DR. BARTOO: On the surveillance, on slide number 40?

DR. DAWISHA: Oh, for the surveillance? Yes. The surveillance is their
product complaint database, which I pointed out is based on voluntary
reporting and is based on the number of implants sold rather than the
implants \-- the number that were actually implanted.

DR. BARTOO: Right.

DR. DAWISHA: And you could see in their data that their product
complaint rupture rate is lower.

DR. BARTOO: Right. So the actual number might be lower, but wouldn\'t
the shape be valid still?

DR. DAWISHA: Well, again, you would have to assume that all the ruptures
that were reported in the complaint database were \-- that there was
active ascertainment for silent rupture and that you were capturing
silent rupture.

DR. BARTOO: Yes.

DR. DAWISHA: Which you\'re not necessarily doing in that database.

CHAIRMAN CHOTI: Dr. LoCicero?

DR. LoCICERO: In terms of this PMA, this includes a variety of devices
including 153. Clearly 153 is very different from the others in terms of
its early rupture rate is 40 percent of the ruptures. Is it appropriate
to analyze that as a separate thing or are we not allowed to consider
that?

DR. DAWISHA: Well, I guess we need to point out that the PMA that the
sponsor submitted to us, in contrast to the slides that they showed you
today, did not break out the rupture rate for 153 to the other devices.
When they submitted their data to us it was all as one group.

I think we should also point out that the sponsor is proposing to market
the Style 153 with the changes that they suggested they would make in
the design, and that they would address the problems with 153 by
physician training and then in vivo studies in animals.

So we did not have data broken out for 153 versus all of the other
implants.

Most of the implants in the reconstruction patients were 153, but not
necessarily for the augmentation patients.

DR. LoCICERO: So the sponsor also said that they were going to make
adjustments to 153. So, just to clarify, we\'re going to be looking at
potentially approving 153 in the state that it\'s in now with the data
from the current model but that it\'ll be something different when it\'s
marketed?

DR. DAWISHA: Yes. That is correct. In fact, this information that they
say they have submitted to us that describes these design changes, we
have not seen this submission. So you\'re looking at all of the styles
as they exist in their current configuration.

CHAIRMAN CHOTI: Along those lines, can you clarify your impression of
this, we\'ve heard this third generation data, third generation? In the
context of the data we\'ve seen; Core, Adjuvant, Danish, I mean, how
many of those were this so-called third generation?

DR. DAWISHA: The third generation is loosely defined by the thickness of
the shell, the thickness of the gel, and then when they were implanted.

One way to define them is those implants put in after 1988. Another way
to define them is the thickness of the shell and the gel.

In the Core Study, obviously, all of the implants are third generation.
And I believe the Adjunct Study as well. So for the sponsor\'s data
we\'re talking about third generation implants.

In the Danish literature, the authors did break out \-- for the
incidence study and the Holmich reference, the authors did break out the
incidence based on first, second and third generation. However, if you
look at the duration of implantation, it\'s also the shortest in the
third generation implants.

So it\'s difficult to conclude that the reason the rupture rate is lower
in the third generation is because of the design. You could also
conclude that the reason the rupture rate is lower is because these
implants have been in less, a shorter duration of time.

And another thing is that, you know, manufacturers are making
incremental changes to the products over time.

And in the incidence study that was reported by Holmich, if you define
third generation based on the year, you get a different incidence than
if you define third generation based on the thickness of the shell and
the thickness of the gel.

CHAIRMAN CHOTI: And similarly, the intercapsular versus extracapsular,
the progression to extracapsular all would likely changed based on the
generation; the consistency of the silicone gel, for example, so that
it\'s a little bit hard to extrapolate the performance of this
generation based on let\'s say extracapsular extravasation using some of
the European studies that use the older models, is that true?

DR. DAWISHA: Right. I mean, the caveat is again the literature, we use
it for illustrative purposes and it\'s a variety of manufacturers, a
variety of implantation durations and use supportive information.

CHAIRMAN CHOTI: Other questions from the panel? Yes, Dr. Li?

DR. LI: A question for Ms. Allen on the gel bleeding test.

This test, as I understand it, the ASTM test where they have a silicone
wafer, in this case a 3M silicone wafer and they put the implant on top
of it and then they measure how much material essentially diffuses out
from the implant into the disk?

CDR. ALLEN: Right.

DR. LI: Now as I read some of the details, the disk they used was
essentially kind of a new disk. It was a 3M disk rather than one that
one normally uses in the ASTM test. As I look through the data, even
Inamed reported that it appears to actually result in about six times
less material bleeding into the 3M disk than the regular disk.

So I guess my question is, isn\'t that kind of going the wrong way? You
know, because we\'re trying to detect things like low molecular weight;
silicone and these small platinum things. But yet they\'ve gone to a
disk that appears to have lower sensitivity or at least a slower ability
to absorb these materials.

So I guess, wouldn\'t you say the test didn\'t really add anything to
our knowledge as far as gel bleed goes?

CDR. ALLEN: Yes. I think we have a lot of problems with the actual test
methodology as a whole. But to answer your specific question, I\'m going
to let Dr. Sam Arepalli address that since he was the lead reviewer of
that topic.

DR. LI: Okay.

DR. AREPALLI: Yes. The test was done only for eight weeks. And at the
eight weeks it levels off. So it could very well be \-- I mean, it must
have reached an equilibrium at the time of eight weeks. So probably
that\'s one of the reasons.

DR. LI: Well, in real life or clinically it doesn\'t level off. Whatever
the bleed rate is, wouldn\'t you expect it to have that rate as long as
it\'s in the patient? I mean, there\'s no reason to suspect in the
patient it levels off, is there?

DR. AREPALLI: That\'s correct, yes.

DR. LI: Okay. So this is really kind of an underestimate, right?

DR. AREPALLI: Yes.

DR. LI: And are you disturbed by the fact that they didn\'t seem to
detect any platinum in this, and we know apparently platinum is readily
detected in these patients that have this device?

DR. AREPALLI: That\'s right. But the sponsor couldn\'t detect any
platinum, but it could very well be that at the time they tested that,
the platinum didn\'t come out through the membrane. But if they left it
for long enough, probably they would have detected it.

Another thing I want to point out is this gel bleeding is a diffusion
process \-- process of diffusion. So unless they tell us there is
something preventing the platinum to come out, I would assume it will
come out sometime sooner or later.

DR. LI: But the test as it\'s reported now doesn\'t really help us at
all, right, to understand how fast something comes out or even what
comes out? Because we know platinum comes out, but yet in the test it
doesn\'t. So the whole gel bleed, that whole section, although it was a
good effort, doesn\'t really teach us anything, does it?

DR. AREPALLI: I would agree with you.

DR. LI: All right.

CHAIRMAN CHOTI: Other questions from the Panel? Yes, Dr. Provost?

DR. PROVOST: I just want to make a clarification about the Style 153. We
heard the sponsor say that they had submitted information describing
their design change. And I\'m sure that that information is at the FDA
somewhere and once we receive it, we will do our usual thorough review
of it.

I wanted to make sure that there wasn\'t this discrepancy about whether
it had or had not been received. We haven\'t actually reviewed it yet,
but it\'s probably just because it\'s making its way towards us if the
sponsor says they\'ve submitted it.

CHAIRMAN CHOTI: Question, Dr. Li?

DR. LI: Just had a question for Dr. Dawisha on the Danish literature.

On one of your slides it said it excluded the implants removed in the
first three years. Do you have any idea what the rupture rate was in
those first three years?

DR. DAWISHA: I would choose not to extrapolate.

DR. LI: Okay, so \--

DR. DAWISHA: I have no idea.

DR. LI: Okay.

DR. DAWISHA: It was women who still had their implants at the time they
did the MRI study.

DR. LI: Okay. So we have no idea really what that first three years
looks like?

DR. DAWISHA: That\'s right.

DR. LI: Okay.

CHAIRMAN CHOTI: Dr. Bartoo?

DR. BARTOO: Talking about the Danish data again. You know, they
obviously have real data over time. Does your model or the different
models, have you looked at which one most closely fits the Danish model
over ten year\'s time, for example?

DR. DAWISHA: The incidence study by Holmich where they projected a five
and a ten year rupture rate, that is also based on the assumption of a
linear shape of the curve.

DR. BARTOO: So they actually extrapolated as opposed to actually having
real data?

DR. DAWISHA: That\'s right.

CHAIRMAN CHOTI: Dr. Miller?

DR. MILLER: Is there no reason \-- I mean, when I listened to the
sponsor\'s presentation it seemed like a reasonable thing to conclude
that a linear curve was a sensible one. Am I mistaken in that? When I
listen to your data I get the sense there\'s no way to know what kind of
curve it is, and the range of projections is absolutely unpredictable.
That\'s the sense I get from your data, which is not what I got from the
sponsor\'s data. And I need some assistance here trying to put in
perspective how to view these two approaches of projecting out.

Are you saying it\'s not possible to project in a meaningful way? We
must have a full ten years of MRI data to make any meaningful
projections?

DR. DAWISHA: The point we\'re trying to make is that with two data
points it\'s very difficult to extrapolate \--

DR. MILLER: I\'d say impossible.

DR. DAWISHA: Okay. To ten years when you don\'t have information on the
way the product will behave in long term. We used the examples of the
different types of models based on information that currently exists
where the linear \-- the rate that increases linearly is in electronic
devices. The rate that increases quadratically are mechanical type
devices.

Where a breast implant fits into those two ranges, we don\'t really
know. And that\'s the point that we\'re trying to make here.

CHAIRMAN CHOTI: If there are no further questions, why don\'t we break
for lunch and resume at 10 minutes after 1:00 for Panel discussion.

(Whereupon, at 12:27 p.m. the Panel adjourned, to reconvene this same
day at 1:24 p.m.)

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

1:24 p.m.

EXECUTIVE SECRETARY KRAUSE: Just a brief summary of the afternoon is
there is going to be Panel discussion of the information that the Panel
heard. There is going to be a number of questions that the FDA would
like to address to the Panel. Those questions will be discussed.
There\'s going to be approximately an hour of some public comment. And
then the FDA and the company will each be given an opportunity to
summarize if they have any last things to say. And then the Panel will
be asked to vote.

So that\'s just a quick overview of what will happen the rest of the
day.

So at this point I\'d like to turn the meeting back over to Dr. Choti.

CHAIRMAN CHOTI: Thank you, Dr. Krause.

Good afternoon.

So this begins our open Panel discussion regarding this sponsor\'s PMA.

Let starts with Dr. Blumenstein, who would like to have a discussion
regarding one of the statistical studies.

DR. BLUMENSTEIN: What I wanted to talk about was the connective tissue
disease signs and symptom analysis. This was the subject of Deficiency 4
in the January 2004 deficiency letter to Inamed from the FDA.

And the FDA requested \-- this is just a brief description of what they
requested, but they requested an analysis of the changes in connective
tissue disease signs and symptoms, additional analysis of fibromyalgia
data and correlation between connective tissue disease and these other
things with dissatisfaction complications and rupture. And finally, they
wanted a comparison of the gel connective tissue disease signs and
symptoms with saline connective tissue disease signs and symptoms.

Because of my own time just to review this, I\'m going to focus just on
the connective tissue disease signs and symptoms in the gel setting.

I just want to give you a preliminary idea of what this is about. The
analysis of signs and symptoms is quite different than an analysis based
on diagnoses. Diagnoses, obviously, we can see this very clearly. They
vary given similar signs and symptoms. In other words, apparently a
woman presenting with various constellation of signs and symptoms can
get different diagnoses. And so this raises questions about the data
that are based on diagnoses and the structure of those studies and so
forth.

So the changes in connective tissue disease signs and symptoms give us
another way of assessing what might be going on within women who receive
these implants. And this is based on observing changes over time, and it
is therefore a prospective analysis rather than a retrospective
analysis.

And the absence of a control group is limiting in these kinds of an
analysis, but it\'s not any more so than not having a control group for
the assessment of efficacy. And as you\'ll see in a minute, there are
ways to overcome these difficulties, in part.

The data that I was looking at was the Panel pack provided by the
sponsor and the FDA, the CD provided was selected, parts of the PMA
amendments in it, and last night I received a something 21 megabyte file
from the sponsor containing additional details, which took me quite a
while to download. Anyway.

So all of this is based on the fact that almost all connective tissue
disease signs and symptoms have significant increases following surgery
not connected for age. Here\'s the data that just came right out of some
of the output I was given. This is baseline and this is follow-up. And
this follow-up is of varying points in time depending on the patient. I
think it\'s the last observation they had on a patient. But as you can
see, that most of these show an upward trend. And the difficulty is
assessing whether that upward trend is something due to aging or due to
the fact that the woman got an implant.

This is just the augmentation group here. This is the data for the
augmentation group.

And as we saw in the last Panel meeting, some of the p-values that would
be associated with these changes are significant. And so, as a result of
that Panel meeting and that observation, I had some communications with
the FDA following the Panel meeting, and specifically I suggested some
modeling based on Generalized Estimating Equations. And I suggested a
class of modeling after the Panel meeting. I sent it to the FDA, the FDA
communicated that to the sponsor, and the sponsor did analyses based on
that class of models.

This suggestion was induced by the data that you just saw and it claimed
that this couldn\'t be interpreted due to the absence of a control
group. And the specific class of models that were suggested were
designed to address the issue of the absence of a control group.

The objectives of this class of GEE models is to estimate the increment
in the probability of a symptom at follow-up after correcting for aging.

The age-related connective tissue disease signs and symptoms are
estimable from the data because women in the study had a broad age
range. And the relationship between the connective tissue disease signs
and symptoms and age serves as a control, if you will. It plays the role
of a control. And the correlations between signs and symptoms at
baseline and follow-up and between signs and symptoms, different kinds
of signs and symptoms, are accounted for in the GEE modeling
methodology, which is why I was suggesting using the GEE modeling
methodology.

Basically the model \-- this is just a diagram of what the model tries
to get to. It\'s not very precise, but it gets the idea across.

That at pre-op if there is no intervention, a woman could be expected to
have a slope in the probability of the symptom that would look something
like this. And this can be estimated from the data related to the range
of ages that exist in the data. And the idea is to estimate this slope
from the data and then find out if the actual two year follow-up, for
example, data are above that which would be expected from just aging
alone having used the data to estimate this slope.

The model I proposed specifically talked about the two year follow-up
specifically. This is just a class of GEE models and there are many
variations on what can be done.

The current Inamed analysis didn\'t do global testing as I had
suggested. The global testing is a methodology whereby you can test
multiple signs and symptoms simultaneously, thereby giving you some
protection against type I errors that come about as a result of looking
at lots of different variables. It used all the follow-up data. I had
suggested using just the two year data. There was no model stated
assessment criteria \-- model assessment criteria, there was none
stated, and therefore, it\'s very difficult to understand how type I
error was controlled in the models that were presented in the documents
received.

The tables that were present were incomplete and poorly formatted. It
was very difficult to follow them. And the text was poorly organized.
And there was no real rationale given for the model chosen and the
objectives weren\'t clearly stated.

So, in summary, it was a fairly low quality presentation of these
models.

Now, Inamed chose to use data beyond year two, and I acknowledge this is
a trade-off. The inclusion broadens the inference, but it also increases
missing data. And there was also some talk about a last value carried
forward method of handling missing data, but in this case if there\'s an
increase in symptoms expected, one has to wonder about the bias of using
this because when you carry forward the last observation, you\'re not
acknowledging that there might be a trend for the missing data.

And finally, I\'d like to point out that focusing only on the two year
data is likely adequate for the purposes that we\'re about here. And
that is, just to discover if there\'s some change in the CTD signs and
symptoms that occur by two years. And by carrying the data beyond two
years introduces all these other trade-offs.

What I found was that an incorrect model was fit. The original suggested
model was based on a single follow-up assessment at a near uniform time
point, that is, specifically using just the two year data. And from what
I could gather, Inamed apparently applied the model to the last
observation and thereby reduced the model sensitivity because subjects
were not followed uniformly.

Finally, the models fit had as the increment due to implant as an
intercept, and therefore, the model kind of assumes that there\'s an
increment at baseline. Let me just illustrate that.

This is more like what the model that was fit was, it was that the
pre-op patients would have a slope like this and the post-op patients
would have a slope like this and there would be a change in the
intercept of this.

So what effectively happened was that the models that were estimated,
this intercept was estimated and this intercept was estimated and the
test that was done was a test on the intercept, not a difference of the
intercepts, which is contrasted to this model where given a specific two
year follow-up that the increment here is what is tested in the
hypothesis testing.

So the conclusions, after looking over this analysis, is that the Inamed
analysis was unimaginative, incomplete and poorly presented. The quality
of presentation didn\'t even approach that which I would have expected
for a positive efficacy result.

The model was incorrectly fit. And as a result of that, I didn\'t go on
to look in detail at some of the other things, but I\'m wondering how
valid all of those things are.

The bottom line is that while there exists data addressing this
connective tissue disease signs and symptoms there\'s no inference
possible at this time. We are still in a state of ignorance with respect
to whether there are notable changes in connective tissue disease signs
and symptoms following an implant.

CHAIRMAN CHOTI: Dr. Blumenstein, while you\'re talking about it, that\'s
based on these data that were presented by the sponsor. What about your
view of the literature regarding this question, the quality of studies,
etcetera?

DR. BLUMENSTEIN: Well, I\'m not familiar with a lot of literature,
especially in implant, where these kind of data are available. The
literature that we have is mostly based on having made a diagnosis, a
traditional case control type of study where the inclusion of a subject
in the study is based on having observed the subject with the disease
and then a look backward to see whether there\'s a difference in the
probability of having been exposed to the exposure of interest, in this
case silicone breast implant. So I don\'t think there\'s really any data
other than what we have here that addresses the issue of changes over
time in connective tissue disease signs and symptoms.

CHAIRMAN CHOTI: Let\'s open to the Panel discussion. Perhaps we can
focus on this health consequences question to start the discussion.
Comments from any Panel members? Dr. Leitch?

DR. LEITCH: Well, I think one point if we say that the two year data
would be some validity, I don\'t think we would answer the questions of
many of the people that spoke yesterday who said their symptoms came on
very late in the course of their treatment. So even if we have the two
year, would that satisfy the complaints that have been raised that these
signs and symptoms can appear quite late?

DR. BLUMENSTEIN: Well, I think that what we\'re looking for here is a
hint in the change in these connective tissue disease signs and symptoms
and distinguishing the change that\'s obviously there, distinguishing
that change from changes due to aging. And if we find that in analyzing
these data that there is something in excess of that which can be
expected from aging, then it\'s a hint to look further. This is not a
definitive analysis.

And my suggestion to stop at two years had to do with the fact that
after two years there\'s a lot of missing data. And the more missing
data you have, the more biased the analysis is going to be.

So, you know, my suggestion for the analysis had to do with assessing
something fairly immediate, something that seemed assessable from the
data that was presented to us and to see if there\'s a hint that is
worth further follow-up.

CHAIRMAN CHOTI: May I ask Dr. Dawisha, please, this question, let\'s say
systemic health consequences, your interpretation of the data both
provided by the sponsor and your understanding of the literature to help
us think about this question: What is the impact, both in the ruptured
and in the unruptured, the extracapsular or not, how can we pull
together our feeling about these data that suggests or lack of data
regarding the systemic impact of these devices?

DR. DAWISHA: Okay. Well, if we just start with the Core Study, remember
there were 25 patients with a confirmed rupture implant and 131 patients
with a confirmed intact implant. And the sponsor compared those two
groups with respect to local complications, patient satisfaction and
connective tissue disease signs and symptoms. About half of the patients
in both of those groups, confirmed rupture, confirmed intact, had not
yet had a follow-up visit after the event. So there\'s limited data from
the Core Study.

In the Adjunct Study, the sponsor compared \-- in their slides they
compared their confirmed ruptured to the entire group of patients rather
than to the confirmed intact patients. So from the Adjunct Study you can
just look. The data to take away from the Adjunct Study are the data
before the rupture had occurred and then if the patient had a follow-up
in the Adjunct Study after the rupture occurred recognizing that the
follow-up rates are about 50 percent in the Adjunct Study.

In the literature there are a lot of publications that have been
reported where they\'ve compared; there\'s open label studies, case
series studies, there\'s also studies where they\'ve taken women with
implants and compared them to women who have had breast reduction
surgery. And there\'s a publication by Fryzek where several connective
tissue disease signs and symptoms were higher in women with implants
compared to women with breast reduction surgery.

This study did not distinguish whether women had ruptured implants or
not. In fact, all of the publications to date with regard to connective
tissue disease signs and symptoms have not distinguished whether women
had ruptured implants or not, with the exception of the Holmich 2004.
And in that study they were looking at primarily local breast symptoms
rather than the connective tissue disease signs and symptoms.

CHAIRMAN CHOTI: What about the Brown study looking at extracapsular and
\--

DR. DAWISHA: Well, there were small numbers in Dr. Brown\'s study which
sort of limits the utility of those data as well. And, again, it did not
look at women after the rupture had occurred.

The Holmich 2004 study compared women with intact and woman with
ruptured implants after the rupture had occurred. And that\'s the only
publication to date that has assessed that.

CHAIRMAN CHOTI: Dr. Walker?

DR. WALKER: If I may, our data has shown no systemic illness, no
connective tissue disease above what you would expect in the general
population. But we have with us here Dr. Joseph McLaughlin, who is one
of the world\'s experts on looking at this and doing a lot of the
epidemiologic data. And I wondered if the Chairman would allow him just
to make some comments, as he\'s a huge source of information in this
area.

CHAIRMAN CHOTI: Yes. Please, go ahead.

DR. McLAUGHLIN: Good afternoon.

My name is Dr. Joseph McLaughlin. I\'m President of the International
Epidemiology \--

CHAIRMAN CHOTI: Please speak into the microphone.

DR. McLAUGHLIN: I\'m President of the International Epidemiology
Institute and Professor of Medicine in the Department of Medicine at
Vanderbilt University and a senior investigator at the Vanderbilt-Ingram
Cancer Center. And my colleagues and I have published over, by now, 70
papers on implants and health outcomes.

Now, if I could have the question repeated, I\'ll try to answer it. The
issue was connective tissue disease?

CHAIRMAN CHOTI: We\'ve heard already from the sponsor regarding their
impression about the systemic effects. But specifically if you can
address the strength of the studies, the issue of extracapsular or
rupture in general and whether an extracapsular rupture?

DR. McLAUGHLIN: Well, I believe that the literature is quite consistent
on this. There are over 20 case control and cohort studies that have
evaluated the association between connective tissue disease and silicone
breast implants. And except for the paper by Brown and a paper by
Hennekens which was then corrected after they did a medical record
review to show that there was no excess, there were only two papers,
actually one now, that shows an excess of connective tissue disease of
any sort.

So in my view the literature is quite consistent and compelling that
there are no long term adverse effects with regard to connective tissue
disease among women with breast implants.

CHAIRMAN CHOTI: Dr. Callahan?

DR. CALLAHAN: Are all these studies based on diagnosis and not signs and
symptoms?

DR. McLAUGHLIN: Our studies have signs and symptoms and diagnoses,
hospital based diagnoses and outpatient based diagnoses.

CHAIRMAN CHOTI: Dr. Miller?

DR. MILLER: Yes. Could you comment on the conclusions from the Institute
of Medicine review, and specifically in this issue of connective tissue
diseases, if I could even read from it, they said there\'s no
association. In fact, the evidence was so strong that they said there
was no justification for the use of resources inferring their
epidemiologic exploration of an association. I mean, could you comment
on that? That\'s a very strong statement in my mind. This should be laid
to rest, in my opinion.

DR. McLAUGHLIN: Yes. It is a strong statement, but similar statements
have been made by other organizations, the United Kingdom Review Panel,
Judge Pointer\'s Science Panel, the International Agency for Research on
Cancer which addressed the cancer issue. The Netherlands also has a
report saying more or less the same thing about connective tissue
disease and other health outcomes like cancers. So there are, at least
that I\'m aware of, six major reviews by government or quasi-government
agencies more or less saying exactly what the IOM said in 1999.

DR. MILLER: Do you feel there\'s sufficient question remaining about
this despite these comments from these groups, these reputable
organizations that we need to continue to study this?

DR. McLAUGHLIN: Well, first, scientifically, science is always
open-ended. Things could change.

DR. MILLER: Well, of course. I mean \--

DR. McLAUGHLIN: But as it stands now, I think it\'s a settled issue.
There is no credible or compelling evidence that breast implants cause
connective tissue disease or cause cancer, for that \-- or any other
serious illness.

CHAIRMAN CHOTI: Thank you.

Yes, Dr. Blumenstein?

DR. BLUMENSTEIN: Yes. Really, I think it\'s extremely important that we
keep in mind that there are two different kinds of analyses that we\'re
talking about here. One is an analysis based on making a diagnosis. The
other is an analysis of prospective data looking for whether changes in
the symptoms that aren\'t necessarily diagnosed as being a specific
disease, whether those changes in symptoms are something that are in
excess of that which can be expected from aging alone.

The fact is that we do not have an analysis of the data that exists. All
we have is a flapping of hands saying that it can\'t be analyzed because
there\'s no control group. It can be analyzed, but it hasn\'t been on
the symptoms.

CHAIRMAN CHOTI: Dr. Callahan?

DR. CALLAHAN: I just wanted to clarify when the sponsor says that in
these data it\'s not in excess of the general population, are you
comparing to the general population or to a population that\'s matched
for your study? Because the data are quite broad, you know, all across
the world, that connective tissue disease, the prevalence is much higher
in individuals with a lower SES, and this population is a much higher
SES than the general population.

DR. McLAUGHLIN: In our studies in Scandinavia we used multiple control
groups. It depends on the study. We used breast reduction patients, we
used patients who had other forms of plastic surgery. And we also used
the general population. So, we had multiple comparisons.

DR. WALKER: And we made our comparisons against those same groups, and
we don\'t see anything that is higher than any of those populations \--

DR. CALLAHAN: But for clarification, when you make the general
population, you\'re saying a general population \--

DR. WALKER: A general population.

DR. CALLAHAN: \-- not an SES matched population?

DR. WALKER: However, we did look and compare them to the controls that
were used in the different Danish studies and worked with Dr.
McLaughlin\'s group on that, and we still don\'t see any thing.

I also would like to point out that signs and symptoms aren\'t a
diagnosis. And you can\'t really make a direct one-to-one correlation
from signs and symptoms in a diagnosis of connective tissue disease.

CHAIRMAN CHOTI: Thank you. Dr. Newburger?

DR. NEWBURGER: I\'m sorry, Dr. McLaughlin, I\'m looking at your 2004
paper here. And, admittedly, my knowledge of statistics is suboptimal.
But the way I\'m reading this there is certainly a marked increase in
joint pain and/or swelling and/or stiffness that lasts for more than
three months compared to the population controls, as well as skin rash
and white fingers and toes. The self-reported symptoms. And they are
also somewhat higher than in the breast reduction population as well as
the general population controls. And, of course, fatigue.

Now these are self-reported, and I imagine that these were self-reported
long after the surgery. To what would you attribute these differences
then? Or do you feel they\'re just not significant?

DR. McLAUGHLIN: The title of the paper, please?

DR. NEWBURGER: The title of this paper is Long Term Health Status of
Danish Women With Silicone Breast Implants.

DR. McLAUGHLIN: Oh, the Breiting paper. Is that the first author,
Breiting?

DR. NEWBURGER: Yes.

DR. McLAUGHLIN: Yes. That\'s an interesting paper. It\'s the longest
study cohort in the history breast implants. The average follow-up of
that study was 19 years with some women having implants up to 35 years.
And there were some symptom differences, but our conclusion was, and the
conclusion of Dr. Breiting and the other surgeons who were involved was
that overall they did not reflect much clinical significance and there
were not major impairments in the lives of these woman.

And it\'s hard to piece out the effect of age here, as Dr. Blumenstein
was suggesting. I mean, connective tissue diseases in general or what is
it, eight or nine to one in terms of women to men. So it\'s a common
problem. And the symptoms related to that are relatively common as women
age.

DR. NEWBURGER: But the population controls didn\'t age?

DR. McLAUGHLIN: Well, they did. I\'m not sure how many of those \-- are
they all significantly different or just elevated?

DR. NEWBURGER: A few of them are significantly different.

DR. McLAUGHLIN: Here\'s a slide that will describe the study. As I
suggested, it is the longest follow-up study to date of any breast
implant cohort. It was an average of 19 years and up to 35 years. Women
with breast implants were compared with women who had undergone breast
reduction and with women in the general population for 23 diseases,
conditions, or symptoms.

Compared with women who had breast reduction, the only statistically
significant finding was increased reporting of breast pain among women
with implants. Fatigue, cognitive symptoms and white fingers/toes were
significantly elevated only when compared with women in the general
population, not when compared with the more relevant breast reduction
controls since they both underwent cosmetic procedures. So you\'re
basically getting the exposed group and the controlled group from the
same source population. In epidemiology that\'s an important issue.

CHAIRMAN CHOTI: Yes, Dr. Doyle?

DR. DOYLE: Just sort of coming at it from a consumer point of view,
you\'re talking about the diagnosed diseases. And it seems to me that
I\'m hearing Brent talking about the signs and symptoms. And as a
patient I have had symptoms that have not been diagnosed as a disease,
but that doesn\'t make them any less meaningful to me. So I\'m really
concerned about \-- I think the point that he\'s making is that you\'re
talking diagnosed disease and he\'s talking about signs and symptoms
that women have.

DR. McLAUGHLIN: That\'s true. Aa mentioned by my colleague in the FDA,
Dr. Fryzek and I and our Swedish colleagues looked at signs and symptoms
and tried to make a comparison and did various statistics techniques to
try to see if there is any kind of clustering or set of symptoms that
may differentiate women with implants from the control group. And we
couldn\'t find any.

And we also did a number of studies and there were a number of studies
in the literature looking at the so called undifferentiated connective
tissue disease, which is the more vague disease outcome or health
outcome. And the literature is pretty uniform there. I have a series of
slides if you want to see them.

For the undefined connective tissue disease, women with implants report
a multitude of symptoms. There\'s a lack of specificity, no identifiable
cluster of symptoms indicative of a specific atypical disease; there\'s
no specific pattern of inflammatory rheumatic disorders or soft tissue
complaints, and there\'s higher rates of hospitalization both before and
after implant surgery in these women.

And we did a review of this issue last year, my colleague Loren Lipworth
and I, and our conclusion was there is no evidence of a higher frequency
of undefined connective tissue disease among women with cosmetic breast
implants or of a rheumatic symptom profile unique to these women and/or
indicative of a specific atypical connective tissue disease. So we
investigated that on our own, a half a dozen studies. And at least
another half a dozen by other people.

CHAIRMAN CHOTI: Thank you.

Open Panel discussion. Yes, Dr. Manno?

DR. MANNO: When I was looking at the data that was sent to us, I looked
at the case reports of, I think it was 90 some devices that failed. When
I looked at these, they started out with the history of the patient,
then the patient had the implant and then they had signs and symptoms
again. And it seemed to me that some of the same things that were
occurring after the implant were also there before the implant. But I
don\'t know if there\'s any way that one could make an objective measure
rather than a subjective measure.

I\'m thinking, for example, what was up here a minute ago with fatigue.
I don\'t think we have a handle on that. But there are things that are
similar that these people reported prior to surgery that are consistent
with the connective tissue disease.

CHAIRMAN CHOTI: Other questions from the Panel? Yes, Dr. LoCicero?

DR. LoCICERO: I\'d like to go back to the issue of the device, and there
is clearly a difference in the way that the data is being presented. And
I had asked the sponsor to recalculate and display the data. If they
have that, I\'d like to see it.

DR. WALKER: I keep getting in this gentleman\'s way.

I do have that data. Could I have the Kaplan-Meier? All right. This is
the Kaplan-Meier data that you requested. As you can see, it\'s a
relatively flat line at the top with a 97.5 percent. This is, again,
from the Core Study.

I\'m going to now expand that so that you can see it more clearly. So
now I\'ve just taken the top ten percent so you can see that 2.5 percent
and what the shape of the curve looks like. And this is the data, I
believe, that you requested.

DR. LoCICERO: Right. I have some follow-up questions.

CHAIRMAN CHOTI: Yes, please.

DR. LoCICERO: Now a lot of that in the first couple of years, 46
percent, I guess, if I remember correctly, is related to device 153. And
that\'s a sizeable amount, as far as we can tell. I understand the data
is pooled.

You, the sponsor, have said that this device has a problem. Do you have
an alternative device in manufacture now?

DR. WALKER: I want to correct first, the 46 percent, those were of the
retrieved implants \--

DR. LoCICERO: Correct.

DR. WALKER: ?- the failure was the posterior \--

DR. LoCICERO: Of the failures?

DR. WALKER: Of the failures. We have \--

DR. LoCICERO: Forty-six percent were 153.

DR. WALKER: Yes. Thank you. And I appreciate the opportunity, actually,
to clarify this.

Our engineers have made design changes and we have submitted that to the
FDA. It is not part of the PMA.

Actually, I\'m going to let JoAnn Kuhne give you the regulatory details
so that you know exactly where we\'re at with the FDA on that. And we
appreciate the opportunity to clarify that.

MS. KUHNE: Yes. We\'ve submitted that design change to FDA as a
modification to the existing 153. The FDA had some questions, and we are
currently addressing those questions with the FDA in terms of providing
them with additional information, which we have not yet provided back to
them.

DR. LoCICERO: Okay. Question for the FDA. We are to rule or give you
recommendations today based upon the current 153 with the data that was
presented today?

DR. PROVOST: You should base your recommendations on the data that\'s
contained in the PMA, and that does include the Style 153 device.

The sponsor may propose to modify that device, but the data that we have
is on the existing device, and so that\'s what you should base your
recommendation on.

DR. LoCICERO: Okay. Now we\'ve seen the curve on the survival of the
device. Another way that we present data in cancer is time to
recurrence. Do you have a time to failure?

DR. WALKER: I\'m going to bring that slide up for you.

I don\'t know that I have that exact data for you. I can show you, this
is not exactly what you asked for. If you wanted a second failure, the
revision cohort gives you what a second failure would be, potentially
that these patients have had a revision, but they don\'t necessarily
have a revision secondary to a rupture. So I don\'t have that data
available for you in the form you asked. We can, again, calculate that.

DR. LoCICERO: Okay. This might be important for the plastic surgeon in
terms of telling a patient when they can expect the device to fail?

DR. WALKER: Rather than the way we\'ve presented it is that you could
say they\'re 97 percent \-- 97.5 wouldn\'t be ruptured in this amount of
time or 2.5 \--

DR. LoCICERO: What is the median survival? What is the median survival
rate of the device?

DR. WALKER: In time? I can\'t give you that exact number. That is
something that we haven\'t calculated, but certainly we can. That\'s a
calculation that can be made.

DR. LoCICERO: Yes. Since you opened a can of worms with the Kaplan-Meier
curve, all of these come up.

DR. WALKER: Yes.

CHAIRMAN CHOTI: Yes, Dr. Bartoo?

DR. BARTOO: While we\'re on the subject of rupture rates, I think there
is still some confusion amongst the Panel in terms of how you got to
your 2.5 number, whether or not false positives were included in that or
not. So could you just sort of walk us through that one more time?

DR. WALKER: I sure can. All right. I\'ve given you an overall projected
rupture rate of 14 percent. This is the Core Study, and the only rate
where we predict, the only data that we do the prediction from is the
Core Study because it includes both silent and symptomatic ruptures.

So the way those numbers are calculated is first we calculate or get a
number for systematic ruptures. Those are in all implants, all patients.

Then we have a silent rupture, which is 30 percent of the patients,
that\'s the MRI cohort. Now we assume that that MRI cohort, which is
distributed across revision, augmentation and reconstruction groups is
representative of the entire population. So then we apply that across
the entire study population.

We use that number along with so the assumed salient rupture rate along
with the systematic rupture rate which is achieved for every patient,
you know across the study, and we use that in calculating the
Kaplan-Meier rate.

That data has given us a determination of a constant yearly rate of 1.4
percent.

I will tell you that we included all suspected ruptures. So the 36
percent that we think is false positive, all the estimates that you saw
today include that number. We did not eliminate the number. This is the
worst case scenario and it is the worst extrapolation that we could do.
We did not take that number out of our calculations.

So we\'ve taken, and we\'ve assumed a constant rate of 1.4 percent. And
this constant rate is based upon what we saw in the surveillance data,
what we\'ve seen in our saline data, what we saw on real empiric data
over ten years from our Style 153 and over five years in our adjunct
data. So those all have constant rates of failure or hazard across that
time. So that\'s what we think is the best estimate of a rupture rate,
and it is an estimate, but we think it\'s the best assumption that can
be made under these circumstances.

CHAIRMAN CHOTI: May I ask a question to Dr. Spear, if I could?

DR. SPEAR: Yes.

CHAIRMAN CHOTI: What is your current recommendation regarding screening
for women? Your patients, lt\'s say, that either participate in the
studies or if this device was approved, specifically MRI?

DR. SPEAR: Well, I think we recognize that as radiological tests go, MRI
is the most useful. And for those of us who do a lot of breast surgery
it\'s becoming more and more commonly used for breast screening for
breast cancer as well, at least for diagnostic purposes.

I think the position of the sponsor and also of the American Society of
Plastic Surgeons is that the proper thing to do is for patients to be
screened, as any other adult woman would be screened for breast cancer,
but also screened by someone familiar with breast implants.

Based upon our survey data of the plastic surgeons, the feeling was that
somewhere around six to ten years would be the right time to consider an
MRI if you were concerned about the possibility of silent rupture. I
think the sponsor has recommended every year or two based upon a
physician\'s recommendation. I think realistically we\'re probably
looking more like six to ten years out would be the time to consider it.

The thing that as a clinician thinking about this issue, between now and
ten years from now we\'re going to have a lot more data from the Core
Study. I think we can give patients much more informed recommendations
about what kind of screening they should have based upon the risk of the
device.

And I just want to correct one thing from Dr. LoCicero. The 46 percent
failures that were 153s were in the retrieval analysis. The Core numbers
are actually probably higher. The percentage of Core patients with 153
failures is probably actually higher. I don\'t know the exact number
right off hand. But that was a whole retrieval analysis group.

So when you look at the Core Study, in fact there were very few failures
that were not the 153 device. Almost all of them were the 153.

But I think as a surgeon or clinician, I still think the first test is
the doctor seeing you before you get an x-ray.

CHAIRMAN CHOTI: But I mean we\'re learning that one out of five \-- five
out of six of the ruptures are silent detected by MRI. So it sounds
like, I mean you are recommending routine MRI screening in women who
have implants?

DR. SPEAR: Well, you have to bear in mind a couple of other things. One
is that we haven\'t seen significant sequelae with these devices even
from silent rupture. If you look at our study, we had one in 20,000
extracapsular ruptures. That\'s an incredibly low rate in terms of
observed extracapsular ruptures, and we haven\'t seen any systemic
medical problems even from patients who have silicone outside of the
capsule.

So I think in clinical practice surgeons will use MRIs as concerns
arise, as there are physical changes in the patient. I don\'t see
honestly as a screening tool in patients with implants less than five
years of age, personally. I think it will be unlikely that surgeons will
do that. I think as they get older, at eight or ten years, we might
consider doing it. I think as this data matures, I mean these same Core
patients will be studied at nine years with an MRI. If we find out what
the failure rate is at nine years, we can have a rational discussion
with the patient and say well based upon the data, the risk of a silent
rupture at nine years is X. Therefore, let\'s decide whether or not we
should or we should not get an MRI. But remember, again, we don\'t have
any evidence of any systemic illnesses associated even with
extracapsular rupture.

We see very few extracapsular ruptures with these Class III devices for
two reasons: (1) they\'re more durable devices with more cohesive gel,
and; (2) probably just as importantly, surgeons have learned better how
to handle these devices. In other words, we\'re not doing close
capsulotomies which I think was a major contributent to extracapsular
rupture with the earlier generation implants.

CHAIRMAN CHOTI: Which is still, even thought I think we heard yesterday,
the survey among plastic surgeons is that 50 percent of plastic surgeons
feel that routine MRI screening should be done in these patients. Now,
it may be after six years, for example.

DR. SPEAR: That was the number. I think the mean for the group for the
group was 6.9 years for routine follow-up. But remember between now and
when these devices ?- if they go on the market, seven years from now
we\'ll have seven years more mature data to make more rational
decisions.

DR. WALKER: Now I would like to add one other point to Dr. LoCicero\'s
question about the 153 and where we sit with the FDA. This is a double
lumen device and it is very unique, and we\'ve been studying it for ten
years. Inamed now has a fourth generation device which we are working
with the PMA with the FDA on which are all shaped implants that are
different which we consider our next move in this direction. So the 153
is the third generation device, but a more natural appearing with the
sloped shape implant which we call our cohesive gel line is coming in
the future.

CHAIRMAN CHOTI: A follow-up question first to Dr. Spear again. Sorry.

So you have a patient, she\'s asymptomatic and an MRI scan shows an
intracapsular rupture. What do you recommend to her? Should the implant
be removed?

DR. SPEAR: Well, I have to speak for my personal feelings and also for
the sponsor on this one. I think the best recommendation is for that
device to be removed and/or replaced. I personally don\'t think it\'s
proper to leave a patient with a broken device, even if we think the
risk is low of any problems with that broken device because
statistically, although an intact device is a very safe device, once
it\'s broken the level of safety goes down somewhat. And the best
analogy I can use is we were wear seatbelts and we have a shoulder strap
and it\'s like losing one of the safety features, like taking a shoulder
strap off. So it becomes a less safe situation once the implant is no
longer intact.

So even though we think the risk is small, I think once the device is no
longer intact, it should be replaced, and the sponsor, I know, has that
in its labeling.

CHAIRMAN CHOTI: But yet if we\'re confident that a ruptured implant has
no or virtually no consequences if it\'s asymptomatic and we haven\'t
heard what the salvage rate, that is if it becomes asymptotic to
systematic that we haven\'t lost anything, if you will, as far as both
local complications and systemic complication, then why subject that
woman to another operation which has risks?

DR. SPEAR: Well, we know statistically from the Danish study that there
is some degree of propagation from intracapsular to extracapsular
rupture. I think logically that makes sense. I think if you think about
the risk as being risk primarily from trauma; that if a patient who has
a broken implant then has trauma, they have one less layer of
protection. In other words, the shell of the device provides a
protection in the case of trauma whether it\'s from an automobile
accident or a fall. So once you\'ve lost that layer of protection, now
the only layer of protection is the scar capsular, which is one less
layer.

So in my opinion the safest thing to do in terms of weighing the risk of
anesthesia versus the risk of a broken device, is for the surgeon to
recommend that the device be replaced.

Now, not all patients will accept that advice, and some patients I know
are walking around with diagnosed broken implants. But my personal
opinion and I think the position of the organized plastic surgery
societies will be that if you have a broken device, you should have it
replaced.

CHAIRMAN CHOTI: Dr. Blumenstein?

DR. BLUMENSTEIN: I\'m looking here at the protocol. And I\'m looking at
the measures that you say are going to constitute your evidence of
efficacy, and you measure change in bra size, I think, patient
satisfaction and quality of life. And then further in the protocol you
compute your sensitivity, the minimum detectable difference and so
forth. And now I\'m going to focus just on the quality of life scales
and subscales.

And what I\'d like to ask is did you meet your efficacy evidence for
your quality of life outcomes?

DR. WALKER: My statistician, Maggi Beckstrand, will answer that question
for you.

MS. BECKSTRAND: Like you mentioned, there was a variety of ways to
determine if the device was effective, and the first one was increase in
bra size post-implantation, which we don\'t have a slide on, but
patients did increase their bra size post-implantation.

Oh, we do have a slide. I\'m sorry.

So significant increase post-implantation.

Another measure was our satisfaction, patient satisfaction with their
breast shape post-implantation. Increased significantly after
implantation.

And as you saw from our Core presentation, just general satisfaction
with their implants at follow-up visit with their physicians was high
after implantation.

DR. WALKER: Did you want to also look at the quality of life? We looked
at that this morning. These are quality of life satisfaction. This is
looking just at the augmentation group. They had statistically
significant improvements in their satisfaction with their breasts, how
well their breasts matched, satisfaction with breast shape, breast size,
and breast feel.

DR. BLUMENSTEIN: But those are the things that you just showed. I\'m
talking about the quality of life scores that are listed in the
protocol?

DR. WALKER: Which ones, specific?

DR. BLUMENSTEIN: Well, there\'s a long list of them. Do you want me to
\--

DR. WALKER: Right.

CHAIRMAN CHOTI: Can you speak into the microphone.

DR. BLUMENSTEIN: Yes. It\'s the MS-20 physical functioning, MS-20 role
functioning.

DR. WALKER: Okay.

DR. BLUMENSTEIN: MOS-20 \-- social functioning. MOS-20 mental health.
MOS-20 health perceptions. MOS-20 pain. SF-36 role limitations due to
physical health problems. SF-36 physical functioning. SF-36 bodily pain
and so on.

DR. WALKER: I can go through all of those if that\'s what you\'d like.
Here\'s the MOS-20. We did have a slight decrease that was statistically
significant for health perceptions and mental health. However, if you
look at those numbers, it\'s 83 versus 81.5 at one year. That is
they\'re still above what are considered often baseline. I don\'t know
that that\'s clinically meaningful, although that is statistically
significant.

Same thing with health perception, 89.5 versus a baseline of 92.4.

In studies such as this it\'s common that you have a ceiling effect and
then a regression to the mean with time. If you\'d like to see the SF-36
this is now we\'re showing here the reconstruction population. There was
a statistically significant increase in the role of limitations due to
physical health problems. So there is an improvement, again, above
baseline norms. There were no changes in the other measures on this
measure.

Looking at quality of life scores for the reconstruction population,
there was a no change in several but in the Rowland Expectation there is
an improvement in social relations, which was statistically significant.
1.7 versus 1.3.

There was a decrease 3.3 versus 2.9 in the Rowland Expectation of
improved daily living.

Are there others? Here\'s body self-esteem. This is in the
reconstruction group. There were no changes in the body self-esteem one
year later that were statistically significant.

Those are the only quality of life ones that I have prepared. I could go
through the different cohorts, but they all are essentially the same.
For instance, this is the SF-36 for the revision population showing
similar results, that you do have some decreases. Again, the decreases
are statistically significant, but within \-- question whether they\'re
clinically significant and again above the population norms.

DR. BLUMENSTEIN: So were these tests adjusted for multiple testing?

DR. WALKER: Yes.

DR. BLUMENSTEIN: And did you have as a criterion superiority or
non-inferiority?

DR. WALKER: The statistician will answer that question directly.

MS. BECKSTRAND: Just difference from baseline.

DR. BLUMENSTEIN: And back to my original very simple question: before
the whole world did you show efficacy with respect to quality of life
based on the data that you presented?

MS. BECKSTRAND: Yes, we did.

CHAIRMAN CHOTI: All right. Dr. Li?

DR. LI: I\'d just like to kind of, and I hope not to beat a dead horse
here, go back to this issue of the mechanism for rupture. Would it be
okay if I showed some of the pictures that you had submitted to us? I
could describe it verbally or I could make it a little more clear if I
show the picture?

DR. WALKER: I\'ll defer to you and the Chairman on that.

CHAIRMAN CHOTI: Why don\'t you go ahead and show it.

DR. LI: Okay.

CHAIRMAN CHOTI: Do we have them up?

DR. LI: Yes. Is it set up?

And while he\'s doing it, the reason I hope I\'m not beating a dead
horse here, I think the mechanism for the ruptures is important for a
couple of reasons. One, it\'s being proposed that at least half of the
ruptures are due to a scalpel or some surgical instrument that\'s
causing the problem. Also, the mechanism is important and I think it
relates to this issue of how you predict what the future rupture rate
will be. In the absence of knowing what the cause is of the rupture, I
think it\'s a little difficult to figure out if it\'s going to slow down
or get faster or disappear with time.

That being said, I don\'t know of any device, medical or otherwise,
where the longer you use it the incident of failure doesn\'t go up; I
mean your car, anything. But it would not make sense that \-- it just
makes sense, actually, that the longer something goes on the more
failures you\'re going to get. I mean, I don\'t know of anything that\'s
contrary to that.

So it might not be exponential, but there would be no surprise \-- for
instances, your car is a lot more problem at 15 years than it did during
the first year. There\'s nothing wrong the car. It\'s just use and
that\'s what happens.

And so the third reason why I address this is that the implant itself
has not been implicated in any of the failure rates, right? I mean, you
talk about folds, you\'re talking about things that are done to the
implant but the implant itself has really not been implicated as playing
any role in the failure. So the question is could the implant \-- are
there features of the implant that could possibly play a role in the
failure?

This is a video that they\'ve provided. And this actually is a very
interesting video.

Actually, before you play it, for those of you who are not used to
looking at retrievables, which is probably everybody, don\'t be too
alarmed at what you see here. Because we\'re looking very, very closely.
We\'re looking at thousands of times magnification at a very small area.
So the whole idea of looking at retrievables is really not to assess a
blame or damn the implant. We\'re looking for reasons of why the implant
could be successful or fail.

It could be that implants that last 20 and 30 years will look exactly
like this in the cross section. So I\'m using these photos not to damn
the implant, but to point out things that we should consider as possibly
contributing to the device. Okay. So I just want to make that clear.

So with that disclaimer. Can you click on the video to make this go?

They actually did some very interesting tests. And one of the things is
puncture and leakage.

Oh, there\'s no video there. Okay. Let me back up. Let me explain what
they did on that.

They took a pushpin, and they poked it into the side of the implant so
the pin punctured the wall of the implant. And then they proceeded to
load this implant between those two plates at a force much larger than
one would normally consider in a patient. And what they found over tens
of thousands, perhaps hundreds of thousands of cycles even when they put
that pin in there, there was no breakage. Okay. So that actually seems
like it\'s pretty good, and that\'s actually a tribute to the viscosity
of the gel that it just doesn\'t come squirting out. Because if it was a
saline implant, you poked that hole in it, it would just all coming
running out.

The bad news is because nothing happened there, it could be that a lot
of your retrieveables that are unruptured actually have holes in them
that could progress to be something else. So this goes back to a plea to
look at unruptured implants for features that might be there.

The other thing is although the silicone doesn\'t come squirting out
here, is there a higher bleed rate, for instance? Are there more low
molecular weight things coming out? Is there more platinum coming out
because of this small hole? And the answer is we don\'t know. But the
good news is even if you poke a hole in it, they don\'t bust.

This is a cross section of one of the implants. What I want you to point
out here, this little dot here, this is the thickness of the implant.
We\'re looking at the edge of a broken implant. And if you look at right
here, there\'s a little dot there. That dot there is probably an
imperfection in the material.

It\'s impossible for anybody to make anything perfect. You know, those
of you who are wearing diamonds, you\'ve got flaws in your diamond.
It\'s impossible to make a perfect implant.

So not surprisingly if you do cross sections of these implants, you will
find imperfections like this. And if you notice there you get this V
shape and it\'s pretty much starting from where that particle is. So a
particle in typical kind of plastic fracture mechanics is the source of
the tear or a crack. So the question is could these happen?

And it\'s a little unusual; they also did the same test where they took
a scalpel instead of a needle and kind of put a nick in the implant.
And, again, when they cycle at a high load for thousands of cycles, it
didn\'t break. So the nick alone doesn\'t seem to be able to cause a
fracture. So could it be, though, a nick in the presence of one of these
that causes a fracture? But the issue is the material has something to
do with it.

Next slide, please.

Here\'s another cross section. And there are supposed to be three layers
here. And I guess it\'s a little hard to tell which is the inside and
which is the outside. But you can see the one, two, three layers, but
the middle layer looks awfully thin. So I don\'t know if that\'s
supposed to be the barrier layer, but if it is, it\'s supposed to be
substantially thicker than that, right? So the question is, is that a
variation or is that just a trick of microscopy? The question is you
don\'t know. Because you see on other things coming, especially in the
textured implants, where there is a variation in layer thickness. So
could this be a variation in the barrier layer?

Next. You just want to stand there, because I\'m going to go kind of
quickly. I didn\'t mean to belabor this. Next, please. Keep going. One
more.

Here is another implant. This is, I believe, on the radius of an
implant. And this actually looks like something that could be a scalpel
cut. But I will say having cut elastomers in the lab, you really have to
kind of exert some force on this to make that sharp of a cut. So it\'s a
little puzzling how this could be done even by accident by surgeon.
Because he would have to basically poke it in there and kind of work it
along, actually, to make that cut. So it might be surgically implanted,
but someone had to work at it.

Next, please. Next.

Okay. Here is a textured implant, and again you can see over here the
layer of the texture is substantially thicker than the layer here,
right? So the question is what does that do? Is that a section where it
could bleed through there or what?

Dr. Brandon believes that these striations are indicative of a knife
cut, but this is the texture layers on the outside. So if these
striations are signs of a cut, this thing somehow was cut from the
inside not the outside. So one question is whether or not the present
striations, how good that is as actual indication of a scalpel cut.

Next.

Again, here\'s a variation in the thickness of the texture.

Next.

Okay. This again, this is upside down. This is the outside, this is the
inside. But see this kind of cone of lines? This would be indicative of
a crack that starts here and as you pull on it, it\'s very common to
have this kind of fracture surface. But, again, this is indicative of a
fracture from the inside out, not the outside in.

So let me just stop there and not belabor the point. But these are great
photos, and they \-- a couple of things. They don\'t really say to me as
we\'ve talked before that a scalpel was involved. And, again, but you
said you have other photos that may show that, and I\'d like to see
those.

But it also points out that there are features in the implant that could
contribute to the failure of the device. And these things would be time
dependent. In other words, it would take a while for the stress to get
down to a particle or to get down to a layer to cause these problems.

Actually, one more thing. There\'s one more feature I want show. One
more. Go again. One more. One more. Okay.

Here is what actually looks to be a delamination between the layers.
Right? And, again, it\'s kind of outside in but here it\'s actually two
layers coming apart. So it\'s possible for these three layers, although
it\'s difficult to imagine how it would happen the way they\'re
manufactured, clearly delamination between the layers can occur, and
maybe those are the cases where platinum levels are high or whatever. I
mean, this is all conjecture at this point. But the whole point here is
that there are implant features that really haven\'t been discussed at
any length.

I\'ll stop there. Thank you.

CHAIRMAN CHOTI: All right, if there are no \--

DR. WALKER: Thank you for that.

DR. MILLER: I have one more question.

CHAIRMAN CHOTI: Question, Dr. Miller?

DR. MILLER: Yes. One of the things that we\'re very concerned about is
projecting the time to rupture. And we\'ve had two very different
portrayals of how to arrive at that number given really an incomplete
set of information on that. The FDA has presented a calculation that
good rationale is made for yields two data points and really makes it
very difficult to make any projections on the life of the implant.

And you presented a method for doing this calculation that makes some
assumptions and gives some meaningful information. I\'m just wondering
if you could comment on your approach and maybe justify why you feel
it\'s a valid approach to understanding this?

DR. WALKER: Our approach is based on empiric data. We based our constant
curve on data that we have out to ten years; surveillance, saline, Style
153, the Adjunct Study. And they all have a constant rate of failure
over time.

I will say that the FDA presented four different options, and our
constant rate and their constant rate are very similar. There are just
some slight numbers that are different. But their constant rate and
Inamed\'s constant rate are very similar. They made theirs on two
points, we made ours on several data points, and I can show you that in
this slide here. This is the slide that I showed you with Inamed\'s data
as well as the FDA\'s data.

Their lowest gray line there and our yellow hatch line are very similar,
there\'s just a difference there in the calculations based on the two
points versus all the data.

So not all of their curves are disparate to our curve. We agree that the
constant rate of change. So if you agree with our assumption, which is
based on all the other data and all the other lines below that, you
could say that we agree.

Dr. Spear would like to add something to that question if we can allow
him.

DR. SPEAR: Okay. So why do the FDA\'s curves and our curves look
different? I\'m trying to understand why they could arrive at such a
dramatically different prediction than we did, and here\'s my
explanation.

They looked at one study and two points. From one study and two points
you can make any curve you want. What we did is we looked at all of the
data. We looked at the Core silicone gel data, we looked at the saline
Core data, we looked at the surveillance data of over a million saline
implants. We looked at the retrieval data. We looked at the Scandinavian
data, which by the way did not assume a linear curve, it plotted linear
data points based upon the evidence. Every single other piece of
evidence out there points to something which looks like a reasonably
constant rate, not a perfectly rate constant rate, a reasonably constant
rate.

The reason the FDA was able to give three or four different possible
curves, they looked at one study and two points. We\'re looking at the
worldwide experience of data associated with devices like this. When you
look at the worldwide experience, an exponential curve is not even a
rational prediction out to ten years.

I agree with Dr. Li. The longer things are around, nobody can predict
the curve at 30 or 40 years. I don\'t care what kind of data you have at
20 years. But at ten years, which is an awfully long time in the life of
a device or in the life of a person, we can predict for you I think with
a very high level of confidence that this is going to be a reasonably
constant rate.

And I\'d like to disagree with the FDA since they don\'t do surgery,
that they think saline implants and silicone implants have nothing to do
with each other. They are very similar devices. They are put in the same
environment; they are done by the same surgeons; they are exposed to the
same risks and the same stresses, and the idea that they think that that
data is not relevant is preposterous to me.

Thank you.

DR. WALKER: There\'s one other piece of data or evidence that I think is
compelling when you look at this rupture rate, and that is from the
Danish study. And I would like Dr. McLaughlin to comment on that because
it is also supportive of our assumptions.

DR. McLAUGHLIN: Thank you.

I will put up a slide that shows our Danish experience, which I think
will address some of the concern about the long-term issues about
rupture rates.

This is the only published paper that has actually calculated the
incidence of rupture over time for breast implants. There is no other
study in the literature.

And what we did is we calculated a rate based on the third generation,
the generation that is most like the kinds of implants that are being
used now rather than the first and second generation. Focusing on the
third generation we calculated a rupture incidence rate of 2 percent per
year or two implant ruptures per 100 implant years.

And then we estimated out to ten years. And this is an empirically based
estimate, a piecewise exponential. We didn\'t make any assumptions. We
simply looked at the data and calculated what the rate would be at ten
years. And at ten years 83 to 85 percent of the implants would still be
intact.

Now, we did exclude the first three years, and that was brought up
earlier today, and I want to make it clear why we did that. It\'s in
order to make sure that we had enough events for the two year time
period when we did the study to calculate a somewhat robust estimate of
rupture rate. If you start with people with brand new implants and
follow them for two years, you we may not have had enough events to
calculate something properly.

So this last bullet on this slide will show you ?- let\'s assume that we
had a one percent rupture rate for years one through three, which is
actually slightly higher than the empirical rupture rate for years three
through five. At ten years then with working in a rupture rate of one
percent for the first three years, we would still wind up with an intact
proportion of 81 to 83 percent of the implants. And I think that this is
actually the only solid evidence in the literature about the long-term
life of implants done in a systematic manner.

DR. BLUMENSTEIN: This is Brent Blumenstein.

Do you have the Kaplan-Meier curve or some other representation of the
data on which you base these?

DR. McLAUGHLIN: No, we don\'t have a Kaplan-Meier curve.

DR. BLUMENSTEIN: Then how was it that you estimated these things?

DR. McLAUGHLIN: It was a piecewise exponential estimation, which is an
empirically based method without assumptions.

DR. BLUMENSTEIN: But I\'d still like to see the raw data if you have it
in some form.

DR. WALKER: Well, that\'s from the published literature. That\'s not the
company\'s data. So I\'ll have Dr. McLaughlin could follow-up.

CHAIRMAN CHOTI: Dr. Bartoo?

DR. BARTOO: I just wanted to ask what percentage of those patients
actually had the Inamed implant?

DR. McLAUGHLIN: Somewhere in the neighborhood of 25 percent of the
implants were Inamed implants.

DR. BARTOO: Okay.

DR. McLAUGHLIN: And another question may be relevant is approximately 50
percent of the implants were third generation. So when we calculated the
estimate just on the third generation, we did have enough numbers to do
that in a pretty reasonable fashion.

CHAIRMAN CHOTI: Okay. We\'ll end the general Panel discussion and move
ahead to the FDA questions if we could, please. Can we get those
projected for us?

I\'ll remind you, it\'s in Tab 2 of your memo. And there are five total
questions. We\'re going to go through one at a time and have a
discussion on them among the Panel group.

The first question is related to the rupture rate information that
we\'ve been discussing, and we\'ll have this up in a minute. But you\'ve
heard that the primary rupture rate information from Inamed\'s Core
Study involves a complete three year data and partial four year data.
And we\'ve reviewed the Adjunct Study as well. Considering the rupture
information provided in their submission and given the majority of
ruptures of silicone gel-filled breast implants are silent, please
discuss whether Inamed has adequately characterized the rupture rate and
how this rate changes over the expected lifetime of their device.

What don\'t we start with Dr. Leitch. Can you tackle that question?

DR. LEITCH: Okay. With respect to the frequency of observed
intracapsular gel and extracapsular gel and migrated gel, I think we
have the MRI study that gives a sense of how frequently rupture occurs,
and so that accounts for both the silent ruptures. And then we have the
symptomatic ruptures which are reported as well.

We have some evidence about the extracapsular gel, and I would
characterize this as gross estimate. This is not micro extracapsular
gel, but macro, which I think is the more significant type, which is why
I asked them the questions about that. Because the extracapsular gel if
it\'s of significant size, can impact mammography and also be palpable
as a mass to the patient on her self-exam. So we have some data about
that, although perhaps not as much as I would like.

With respect to migration and the destination of the migrated gel, we
don\'t have biopsies of nodes and that sort of thing. We do have two
examples where they could comment of known migration to axillary nodes
but nothing beyond that.

CHAIRMAN CHOTI: The question really focuses on do you think they\'ve
characterized the rupture rate and how the rupture rate changes over
time?

DR. LEITCH: I think that they have characterized the rupture rate and
with respect to over time, I do think that the saline data is material
to this. And so I think the curve that they have drawn looks reasonable.
And because the curve that the FDA has using that same type of
calculation is pretty similar, I think that that is a reasonable
estimate of what happens over time to ten years.

And so part of it is what do you consider the lifetime of the implant?
So I think that\'s a reasonable ten year estimate. What happens after
ten years I think we don\'t know. And that might then develop a
different curve after the ten years. But the Danish data at 16 years, I
think they had studies in the range, you know after the ten year period
of time, of anywhere from rupture rates around 25 percent at that time
period.

CHAIRMAN CHOTI: Dr. Miller?

DR. MILLER: I think the key word in this question is \"adequately.\" I
mean, if the question were has the rupture rate been characterized, I
would have to say no. Because the only way to competently know the
rupture rate would be to run a study for as long as you want to know
what the question is. But I think that taking the approach of looking at
the composite information as in the literature, to making rational and
reasonable assumptions based upon the data that has been gathered by the
sponsor, I think that an adequate characterization of the rupture rate
has been accomplished.

CHAIRMAN CHOTI: Dr. Callahan?

DR. CALLAHAN: I tend to agree with Dr. Miller. You couldn\'t really just
definitively say it\'s been captured. But I think based on the
assumptions \-- I do not know if I feel completely that \-- comfortable
with the constant being used as the estimate, and particularly in
thinking about devices and how they last over time. But I don\'t know
enough to how to compare silicone to the saline, so I\'m not sure that I
feel that \-- and it\'s certainly only ten years, even if we do estimate
with that. But I\'m not sure that it might not be more. I don\'t think
it would be to the extreme of a quadratic, but it may be more like the
linear \--

CHAIRMAN CHOTI: Let me pin you down. So do you think that the sponsor
adequately answered the question of the rupture rate and how the rupture
rate changes over the lifetime of the device?

DR. CALLAHAN: Both together, those questions?

CHAIRMAN CHOTI: I mean, to help the FDA answer that question, do you
think that the information you\'ve seen today \--

DR. CALLAHAN: Not completely.

CHAIRMAN CHOTI: Not completely. All right.

Dr. Li?

DR. LI: I think the rupture rate probably is reasonably well estimated
to as far as you\'ve measured, which is to the three point with the MRI.
And even then, there\'s some adjustments to be made with false
positives/false negatives. So we have kind of a good idea at what three
years is. But in the absence of a mechanism, I would say that a linear
estimation of the rupture rate is a best case scenario, right? I mean if
you ask me to bet did I think the failure rate at ten years was going to
be higher than five, I think I\'d take that bet. But, again, the data
doesn\'t really allow us to project out past the length of time that the
data is collected at this point in the absence of the failure mechanism.

So, I guess it\'s adequately described to \-- as long as they measured,
which is three years, but inadequate after that.

CHAIRMAN CHOTI: All right. Dr. Manno?

DR. MANNO: I think it\'s adequate, as Dr. Li said, in the short term but
not past the five years. It\'s not clear.

CHAIRMAN CHOTI: All right. Dr. LoCicero?

DR. LoCICERO: The rate has been adequately looked at. I don\'t think you
can look any better than using the MRI data, even if you strip
everything else out and just look at the MRI group, it still is pretty
adequate.

I have concerns about projecting beyond that point, particularly with
the Kaplan-Meier curve. We can put some dashed lines, but I\'m not sure
we can actually say much more than that.

And the sponsor has obscured the data by promising to change the device.

CHAIRMAN CHOTI: I\'m sorry I butchered your name, Dr. LoCicero.

Dr. Newburger?

DR. NEWBURGER: I don\'t recognize any characterization that I can feel
comfortable with beyond the three year point.

I\'m also having trouble since all of the categories are lumped
together, and I think that there\'s a very different rupture rate for
the indications.

CHAIRMAN CHOTI: Dr. Ewing?

DR. EWING: I think if \--

CHAIRMAN CHOTI: Speak more clearly so everyone can year.

DR. EWING: I think it\'s best to be predicted, that they have adequately
presented the rupture rate, at least up to ten years, particularly given
the MRI cohort and when they compared the saline implants, which is
treated exactly the same way as the clinician. You know, there\'s no
difference in how they\'re placed.

So I think they have adequately presented rupture rates to ten years.

CHAIRMAN CHOTI: To ten years.

Dr. Blumenstein?

DR. BLUMENSTEIN: Well, I think that the rupture data have been
adequately represented with respect to the limitations of the study
design. The projections beyond where the data end are very risky. And I
think that it\'s a great risk to assume that the hazard rate won\'t
change, but I don\'t how to characterize what change in the hazard rate
might occur. So I feel very uncomfortable taking the data beyond where
it is.

CHAIRMAN CHOTI: Dr. Doyle?

DR. DOYLE: I think I have trouble extrapolating from beyond the solid
data from year \-- up to year three, as the FDA pointed out, which seems
to be \-- everyone agrees is very solid data. And after that the
projected data seems to have weaknesses that we may not have talked
about.

So if you only use the solid data, then I think the point is that if you
only have two points, you could use any one of the models that was set
up with equal surety which it does not give you, I don\'t think,
anything about the rupture for the life of the device which isn\'t
really specified. That\'s the other thing; what are we talking about the
life of the device?

CHAIRMAN CHOTI: Dr. Bartoo?

DR. BARTOO: Like everyone else, I do believe that it\'s been well
characterized for the data that they do have. I do acknowledge that they
have extrapolated, of course, to the ten years, but I think their
extrapolation is fairly well supported by the Danish studies and their
other studies that do have empirical data out to ten years.

CHAIRMAN CHOTI: So that\'s the Panel discussion. Somewhat a mixed view.
Most feel that to answer question number one that has the sponsor
adequately characterized the rupture rate, I think most felt that we
were confident about the early time periods. Some had some questions
whether the linear extrapolation is adequate, and there are still some
questions among some Panel members as to what the rupture rate is for
the full lifetime of the device.

Does that meet your requirements for question number one?

DR. PROVOST: Yes, it does. Thank you.

CHAIRMAN CHOTI: Let\'s move on to question number two. This is related
to the consequences of the rupture. Please discuss whether Inamed has
adequately characterized the consequences of rupture for their devices
with regard to:

\(1\) frequency of observed intracapsular gel, extracapsular gel and
migrated gel and destination of migrated gel;

\(2\) the local health consequences;

\(3\) silent ruptures progressing to symptomatic ruptures, and;

\(4\) intracapsular rupture progressing to extracapsular ruptures.

Let\'s start with Dr. Greenburger. I\'m sorry, Newburger. It\'s been a
long day. Sorry.

DR. NEWBURGER: Iceberg, Goldberg.

I don\'t see that the frequency of observed intracapsular gel,
extracapsular gel, migrated gel and destination of these have been
characterized because of the lack of sampling local tissue. I recognize
that it may be difficult to sample an axillary node when you\'re not in
that area and you\'re doing an explantation. But it\'s not difficult to
take a sample of the capsule. And that\'s certainly important to me in
my practice where we have a patient base of over 43,000 patients and do
full body exams every day long. We will sometimes find granulomas in our
many patients who have had breast implants that they were unaware of.
And then, of course, if it\'s a case of a reconstruction, then you\'re
obligated to biopsy that to see are dealing with a cutaneous metastatic
disease or a granuloma. So it does have some significance to those of us
who see patients over the very long term.

The local health consequences, without the characterization of signs and
symptoms, I can\'t say that that\'s been assessed either.

Should I go on?

CHAIRMAN CHOTI: Yes. Just touch on each of them, if you would, please?

DR. NEWBURGER: Okay. The incidence, prevalence and timing of silent
ruptures that progress to symptomatic ruptures, well I don?t think that
was determined at all because the silent ruptures were either explanted
or not, but I didn\'t see that data. And the same for item D.

CHAIRMAN CHOTI: Dr. Ewing? Please use a microphone.

DR. EWING: In regards to the frequency of the observed intracapsular and
extracapsular gel migration, I think that the MRI cohort did a very good
job of demonstrating the type of migration that happens.

The local health consequences I think given the Danish studies and the
IOM studies, and it\'s very difficult to categorize signs and symptoms
when you\'re comparing an aging population. What is more of a closer
comparison is signs and symptoms in a cohort of patients with or without
implant with previous surgery. So I think that that\'s a very difficult
thing to nail down. But given that the previous historical data has not
shown any significant health consequences, I don\'t have any comment on
that.

The silent ruptures and the intracapsular ruptures I think would be
difficult to identify. Because the silent ruptures, how would you know
that they were silent ruptures when they become symptomatic? I mean,
that may be the occurrence of the rupture. It\'s very difficult to \--
and the same thing for the intracapsular and extracapsular rupture.

CHAIRMAN CHOTI: Dr. Blumenstein?

DR. BLUMENSTEIN: I don\'t think we have complete data on these issues
because there wasn\'t a study designed to collect these kind of data.
Some of it we have, but not all of it.

CHAIRMAN CHOTI: Dr. Doyle?

DR. DOYLE: I have nothing to add.

CHAIRMAN CHOTI: Dr. Bartoo?

DR. BARTOO: Nothing further to add.

CHAIRMAN CHOTI: Dr. Leitch?

DR. LEITCH: Again, I think the MRI gives us data about observed
intracapsular versus extracapsular gel. And my comments I\'ve already
made about the migrated gel.

With respect to local health consequences, I think those have been
presented. In terms of the systemic health consequences, which we\'ve
been discussing earlier today, I think the data from numerous studies
other than the applicant\'s give us information about the long-term
health consequences.

I think the local ones are not inconsequential, and they are concerns I
have which are with respect to having gross silicone in the parenchyma
of the breast tissue which can cause problems as were mentioned in terms
of is this recurrence of breast cancer, is it a breast cancer in a
person who has never had breast cancer, is the mass that\'s felt, is
that a problem? It has to be evaluated as well as it \-- obscuring
mammography if the silicone is outside of the implant.

With respect to progression to a symptomatic rupture, again, in this
circumstance the plan in this study was to take out implants that were
identified as being ruptured silently, so you can\'t comment on the
progression, although, again, the Danish data does speak to that issue
suggesting around 11 percent becoming symptomatic over a period of
observation before the next MRI was done.

Yes, again, this study won\'t help you with the progression because they
acted on the silent ruptures.

CHAIRMAN CHOTI: Dr. Miller?

DR. MILLER: I think as far as the observed intracapsular and
extracapsular gel, I think our knowledge is incomplete on that but I
think we have some idea based upon the MRI cohort particularly, and plus
the composite of other studies in the literature.

As far as migrated gel and the destination of that gel, I think we still
know very little about that.

As far as the local health consequences, I think those are pretty
clearly delineated, not only by this data prepared by the sponsor but
just in general.

As far as C&D, we don\'t really know very much about the natural history
of a silent rupture or of an intracapsular rupture because once we
discover these things, we don\'t allow them to run their course.

CHAIRMAN CHOTI: Dr. Callahan?

DR. CALLAHAN: I agree that C&D we don\'t have information because of
just the design. And that it\'s pretty adequate information about A, the
frequency of the intracapsular gel.

I think the local health consequences if you ask it in reference to
their device, are not \-- we don\'t have as much information. I mean,
the other data, I think they said the Danish data was like 25 percent
had their device. So you can\'t just say it\'s all the other data are
relevant to their device.

CHAIRMAN CHOTI: Dr. Li?

DR. LI: I don\'t really have anything to add other than I\'m extremely
uncomfortable using the Danish data, especially on clinical type of
related issues as projection of how these implants do as the devices
were from different manufacturers, the chemistry of the gels were
different, failure mechanisms, perhaps, were different. So although the
Danish study perhaps gives us some indication, I think it\'s extremely
risky to say that those same numbers would apply here.

CHAIRMAN CHOTI: Dr. Manno?

DR. MANNO: The only one that I have \--

CHAIRMAN CHOTI: Would you please use the microphone?

DR. MANNO: The only one that I have anything to add that\'s different
would be on the local health consequences of the patient with the
ruptured implants.

There was a lot yesterday in discussions about the platinum and the
silicone and the siloxanes, less on the siloxanes. And I asked a
question earlier what I had trouble is shifting between parts per
million and parts per billion to what I\'m used to working with in a
hospital situation of nanograms per ml or per liter or deciliter. And so
I think it would have been a lot easier on us if it had been taken out
of the OSHA environmental presentation of units. So I really can\'t
compare that.

And I just don\'t think we have enough information yet because I\'m not
sure whether their numbers are similar to the numbers that were in the
article from Analytical and Bioanalytical Chemistry in 2004. And that
would have been with Maharaj.

CHAIRMAN CHOTI: We\'re talking about local health consequences.

DR. MANNO: Yes. But there may be. Platinum is a metal. We already know
several of the heavy metals that cause neurologic damage. We\'ve been
hearing people complain of this. We can\'t nail it down to the implant
until we can get some measure or some particular analyte, if you will,
or reason for that occurring. And if we can\'t measure it, we\'re in
trouble.

CHAIRMAN CHOTI: Dr. LoCicero?

DR. LoCICERO: I don\'t have a great deal to add expect under local
health consequences. Although we\'re talking about rupture here, the
difficulty in looking at whatever breast tissue remains is a problem.
And mainly to health issues concerning the potential for breast cancer
in those susceptible patients. And it\'s pretty clear. I think they\'ve
defined very well, the sponsor has, the local health problems that do
occur when there is a rupture. Otherwise, I agree with the majority.

CHAIRMAN CHOTI: Dr. Provost, so you heard the Panel\'s discussion
regarding question number two. Again, a little bit mixed, but I think
the consensus is in general that most of the Panel were somewhat
confident that we do have somewhat of a grasp, I guess, on the
consequences including the frequency of intracapsular gel and
extracapsular gel and migration as well as some of the local health
consequences of ruptured implant, although there were some questions
regarding that.

As far as the incidence or the progression from silent to symptomatic or
from intracapsular to extracapsular, I think the consensus was that that
information is less clear, although we have some information regarding
that.

Is that sufficient?

DR. PROVOST: Yes. Thank you.

CHAIRMAN CHOTI: Let\'s move to question number three. I want to start
with Dr. LoCicero so he can have a chance to look at it.

The question number three for the Panel, Inamed\'s proposed labeling
includes recommendations for:

\(1\) the method and frequency of screening for silent rupture;

\(2\) clinical management of suspicious and confirmed intracapsular and
extracapsular rupture, and;

\(3\) potential health consequences of extracapsular and migrated gel.

Please discuss the appropriateness of these recommendations and the
extent to which the proposed labeling is supported by the available
information.

DR. LoCICERO: I think the sponsor has well outlined number one, that MRI
is the best way to go and they have given a recommendation for timing,
although it\'s different from what the plastic surgical community wants
to do at this point.

Under number two, they\'re clear at least in their Core Study and I
believe they continue that recommendation that these implants that are
leaking should be removed.

And number three, we\'ve had some discussion here about the differences
in these consequences, and I think it\'s just important that the sponsor
list these, although it\'s hard for us to place numbers on them, it\'s
important that they list the potential consequences.

CHAIRMAN CHOTI: How would you recommend screening, and what frequency
would you recommend based on what you\'ve heard? I\'m pinning you down
here.

DR. LoCICERO: Yes, you\'re going to pin me down. I think that they
probably should have at least\--

CHAIRMAN CHOTI: Use a microphone. Yes.

DR. LoCICERO: They should have at least one evaluation before five
years, and then I would probably agree with the plastic surgeons after
that point.

It\'s clear that there is a percentage of rupture in the first couple of
years and they need some evaluation at that time.

CHAIRMAN CHOTI: Dr. Newburger?

DR. NEWBURGER: I think that the recommendations for method and frequency
of screening are well delineated. The clinical management of suspicious
and confirmed rupture is really, to my mind, left up to the surgeon.

The potential health consequences of the extracapsular and migrated gel
I don\'t find described to my satisfaction. I see a lot of changes that
I think should be included in it, including under the section on rupture
there\'s no evidence that silicone gel that moves beyond the breast
capsule causes any symptoms or disease elsewhere in the body. I don\'t
know that, and without the study of signs and symptoms, that makes it
very much more difficult for me.

And there\'s a sentence, too, the Inamed clinical study results in other
published reports that have found that in some cases MRI may falsely
show a breast implant rupture when there is none, but it can also go the
other way around. And I just would clarify that.

CHAIRMAN CHOTI: So what should we recommend to a woman who has evidence
of extracapsular migrated gel? Okay. The implant is removed. Anything
else should we recommend?

DR. NEWBURGER: My sense is explantation.

CHAIRMAN CHOTI: Okay. Dr. Ewing?

DR. EWING: I am in agreement with \--

CHAIRMAN CHOTI: Again, use the microphone.

DR. EWING: I\'m in agreement with the panelists so far. I think that the
method and frequency of screening for silent rupture has been well
described by the sponsors. I think clinical management of suspicious and
confirmed extracapsular and intracapsular rupture, the recommendations
to explant the implant. And the potential for health consequences of
extracapsular migrated gel, again, I refer to the historical data and
the data that they present that there is some risk, but the risk seems
to be very small.

CHAIRMAN CHOTI: Can I pin you down? What would you recommend? How
frequently should a woman be screened? Or should a woman be screened,
how frequently?

DR. EWING: I think in a screening program where there seems to be,
obviously, a peak incident that we know of probably around ten year, I
would recommend a five and ten year MRI screening.

And to reduce the possibility of false positive, if you have a positive
MRI it can also be backed up with a breast ultrasound to confirm that
diagnosis.

CHAIRMAN CHOTI: Dr. Blumenstein?

DR. BLUMENSTEIN: Oh, I think a referral to the statistician is in order
here, right? I have no comment on this.

CHAIRMAN CHOTI: Dr. Doyle?

DR. DOYLE: I have a little problem with the method and frequency because
it seems to me that there\'s a big difference in one to two years which
is recommended in the insert or what the physician plastic surgeon says
which seems to be 6.3. So I don\'t find that really helpful. That\'s an
awfully big gap in the guideline. As far as the other two, I don\'t have
as much problem.

CHAIRMAN CHOTI: Dr. Bartoo?

DR. BARTOO: In the labeling it suggested to do annual breast exams with
the physician and then, perhaps, with the screening on top of that if
necessary. The only question I would have is that if it\'s a silent
rupture, then I\'m not sure how adequately you\'d be able to find it on
a physician exam. But, of course, I\'m not a physician so I don\'t know
for sure. But that would be one question I would have is that an
adequate way to find silent ruptures. But then again, what we\'re seeing
is that the silent ruptures even if they are there, haven\'t shown to be
any major health consequence at this point. So, you know, that negates
some of my concern. But the other two are definitely well described.

CHAIRMAN CHOTI: Dr. Leitch?

DR. LEITCH: Well, I think the method of filing is well-defined. But I
think probably the realistic probability of being able to do one to two
year MRIs is not there, and so probably a longer interval would be more
appropriate. And I would say something within the range of three to five
years for the first one and then probably five year subsequent to that.

But I do think the patient should be seen by a physician because even
though it may be asymptomatic to the patient, there may be physical
findings that the physician could perceive that would give a hint that
there\'s a problem. And I know when I see patients often who come in,
you know, they\'re not aware. You know, I\'ll look at them and I\'ll see
asymmetry or I\'ll feel asymmetry that the patient\'s unaware of. And
then we embark on a workup and find, in fact, she does have rupture of
the implant. So a physician examine does have a role as well as the
physician asking the patient questions that might elicit symptoms that
the patient might not have reported outright, but in fact if you query
them about them, they might have some symptoms that would give you a
hint that there was, in fact, a rupture problem going on that you could
then pursue with other screening.

The patient should, of course, if she is of age, that being 40 years of
age or older to be in routine screening for breast cancer. That should
go on, of course, on an annual basis regardless of the MRI.

With respect to the management, I do agree with removal of the
identified ruptured implant. I think what \-- we do have to weigh that
in the context of the patient\'s general health. I think all of us have
patients who are well into their 70s and 80s who have implants that have
been there for 30 years. And we probably know in our hearts that they
are ruptured, but the patient is asymptomatic, has no difficulty, has
other intercurrent medical problems. That patient\'s probably not the
ideal patient to take around to remove the implant. On the other hand,
if you have a young patient who has many years of life to live in which
to accumulate some of the problems locally of silicone extravasation,
then I think for them having the implants replaced is a good idea.

And, again, primarily my concerns are the gross contamination of the
parenchyma around the implant which could obscure screening for breast
cancer.

And then the potential health consequences. I would emphasize in the
document the issue of the risk of the intracapsular becoming
extracapsular that could interfere with mammography.

The other thing that should be I think emphasized in the document to
both the physicians and to the patients regarding MRI is that you do
need to have the MRI done at a facility with dedicated breast coils that
has experience in breast MRI. I think Dr. Brenner\'s comments which
suggested that when he\'s trying to review these films, if he doesn\'t
have good files he can\'t make the appropriate recommendation in terms
of the status of the implant. So patients need to be aware that MRI is
not uniformly performed across the country and that they want to go to a
facility that does have experience, and the physician should take care
in their referral for MRI evaluation as well.

CHAIRMAN CHOTI: Dr. Miller?

DR. MILLER: Yes. I think as far as the method and frequency, I think
it\'s important that the patients once they get an implant, part of the
deal is that they return to their plastic surgeon for an examination.
And we\'re just guessing on the best timing on these things, but
certainly one to two years seems like a reasonable guess.

As far as an MRI, I think it\'s not realistic to recommend an MRI every
one to two years. I think it would be important to inform the patient
that if she wants the absolute greatest assurance of the status of her
implant, that she can choose to have an MRI as often as she wants. That
would be up to her. If her level of comfort is such that she doesn\'t
require that, then as a minimum just returning to see the plastic
surgeon for an examination and a discussion about how she\'s doing is
good every one to two years.

As far as the clinical management of rupture, I still am sort of in
favor of exchanging the implant if you know it\'s ruptured just because
of the \-- you know, it\'s not in the condition it was designed to be,
and it just makes sense to me to exchange it. So that maybe a little bit
emotional, but that\'s how I feel about it.

As far as the potential health consequences, I think the company has
outlined that on page 13 of their handout fairly well. But I think that
they might be encouraged to be even be more \-- oh, add some things that
are well beyond what\'s been proven.

The thing that I find that patients get disturbed about is when they
learn things in public domain or from the press or from areas that
surprise them. And if they are not told that some people have alleged
that their implant has made them unable to work and taken away their
life and all this type of thing, it\'s a very frightening thing to learn
that from a source that\'s not your physician. So I think that you can
make a case for adding into this informed consent that there are some
who think that the implants lead to these kind of consequences. And you
can make a case for that.

This is not a part of the question, but as far as the labeling, I would
like to mention that I\'m not that happy about the proposed labeling in
terms of the instructional pieces related to breast reconstruction. If
you look on the reconstruction material on page \-- starting on page 26,
they go through a series of pages describing some of the different
options for breast reconstruction with some of the advantages and
disadvantages with some illustrations. The discussion I\'d like to see
it be a little more objective seeming to me about the options for breast
reconstruction.

If you look at the drawings for the breast implant, they show just a
wonderful, beautiful result that anybody would want. And if you look at
the drawings for the TRAM flap procedure, you look at that and if
you\'re not informed patient you would say well who would want that. And
so I think either some idealized drawings for all the techniques.

Also, there\'s a little bit of an excessive emphasis on some of the
disadvantages of the TRAM flap which I think is a little misleading. I
think that should either be deleted or just a more through discussion of
the pros and cons of each technique would be appropriate if this is
intended as something to help a patient make a decision.

So I\'d like to see some of the those changes made in the labeling.

CHAIRMAN CHOTI: Thank you.

Dr. Callahan?

DR. CALLAHAN: I have nothing to add to the clinicians on 1 and 2 about
the screening and the clinical management.

And in terms of the health consequences, I agree with Dr. Miller. It
would probably be wiser to have more listed up front and not sort of
have people hear it from another source.

CHAIRMAN CHOTI: Dr. Li?

DR. LI: Nothing to add.

CHAIRMAN CHOTI: Dr. Manno?

DR. MANNO: Nothing to add.

CHAIRMAN CHOTI: But in response to question number three which relates
to the labeling recommendations of both the method and frequency of
screening for silent rupture to the management of suspicious or
confirmed rupture, and (3) the potential health consequences, again,
somewhat of a mixed response. But I think that many felt that for number
one that the method and frequency is fairly well defined.

I must say personally I don\'t think that\'s the case. I think that we
really don\'t know how to follow these patients, particularly in
response to the silent rupture. By definition, that\'s not picked up by
that annual every one to two year examination. I didn\'t hear a clear
consensus about the recommendation for screening for silent rupture nor
the frequency. There was some recommendation, some felt that we should
be doing routine MRI scan, others felt not to be the case. And the
timing or the frequency of those screening studies I didn\'t hear a
clear consensus.

As far as the management of suspicious or confirmed rupture, I think
there seemed to be a consensus among the group that the implant should
be removed.

And third, regarding the health consequences, based on the first
questions we discussed regarding the knowledge of the health
consequences I think the group felt that it was appropriately included
in the labeling with some recommended changes.

Is that a sufficient response?

DR. PROVOST: Yes. Thank you.

CHAIRMAN CHOTI: Let\'s move on to question number four. If the Panel
could please discuss whether the plans are adequate to address the
issues previously noted by the Panel or any other post-approval concerns
that you might have. Perhaps we can go through some of those.

In October 2003 Panel meeting, the Panel recommended that patient
follow-up after explantation, rupture rate data, data on children of
women with silicone gel breast implants and connective tissue disease
data be collected in a post-approval study. And to address these issues
Inamed proposes the following.

First, they propose a continuation of existing Core Study with a yearly
physician follow-up through ten years with MRIs continuing at years
three, five, seven and nine.

They also propose a requirement for a quality of life questionnaire. But
the post-approval study will not collect data on children of women with
breast implants.

They also, second they propose using the Danish registry or a third
party organization such as the NIH to collect additional data to address
some of the previous Panel\'s concerns, although there was no specific
description of how they would use those sources of information.

And third, Inamed proposed to link their current voluntary registry
which collects baseline and demographic data.

So, again, can the Panel please discuss whether the plans are adequate
to address the issues previously noted by the Panel or any other
post-approval concerns that you might have?

Can we start with you, Dr. Callahan?

DR. CALLAHAN: Okay. Well, with the first, I\'m not sure that I agree
with \-- this says that they propose to remove the requirement of the
quality of life. And I think since that\'s just a few simple
questionnaires, that that should not be removed.

And also I\'d like to see that they are continuing to collect the
connective tissue disease data.

And then last, the post-approval study will not collect data on children
of women with breast implants. And since that was recommended before,
I\'m not sure why they want to withdraw that information, so I think
that they should continue to do that, continue to follow the
recommendations of the 2003 Panel, which seemed reasonable things to me.

In terms of I think these are good proposals to use the Danish registry
or third party organizations. But it would be useful to see what the
specific plans are as to how they plan to use those.

And also, in terms of linking the voluntary registry, you still always
have the problem with the voluntary registry in terms of what is your
denominator, and it is just the people who volunteered to do. So, you
know, the data can be collected, but it\'s always with a caveat of what
you really get that when you link that.

CHAIRMAN CHOTI: Dr. Li?

DR. LI: I?m not sure ?- one of the proposals was to continue using the
Danish registry or a third party organization such as the NIH. I\'m not
sure that\'s completely useful unless you\'re somehow able to separate
implants that are directly comparable to yours. I\'m not sure how
gathering data over a large variety of designs and materials, I\'m not
really sure that gives you a good view of how your implant fits under
that scheme. It\'s either going to give you an overly optimistic or an
overly pessimistic view of what happens to your implants.

I think if you use these third party things, there ought to be some
culling of the information that you actually collect so we could have
some confidence that it is indicative of some of the performance.

The registries, I have mixed feelings about registries. Registries, I
love the registries that have been around 20 and 30 years because
they\'ve been around 20 and 30 years and there\'s tens of thousands of
devices on them. The problem with starting new registries is, of course,
not everybody is into the registry in this country, and then there\'s
always the issue of what you do with the registry once you get it.

So I think if you\'re going to do that, I\'d like of like to see a plan
for what you\'re going to do with that registry and how one interprets
what you get from that. Because we\'ve seen in other devices people that
have started to create registries, but because of the information they
collected or the way they analyzed it, they actually sent themselves off
in the wrong direction. And I\'d hate to see that on this implant
that\'s already got so many questions associated with it.

Some of the things that aren\'t on here that were raised in the 2003
Panel. One I have say, let me congratulate you on developing the
retrieval study that you\'ve got. It\'s substantially better than what
you had 18 months ago, and you\'ve done a nice job. But I think I would
say it\'s a nice start. I think that there\'s lots of things that you
could \-- there\'s a whole host of things that you could do on this
retrieval and in your in vitro study because I find it extremely
frustrating that after however long these devices have been around, we
don\'t know how they break. It\'s just completely puzzling to me why we
can\'t get to that answer. But I think you\'ve got the beginnings and
the foundation to actually answer that question, and that will not only
help you predict how these devices will perform, but as you modify and
make new devices, they\'ll give you some standardized tests with some
clinical connections that you\'d have some confidence that they\'d
actually \-- predictive of new designs.

So I think I would encourage you, in fact I would almost demand that you
continue to develop your in vitro testing, especially the bleed test.
Again, it\'s a little frustrating to me that we can\'t get a definitive
answer to how much platinum is bleeding out of your component in a
laboratory. I just don\'t understand why that is such a difficult thing
to do. And it\'s one of these questions that keeps popping up, and it
would behoove you, I think, as a company to be able to just answer that
questions once and for all.

The mechanical testing you\'re doing also I think is inadequate in the
sense that again it does not let you predict or explain what you see as
clinical failures. Things like modulus, elongation of break, those
things are good to characterize the material. But as you pointed out in
your own application, none of these correlate to rupture and failure. So
I think the in vitro tests should be completely aimed at being able to
explain what you see clinically.

CHAIRMAN CHOTI: Dr. Manno?

DR. MANNO: On the first item, the only thing that I would comment on is
that they\'re not collecting data on the children of women with breast
implants.

CHAIRMAN CHOTI: Speak directly into the microphone, if you would.

DR. MANNO: I am, I thought.

At any rate, I envision this as a start, and it doesn\'t have to be a
broad based start as simply knowing if a woman has breast fed and if she
has born a child with a problem, and what is the problem and when the
onset was. So that\'s about roughly four questions. And that\'s what I
mean when I say to start that.

I don\'t know, I\'m with Dr. Li on the second item with the Danish
registry or third party organizations. I think that\'s going to be a
humongous

task and a costly task. So I just don\'t see right now the practicality
of it.

I think the third item if you\'re going to tie your own data programs
together with the warranty program, that\'s more beneficial to you than
\-- I think it\'s in your court on that one to help you. But again,
there\'s no plan on how this is to be done.

And that\'s all I have to say.

CHAIRMAN CHOTI: Dr. LoCicero?

DR. LoCICERO: I agree with everybody who has spoken so far, but I want
to reiterate what Dr. Li has said, what Dr. Manno has said. Registries
are a problem. They\'re voluntary, and until you have sufficient data,
they are of very little value.

The National Adult Cardiac Surgery Database was questioned for about ten
years. Now it\'s over 20 years old. It has over 10 million patients. And
one can say a great deal based on that data. But when one starts a
registry you only have a few 100,000 patients, it\'s a very difficult to
draw any conclusions whatsoever, and it can lead you in bad directions.

It\'s expensive. You require the physicians to enter the data. The
database is expensive. And although the plastic surgical societies have
decided that they want to begin a database, come over and talk to the
thoracic surgeons.

CHAIRMAN CHOTI: So you\'re saying I think they propose to link the
registry with the \--

DR. LoCICERO: It\'s all voluntary. It\'s not going to be of any value
for some years, maybe 20 years.

CHAIRMAN CHOTI: But link to the warranty, do you think it should be?

DR. LoCICERO: If you\'re going to do it, it needs some sort of financial
incentive, otherwise it gets no place.

CHAIRMAN CHOTI: Dr. Newburger?

DR. NEWBURGER: I think at this point it\'s of compelling importance to
not cut back on the amount of data that\'s accumulated, but to increase
it. So I agree with the other panelists that there should not be
discontinuation of the quality of life questionnaire. Otherwise, I have
nothing to add.

CHAIRMAN CHOTI: You think the same recommendation should be made as the
last Panel on these findings, basically?

DR. NEWBURGER: Oh, I\'m sorry.

In terms of the first condition.

CHAIRMAN CHOTI: Okay.

DR. NEWBURGER: I have nothing else to add except I think the quality of
life information should be accumulated with even more vigor.

CHAIRMAN CHOTI: Okay.

DR. NEWBURGER: Registries are unwieldy, for sure, but I think it\'s
important to start.

CHAIRMAN CHOTI: Dr. Ewing?

DR. EWING: I agree with the prior Panelists. The American Society of
Plastic Surgeons showed some interest in establishing a registry, and so
that may be a beginning point to at least to begin discussions. I think
that that information, although it would be unwieldy and difficult, but
may be very important particularly five, ten years from now.

And I do also agree that they should continue the quality of life
evaluations and also to include infants and children because I think
that there are some unanswered questions in that aspects of breast
implants.

CHAIRMAN CHOTI: May I ask you the question about the African-American
women, and we\'ve heard some positives regarding that. I\'m deviating a
little bit here, but do you think that there should be some, if this is
approved, in either the registries or the some of the post-approval data
collection do you think that that should be something that somehow more
information can be derived?

DR. EWING: I think that that would be a very important piece of the
registry, particularly women of color because they don\'t receive
implants as often as Caucasian woman, as we saw in the data, and there
may be a reason why that that may be an issue. But I think that it would
be an important piece of data.

CHAIRMAN CHOTI: Dr. Blumenstein?

DR. BLUMENSTEIN: The problem with a registry that has voluntary
participation is that even if it is large, you have the opportunity to
become very precisely inaccurate. So I have grave misgivings about the
value of a registry. I\'d rather see the resources spent on doing really
well controlled studies, at least studies controlled as well as
possible.

I would like to add to the list of things that we have talked about
before a correct analysis of the connective tissue disease signs and
symptoms and other signs and symptoms data. And I would even go so far
as to suggest that perhaps these data could be turned over to an
independent body and allowed to be analyzed in that fashion rather than
by the company.

CHAIRMAN CHOTI: Dr. Doyle?

DR. DOYLE: I think it\'s of paramount importance that the children be
followed, because I think this is something that we\'re only beginning
to see. And you need long term follow-up to see if there are going to be
any problems.

The other thing I think the quality of life surveys are very important
because at this point the quality of life that we heard from individual
patients, they seemed to indicate that it was improved. But the
statistics that the company presented to me don\'t show any improvement
in the quality of life, and that\'s the basis of the efficacy measure
and yet only in a couple of parameters that had to do with the actual
implant itself and one or two others. So I think it\'s imperative that
they continue and get better data on the quality of life.

CHAIRMAN CHOTI: Do you think in the Core Study we\'re talking about
collecting data on children, do you think that we really will have any
kind of power to be able to even answer any questions related to that in
that small number of patients? Is it really worth recommending the
effort to collect information on the children of patients?

DR. DOYLE: Well, if we don\'t it get there, where are we going to get?
Because I think we need to get it somewhere. I guess I don\'t have a
good answer to your question. But if not there, where?

CHAIRMAN CHOTI: Dr. Bartoo?

DR. BARTOO: Regarding the post-approval studies, I have to commend the
sponsor for committing to doing the ten year follow-up. I think in my
experience with medical devices for over 20 years, this is one of the
most extensive studies I\'ve ever seen. And so I commend them for
committing to doing it and carrying it out. I do think it\'s important
for this particular device, and so I think it\'s well warranted.

Regarding the quality of life questionnaires, I think it is important to
collect that data. But I\'m not so sure if it\'s so important to collect
it at years six, eight and ten because you\'re getting pretty far out in
terms of aging of the patient. And so my question would be how do you
interpret that data since so many things may have happened to those
patients later on, ten years out.

With regards to the post-approval study on collecting data on children,
I think that is important. I would like to suggest that they consider
that, since it has been raised as a concern and there are no other
studies, it seems like, that have addressed that in a randomized
fashion.

Regarding a registry, I agree that it\'s a pretty difficult and an
unwieldy thing to do. And I wasn\'t at the previous Panel, so I\'m not
quite sure what drove the recommendation to do the registry, but maybe
it should be reconsidered.

So I think those are the three.

CHAIRMAN CHOTI: Dr. Leitch?

DR. LEITCH: I do agree that continuing the study to ten years is great,
because I think it will help to answer some of the questions about how
these patients are followed and what are the appropriate guidelines for
following.

I also strongly agree that the quality of life questionnaires should
continue. Now whether or not it might be appropriate to get a little
more advice and expertise about how to design that questionnaire so that
the data is meaningful with respect to the aging patient and that one
has data that\'s meaningful over time and also perhaps addresses some
other health endpoints that aren?t included in the current evaluation.

With respect to the data on children, while this would be great to get,
I think that may be very difficult to accomplish. And so perhaps
something simple as was proposed earlier in terms of the questions, but
to actually approach the children in some way or, you know, delve into
their medical records in great detail, I think that may be unrealistic
to be accomplished by the company. However, they might try to get some
young investigators who would be interested in working on a grant to
address that sort of issue.

I also agree that you probably, because again because of the size of
this group, that may be insufficient to make conclusions for this group
of patients.

With respect to the registry, you know registries are great, but I think
all the problems have been mentioned about those. But using the rupture
warranty program as a way of getting more data about implant rupture and
however best you think you could do that. I think collecting more data
from that program would be helpful in addressing some of the problems in
rupture and how you might do something to make that better.

CHAIRMAN CHOTI: Dr. Miller?

DR. MILLER: I like the idea of completing the Core Study. I would like
to see the quality of life information continue to be gathered so we can
understand better the impact of implants on quality of life.

I\'m not sure that collecting data on children is essential. Of course,
it\'s hard emotionally to say, well, we\'re not going to collect data on
children when there\'s some question of ways. But, again, I apologize
for keeping pulling out the Institute of Medicine report, but it feels
so important. I mean, the Institute of Medicine looked at this issue and
felt that there was evidence for an association with internal silicone
breast implants and children\'s health was insufficient or flawed and
that there was no plausible biologic explanation suggested.

So, I mean you know you have to have a reason to go looking for
something. And it takes effort and resources to look for these things. I
would want to be assured that there\'s no health related issues with
children. But I think we need to go with what the data shows on that.

I may need to spend more time with my thoracic surgery colleagues, and
maybe I\'m naive, but I like the idea of keeping track of these
implants. I like the idea of a registry. And the model that comes to my
mind is, I mean I\'ve never been so impressed when I had a patient with
a pacemaker, and there was a problem with the pacemaker and you could go
to the telephone, put a number into the person\'s ear on the other end
of the phone, and they could tell you instantly the entire life history
of that pacemaker. Now that\'s an extreme example of following these
devices. But I think that some mechanism for following the device is
important, especially given the controversy related to these devices and
the issues that we\'ve raised at this Panel. I think that more than
perhaps other devices, an effort should be made to track these devices
and who has them and what happens to them over time.

One thing I would like to add is, and it\'s not in here but I think we
discussed it at the last Panel, was a commitment on the part of the
sponsor to be very reasonable about who these implants are given to for
implantation. And that a surgeon ordering one of these devices must
document that they have been trained to put these devices in, that
they\'re competent in doing it, and that they have the skills that are
necessary to minimize the chance of problems. And this is something that
I think the sponsor can easily control if they are mindful of this when
they ship an implant, and I\'d like to see some discipline as far as
that\'s concerned.

And I agree with Dr. Li\'s comments as well, about the mechanical
testing. I would like to see a continued effort to understand what\'s
happening to these devices in vivo and why they fail and coming up with
better in vitro tests that simulate the type of forces that the implants
are exposed to; all of this needs to be better characterized. And I\'d
like to include that in the qualifiers here.

CHAIRMAN CHOTI: So to summarize question four, the Panel discussed plans
for adequately addressing some of the post-approval concerns including
the long term follow-up of the Core Study out to ten years, including
quality of life issues, to link to other third party registries and
organizations, and (3) the linking the voluntary register with a rupture
warranty program.

I think the group was somewhat more of a consensus here that most felt
that these things were a good thing, particularly the long-term Core
Study follow-up. And the Panel, I think, to summarize, felt that quality
of life is an important issue to incorporate.

There are some mixed feelings regarding whether collecting data on
children is useful or not, but some felt that this was quite important.

Regarding using the other registries and information, I think the
consensus was that information is important and that all efforts should
be made in that direction.

There was some concerns about voluntary registry information and how
useful that will be. But I think that several on the Panel felt that by
linking it somewhat to the rupture warranty program that would
strengthen the validity of the data that would perhaps strength the
voluntary registry information. Does that answer some of the questions
the FDA had?

DR. PROVOST: Yes. Thank you.

CHAIRMAN CHOTI: The final question for the Panel, question five. Please
discuss whether you believe that there\'s a reasonable assurance that
this device is safe over its expected life span for the proposed
indications of breast augmentation, reconstruction, and revision? So
this is really a key question really building off of the first four
questions.

Dr. Leitch?

DR. LEITCH: Well, I think with respect to \--

CHAIRMAN CHOTI: Use the microphone.

DR. LEITCH: \-- the ?- what we describe about safety that there is
reasonable assurance that the device is safe with respect to systemic
health problems, that is it safe with respect to local issues as long as
the patient is monitored closely.

One exception and concern that I do have is with respect to the 153
model which appears to have very high rupture rates. And while the
rupture rate does not pose serious problems to the patient with respect
to systemic disease, these are mostly in patients who have undergone
reconstruction for breast cancer, and so these are happening, actually,
you know in these \-- significant proportion in the early years after
their diagnosis. And so that presents another thing that they have to
deal with during the course of their care.

So if those implants were to be approved for use, I think the labeling
has to be very clear about their rupture rate so that patients and
physicians have the choice of is the shape more important or the lower
rupture rate more important for them in terms of selecting the implant
for use.

CHAIRMAN CHOTI: Dr. Miller?

DR. MILLER: I think as we\'ve discussed frequently at both this meeting
and the last meeting, safety is a ratio. And I think that for these
implants we have a good characterization of the risk profile. And
whether they\'re safe for an individual depends on the benefit that
individual feels they can derive from using the device, and it\'s a very
individualized thing. I think that the device is \-- for many people can
be safe over the expected life span of the device. I think for some it
may not be safe because they may receive a benefit that exceeds the
risks. But I think that those who calculate a favorable risk benefit
ratio should be permitted to have the device.

CHAIRMAN CHOTI: Dr. Callahan?

DR. CALLAHAN: I agree that the reasonable assurance ?- for most people
it is safe. I do think that not all people are the same, and so there
are going to be some people that \-- you know, this happens with not
only devices, but with medicines where things aren\'t ?- but for the
majority I do think that there is a reasonable assurance of the safety
over its expected lifetime.

I think the expected lifetime is not the lifetime of the patient,
though, and that that\'s very clear. And we\'re not sure on exactly what
that is.

I also agree with Dr. Leitch in terms of the concerns about 153. I think
that\'s really different. And I think having the labeling or having
things very clear so that the surgeon and the patients can make the
decisions, like she said, about the shape versus round is a very
important issue.

CHAIRMAN CHOTI: Is your feeling, perhaps, that that one particular
device, are you having some questions as to whether there\'s reasonable
assurance of safety for the one device, 153, or are you fairly assured
for all of them?

DR. CALLAHAN: Well, it\'s not really safety since the data are pretty
reasonable right now that even if it leaks, you don\'t have some of
these problems. But it\'s the issue that was brought up of having
another surgery and particularly in these women who are having
reconstruction and this is soon after their disease. I think if you want
to call having another surgery an issue of non-safety, then that would
be it. But, you know, in terms of the other things we looked at, I
don\'t have a problem with the safety. It\'s just the issue of having to
have the resurgery.

CHAIRMAN CHOTI: Dr. Li?

DR. LI: Yes. I hate to parse words, but I\'m a little \-- I\'m not sure
what the expected lifetime of the device is. I mean, we really never
have talked about that as a number. We\'ve talked about, perhaps, what
the failure rate would be at ten years or at five years, but I don\'t
feel like we\'ve discussed exactly what the expected lifetime of the
device is. So I\'m not quite sure what that \-- I don\'t know what that
means.

As I said earlier, I\'m only comfortable with the rupture rate
prediction up to as long as it\'s measured. So I\'m not quite sure what
the rupture rate is going to be at ten.

And as Dr. Callahan just said, I guess there\'s an issue of whether or
not you\'re going to call a reoperation a safety issue. Not being a
woman and not having to have this surgery, I would think risking a
second surgery is a safety issue or a risk issue. So being that said \--
and you can say ten years is the lifetime, then I\'m not sure I have the
information to assess whether or not it\'s reasonable to be safe or not
at that time.

CHAIRMAN CHOTI: Dr. Manno?

DR. MANNO: I pretty much agree with the comments about the 153, the
concern there. I think it doesn\'t matter who you are, how healthy you
are, what; the more surgery you have, the more at risk you are. But I
would certainly hope that the physician who is doing the implant or the
explant would be good enough to recognize when a problem may exist and
if he\'s supplied with all the information, he\'ll know what to do at
that point.

I think the key word is \"reasonable assurance.\" And I\'ve had the
feeling throughout the day that the company has been very forthcoming
with giving information that we\'ve asked for, which I didn\'t have that
feeling the last time. And so I think it\'s \-- we\'ve got enough
assurance that we can move on it.

CHAIRMAN CHOTI: Dr. LoCicero?

DR. LoCICERO: Just to reiterate, I have very significant concerns about
model 153 in recommending approval for a model that is about to change.

The evidence of safety for the other device is reasonable. When half of
the ruptures occur with 153 and particularly in patients who are being
reconstructed, I\'m not sure that the same safety profile exists.

CHAIRMAN CHOTI: Dr. Newburger?

DR. NEWBURGER: With the exception of model 153, I feel comfortable with
the safety to the three year point. I feel that that\'s predictable.

I think that more precision for the longer term follow-up is really
needed. I think we have to be really stringent in terms of determining
these risks. We\'re looking at big, big numbers of people who will take
advantage of the availability of these devices. And so we\'re going to
see the 1 in 1,000, 1 in 10,000, 1 in 100,000 adverse events. And I
don\'t have a real good feeling that people are going to follow up in
the recommended fashion because, you know, if it ain\'t broke, don\'t
fix it. And so if people don\'t perceive symptoms, if that\'s the silent
rupture rate again, I don\'t think that we\'re actually going to know
that number until there are longer term consequences. So I\'m not
comfortable with the safety beyond three years. I\'m not comfortable
with the lifetime safety of the device.

CHAIRMAN CHOTI: Dr. Ewing?

DR. EWING: I agree with the other Panelists that I think that a
reasonable assurance has been made, but it\'s also multi-focal \--
assurances need to be made that the patient is given adequate informed
consent about possibilities of complications in a language that they can
understand as the second part of that reasonable assurance. And then the
third part, I totally agree with Dr. Miller that it has to be someone
who is well trained and understands the indications and how to place the
implant and how to remove the implant and how to follow these patients.
In addition, too, the patient must understand that to maintain good
health that she will have to participate in a follow-up program of some
sort.

CHAIRMAN CHOTI: Dr. Blumenstein?

DR. BLUMENSTEIN: I think the whole thing here is based on whether an
adequate informed consent can be created. And informed consent comes
about when there\'s good data. And I think the data are lacking, and
therefore I can\'t answer this question that there\'s a reasonable
assurance that the device is safe, because there\'s a big part of the
data that hasn\'t been analyzed correctly yet.

Furthermore, we don\'t have data beyond about three years, and I don\'t
know how we can possibly say anything about safety beyond three years.

CHAIRMAN CHOTI: Dr. Doyle?

DR. DOYLE: My first problem is one that\'s been stated before; we don\'t
have what is expected lifetime. I don\'t know whether you\'re telling me
ten or 20 years, and I\'m not even comfortable beyond three years based
on the data we have.

The other thing I agree with Dr. Miller is that it\'s an individual risk
benefit that a patient has to determine in consultation with her
physician for herself. However, when you think of all the individual
patients we heard yesterday and take into account \-- one of the things
that bothers me is you were also talking about that safety is determined
in part on a risk benefit ratio. And while I heard individual patients
telling me how they felt, so I heard what they thought about their own
individual risk benefit ratio, what we\'re using as the benefit here is
primarily a quality of life, and I don\'t see that the overall data that
I\'ve seen in this submission shows that there\'s any really increased
quality of life overall. In a few parameters, yes; many of them stayed
the same, and a few went down. So I find it really difficult to
calculate the true safety without having some better idea of efficacy
that convinces me that this is really worthwhile taking any of the risks
that the patients are taking.

So I\'m concerned about the lifetime being defined and how to determine
the risk benefit ratio with the paucity of data we really have on the
improvement \-- quality of life.

CHAIRMAN CHOTI: Dr. Bartoo?

DR. BARTOO: I think I agree with LeeLee in that I don\'t know what the
expected life is, but if it\'s, say, ten years I feel comfortable that
there is reasonable assurance of safety for ten years. I don\'t know
about 20 years. Maybe that\'s something that could be addressed in the
labeling.

I think I am also a little concerned about device number 153 because of
the high reoperation rate, so I would have to qualify my reasonable
assurance of safety to exclude 153.

CHAIRMAN CHOTI: Dr. Provost, you\'ve heard our discussion regarding
Panel question number five. Most of the Panel members, I think,
expressed a reasonable assurance that the device in general is safe for
the expected lifetime. There was some discussion regarding really what
is the lifetime, and there was some discussion particularly about the
one specific product, the 153 product. And does that suffice?

DR. PROVOST: Just one thing that I want to make sure that we have clear,
and that is in this question we asked about the indications of
augmentation and reconstruction and revision, and that didn\'t really
come out in the discussion. And I guess I assume that the Panel members
believe that in their answers, the answers that they gave are applicable
to all of the indications that are mentioned in this question?

CHAIRMAN CHOTI: Any open comments regarding the specific thing we
perhaps failed to mention, the difference between augmentation,
reconstruction, and revision?

Dr. Leitch?

DR. LEITCH: You know, I would just like to say that obviously my
preoccupation is a little more with the reconstruction patients, and so
I must say I was dismayed about the 153 implant. So I think that has to
be very specifically addressed. And when we talk to breast cancer
patients about having reconstruction and saying, well, you can have
implant, but everybody else can\'t because it\'s considered to be too
dangerous, the reconstruction patient is effectively denied the
procedure. So I think for this group since their implant, the one they
got the most has the most problems, I think that \-- in my mind that
kind of has to be fixed. But I think if we have this rule that it\'s
okay for the reconstruction patients, then I think it\'s okay for the
augmentation patients. And certainly from this data those augmentation
patients, you know, had less problems actually than the reconstruction
patients. So in that sense, I think you can say that it is okay across
the board. But we need to address the implant that is most commonly used
for the reconstruction patients, which has difficulties.

CHAIRMAN CHOTI: Does that somewhat clarify that question?

DR. PROVOST: Yes. Thank you.

CHAIRMAN CHOTI: Well, that ends the discussion of the FDA questions.
We\'ll take now a 15 minute break, and we\'ll resume with a public
session.

(Whereupon, at 3:57 p.m. a recess until 4:21 p.m.)

CHAIRMAN CHOTI: So resuming the afternoon session.

First I\'d like to clarify for the FDA regarding the question number
five. There were some concerns about Panel members that I perhaps did
not summarize totally.

I think there was consensus from most of the Panel members that there is
an assurance of safety, at least in the short term. But some Panel
members expressed concern about the long term safety, particularly as
defined by the duration or the lifetime of the device and really what is
the definition of the lifetime of the device.

So without having a clear definition, some Panel members had a concern
regarding how safe it is for some ill-defined duration of time.

Does that summarize a little better?

DR. PROVOST: Yes. Thank you.

CHAIRMAN CHOTI: All right.

We\'re ready now to proceed to proceed to today\'s open public comment
session of this meeting. We ask that all persons addressing the Panel
speak clearly into the microphone, as the transcriptionist will depend
on this as a means of providing an accurate record of this meeting.

Both the Food and Drug Administration and the public believe in
transparent process for information gathering and decision making. To
ensure such transparency at the open public hearing session of this
Advisory Committee meeting, the FDA believes that it is important to
understand the context of an individual\'s presentation. For this reason
the FDA encourages you, the open public hearing speaker, at the
beginning of your written or oral statement to advise the Committee of
any financial relationship that you may have with the sponsor, its
product and, if known, it\'s direct competitors.

For example, this financial information may include the sponsor\'s
payment for your travel, lodging or other expenses in connection with
your attendance at the meeting.

Likewise, the FDA encourages you at the beginning of your statement to
advise the Committee if you do not have any such financial
relationships. If you choose not to address this issue of financial
relationships at the beginning of your statement, it will not preclude
you from speaking.

We will begin with those individuals who have notified the FDA of their
intent to testify during the open session.

May we have the first public speaker?

MS. PEARSON: My name is Cynthia Pearson. I\'m the Executive Director of
National Women\'s Health Network, a women\'s health advocacy
organization. We\'re supported primarily by members. We have no
financial relationship with the sponsor or any of its competitors.

I appreciate the opportunity to testify before you today, and I\'m
especially grateful because I also spoke before you in October of 2003.
And I see these meetings as sort of a matched pair; where the sponsor is
coming with the same basic PMA, along with some additional information
at your request and at the request of the agency, and trying to get to a
final answer of whether these implants are reasonably safe for the
indicated use.

I have to say, I\'m very very concerned that the questions that have
been raised are not being adequately addressed. And the questions that
trouble me and the women who contact our organization, and some of the
women who spoke yesterday, are if I\'m healthy when this starts when I
choose to have an implant, what is the chance that the implant will
cause me trouble, what is the chance that I feel less healthy after
having the implant inserted.

There are some of you, I know, who have been very articulate about how
you believe that this question is answered, and it has been answered for
a while. But others have spoken about how there are good studies in the
literature which find associations either between ruptured implants and
increased risk of fibromyalgia or between long-term users, presumably
some of whom have ruptured implants and increased risk of suicide,
cancer and other conditions.

Now, we acknowledge those aren\'t cause and effect; those haven\'t been
answered. But the questions linger. And they\'re reasonable scientific
questions. And the fact that the sponsor\'s experts say that there 20
studies that show no effect doesn\'t really answer the question. There
were 20 studies that showed that HRT was associated with less risk of
heart disease. It took one good study that was prospective and
randomized and controlled to show that in healthy women HRT actually
increased the risk of heart disease.

So what we\'re asking you for is to be the place where women can turn to
to feel that their questions will be answered. And it appears as if the
only way we\'re likely to get answers to these questions if they come in
the preapproval setting. And I know you\'ve struggled both in your
discussion and in listening to speakers yesterday about how much is it
fair to ask of a sponsor to do preapproval? Is it necessary to ask for
ten years data preapproval? It is doable? Is it even practical to get
ten years data preapproval? And is it fair?

Well, I\'ve spoken in the first part of my testimony about why our
organization and women who spoke yesterday think it is necessary. It\'s
obviously doable. These third generation implants were on the market for
several years without restrictions, they\'ve been provided to tens of
thousands of women in the United States since the restrictions were put
in place. Women abound who could take part of a well designed
epidemiology study of women who are all long-term users, which is where
we\'re going to have to go to get the questions answered. So it\'s
doable.

And is it unfair? You heard yesterday that some people believe it\'s
just wrong and maybe even unlawful to ever ask a sponsor for more than
three years data. Well, it\'s not wrong, it\'s not unlawful, and it\'s
not even unique.

One heart valve manufacturer, CarboMedics, was asked to provide 14 year
follow-up before its study was approved. They began enrolling in 1984.
They followed for over 14 years, and they got approved in 2001. Now what
were the circumstances that made that the right thing to do for heart
patients? There had been earlier questions about the safety of other
heart valves. There were other alternatives on the market, not ideal but
some alternatives. And the FDA stood firm and insisted that the company
go all the way to get the information about long-term safety.

Now what is similar for women and breast implants? There are other
options available. There exist a pool of people that could be studied.
And I\'ll point out that implant manufacturers first started coming
before the FDA and hearing interest in data in that same time period, in
the early 1980s. And it\'s very, very frustrating to us that if
manufacturers had decided then to do the kind of study that the heart
valve manufacturers did, over five years ago we would have had enough
data to completely answer the questions about the long-term effects.

Women deserve that much, and they are depending on you to ask for this
information. So we recommend that you don\'t take the vote that you look
like you\'re about to take in favor of approval, but that you really
consider asking for more information before the devices are approved.

CHAIRMAN CHOTI: Thank you.

Good afternoon.

DR. GARTSIDE: My name is Roberta Gartside. I\'m a plastic surgeon in my
private practice.

I have no financial interest in any health care company. I derived no
income from a consulting basis from either Inamed or Mentor Corporation,
and the decision of this Advisory Panel will have no financial impact on
my practice. It can however significantly impact the quality of life of
my patients and help me to provide the best care possible.

I have been in practice over 16 years and have used gel implants over
most of that time. I participate with the adjunct studies and would like
to be able to offer silicone gel implants to all of my patients, not
just those that qualify.

I am sure that you\'ve already heard the results of the many studies
including the Institute of Medicine\'s. Like all the studies, it has
been experience that silicone gel implants are safe to recommend to my
patients. There is no other product that I use that has been studied
more or for a longer period of time.

As a physician I feel it is important to be able to fully discuss with
my patients all options and treatments that may benefit them. To say to
a woman that there is a device that would give them an improved surgical
result but it is unavailable to her in the United States gives me a
sense of failure as a physician. There are many women whose surgical
results could be enhanced and quality of life improved if they were to
have access to silicone gel implants.

For the women who has thin tissues either as a result of mastectomy or
their own body habitus, it is my experience that although saline
implants provide enlargement and replacement of a lost breast, water is
not at all like the cohesive gel of today\'s implants and cannot mimic
the feel of a breast that is lost or give a woman the sense that her
implant is like her own overlying breast.

I find that my patients are intelligent educated women, wives and
mothers. It is time to empower women to make their own educated choice
as to the type implant they want to have in their own body. Decisions
such as this should be between a physician and their patients and not
dictated to us by politics or special interest group.

It is time now to approve again and finally make available for all women
silicone gel implants.

In addition, I\'m authorized on behalf of organized plastic surgery to
reaffirm our commitment to addressing the following issues regarding
silicone breast implants.

First, the education and certification of surgeons with emphasis on
techniques to minimize device trauma and to ensure patient safety.

Second, the algorithmic approaches for management of implant related
conditions including silent rupture.

To provide post-market surveillance to facilitate the collection of data
regarding implant quality and outcomes in the general population. Such a
registry could be multi-disciplinary managed by a reputable third party
entity such as Duke Clinical Research Institute and have the oversight
of the FDA, public representatives, device manufacturers and involved
medical specialties.

And lastly, developing informed consent documents that emphasize
doctor/patient collaboration involving risk and accountability for
clinical decisions involving breast implant surgery.

Thank you for your attention.

CHAIRMAN CHOTI: Thank you.

Yes. Okay.

DR. LoCICERO: A quick question. As a deputized official of the plastic
surgery organizations are you willing to limit the use of these devices
to plastic surgeons who are certified?

CHAIRMAN CHOTI: I\'m sorry, can you repeat the question for her?

DR. LoCICERO: As a deputized official of the plastic surgery
organizations are you going to limit the implantation of these devices
to only those surgeons who have been certified?

DR. GARTSIDE: You\'re asking me a question I can\'t fully answer for
you. I was asked to give this \-- so say it one more time.

DR. LoCICERO: Are you limiting the use of this device to certified
surgeons only?

DR. GARTSIDE: I think that\'s something we have to come up with. Right
now the American Society of Plastic Surgeons is made up of all board
certified plastic surgeons and has to go \--

DR. LoCICERO: You said that you were going to have a specific training
session for surgeons. Are you going to limit the use of this device to
those who have been certified?

DR. GARTSIDE: That specific question I think we\'d have to say yes.

CHAIRMAN CHOTI: Thank you.

Yes. Good afternoon.

DR. KATZIN: Good afternoon.

I\'d like to thank the Panel members for giving me the opportunity to
address you this afternoon.

My name is Dr. William Katzin. I\'m a practicing pathologist from
Cleveland, Ohio and a part time faculty member at Case Western Reserve
University of Medicine in Cleveland, Ohio.

I have no conflicts of interest with Inamed, Mentor, or with their
competitors.

I was told earlier that I had five minutes for this presentation, so
hopefully I\'ll be able to get through it in less than that.

Next slide, please.

Very little is known about the interaction between silicone and the
various components of the immune system in women with silicone
gel-filled breast implants. Over a period of around four years I had the
opportunity to examine a large number of lymph nodes from patients with
silicone gel-filled breast implants \--

CHAIRMAN CHOTI: Just a comment. You have a three minute period, so just
so you could summarize it.

DR. KATZIN: I\'ll try to get through it quickly.

The escaped silicone from breast implants is a well recognized
phenomenon and most extensively documented in capsular tissue that
surrounds breast implants. However, only around 40 cases of silicone
lymphadenopathy have been published, and spectroscopic confirmed has
been provided in only two cases.

We studied regional lymph nodes.

Next image.

From 96 patients with breast implants using conventional histology as
well as well as Fourier transform infrared microspectroscophy and
laser-Raman spectroscropy which were used for analytical confirmation of
the presence of silicone and/or polyurethane.

Next image.

Most of the lymph nodes were obtained from women who had either single
lumen breast implants containing silicone gel in smooth surfaces or
single lumen gel implants with a polyurethane coating.

Next image. Those types are listed there.

Among the 96 patients, 47 had gross evidence of rupture and in 49
patients the implants were removed at or around the time of surgery \--
lymph node biopsy, that is, were completely intact.

Next one.

Most of the regional lymph nodes were from the axilla. We also had
control patients who did not have implants in this study.

Next image.

Lymph nodes from around 95 percent of the patients with implants contain
macrophages with vacuolated cytoplasm as are shown here in this portion
of the image. In some of the sections the macrophages have replaced much
of the lymphoid tissue normally present.

Next image.

Multinucleated giant cells as seen right here which were
macrophage-derived were also frequently seen. Macrophages are known to
act as antigen-presenting cells in their interaction with their
lymphocytes and a mixture of macrophages and lymphocytes is clearly seen
in this photo micrograph. In around 90 percent of the cases with
implants refractile material consistent with silicone was observed \--
next image \-- and that can be seen here.

A relatively infrequent finding not previously reported \-- next image
\-- was the presence of polyurethane. And this was seen in 16 patients.

Well formed sarcoid-like granulomas \-- next image \-- were infrequently
seen.

Next one.

Spectroscopic confirmation of silicone was present in 74 percent of the
patients.

Next.

In summary, silicone and polyurethane can both migrate to regional lymph
nodes of patients with silicone gel-filled breast implants, and we
confirm the presence of both these compounds using spectroscopic
methods.

And last one. The presence of silicone in macrophages cells whose
function includes antigen presentation in lymph nodes, lymph nodes whose
function it is to coordinate and amplify activities of the immune system
provides a rational basis for a model in which silicone has a direct
impact on the immune system in patients with silicone gel-filled
implants. Considering the certain access of silicone to regional lymph
nodes in patients with gel-filled breast implants, I would conclude that
such implants should not be considered safe until the molecular details
of that potential impact have been thoroughly assessed using lymph node
tissue.

Thank you very much.

CHAIRMAN CHOTI: Thank you. Question, Dr. Li?

DR. LI: Two quick questions. One, do you know if any of these implants
were of the type of that we\'re discussing today from Inamed?

DR. KATZIN: All of these implants were removed prior to 1997. So I
believe that none of these were from patients who had the present type
of implant from Inamed.

DR. LI: Okay. And the second quick question is have you studied women
that don\'t have implants at all?

DR. KATZIN: Yes, we did. We had 12 patients in the study who had no
implants, patients whose lymph nodes were biopsied almost all for
staging of breast cancer, and in none of those patients was silicone
observed either histologically or using the spectroscopic evaluation. So
the sensitivity of our study in terms of the detection of silicone
really was that which is appropriate for patients with a significant
amount of silicone derived from the implants.

CHAIRMAN CHOTI: Dr. Ewing, question?

DR. EWING: My question is of the lymph nodes that you examined that
harbored the silicone particles and the polyurethane particles, what
percentage were intramammary nodes and percentage was extramammary
nodes?

And the second question, were any of those patients are patients who was
directly injected with silicone, which we know from the past there are
patients out there floating around that have liquid silicone in their
breast?

DR. KATZIN: Yes. To my knowledge, I\'ll answer the second question
first, none of those patients had silicone direct injections. All the
patients were known to have either one or multiple sets of silicone gel
containing breast implants.

And the data regarding the location of the lymph nodes was included on
one of the slides. But at least somewhere in the 80 percent range of
lymph nodes in the patients with breast implants were axillary lymph
nodes. A smaller number were intramammary, a small number were
intracostal lymph nodes or Reiter lymph nodes, and I think there was a
supraclavicular lymph node as well, but the vast majority were from the
axilla.

CHAIRMAN CHOTI: Another question. I may have missed it. Was there a
difference in ruptured versus non-ruptured?

DR. KATZIN: I didn\'t specifically look at that information. But I can
say that there was a significant amount of silicone in macrophage
infiltration of lymph nodes in patients who had intact implants, at
least the implants that were removed most recently.

CHAIRMAN CHOTI: I mean, you\'ve showed the ratio of ruptured and
unruptured, but you don?t have that information?

DR. KATZIN: I don\'t have the separate data, no. The intent of the study
was really to correlate histologic parameters with the spectroscopic
evaluation and not so much on the nature of the implants itself. We did
include that basic data, but that\'s all.

CHAIRMAN CHOTI: Okay. Thank you.

Next. Good afternoon.

DR. DISA: Good afternoon.

My name is Dr. Joseph Disa. I am an academic plastic surgeon at Memorial
Sloan-Kettering Cancer Center in New York City. I did my plastic surgery
training at the Johns Hopkins Hospital.

I\'ve recently co-authored a book dedicated to the education of women
contemplating or requiring breast surgery entitled 100 Questions and
Answers About Breast Surgery.

I have no financial relationship with any implant manufacturer, nor do I
own any shares of these companies. The ASPS has paid for my travel
expenses.

Since 1997 I\'ve placed over 800 breast implants for reconstruction. As
a certified investigator of the FDA sponsored silicon implant Adjunct
Study I\'ve placed 230 silicone implants in 166 patients between 1999
and the present. During these six years, 7 percent of patients with
silicone implants for breast reconstruction have undergone revisional
surgery. Of these 7 percent the indications for revision were for a size
change that was not device related and 3 percent to treat capsular
contracture in 3 percent and to replace a single ruptured implant in one
patient.

Silicone breast implants are a very important part of my practice. In
distinction to patients undergoing breast augmentation, a woman who has
had a mastectomy has no breast tissue. Thus, her entire breast volume is
created by the implant. The shortcomings of saline implants are readily
apparent in this setting. Saline implants are relatively noncompliant
and generally feel firm or hard to the patients. Patients complain that
they can no longer sleep on their stomach, and when they hug another
person, the implant feels hard and unnatural.

Because the saline implant is essentially a bag of salt water, the
physical properties of water are visually apparent. After a mastectomy
there is no breast tissue to camouflage the ripples, and rippling is
readily apparent through the skin.

The unnatural feel and appearance of saline implants are a source for
anxiety for my patients. Conversely, silicone breast implants are much
softer and more compliant. They feel more like breast tissue in their
consistency. Patients find them more comfortable and less noticeable in
everyday life. Due the physical properties of silicone they ripple less
and as a result appear more natural.

Silicone implants have been an enormous benefit for my patients facing
the permanent disfigurement that results from the loss of a breast.

As a surgeon, it is my duty to educate my patients about these devices.
In addition to explaining the known risks of a given procedure or
device, I give them the handbook published by the Institute of Medicine
entitled Information for Women About the Safety of Silicone Breast
Implants. I explain that in 1997 the FDA chartered the Institute of
Medicine to conduct an independent review of past and ongoing scientific
research regarding the safety of silicone breast implants. The Institute
of Medicine found no evidence linking silicone implants to cancer,
connective tissue disorders, auto-immune disease or other significant
health problems.

Patients are also referred to the websites of various implant
manufacturers, the American Society of Plastic Surgeons and the recently
created website breastimplantsafety.org.

The Adjunct Study requires follow-up at one, three and five years after
implantation of a silicone implant. I suggest my patients follow-up on
an annual basis and continue with their follow-up annually after
completing the study requirements. This provides an opportunity to
monitor the status of the implant and address any concerns they may have
regarding their breast reconstruction.

Silicone implants are used worldwide and are currently the most
efficacious device for breast reconstruction. Their track record is
sound, and their results are far superior to saline. Patients deserve to
have a choice, specifically since there\'s no convincing evidence that
patient safety is compromised with these devices.

Thank you for your time.

CHAIRMAN CHOTI: May I ask you a question? You said you had one rupture
in your experience of silicone implants?

DR. DISA: Yes.

CHAIRMAN CHOTI: Out of?

DR. DISA: One that I\'ve explanted.

CHAIRMAN CHOTI: Out of 600?

DR. DISA: No. Out of 230 implants and 166 patients, there was one for a
.6 percent rupture rate, since 1999.

CHAIRMAN CHOTI: Yet we\'re hearing rupture rates much higher than that.
I guess you\'re not seeing these patients?

DR. DISA: I\'m seeing them in follow-up as part of the protocol. I\'m
not doing MRIs, so I\'m not sure what the silent rupture rate is. But
there was one clinically \-- you know, a patient who presented and
underwent a revision and then a ruptured implant was discovered.

CHAIRMAN CHOTI: Dr. Miller?

DR. MILLER: Dr. Disa, how assured do you feel when you examine a woman
who has had a breast reconstruction with an implant that you may be able
to detect a rupture just by physical examination?

DR. DISA: I find that if the patient\'s developed a unexpected capsular
contracture and she is \-- causing her discomfort or it\'s
dissignificantly displaced or there is some reason to have a revision,
then we go to the operating room for a revision. At that point you
figure out whether or not the device has ruptured.

If the device has changed a little bit and it\'s a little bit firm but
it\'s not bothering the patient, then we continue to follow her on a
regular basis.

If I\'m not happy with the status of the device in that it\'s become
firm or displaced to an extent that I think there may be a problem,
I\'ll recommend an MRI and base my treatment options on the results of
that study.

DR. MILLER: Thank you.

CHAIRMAN CHOTI: Good afternoon.

DR. WOLFE: I\'m Dr. Wolfe from Public Citizen\'s Health Research Group.

I do not have any financial conflict of interest, nor does Dr. Tunie
Dweck, who is a resident who is doing rotation with us from Johns
Hopkins School of Public Health who did some work on this as well.

Despite an extra year of data on silicone gel breast implants since the
last hearing, the FDA approval standard for medical devices \"reasonable
assurance of safety\" clearly has not been met for these devices.
Whereas at the last hearing we advocated waiting at least five more
years to collect more information on the thousands of women who have
already had this essentially third generation of implants rather than
precipitously approving them for marketing, there are now several new
lines of evidence that argue strongly for ending the quest for approval
of the current generation of intrinsically flawed silicone gel breast
implants before any more women injured.

The first point I was going to make, which has been discussed in some
detail but I will mention a couple of things that Dr. Katzin didn?t have
a chance to mention, is the study he just presented.

In addition to what he presented, they concluded that \"in a patient who
has had post-mastectomy reconstructive surgery using silicone gel breast
implants, the clinical differential diagnoses of regional lymph node
enlargement should include silicone lymphadenopathy as well as
metastatic breast cancer. And he went on to say that in most individuals
with silicone gel breast implants who have had surgery for augmentation,
one must also consider the potential for adverse health consequences of
silicone migration to the regional lymph nodes.

In FDA\'s criticism of the proposed patient brochure, they criticize the
company for assuming that the migration of gel or gel going into the
lymph nodes is a rare occurrence. Certainly Dr. Katzin\'s study
contradicts that.

The second line of evidence which has been discussed somewhat is the FDA
extrapolations of the rupture data from the Core Study. It\'s
interesting that people have mentioned the analogy to consumer goods
like automobiles and so forth. I would bet that if you look at the
failure rate for an automobile, it is probably much more a quadratic
function than just steady linear every year. And, of course, like other
consumer devices, they are not implanted in the human body. The kind of
important medical device that\'s implanted in the human body, a heart
valve, if it had even an increasing, let alone quadratically increasing
rate, it would be unacceptable just as this device is.

The third line of evidence has to do with some data that have been
submitted to the FDA but which aren\'t being discussed with these
hearings, and they have to do with the so called \"gummy bear,\" the
really cohesive gel implants. Now the data had been submitted but FDA
has, I think wisely, asked for more information from the company
including longer term follow-up.

I just want to mention a couple of things that Inamed itself says. You
want the safest results with Style 410, which is the gummy bear, you can
achieve these aims. So the company believes that this is the safest
model.

The purpose of making the gel more cohesive was that it\'s less
liquid-like, more solid than other silicone gel breast implants. If
it\'s cut in half, there\'s no gross movement of gel.

What happens if a cohesive gel ruptures? At the time of the writing,
this is from websites, there\'s a report of a single rupture in a series
of several thousand patients in Sweden. The company admits, though, that
microscopic migration of gel could \-- would probably occur. This is the
subject of an ongoing investigation.

In the data submitted to the FDA on 4/10, which will be discussed
sometime in the future when there\'s longer term data, the rate at two
years in the augmentation patients was .1 percent, 0.1 percent, and
there was no ruptures in those patients getting these implants for
reconstruction. Contrast that to the data in the Core Study of the
current generation of implants where, according to the table on page 19
of the FDA review, there\'s a rate of silent plus symptomatic of 4.8
percent in the MRI cohort.

Although the data in the Core Study are three plus years as opposed to
two, the total rate of rupture, symptomatic and asymptomatic, in this
cohort is almost 50 times higher than the two year rate for the cohesive
model of .1 percent. The actual rate is lower than that, because as I
said there were no ruptures in the women getting for augmentation.

In summary, we strongly urge the Panel to reject the approval of the
inherently flawed Inamed and Mentor silicone gel breast implants being
considered at this hearing.

In addition, much more data are needed for longer periods of time on the
cohesive gel or so-called gummy bear implants. Although the rupture rate
for two years are much lower, there is the concern that I expressed
above that the company is aware of of microscopic migration of gel.

Just as the FDA has required longer term data on the implants being
discussed at these hearings, at least five more years of data on the
cohesive implants will be needed to answer questions about their safety.

And I think that to approve the third generation of devices would really
be to negate the entire letter and certainly the spirit of the 1976
device law in terms of the lack of reasonable assurance of safety.

CHAIRMAN CHOTI: Thank you.

Good afternoon.

DR. LOCKWOOD: Dear ladies and gentlemen of the Committee, my name is Dr.
Michelle Lockwood. I am on faculty at Georgetown University in the
Department of Plastic Surgery.

I do receive money from Mentor as a patient as part of the study. I do
not receive any money as a consultant.

Thank you very much for this opportunity to express my support for the
use of silicone implants.

I am an engineer, a plastic surgeon as well as most recently a breast
cancer survivor.

Ten years ago I completed a three study on the mechanical properties of
silicone breast implants for my master\'s thesis in engineering at
University of Illinois. Little did I know that eight years later I would
be making a decision for myself whether or not to use this device in my
body.

After completing my master\'s degree in engineering, I went on to
medical school and then on to residency in plastic surgery. Throughout
my plastic surgery training under this moratorium I\'ve had to educate
patients on the use of breast implants. Some patients who have wanted to
use silicone implants were ineligible because their procedure was deemed
too cosmetic. Others who were eligible and were good candidates for
silicone implants were too scared to use silicone due to the media hype
in the last decade.

Last year only one week before starting my chief resident year in
plastic surgery I was diagnosed with ductal carcinoma in situ. My
options for treatment were lymphectomy with radiation or mastectomy.
Having seen the detrimental effects of radiation, I choose mastectomy.
With a body mass index of only 17 and my need for minimal recovery time
to get back to my residency, my best choice for breast reconstruction
was expander and implants.

To achieve better shape symmetry for my reconstruction, I also elected
to have a small implant placed on the opposite breast. Due to the
thinness of my tissues, I was quite concerned that saline implants would
produce a significant rippling of the reconstructed breast, a known
problem of the saline implants. Because of the restricted use of
silicone implants, I had to go to a hospital across town in order to
find a plastic surgeon who was part of a silicone implant study.

What I find ironic in this issue is that under the current guidelines
had I presented to a plastic surgeon wanting a cosmetic augmentation, I
would be ineligible for silicone implants, regardless of my education on
these devices or my ability to make an informed decision. But now the
same noncancerous breast is eligible for silicone because of the
reconstructive setting after mastectomy.

Ladies and gentlemen, I implore you to vote in favor of returning
silicone implants back on the market. As an engineer I know that the
data of these implants produced today are the most durable to date. As a
physician I know that the data presented in the last decade do not
substantiate any significant health risks to the general population. And
as a female patient I know that in many situations silicone implants
offer superior aesthetic results over saline. Please give women the
chance to make an informed decision regarding the use of silicone
implants by voting to lift the restricted use of these devices.

Thank you.

CHAIRMAN CHOTI: Thank you.

MS. MULLEN: Good afternoon, ladies and gentlemen.

My name is Betsy Mullen, and I am presenting a statement on behalf of
LaSalle D. Leffall, Jr., M.D. F.A.C.S. Dr. Leffall, the Charles R. Drew
Professor of Surgery, Howard University College of Medicine, is a
surgeon, oncologist, medical educator and leader in professional and
civic organizations.

He is a diplomat of the American Board of Surgery and a fellow of the
American College of Surgeons and the American College of
Gastroenterology.

Dr. Leffall\'s professional life has been devoted to the study of
cancer, particularly among African-Americans. In 1979 he launched a
program on the challenge of cancer in black Americans paying special
attention to the increasing incidence and mortality of cancer in this
population and its implications for similar studies in other racial and
ethnic minorities, the first program of its type in our nation.

His major areas of interests are soft-part sarcomas and cancer of the
breast, colorectum, head and neck.

Dr. Leffall was the first African-American President of the American
Cancer Society, Society of Surgical Oncology, Society of Surgical
Chairman, Washington Academy of Surgery and American College of
Surgeons.

His numerous honors and awards include the first heritage award given by
the Society of Surgical Oncology in 2001 to a past president for
significant contributions to the field of oncology.

In 1987 the Biennial LaSalle D. Leffall, Jr. Award was established by
the M.D. Anderson Hospital and Tumor Institute and Intercultural Cancer
Council recognizing his contributions to cancer prevention, treatment
and education in minority and economically disadvantaged communities.

As the principal civilian consultant to the General Surgery Service and
the Department of Surgery of Walter Reed Army Medical Center for 25
years, he received the Commander\'s Award for Public Service from Walter
Reed Army Center in 1995.

In 1998, Dr. Leffall became Chairman of the Steering Committee of the
National Dialogue on Cancer, a committee co-chaired by former President
and Mrs. George H.W. Bush. The Dialogue represents a group of 140
collaborating partners from the public, private and nonprofit sectors
dedicated to eradicating cancer as a major health problem at the
earliest possible time. In 2002, President George W. Bush named him
chairman of the President\'s Cancer Panel, a three member group that
oversees the national cancer program and reports directly to the
President.

The following was Dr. Laffall\'s statement:

As a practicing \-- longest intro, shortest statement. Bear with me.

As a practicing surgical oncologist at Howard University Hospital, I am
writing to support the approval of two applications for silicone
gel-filled breast prostheses. The efficacy of these materials has been
reaffirmed in peer-reviewed published scientific studies including a
2004 publication of a study conducted by the NCI of over 7,000 women,
for an average of 12 years, finding no evidence of causation of
connective tissue disease. Since my practice is primarily concerned with
breast tumor patients and having been asked by many patients about the
value of silicone gel-filled breast prostheses, I again want to express
my support for approval of these materials.

Thank you.

CHAIRMAN CHOTI: I\'m glad he didn\'t win any other awards.

MS. MULLEN: Well, this is severely edited. I just wanted to put it in
context. You know, brevity is great. His statement is short and to the
point, but it has a lot of credibility behind it.

CHAIRMAN CHOTI: Thank you.

MS. MULLEN: Just wait until my testimony tomorrow. Thanks.

CHAIRMAN CHOTI: Thank you.

Yes. Good afternoon.

MS. FERRELLI: Hi. My name is Vanessa Rose Ferrelli.

I\'ve not been given any financial assistance from anyone related to
this testimony.

I got Inamed silicone implants on August 7, 2000. And apparently I was
part of a study, but I was not properly informed about the study or the
risks prior to getting the implants. I was told by more than one plastic
surgeon that they were recently put back on the market, that they had
conducted years of studies, and that they were proven to be 100 percent
safe. They said all the women that had complained in the past were just
after money. And my plastic surgeon had said that all I needed to do was
to promise to show up for some appointments because they had recently
been brought back on the market, so that he could just document how they
were.

Unlike most women that get sick five to ten years later, I got sick
right away. At first I experienced abnormally heavy periods that lasted
several months at a time. Fatigue so bad that I would sleep 16 or more
hours a day.

Then the second year things got a lot worse for me. Numbness and pain in
my hands and my arms so bad I couldn\'t even brush my teeth or hold a
cup. I lost my hair. I had sores all over my face and skin, and I
couldn\'t breath. I was put on oxygen at different times. I developed
some heart issues. And I was passing out.

I was a healthy 26 year old before I got silicone implants. Then I was
deathly sick for two years.

I had the implants removed, and I got a little better. Then I had my
natural breast tissue removed, and it showed bilateral silicone
contamination and granulomatous inflammation.

I\'m now much better since I had that removed and I lost my natural
breast tissue.

I don\'t know if that was put in the Inamed study, but I don\'t think it
was.

The worst part of the whole ordeal for me was the lack of information
that I got and the lack of help, because I didn\'t know what was wrong
with me.

Silicone implants, I believe, are dangerous, and I just \-- I believe
that the informed consent has not, and I don\'t think it could be
properly regulated. And it\'s difficult for me to call myself lucky, but
I know that I am because I\'m better. Much better now.

Please make sure that this doesn\'t happen to any other woman. You can
trust Inamed\'s studies. And make sure that these implants are safe
before they\'re approved because they won\'t be studied afterwards.

Thank you.

CHAIRMAN CHOTI: A question? Dr. Doyle?

DR. DOYLE: Were you at any time told any particular diagnosis, were any
diagnoses given to you?

MS. FERRELLI: No. They were just saying that you had to have saline
implants first to be able to get the silicone implants, and that they
were just brought back on the market so there were some things that you
had to follow.

DR. DOYLE: But when you went to the physician with all of the symptoms
you were having, did anyone ever say what you had?

MS. FERRELLI: Nobody said, and I even have documentation from the
plastic surgeon that put them in that said I told her that it\'s not
from the implants, that they\'re safe. They\'re inert, they\'re the
purest substance on earth, they\'ve been studied for all these years. If
I would have known that, then I wouldn\'t have been sick for two years,
and I would have them out. But it took me two years to figure out what
it was, and then once I did I had them removed right away. And I got
much better, but not totally better. And then I researched and found a
doctor that suggested to have my natural breast tissue removed. And I
did it, and I got better.

CHAIRMAN CHOTI: Dr. Li?

DR. LI: Perhaps a question for the sponsor related to this. We heard at
least one case yesterday of a similar incident where a woman received a
silicone implants as a part of the study, but then was subsequently
apparently dropped from the study or somehow disappeared out of the
study.

I was under the impression that because these are all under special
conditions that every one of these implants that got placed in had to be
tracked to a patient and physician. So my question is how does this
happen?

CHAIRMAN CHOTI: If it\'s all right \-- do you want this question
addressed now or perhaps when the sponsor addresses us at the end?

MS. FERRELLI: Can I say something?

DR. LI: Either way, but I would like to hear their comment on this.

CHAIRMAN CHOTI: Perhaps you can comment on that at the summary statement
if that\'s okay.

MS. FERRELLI: I just want to say that I had contacted Inamed several
times, and they were not interested at all to hear about anything that
had happened to me. And I had a letter from them from the date that my
doctor removed the implants, sent them back to Inamed, they didn\'t even
contact me for six months later. And it was a letter stating that they
would give me \$1500. It had nothing to do with asking what happened,
what were my symptoms, nothing. And that is still to date, except for
the last time when I testified two years ago suddenly there was some
interest in me.

And I have all of the documentation here.

DR. LI: Okay. If the sponsor could comment on that at some time, I would
appreciate that.

MS. FERRELLI: Is that it?

DR. SPEAR: I think probably Dr. Walker would like to comment on it
later. But I will say that there are two studies. There\'s a Core Study
and an Adjunct Study. I think pretty clearly this young lady was not in
the Core Study. She was in the Adjunct Study, and, of course, we\'d love
to see the medical records which would explain what happened. And
causality, of course, is another question. But I think Dr. Walker could
perhaps address that during the summation.

CHAIRMAN CHOTI: Thank you.

MS. FERRELLI: Thank you.

CHAIRMAN CHOTI: Good afternoon.

MS. NAWAR: Good afternoon.

My name is Michelle Nawar. I\'m reading the testimony of Dr. Barbara
Philipp, Fellow of American Academy of Pediatrics and fellow at the
Academy of Breast Feeding Medicine. She\'s an Associate Professor of
Pediatrics at Boston University School of Medicine and Director of the
Breastfeeding Center at Boston Medical Center.

I have no conflicts of interests.

More U.S. teens than ever before are exposed to marketing campaigns for
getting breast augmentation. There is debate within the plastic surgery
community about the exact numbers of teens in the United States who are
seeking breast augmentation for cosmetic purposes, but the two plastic
surgery medical societies have provided statistics that indicate a
substantial increase in young women 18 and under seeking breast implants
since the late 1990s. One plastic surgery medical society has suggested
that only 5 percent of college women have breast implants. As is obvious
from any systematic survey of popular culture, more teens in this
country are now exposed to marketing campaigns for breast implants than
ever before.

Currently, most of the girls 18 and under are getting saline breast
implants, since silicone implants are restricted. If silicone gel breast
implants are approved by the FDA for ages 18 and over, we know that
physicians will can use them off label with younger women.

There are no studies of breast implant risks for girls under the age of
18, or even specific to 18, 19 or 20 year olds. There should be. Breast
development can still occur during the late teen years, and weight gain
also contributes to bra size and how women and girls feel about their
breast size.

Should we be concerned about this? Can young girls make an informed
decision about breast augmentation, weighing the risks and benefits? All
women, of every age, have trouble making an informed choice about breast
implants because of the lack of conclusive research. The plastic surgery
medical associations do not include any complication statistics, not
even those that the companies are required to provide to patients on
their websites. In the absence of clear evidence of harm, many women
believe that implants are safe.

Combine that with other factors. Research shows that teenagers are
especially self-conscious about their bodies. They are more
self-confident at 16 than 15, and more self-confident at 18 than 17. So
a teenager who wants augmentation when she is 17 might feel fine about
her body when she\'s 19, even without surgery.

In addition, the teenage brain is not well-developed in terms of risk
aversion, a finding that helps explain teen car accidents but is also
relevant to the choices they would make about silicone breast implants.

The expenses might be a deterrent, except that many plastic surgeons
encourage implants by offering finance plans that even college students
can afford. But, if anything goes wrong, those same young women probably
will not have the \$5,000 or more they would need to get their implants
removed or to deal with some of the medical problems that may arise.

In summary, if you approve silicone gel breast implants for women ages
18 and older or even 21 and older, young women will still be able to get
them as an off-label use;

Teenage girls are often very self-conscious about their bodies in a
transient fashion, and this could influence their ability to make an
informed choice that will serve them for the long term.

True informed consent is unlikely because even the plastic surgeon
medical societies are not providing complication rates on their
websites, leaving it to individual doctors to decide what to tell their
patients.

Thank you.

CHAIRMAN CHOTI: Thank you.

Yes, good afternoon.

DR. ZONES: I\'m Dr. Jane Zones, here to read the statement of Arthur
Caplan, Director of the Center for Bioethics at the University of
Pennsylvania.

Dr. Kaplan is one of our foremost biomedical ethicists. He has no
financial conflicts of interest.

There are two key ethical issues involved in your decision. Do women
have a right to choose silicone breast implants, and is informed consent
possible or likely?

When breast implants were at risk of being removed from the market in
the early 1990s, the American Society of Plastic Surgeons hired two PR
firms that came up with the slogan \"Women have a right to choose.\" The
mandate of the FDA however, is to require companies to prove their
product is safe before it can be sold and people can choose it. And the
slogan implies an understanding of the information necessary to make an
informed choice. I do not see any reason to believe that such a
situation exists.

Have the companies proven safety? Breast implants were sold for 25 years
before epidemiological studies were published. Companies were asking
women to make a choice based on no meaningful safety data.

Almost all of the published epidemiological research is co-authored by
Joseph McLaughlin, who spoke earlier this afternoon. According to
disclosure statements on his articles, his research on breast implants
is funded by Dow Corning, and he has also been a consultant to Inamed.

The articles that McLaughlin co-authored conclude that breast implants
are safe. Much of that research does not measure long-term safety. When
his team has done longer term studies, they have found serious problems.
For example, a Danish study found a doubling of auto-immune symptoms.
The question of long-term safety is still out.

The second key ethical issue is whether informed consent is likely to be
achieved. Organized plastic surgeons have created a website that they
claim presents the pluses and minuses of breast implants. In fact,
however, the website barely mentions risks. The only statements are
\"like all surgery, breast implant surgery may pose some risk.\" And
?Like all medical devices, breast implants may not last a lifetime.\"
That\'s it.

Women are told to ask their surgeon about the risks. If this is the type
of information that is supposed to undergird informed consent, then it
is not adequate.

There are those who would argue that it is sufficient to provide women
with information and then leave decisions about elective surgery up to
them. That is not the policy that FDA has adopted with painkillers such
as Vioxx, and it is not the policy that should be adopted here.

FDA must act not in response to an industry trying to get a product back
on the market, but to ensure that women are protected and truly
informed.

Thank you.

CHAIRMAN CHOTI: Thank you.

Yes. Good afternoon.

MS. FAIR: My name is Amber Fair and I am reading the testimony of
Margaret Galloway, who could not be here today.

Neither of us have any conflicts of interest.

My name is Margaret Galloway, and I lead a breast cancer survivors group
in Albuquerque, New Mexico.

I was diagnosed with breast cancer in 1986 and had a right modified
mastectomy. The following year, I had a left modified radical
mastectomy. Following the second mastectomy, my oncologist recommended
that I have a reconstruction with silicone gel implants. She assured me
that they were safe and referred me to a plastic surgeon. He was very
reassuring and never warned me of any risks or complications. In fact,
he stated that none of his patients ever had any problems, a claim I
later found out was false.

So, I trusted my doctors and was reconstructed with silicone gel
implants. Two months after my initial surgery, however, problems began.
One of the tissue expanders ruptured and had to be replaced. I then
developed an infection and the procedure ended up taking eight months to
complete. After the silicone gel implants were put in place, I developed
another infection, which took another several weeks to control.

Three months after getting the silicone implants, I began to have joint
and muscle aches and pains. I experienced so much pain that I became
limited in my activities. I had worked for 44 years as a registered
nurse and had never been so seriously ill, so it was very upsetting for
me to have to take days off and to be unable to do the things I normally
do.

I had looked forward to retirement, but my life as a retiree has been
very disappointing because of the illness and the pain caused by my
implants. I was unable to take plane rides because my breasts would
swell during the flight, causing extreme pain and discomfort. I was not
even able to play with my grandchildren because of the chronic aches and
pains I experienced. The problems increased and became so intense that I
finally decided to have the implants removed.

It is important that women with mastectomy have reconstruction choices.
Unfortunately, there are many today, including TRAM flaps. But it is
important that these choices be safe ones because fighting cancer is
tough enough, without putting us through additional surgeries and
complications.

I feel that I have lost 17 years of my life and my family has suffered
because of that loss. I ask this Panel not to ignore my story and the
stories of all the other women that have come before you today. In 2004,
I was relieved when the FDA decided not to lift restrictions on silicone
breast implants because the data did not address safety concerns. I
hoped that meant that other women would not have to suffer as I did. Why
are we here just barely a year after the FDA asked for long-term safety
data? Four years of data are not enough to tell women about the risks of
silicone gel-filled breast implants.

Thank you.

CHAIRMAN CHOTI: Thank you.

Yes, good afternoon.

DR. ZUCKERMAN: Hi there. I\'m Dr. Diana Zuckerman. I\'m President of the
National Research Center for Women and Families, and I\'m very pleased
to be here.

I have no conflicts. I\'m a psychologist and epidemiologist and
president of a nonprofit center that scrutinizes research to see what
the implications are for health and safety.

We\'ve heard that implants are the most studied medical product in the
United States, but in 1991 there were about a million women with breast
implants. The number of empirical published studies at that time was
zero.

Next, please.

And at that time when they submitted their PMA, Inamed had only studied
39 breast cancer patients. Thirty-nine. And in their augmentation sample
they had lost 65 percent of their augmentation patients at three to six
months, according to the FDA summary.

Now, it brings us to 2003. Things have changed a little. We\'re looking
at the two to three year data that was available in 2003. It showed very
high complication rates, including a lot of reoperations. It showed an
increase in auto-immune symptoms, just about all of them that were
measured. And it also showed no improvement and some worsening in most
self-esteem and self-concept measures.

Now we know that most of the people talking have said this product has
improved the quality of their life. But as has been pointed out by Panel
members, the data just don\'t support it. There is some improvement on
body image, but not on quality of life, not on all of these other
measures that have been touted as the main advantage of implants.

Next, please.

It\'s very worrisome that this slide is off the screen, but it\'s also
very worrisome that all the patients in these studies are white, just
about all of them. And, yes, I understand that most people getting
breast implants for augmentation are white, but that is certainly not
true of reconstruction patients. There are many, many thousands of
reconstruction patients in this country that are women of color, and yet
just a handful \-- I thought it was six African-American women, and five
Asian American women, but according to the data shown this morning,
it\'s actually even lower. And I don\'t really understand how it could
possibly be acceptable to approve a product with no data.

The reason why it\'s important to have racial diversity in these samples
is because there are racial differences in scarring and in auto-immune
disease. African-American women are more likely, more susceptible to
auto-immune disease. So we\'d want to know are they more at risk, and we
can\'t conclude that because there\'s just \-- I mean, not only weren\'t
they analyzed separately, there weren\'t even enough women to analyze
separately.

Next, please.

That brings us to 2005, and I\'d sure be glad if you could get that to
fit.

I felt that we\'d have additional year of data. I mean, I was very
interested to see what would the new data show and how would it be
different. So I thought there\'d be more data on complications compared
to last time, but no there aren\'t. And I thought that there\'d be
another year of data on auto-immune, and no, there aren\'t. And I
thought there\'d be another year of data on self-esteem and quality of
life, and no, there aren\'t. There is rupture data, and that\'s great.
But it was really for the three-year MRI data. It\'s called four-year
data, but since MRIs were done in the third year, it doesn\'t take us
very far.

Next, please.

When Inamed compared ruptured and intact implants, they did not evaluate
connective tissue disease symptoms for most women with ruptures. I say
that based on the FDA\'s scientific analysis in your package.

They did find a significant increase in muscle pain. They didn\'t find
too many increases, but they had a very, very small sample to work with,
partly because it just wasn\'t measured.

Next, please.

This will take not much time. The Adjunct Study has, according to
Inamed, 25,000 paients, but they basically didn\'t follow-up on them.
Now, this is very upsetting because this was such a great opportunity to
provide really good data and longer term data. And let me say that the
young woman who testified about her problems not being reported, whether
she was in the Adjunct Study or the Core Study, her problems should have
been reported. And it says something about the commitment of the sponsor
that they seem to think as long as it was the Adjunct Study, it doesn\'t
matter. I think it does matter. They should be taking care of patients
in their studies, and they should be reporting them regardless of which
\-- I don\'t know which study she was in, but whichever one it is, she
should have been reported.

And also just to say that in 1990 when Inamed started their studies, had
they followed those women, we\'d have at least a dozen years of data,
safety data, the data we want. But they didn\'t do that.

The literature review that FDA did talked about the Danish registry, but
the mean number of years of women, and that was less than four years,
not long enough.

It talked about the Danish rupture study. Forty percent of the implants
were fault-tested with a faulty MRI, so that study was not helpful.

And basically the data that many of you talked about showing up to ten
years of rupture is faulty data. And I hope that Dr. Blumenstein will
say something more about that later.

CHAIRMAN CHOTI: If you could sum for us, please.

DR. ZUCKERMAN: Sure. Thank you.

Next, please. Next, please.

There other rupture studies, and please feel free to ask me questions.
I\'m sorry I didn\'t get very far of this. I just have a couple of more
minutes, but I know I don\'t have the time.

But just to say the FDA study did have a 21 percent extracapsular
leakage for implants that were seven years old or more, and they also
did find an increase in fibromyalgia, which has not really been
discussed.

CHAIRMAN CHOTI: Thank you.

Next speaker? Good afternoon.

MS. RUSSELL: Good afternoon.

My name is Cynthia Russell. I am a \--

CHAIRMAN CHOTI: Is the microphone on?

MS. RUSSELL: Good afternoon.

My name is Cynthia Russell. I am a personal speaker and survivor of
breast cancer. I was diagnosed in \'97 at the age of 27.

In the interest of full disclosure, I will say that the Mentor
corporation paid for my lodging due to physical logistics. No traveling
or other options were\-- did I take part in.

I\'m a breast cancer survivor restored to normal appearance by the
Becker 50/50 implant. I am in favor of them, although I do have current
concerns about the rules and laws governing the ban.

I question: (1) that the implants deemed risky were approved by the FDA
and made available to vulnerable and cancer chemotherapy patients while
(2) the implants and information regarding them were denied to women who
choose to have implants, thus creating (3) a form of discrimination and
censorship by not allowing them to make an informed choice with all
products available to everyone else on the markets.

Dr. Nahabedian of Johns Hopkins gave me hope of femininity as a single
woman at the age of 27 with these implants. I was shown many different
sizes, shapes and manufacturers. What was most noticeable to me were the
ripples and irregularities the saline implants had at rest.

I was drawn to the Becker 50/50 implant that had a silicone capsule
contained within a saline one because of the markedly thicker membrane
and the texture to it. It gave me confidence about the safety of the
silicone.

My battle against breast cancer had multiple complications. The sources
of my remissions were not only numerous, but for numerous causes.
However, at no time were the implants found to have any role in the
difficult course of my reconstructive surgery and through chemotherapy.

That brings me to another point I feel strongly about. A simple cold or
flu virus can be life threatening to chemotherapy patients. If the
silicone implants were dangerous, why had they been only available to
those with depressed immune systems? If they were not dangerous, why
they have not been available to all patients?

It seems logical that if the implant is safe, it should be available to
all women needing or wanting cosmetic change. Isn\'t it the
responsibility of FDA, the doctors and even the people to make sure that
all information and options are provided. This decision is a personal
one. Everyone should be permitted to make their own choice and the
matter of restrictive choice is another issue I have questioned. This
question was founded on freedom of choice. If you aren\'t happy with the
government representative, vote. In addition, if you don\'t like the
implant, don\'t get it. However, choices should be given as well as
information.

To restrict a viable alternative is nothing less than somewhat a well
hidden form of discrimination or deceitful. It presumes women to be
unintelligent, doctors to be uninformed or even unethical, and both to
be incapable of making informed and educated decisions.

CHAIRMAN CHOTI: If you could sum up for us.

MS. RUSSELL: In overview, I would like to ask you the reviews and issues
that are personally important to me and that I have explored.

One, didn\'t the FDA already allow implants to be a safe, viable option
even for those most vulnerable of patients?

Two, what is the reason behind the restriction of availability to the
implants to these broad spectrum of potential users if it is safe?

Three, do you believe the lack of information and availability of choice
to women be an act of discrimination?

I will be happy to answer any questions you may have.

CHAIRMAN CHOTI: Thank you.

MR. SCHULTZ: Good afternoon.

CHAIRMAN CHOTI: Good afternoon.

MR. SCHULTZ: My name is William Schultz. I\'m speaking for Dr. Harold
Glick, clinical professor at the University of Pittsburgh Medical
School.

The FDA has posed five questions to the Panel, the first two are
critical to the issue of approval.

The first question asked whether Inamed has adequately characterized the
rupture rate and how the rate changes over the expected lifetime of the
device. Inamed has the burden of proof. They must show what the rupture
rate is and that it\'s reasonably low over the lifetime of the product.

I think the first point, as someone from the Panel pointed out in the
discussion, is there has really been no data and no discussion of what
the lifetime of the product is. We don\'t know what the lifetime of this
product is, and certainly the sponsor has the obligation to define it.

Hypothetically I think there\'s been discussion about what\'s the data
over ten years \-- can you characterize breakage over a ten year period?

FDA has taken the position that there really isn\'t sufficient data to
answer that question. Depending on the analysis, the breakage rate could
be 21 percent, it could be 77 percent, the sponsor says it\'s 14
percent. But if the rate is 77 percent, then certainly the product is
not safe because the underlying assumption here has been that breakage
leads to another surgery. Even if the rate is 21 percent or somewhere in
between, it seems that serious questions are raised. But I just would
ask, I think that the Panel has to really think about whether they can
recommend approval when we don\'t know the lifetime of the product or
what the breakage rate is over ten years.

Question two is if it does break, if there is a rupture, what are the
health consequences. And there\'s been a lot of discussion about various
studies that say there are no health consequences. But I would just like
to point out it\'s one thing to look at the available data and say it
doesn\'t demonstrate health consequences. That\'s one thing to do. But
here Inamed coming to FDA for approval, they have to submit data to
affirmatively show that there\'s a reasonable assurance of safety. And
that\'s a very different thing than saying a problem isn\'t proven. And
I think the Committee needs to really address that issue, obviously.

And there\'s one very telling point, which is it\'s the standard of care
among plastic surgeons to even where there\'s a silent break, to do a
surgery and replace the breast implant. The underlying assumption of
that surgery is that there is a safety issue. If there was no safety
issue, there\'d be no reason to do that surgery. And I just would ask
the question of how Inamed and the plastic surgeons can say on the one
hand there are no risks and on the other hand when there is a silent
break, the implant ought to be replaced.

Questions three and four, and I am about to sum up, go to the issue of
additional conditions and post-market studies, the idea of restrictions
on surgeons was raised. None of those are a substitute for showing
safety. The fundamental question is is there a reasonable assurance of
safety. And I would submit to you on behalf of Dr. Glick that the answer
to that question is no.

Thank you very much.

CHAIRMAN CHOTI: Thank you very much.

I think that\'s the end of our public session.

Before we go the FDA final statements, there was a request to briefly
open again for public discussion about, perhaps, any loose ends.

Dr. Newburger?

DR. NEWBURGER: I feel a pressing urgency on us to approve this device at
this time, and I don\'t know why. We don\'t have a third data point on
the MRI data so that we can accurately characterize device persistence
or failure. I don\'t have confidence thus far \-- actually, on the basis
of some of the things we\'ve been hearing that we\'ve been given all of
the data that we should have been given.

And on the basis of that, how can we get an informed consent from our
patients, how can we give an informed consent with this vagueness. It
makes me very uneasy, and I\'m wondering what is the urgency at this
time? There are alternatives. What is the difference between now and
another 18 months?

My sense was when the FDA asked the company for more long-term data,
that long-term would be more than what is it \-- 17 months?

CHAIRMAN CHOTI: Dr. Li, did you have a statement or a comment?

DR. LI: I had a question for Dr. Provost. My understanding is we\'re
asked to recommend approval or not approval on all the models of
implants in the study, including the 153. So is it an all or nothing; in
other words, can we approve everything but the 153, or do we have
approve them all, or not approve any of them?

DR. PROVOST: Regarding the Style 153, you can make that recommendation
that we approve all the styles except 153 if that\'s what the consensus
of the Committee is. But I would just point out, though, that the
sponsor has not proposed to remove that model from consideration, but
has mentioned today that they plan to modify the model to address the
failure mode that they identified.

And the other point I would make is that we don\'t have a data set that
has Style 153 data removed from it. So we\'re not sure \-- I mean,
you\'d making the recommendation, which is fine, but I do want to point
out that we don\'t know what the data looks like if you take Style 153
out. We don\'t know what the N looks like for the reconstruction cohort,
for example. And we don\'t know what the complication rates look like.
But, again, you can make that recommendation to us if that is what the
Committee would like to recommend.

CHAIRMAN CHOTI: Dr. Newburger?

DR. NEWBURGER: I have another question, I guess for the sponsor. Since
we\'re not clear what the lifetime of this device is, can, on the basis
of your three year MRI data, can you make a recommendation regarding
when a replacement should be made since you\'re going along with
replacing these when they rupture and they will?

DR. WALKER: Yes. We have four-year data at this point. But you\'re
right, the MRI, the next MRI would be at five years.

I\'d also like to point out that silicone breast implants have been on
the market for 30 years. They\'ve been available in Europe. There is an
extensive body of literature supporting the safety of these products.

What the actual lifetime is, we can\'t give an actual lifetime because
it does depend on an individual implant in an individual patient. And we
feel that serial MRIs examining that implant as well as the physician\'s
assessment of a patient is the most appropriate thing. And with a
prediction and clear labeling, patient and physician education out to
ten years is our recommendation. There\'s not a clear recommendation.

As data increases a label is written at one point in time, but it is
updated and modified every year. And Inamed will continue to collect
data. The Core Study will continue. And the label would be modified
annually, if necessary.

DR. NEWBURGER: So then this is an open-ended financial investment for
the patient?

DR. WALKER: The patient, part of the informed consent and part of the
patient education and part of the labeling is that these are not
considered to be lifetime devices.

DR. NEWBURGER: So that with the initial outlay average being for cost of
implants and the surgeon and the operating facility, about
\$6,000/\$7,000, and then the patient should get MRIs at an interval at
a certain other cost to the patient?

DR. WALKER: Yes. The patient would need to be informed, and maybe Dr.
Spear \-- I\'m not really prepared to talk to you about cost of having
breast augmentation or reconstruction. But a patient would need to be
informed, and it is part of the process now that these are not
considered lifetime devices. And part of the ongoing care may require
revision later.

Dr. Spear will add to that.

DR. SPEAR: It\'s a very interesting question what is the lifetime of
this device. You know, I feel very comfortable saying that it is at
least ten years, because the failure rate of the whole class, 14 percent
at ten years, I feel very comfortable with that number. The failure rate
of the devices other than the 153, 3 percent at ten years.

Now, as a doctor if you\'re doing your job, and the patient comes in to
see you and says I\'ve had my implant for ten years, what you do is say
what implant do you have? Let\'s look at the data. The data on your
implant says failure rate at ten years is 20 percent. That\'s a high
risk. Maybe we should do an MRI.

Suppose you have the device which has a failure rate of 1 percent at ten
years? Do a physical examine and say I don\'t recommend you get an MRI.

I mean, you know, most doctors are capable of looking at the data and
making good judgments. Not all doctors. Not all doctors are good
doctors, they\'re not all perfect.

But I think what\'s challenging about this is that the devices actually
now are very durable. They have a long lifetime. How long a lifetime
it\'s hard to say, because we know 85 percent are going to go at least
ten years. I think for the single lumen devices, probably 95 percent are
going to go at least ten terms.

In terms of the finances, every patient I talk to I tell them it\'s not
a lifetime device. In fact, one of the jokes I have with patients is I
tell them I hope you have to come back for a replacement. It means that
we\'re both alive that long.

CHAIRMAN CHOTI: Thank you.

Dr. Li?

DR. LI: I\'m sorry. I\'m still struggling with this 153 issue.

So if we take the 153 issue out because it\'s got a higher rupture rate
than the others, I don\'t know if Dr. Blumenstein or one of your
statisticians can tell me this, but is there any other feature of 153
that\'s different than the rest?

For instance if I take the 153 data out of all of the data sets, do we
have any sense of what that does to the numbers, in other words quality
of life, connective tissue disease? I mean it could be \-- I mean is it
possible that 153 is bad in rupture but really good in quality of life
so if you take it out, it makes the rupture rate go down but also the
quality of life go down?

DR. WALKER: Well, the 153 was 64 percent of the reconstruction patients.
We\'ve taken that out, and we certainly can provide to the FDA those
data sets. And that\'s not a problem.

We\'ve taken that data out, we\'ve looked at it alone, and we\'ve looked
at it together, and it does not change the statistics either direction.

So 153, although it has a unique rupture rate, it does not change any
other parameters and the data looks the same essentially. But in
fairness, the FDA may not have divided those out, and our PMA does lump
them together.

DR. LI: Okay. Do you have a comment on that, Dr. Blumenstein?

DR. BLUMENSTEIN: I haven\'t seen any breakdowns, and I think it would
require extensive reanalysis of the data that\'s there.

CHAIRMAN CHOTI: Thank you.

Let me ask Dr. Miller, so there was some concern about some of the Panel
members regarding the \"lifetime.\" What is your feeling? I mean, is
there a time point? Is it like changing your tires? You don\'t wait for
a blowout. Should we be waiting at ten years, should we be changing
these out, or what do you recommend? What do you think we should as a
Panel think about in the implants that have been in for a while?

DR. MILLER: Well, the problem is that it has yet to be demonstrated that
a ruptured implant poses a health hazard. I mean, it\'s not \-- I don\'t
like the idea of ruptured implants being in somebody, but the fact that
they\'re silent is just the fact that they\'re silent. They\'re
asymptomatic, the patient has no manifestations; that\'s why it\'s a
silent rupture.

If they ruptured and the patient began to experience health problems,
then we would know the lifetime. We don\'t know the lifetime, and I
would like to know the lifetime. But is it required to know the lifetime
in order to judge these to be adequately \-- for the benefit that women
derive from them to exceed the risk? I mean, that\'s the difficult thing
about this whole question.

CHAIRMAN CHOTI: Dr. Newburger, you had expressed some concerns regarding
the lifetime of the device, yet you were assured of safety early on but
had some concerns later on. Have you heard any information or do you
have a comment on regarding whether there\'s a time point or a
threshold?

DR. NEWBURGER: I don\'t have a feeling about what the time point or
threshold is, because on the one hand we\'re supposed to be looking at
the European data, and on the other hand we\'re being told well, that\'s
not this device. So I don\'t really have anything to extrapolate to. I
just would feel a lot better if I could see what the shape of that curve
is.

CHAIRMAN CHOTI: Dr. Doyle?

DR. DOYLE: Is there any analogy with this and the copper-bearing
intrauterine device which was approved for a short period of time
because that was all the data that was available at the time and it was
subsequently extended when more data became available? They clearly
defined life span on that by the amount of data that was available.

CHAIRMAN CHOTI: Any other comments from the Panel?

DR. MILLER: Yes, could I make one more comment?

CHAIRMAN CHOTI: Yes. Dr. Miller?

DR. MILLER: I heard Dr. Newburger talk about feeling an urgency to
approve this, and I wouldn\'t agree with that. I don\'t feel an urgency
like there\'s a pressure to agree with this. I mean, I think we need to
vote our conscience on this and be very comfortable with the vote that
we make.

You know, there are women who would benefit from these implants who
don\'t have access to them. And I guess I feel that more critically
because I care \-- I take care of women like this for 15 years who need
a breast reconstruction, and I know the implications in my own personal
experience about the importance of this type of thing for women \--
breast cancer.

And so this is why if I feel any like wanting to get this resolved,
it\'s because of the women I\'m going to see in the next year. I mean, I
have access to these implants because I\'m a part of the Adjunct Study,
but there are many who don\'t. And if there\'s any motivation for me to
resolve this, it\'s really for the benefit of these women.

DR. NEWBURGER: I\'m very sympathetic to that as a clinician about the
urgency of any particular individual situation at that moment. But are
you sacrificing something in terms of real confidence and safety by not
having your data for another year and a half?

DR. MILLER: That\'s a very valid question. And I asked myself that
question long before even this meeting took place. And the \-- of
course, I would like to know everything about the implant, exhaustively.
I\'d love to know that; all the failure rates and the modes of failure,
everything I could possibly know I would like to know about the implant.
But we can never know everything. So at some point you have to start to
do this trade-off between the benefit that some people can experience
from it and depriving them of that benefit because we want more
information. And this is a calculation that each of us sort of has to
make. When do we cross that line when the information is adequate to
allow people access to this device?

Now for me, and we haven\'t talked about our vote yet so I won\'t
preempt everything, but I think we need to look at the data that does
exist. And the studies that have been done, the Core Study and all these
studies that have been mandated to be completed, they address some very
specific things but not everything. And it\'s valid to look at the body
of information we have over many years of these devices, and especially
the comprehensive reviews that have been done by bodies like the
Institute of Medicine and others that have been mentioned many times
here. I consider that evidence pretty compelling about the lack of
systemic disease and the risk of local complications.

I mean, I searched for a reason to doubt that, and I haven\'t seen it at
this point. I welcome it if it exists because I don\'t want to make a
mistake here either. Trust me. It\'s the last thing I want to do because
my personal number one concern are the women that I care for in my
practice, and that trumps everything. I want to make sure that we make a
sound decision here based on evidence.

CHAIRMAN CHOTI: Dr. Blumenstein?

DR. BLUMENSTEIN: I might as well jump in here. We don\'t have data on
systemic symptoms. We have no data on it except the hint that there is
an increase in them.

We also have a hint that there\'s something going on with quality of
life that\'s sort of unexpected.

And we don\'t have enough follow-up to know about systemic diseases.

That\'s the state I\'m in.

CHAIRMAN CHOTI: All right. Why don\'t we end our Panel discussion.

First of all, I\'d like to thank the public session as well for those
individuals that gave their time to speak here today, as they did
yesterday.

Are there any further comments from anyone at the FDA?

DR. PROVOST: No comments.

CHAIRMAN CHOTI: No comments.

And from Inamed Corporation, any final comments? Dr. Walker?

DR. WALKER: I can show you the international data if you\'d like to see
that, and I also just have some closing remarks.

CHAIRMAN CHOTI: Why don\'t you proceed with your closing remarks.

DR. WALKER: I will proceed with my closing remarks.

On behalf of my colleagues at Inamed I want to thank you all for your
time, your effort and the valuable input. Before you vote, I want you to
know that we\'ve heard what you\'ve said today. We have listened
closely, and we would like to make the following commitments.

We will continue our ten year Core Study which will include biennial
quality of life questionnaires. We will continue our retrieval study,
and we will make efforts to improve our data collection and the
analysis.

We agree that registries are difficult. Therefore, we intend to link our
registry with the warranty program to provide financial incentives to
encourage patients and physicians to participate.

We have heard your recommendation to provide strong and clear labeling
for Style 153, and we agree to do so. Inamed is committed to labeling
which adequately informs the patients and physicians regarding this
style implant.

As well, we will continue to work with the FDA to complete
implementation of design modifications for Style 153.

In addition, we will work through the Inamed Academy, surgical
societies, and continuing medical education programs to ensure that
physicians who use these products are properly trained.

In summary, based on the data and the evidence that we have presented
today, we believe that PMA application has met the statutory
justification for approval.

Thank you once again for your time and your attention.

CHAIRMAN CHOTI: Thank you.

Now it\'s time to proceed to the vote.

Sorry, Dr. Li has a follow-up question.

DR. LI: Sorry. I didn\'t mean to drag this on any more, but we had this
one patient that appeared, perhaps, to be in the Adjunct Study and was
apparently lost in the shuffle. Can you comment on that?

DR. WALKER: I can\'t comment on that particular patient because I don\'t
know her or her specifics without looking at the records. But what I can
comment on is what we do for any patient who is like the patient who
presented here today.

First of all, all of our devices are limited to patients who are
enrolled in either the Core Study or the Adjunct Study. Each device is
tracked to physician offices and then further tracked to individual
patients.

In the event of a complication, all physicians are requested to fill out
a case report form and to also report the adverse event to the company.
Each physician is incentivized if they should explant the implant to
return that explanted device to the company for analysis.

Further, every patient who calls or writes in to the company, we keep
scrupulous records of every call and every report which we file, and
then that would be included in our surveillance data.

DR. LI: Well, then as long as you\'re all together here, could I perhaps
suggest you contact this woman and see where the \--

DR. WALKER: Absolutely.

DR. LI: Thank you.

CHAIRMAN CHOTI: Now we can proceed to the vote.

Dr. Krause, will you read the voting instructions for the Panel at this
time?

EXECUTIVE SECRETARY KRAUSE: The Medical Device Amendments to the Federal
Food, Drug and Cosmetic Act as amended by the Safe Medical Devices Act
of 1990 allows the Food and Drug Administration to obtain a
recommendation from an expert advisory panel on designated medical
device pre-market approval applications that are filed with the agency.
The PMA must stand on its own merits and your recommendation must be
supported by safety and effectiveness data in the application or by
applicable publicly available information.

Safety is defined in the Act as a reasonable assurance based on valid
scientific evidence that the probable benefits to health under
conditions on the intended use outweigh any probable risks.

Effectiveness is defined as reasonable assurance that in a significant
portion of the population the use of the device for its intended uses
and conditions of use when labeled will provide clinically significant
results.

Your recommendation options for the vote are as follows.

\(1\) Approval if there are no conditions attached;

\(2\) Approvable with conditions. The Panel may recommend that the PMA
be found approvable subject to specified conditions such as physician or
patient education, labeling changes, or a further analysis of existing
data. Prior to voting all of the conditions should be discussed by the
Panel.

\(3\) Not approvable. The Panel may recommend that the PMA is not
approvable if the data do not provide a reasonable assurance that the
device is safe, or if a reasonable assurance has not been given that the
device is effective under the conditions of use prescribed, recommended,
or suggested in the proposed labeling.

Following the voting, the Chairman will ask each Panel member to present
a brief statement outlining the reasons for their vote.

CHAIRMAN CHOTI: Thank you, Dr. Krause.

Is there a motion? Dr. Newburger?

DR. NEWBURGER: I move that the device be voted nonapprovable at this
time.

CHAIRMAN CHOTI: There\'s been a motion for nonapprovable. Is there a
second to the motion?

DR. BLUMENSTEIN: I second it.

CHAIRMAN CHOTI: Dr. Blumenstein seconds the motion.

So a move has been made for not approvable for the application of the
silicone-filled breast implants for the Inamed Corporation. Would those
in favor of the motion please raise their hands? In favor of
nonapprovable.

Let the record show that the following vote yes for nonapprovable: Dr.
Blumenstein, Dr. Newburger, Dr. LoCicero, Dr. Manno, and Dr. Li. Those
voting no for the nonapprovable.

And the remaining, let the record show Dr. Leitch, Dr. Miller, Dr.
Callahan, Dr. Ewing.

So it\'s been voted five to four nonapprovable.

The recommendation of the Panel, again, is the pre-market approval
application for the silicon-filled breast implants for Inamed
Corporation be recommended for nonapprovable.

We\'ll now go around the room and get comments from various Panel
members. Let\'s start with Dr. Blumenstein.

DR. BLUMENSTEIN: I believe that there is not adequate data to allow us
to assess safety of this device, and some of the targeted efficacy data
that was part of the study was not realized.

CHAIRMAN CHOTI: Dr. Ewing?

DR. EWING: I voted against the nonapproval because I think that the
sponsor made their case.

I voted for nonapproval because I think the sponsor made their case for
safe \-- applicable implantation of this device to patient and that they
were committed to follow-up and with a long-term plan to monitor their
patients. And as a clinician, I\'m somewhat disappointed.

CHAIRMAN CHOTI: Thank you.

Dr. Newburger?

DR. NEWBURGER: I voted nonapprovable at this time, in no way denigrating
the data collection that\'s been done thus far. I feel that it\'s
premature. I don\'t feel secure about the safety. I don\'t think that at
this time patients can give informed consent, and informed consent
really is what this has to be about. And that\'s why I voted that way.

CHAIRMAN CHOTI: Thank you.

Dr. LoCicero?

DR. LoCICERO: I voted for not approvable because the data, although
magnificently manipulated, is only two real data points. We need more
data.

CHAIRMAN CHOTI: Dr. Manno?

DR. MANNO: I voted for nonapproval for the reasons stated by the other
speakers.

CHAIRMAN CHOTI: Dr. Li?

DR. LI: I\'m in a little personal agony here. This is the \-- my ?no? is
perhaps the weakest of no\'s. I think in October of 2003 I perhaps had
the weakest of yeses. So I\'m really kind of on the fence on this. So at
the end of the day I erred to go a little bit on the conservative side.

I think \-- I hope the FDA will allow you to continue to conduct your
business in a manner that you have allowing the use in reconstruction
and revision and you continue to gather the data. I think I would
probably vote for this unequivocally if you got a third data point, so
we just had some idea of where this line was going.

And the reason I\'m kind of perhaps leaning strong on that is because we
don\'t really know why this device is failing when it fails. If I had a
better idea of the mechanism of failure, I might be able to go along
with two data points because then I could make some of engineering or
some kind of calculation to make some kind of informed prediction. But
in the absence of that, I don\'t really know where the line is going
after those two data points.

So if you have the wherewithal for this, and I hope that you do, if you
could come back with the five year data and it looks as good as this,
then you got my ?yes.?

CHAIRMAN CHOTI: Dr. Callahan?

DR. CALLAHAN: Okay. Well, I\'m probably the weakest yes. But I voted not
\-- against not approval for the reason that I feel like it is a risk
benefit issue, and although I\'m not comfortable with all the data that
are being presented in terms of what\'s \-- from this particular study
about the connective tissue disease, I am comfortable with the studies
that have been done to date and published, like the IOM report. And I
think that a lot of case has been made that \-- I would not have voted
for complete approval, but if a lot of the constraints that have been
discussed were in place, I think I would have felt comfortable with
having this available for women to make a choice, and that they were
making a choice with all available data.

CHAIRMAN CHOTI: Dr. Miller?

DR. MILLER: Well, I voted against the motion. It\'s a difficult vote.

CHAIRMAN CHOTI: Use a microphone.

DR. MILLER: I appreciate the efforts of all the Panelists to try and
sort through all this. I can tell you, I think that each of us on the
Panel goes through a similar thing like a cost benefit analysis where we
look at the data available, and we have to judge whether it\'s adequate
to justify the benefit that we perceive patients will enjoy.

I\'m one of the few people on the Panel who \-- care for these women is
not a theoretical construct. I see these women \-- for 15 years I\'ve
cared for them. And I insert these devices. I care for the
complications. I\'m intimately personally failure with all the issues in
addition to the data. And this is one of the reasons why, maybe, the
threshold for me of the requirement for a full knowledge of these
devices may be a little lower.

I would love to know everything about the device, an impossible
standard. At some point we\'ll have to cross over and say we know enough
to have them available.

Now, for me I\'ve crossed that point, and I feel I know enough. And I
appreciate that for others it may not be the case. More data is only
going to help us understand this better.

And, again, as a plastic surgeon I\'ve heard lots of comments. It\'s
been interesting to be the only plastic surgeon on this Panel.

But any evidence that unfolds in the future which shows these are not
healthful to women, I can guarantee you myself and my colleagues would
be the first ones to oppose their use. And so I\'m open to the data that
unfolds in the future.

I guess that\'s all I would have to say. Thank you.

CHAIRMAN CHOTI: Thank you.

Dr. Leitch?

DR. LEITCH: Well, like Dr. Miller, I take care of patients who have to
deal with the damage I do to them in surgery to get rid of their cancer.
And so they are faced with trying to select a reconstructive option that
they will be happy with, because we expect to fix them. We expect to
cure them of their cancer so that they can live a long time. And we want
the life they live to be as high in quality as it can be.

I also, like everyone here on this Panel, the data that\'s being
presented, you like to scrutinize as much as you can, get every bit that
you can out of it, which is why in looking at the data with respect to
the model 153, if I had been able to vote yes for approval, I would have
accepted or had that be an exception that 153 would not be approved
because I feel like maybe the rupture rate is too great for the patients
it\'s most used in, which is those patients with reconstruction. And so
perhaps in that particular circumstance the risk benefit with respect to
rupture issues and having to be reoperated at a time when they\'re very
vulnerable would not be in their best interest.

Nevertheless, I think that overall the use of silicone implants dose
improve the quality of reconstruction for breast cancer patients. And I
would like that option to be available widely and not for them to have
it on the idea that it\'s something really bad and that they\'re somehow
being the guineau pigs for testing for this particular device.

The other thing I think which the sponsor\'s pointed out is that some of
the issues in rupture are related to perhaps technical issues. And as a
surgeon, I would certainly expect the surgical societies to have a
commitment to certification and education of surgeons to make sure they
do everything as well as they can to have these devices do well inside
the patient once they implanted. And that would have been something I
would have recommended.

As I mentioned, I also would have felt strongly that quality of life
data should continue to be collected, and I hope that it will continue
to be collected as it stands.

I think we, on a panel like this, are all effected by the stories we
hear of the patients who come up and present their information, both pro
and con. And a physician never likes to hear about a patient having a
bad outcome or being unhappy or feeling they weren\'t treated properly.

And I suppose the other admonition I would have to the sponsor is that
when I hear stories of patients who participate in a study or think they
participated in a study and feel they are not being followed up in that
study, that is \-- the only way we can accumulate this data is if there
is good follow-up in the studies. And I think both you and the plastic
surgeons who participate need to be committed to trying to obtain that
follow-up. I know it is not easy to do it perfectly. We certainly have
the same problem in cancer trials of maintaining follow-up, particularly
when patients are doing well. You know, once they\'re doing well maybe
they don\'t want to come back as frequently for checkups. But I think
what you\'re hearing is that the only way you\'re going to convince a
panel such as this is to have that continued follow-up and further data
to make your case so it\'s convincing to a panel such as this.

Thank you.

CHAIRMAN CHOTI: Thank you.

Yes, follow-up, Dr. LoCicero?

DR. LoCICERO: Yes. I just don\'t want to leave you with the feeling that
the clinicians are on one side and the scientists are on the other side.

I\'m a clinical thoracic surgeon. I take care of lung cancer patients
everyday. And I have the same commitment and Dr. Leitch have to the
breast cancer patients.

In terms of lung cancer, we have literature rife with great studies at
three years. At five years they don\'t look so hot. Give us a little
more data.

CHAIRMAN CHOTI: Dr. Bartoo, our industry representative?

DR. BARTOO: Obviously, I was not allowed to vote. But I would have voted
against the motion. And the reason why I would have voted against it is
because of our instructions, which is we would vote not approvable if
there was not reasonable assurance of safety or reasonable assurance of
effectiveness. And I think \"reasonable\" is the reason why I would have
voted against it.

I feel the sponsor has provided reasonable assurance. They\'ve provided
a lot of data, although not perfect, but enough to show reasonable
safety and showed commitment to continue on gathering that data.

CHAIRMAN CHOTI: Dr. Doyle, our consumer representative.

DR. DOYLE: I would have voted in favor of the motion. I find myself in a
unique position where I\'m supposed to forget my scientific expertise
and be the consumer. And as a woman I could relate in many ways,
although I have not been either an augmentation or breast cancer
reconstruction patient. But I tried to listen as carefully as I could to
the women who talked from both sides. And I think the commonality that I
found in both groups was that they both felt that it was an issue of
choice and that the decision should be made on the data, not on our
feelings or our interpretations.

And I think that had I been given a life span for this or had I been
told three years, I might have felt comfortable. I just did not feel
that the data justified approval at this time.

CHAIRMAN CHOTI: Thank you.

What I\'d like to do now is go through each Panel member, and starting
with Dr. Leitch who already started to do this relatively eloquently,
and that is to address the sponsor to make recommendations regarding
what you feel could be done to come back to the next Panel and be
approved.

DR. LEITCH: Well, I think clearly improving the follow-up on the
patients who are in studies so that the follow-up is better than 30
percent or 50 percent; that you have good follow-up is critical.

That the people who have spoken here who said they were in study and had
complications, that apparently have the feeling their data was not
included, that that data is obtained.

And you don\'t really have the opportunity at this moment, but when it
comes to the point of having approval that there would be an intent for
a specific certification of surgeons to put the implants in. Not that
you would certify them as surgeons, but you would certify that they have
participated in a training program specific to the placement of the
implants.

And I would certainly encourage working on model 153 to get that in
better shape.

CHAIRMAN CHOTI: Dr. Miller?

DR. MILLER: I think between the last Panel meeting and this one, I think
it\'s fairly clear what the task that you have is to do. And I think you
need to continue gathering the data as you have, and things will only
become more clear as time passes and the same sort of rigorous and
diligent data gathering and analysis is performed.

CHAIRMAN CHOTI: Dr. Callahan?

DR. CALLAHAN: Well, I would agree about definitely improving the
follow-up and continuing to collect the quality of life measures and
analyzing that over time, as well as perhaps trying to analyze the data
separately with 153 so we just knew what the differences were without
153 in there, and then continuing to work on improving or modifying or
changing, reengineering 153.

Analyzing the symptoms, not just looking for diagnoses a little more
carefully. And perhaps considering Dr. Blumenstein\'s suggestion to have
it go out to sort of an outside source for analysis.

CHAIRMAN CHOTI: Dr. Li?

DR. LI: Well, I think the thing I would like to see, and I think this
would for me, anyway, alleviate the need for say eight or ten year data.
I mean, I think you must feel how long do we have to collect the data
before this is considered to be safe. And I think for me the missing
thing is understanding of what limits the life of these devices. So
it\'s a little frustrating still to not know exactly what the gel bleed
rate is. We don\'t know exactly what the platinum leaching rate is. We
don\'t know how and why these things are rupturing or fracturing when
they do. If we had the answer those questions it makes it a lot easier
to accept three, four, five year data and be able to project it to ten.

So I think you\'ve done a nice job from the last meeting in 18 months or
17 months or whatever it is to up your retrieval collection. And you\'ve
actually made good attempts, I think, on the material testing side. But
it\'s still a little bit off, I think, of what the critical questions
are for the performance of the device.

So I mean I think your commitments are excellent. I think I would add to
that an increased commitment, if you will, to understanding the actual
nature of the failures of these as it applies clinically. So the idea
isn\'t to develop some laboratory test to make some measurement. The
idea would be to make some laboratory test that\'s clinically relevant
to the things that you see in the retrieved devices.

And I guess maybe a note to the FDA. And I don\'t know if this is
actually appropriate or not. But whatever letter you write to the
sponsor, I\'d hope you write it in such a way that actually encourages
them to continue their study, to continue their use and collect the data
that we need. Because I would like to see this device available for
women, because it seems to be the device of choice and have some
advantages. But I certainly don\'t want to do that unless I have some
\-- a little more assurance that actually it\'s projected to be safe.

So I\'ll leave it at that.

CHAIRMAN CHOTI: Dr. Manno?

DR. MANNO: I think I\'d like to make a comment first that I think all of
us on the Panel feel very strongly that the women should have a choice.
But we weren\'t charged with giving them the choice.

So if I had to vote entirely on that, I would have. But when I got right
down to it, this short time of gathering data bothered me more than I
thought in that the things that we\'re seeing is at that five year mark
as the thing gets fatigued, I\'m afraid that it will get a different
slope of a line and you will be legally at risk.

The reason I say it quite that way is I am trained originally as a
general toxicologist. So I look at things like you\'re supposed to look
at these type studies, but I have a subspecialty in forensic toxicology,
so I get involved in cases of failures of drugs or medical practice. And
a lot of the problems associated with losing in that situation is not
having the data available.

I just encourage you to continue. You\'ve made fantastic progress from
the last time. I\'m like Dr. Li, I think that if you go back home and
take a deep breath and sit down and take a few hours to rest and then
get back on the horse again and ride, I think you\'ll probably be there
soon. And I encourage you to keep it up because overall you have a
concept of a good product.

CHAIRMAN CHOTI: Dr. LoCicero?

DR. LoCICERO: I want to thank the sponsor for really doing a very good
job at collecting data.

As I went through this stuff, I was really conflicted about Style 153,
and I know that you knew that. In fact, 60 percent of your devices are
153 in this series. It\'s fairly large. I\'m sure that if you divided it
out you would find that there is still statistical difference between
the devices.

I think that you should be encouraged to look at that. I know that
you\'re planning to replace 153, maybe that\'s something that you ought
to think about doing now.

In terms of your primary endpoints, you met those. There\'s a lot of
discussion about secondary endpoints, though secondary endpoints are not
in question ?- or for me they\'re not in question.

The fact that you\'ve proven your efficacy is fine. I don\'t have an
issue with that. It\'s this particular problem, and it\'s the issue not
so much of long-term complications, it\'s the short-term complication. A
rupture means a reoperation. And so you\'re exposing \-- and that may
not be true in all cases. But you\'re exposing a patient to another
operation when you know that there\'s devices that you\'re going to be
replacing it with or where the other device would work just as well.

So, again, I encourage you to continue your work, and I look forward to
seeing you back.

CHAIRMAN CHOTI: Dr. Newburger?

DR. NEWBURGER: I echo the comments of my colleagues on the Panel. I
think your data collection is good. I ask for when you do your data
analysis it would be a lot easier for us if the data wasn\'t merged
across all the indications because there are clearly very, very
different incidences of adverse events. And I just would encourage you
to persist, and I\'m sure you will.

This is a device which will be used by hundreds of thousands of
individuals, and I hope that the five year data is forthcoming.

CHAIRMAN CHOTI: Dr. Ewing?

DR. EWING: I appreciate your dedication to getting your product out on
the market.

CHAIRMAN CHOTI: Speak directly into the microphone.

DR. EWING: I really appreciate your dedication of trying to get your
product out on the market and providing us with the information.

I look forward to your next presentation when we have the third data
point and more information about the 153 model, maybe with the
modifications.

CHAIRMAN CHOTI: Dr. Blumenstein?

DR. BLUMENSTEIN: I don\'t have a lot to add to what I\'ve already said.
But I think that one thing to consider is to take this opportunity to
perhaps launch a randomized clinical trial between saline and silicone
gel and limit access to silicone gel except through the participation in
the randomized clinical trial. That would provide the kind of definitive
answer that we need.

CHAIRMAN CHOTI: Something told me you\'d recommend the randomized trial.

Dr. Doyle?

DR. DOYLE: I, too, want to commend the sponsors for the data that they
gave us, and I would just hope that they would give us the kind of data,
and when we have more data that we will be able to vote a positive next
time.

CHAIRMAN CHOTI: Dr. Bartoo?

DR. BARTOO: I agree with the other members of the Panel.

The only other thing I might add is that there\'s been a lot of concern
about 153, and I know you are working on modifying that device. Maybe
recommend that you start collecting data as soon as you can on that new
device so that, hopefully, we can see some of that data at the next
Panel meeting.

CHAIRMAN CHOTI: Comments, Dr. Provost?

DR. PROVOST: No. I just wanted to thank the Panel for your service today
and for all of your helpful comments and discussion.

CHAIRMAN CHOTI: I also want to thank everyone yesterday and today that
helped educate the Panel, helped them with their deliberations.

I know I can say, I think, to speak for the others of the Panel, it was
an extremely difficult decision, and I think they were a very thoughtful
group. We spent a lot of time thinking about this.

I also want to remind them that we have another day tomorrow. So we\'ll
see you all here promptly at 8:00. Thank you.

(Whereupon, the Panel was adjourned at 6:17 p.m., to reconvene again
tomorrow, April 13, 2005 at 8:00 a.m.)