UNITED STATES OF AMERICA

P‑R‑O‑C‑E‑E‑D‑I‑N‑G‑S

(7:59 a.m.)

CALL TO ORDER

EXECUTIVE SECRETARY KRAUSE: All right.

Good morning. We are going to be running on a fairly

tight schedule today. So I would like to try to get

the meeting started as soon as possible. If everybody

could please have a seat? Thank you.

Good morning, everyone. We're ready to

begin this, the 64th meeting of the General and

Plastic Surgery Devices Panel. My name is David

Krause. I am the Executive Secretary of this panel.

I'm also a biologist and a reviewer in the Plastic and

Reconstructive Surgery Devices Branch.

I would like to remind everyone that

you're requested to please sign in on the attendance

sheets, which are just outside the door. At that

table out there, you can also pick up an agenda, a

roster of the panel members, and information regarding

today's meeting. 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.

I don't know if everybody knows, but the

FDA normally posts the transcript of these meetings

within about two or three weeks after the meeting on

our Web site. So you can get them there.

CONFLICT OF INTEREST, TEMPORARY VOTING MEMBER

DEPUTIZATION AND OPENING REMARKS

EXECUTIVE SECRETARY KRAUSE: Before

turning this meeting over to Dr. Chang, I am required

to read two statements into the record. The first

statement that I read is the deputization of temporary

voting members. And the second is the conflict of

interest statement.

I am going to read the deputization

statement first, "Pursuant to the authority granted

under the Medical Devices Advisory Committee charter

dated October 27, 1990 and as amended on August the

18th, 1999, I appoint Joseph Boykin, Robert

Diegelmann, John Doull, John Halsey, and Michael

Olding as voting members of the General and Plastic

Surgery Devices Panel for this meeting on November 21,

2003. In addition, I appoint Phyllis Chang, a voting

member, to act as temporary chair for the duration of

this meeting.

"For the record, these individuals are

special government employees and consultants to this

panel or other panels under the Medical Device

Advisory Committee. They have undergone the customary

conflict of interest review and have reviewed the

material to be considered at this meeting." This memo

is signed by Dr. David Feigal, who is the Director,

Center for Devices and Radiological Health.

The second statement that I read into the

record is the conflict of interest statement, "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 an

impropriety. To determine if any conflict existed,

the agency reviewed the submitted agenda for this

meeting and all financial interests reported by the

committee participants.

"The conflict of interest statutes

prohibit special government employees from

participating in matters that could affect their or

their employers' financial interests. 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 Drs. Diegelmann, Halsey, and Miller. Each

of these panelists reported current and/or past

interest in firms at issue but in matters not related

to today's agenda. The agency has determined,

therefore, that they may participate fully in today's

deliberations.

"In the event that the discussion involves

any other products or firms not already on the agenda

for which an FDA participant has a financial interest,

the participants should excuse him or herself from

such involvement, and the exclusion will be noted for

the record.

"With respect to all other participants,

we ask in the interest of fairness that all persons

making statements or presentations disclose any

current or previous financial involvement with any

firm whose products they may wish to comment upon."

I would also like to remind anyone who has

a cell phone to please put that cell phone on some

kind of a silent mode so we don't hear phones ringing

all day.

At this point I would like to turn the

meeting over to Dr. Chang.

ACTING CHAIRPERSON CHANG: Good morning.

My name is Dr. Phyllis Chang, and I am the acting

panel chair for this session. I am an associate

professor in the Department of Surgery and staff

surgeon, plastic surgeon, and hand surgeon in the

Department of Surgery and Orthopedic Surgery at the

University of Iowa Carver College of Medicine.

Today the panel will be making

recommendations to the Food and Drug Administration on

two pre‑market approval applications. The next item

of business is to introduce the panel members who are

giving of their time to help the FDA in these matters

and the staff here at this table.

I am 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, whether voting member, industry or consumer

representative, or deputized voting member. I would

like to begin with Dr. Witten on my far right. And

then let's please go around the table.

DR. WITTEN: I'm Dr. Celia Witten with

FDA. I'm the division director of the reviewing

division for these products.

MEMBER LoCICERO: I'm Joseph LoCicero.

I'm professor and chair of the Department of Surgery

at the University of South Alabama. I'm a thoracic

surgeon by training. And I'm a voting member of the

panel.

MEMBER MILLER: I'm Michael Miller. I'm

a professor of plastic surgery at the University of

Texas, M. D. Anderson Cancer Center. I do clinically

primarily cancer reconstructive surgery. And I am a

voting member of the panel.

MEMBER NEWBURGER: I'm Amy Newburger. I'm

director of Dermatology Consultants of Westchester,

which is a private practice in dermatology in

Scarsdale, New York. I teach at St. Luke's Roosevelt

Hospital Medical Consortium. I am a voting member of

the panel.

MEMBER DIEGELMANN: I'm Robert Diegelmann.

I'm a professor of biochemistry at the Medical College

of Virginia, Virginia Commonwealth University in

Richmond, Virginia. My specialty is in the area of

tissue repair. And I'm a deputized member of the

panel.

MEMBER BOYKIN: Dr. Joseph Boykin,

clinical assistant professor of plastic surgery at the

Medical College of Virginia in Richmond and also the

medical director of the Wound Healing Center Retreat

Hospital. I'm a deputized voting member. And areas

of interest are wound healing, reconstructive and

cosmetic plastic surgery.

MEMBER HALSEY: John Halsey. I'm the

owner and director of IBT Reference Lab, a clinical

immunology laboratory and a contract research facility

in the areas of allergy and immunology. I'm also

chair of the Clinical Laboratory Immunology Committee

for the American Academy of Allergy, Asthma and

Immunology and a member of the Immunology Devices

Panel.

MEMBER BLUMENSTEIN: I'm Brent

Blumenstein. I'm a biostatistician. I had my own

company, TriArc Consulting, out of Seattle. And I am

a voting member.

MEMBER DOULL: I'm John Doull. I'm a

clinical toxicologist from the University of Kansas.

I'm a deputized member.

MEMBER OLDING: Michael Olding. I'm chief

of the Division of Plastic Surgery, George Washington

University, associate professor at that institution.

And I am a deputized voting member.

MEMBER DOYLE: I'm LeeLee Doyle. I'm

professor emeritus of obstetrics and gynecology. I'm

the associate dean for continuing medical education

and faculty affairs at the University of Arkansas for

Medical Sciences College of Medicine. I am the

consumer representative, which is a nonvoting

position, on this board.

MEMBER BARTOO: Finally, I'm Grace Bartoo.

I'm the vice president of clinical and regulatory

affairs at a company called Instruments for Science

and Medicine, which is a small consulting firm to the

biomedical device industry. My expertise is in

biomedical engineering and software development. And

I'm the industrial representative, which is a

nonvoting member.

ACTING CHAIRPERSON CHANG: Thank you.

I would like to note for the record that

the voting members present constitute a quorum, as

required by 21 CFR Part 14.

Now I would like to introduce Commander

Stephen Rhodes, the branch chief of the Plastic and

Reconstructive Surgery Devices Branch, who will update

the panel since the last meeting.

CDR RHODES: Thank you, Dr. Chang.

UPDATE SINCE LAST MEETING

CDR RHODES: I am the branch chief here at

the Plastic and Reconstructive Surgery Devices Branch.

My update today will be brief since this panel last

met about five weeks ago to discuss a PMA for a

silicone gel‑filled breast implant, which the FDA is

still reviewing the recommendations from the panel for

that.

Today we are going to be talking about two

wrinkle products. In the morning, we will be

discussing a product called Restylane from Q‑Med and

in the afternoon a product called Hylaform from

Genzyme Corporation.

I want to extend my appreciation to you

for your participation. I also want to thank the

public speakers, who have chosen to elect to speak in

the public sessions and also the two companies who are

going to be presenting their safety and effectiveness

data in their PMAs.

That concludes my update. Thank you very

much.

ACTING CHAIRPERSON CHANG: Thank you,

Commander Rhodes.

We will now proceed with the open public

hearing session of this meeting. All persons

addressing the panel are asked to speak clearly into

the microphone as the transcriptionist is dependent on

this means of providing an accurate record of this

meeting.

Both the Food and Drug Administration and

the public believe in a transparent process for

information gathering and decision‑making to ensure

such transparency at the open public hearing session

of the advisory committee meeting.

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, its

direct competitors.

For example, this financial information

may include the sponsor's payment of your travel,

lodging, or other expenses in connection with your

attendance at the meeting. Likewise, FDA encourages

you at the beginning of your statement to advise the

committee if you do not have any such financial

relationships. If you choose not to address this

issue of financial relationships at the beginning of

your statement, it will not preclude you from

speaking.

We will start with those individuals who

have notified the FDA of their intent to testify

during the open public session. Is Elizabeth Santoro

present? Please come to the microphone and make any

disclosures that you wish.

OPEN PUBLIC COMMENTS

MS. SANTORO: Good morning. My name is

Elizabeth Santoro. I'm a registered nurse and also

have a Master of Public Health with a concentration in

health policy. In addition, I'm a health policy

fellow at the National Center for Policy Research for

Women and Families.

This morning I will be reading the

testimony of our president, Dr. Diana Zuckerman, who,

regretfully, could not be here today. Please note

that I am waiving my testimony for her. She has no

conflicts of interest. Neither do I.

Our center is a think tank that translates

research findings into meaningful information for the

public. We use that research information to advocate

for policies to benefit the health and safety of

women, children, and families.

It is clear that both women and men alike

search for the Fountain of Youth. We know that these

products are used widely. And that's why they should

be carefully studied. They should be approved if they

are safe and effective.

Of course, it's difficult to make this

statement before the data are presented, but based on

what was made available by the FDA yesterday on their

Web site, these are our concerns. Our main concern

about Restylane is the lack of data for African

Americans and Asian Americans. Only two of the

patients are African American, and only two are Asian

American.

Research clearly shows that African

Americans are more likely to produce keloids and can

respond differently to procedures involving the skin.

In addition, African Americans are more likely to

develop autoimmune diseases than white women. The

company has not studied a reasonable number of African

Americans or Asian Americans to approve the product

for those populations.

Our center has joined with the National

Medical Association to express our very strong

concerns on this issue to the FDA commissioner. It is

a great concern for all of the products of this type,

not just the products under review today.

The FDA has suggested one solution:

post‑market studies. We strongly believe it is not

appropriate to require studies for minority

populations on a post‑market basis since the FDA has

no authority to enforce these requirements. The

company should be required to do the studies before

the product is approved.

It is also inappropriate to label the

product "For whites only." I am sure that I am not

the only person in the room who believes that it would

be inconsistent with the values of our country to

approve products only for white people unless there

was a compelling reason; for example, if a product was

found to be safe for whites but unsafe for other

racial or ethnic groups.

Such a label is not an appropriate way

around a sponsor's failure to conduct research on

people of color. Moreover, if there are no data on

people of color, it is likely that the product will be

used off label by them anyway. And that could be

potentially very dangerous. Research is needed. And

it won't take long to do it. And it should be done.

Another shortcoming on the research on

Restylane is the relatively small sample size. The

sample starts with only 138 people. And only 125 are

still in the study after 12 months. Since this is a

cosmetic procedure that is likely to be used by

hundreds of thousands, perhaps millions of people, the

product should be tested on a larger sample to

determine if there are rare adverse reactions that are

serious enough to be considered before approval.

Our final concern is a lack of long‑term

follow‑up and a lack of research on women who undergo

the procedure multiple times. It is clear from

published reports that women who have a good outcome

the first or second time they use this product may

have serious adverse reactions after the third or

later procedure. This needs to be studied before

approval since it is clear that their product will be

used more than once or twice.

We would like to make a final comment

about the risks and benefits of this product.

According to the company's own data, the product is

not necessarily better than the comparison product

Zyplast. For that reason, we believe rushing this

product to market without gathering the additional

data listed above is unwarranted.

Thank you.

ACTING CHAIRPERSON CHANG: Thank you, Ms.

Santoro.

And now is Dr. Lowe present?

DR. LOWE: Yes. Good morning. Thank you

to the FDA for allowing me to present some

information.

I am clinical professor of dermatology at

UCLA, but I also have private practices in London and

Santa Monica and also research, clinical research,

facilities.

I am presenting experience with the

Hylaform and Restylane products, particularly since

1996, in my London practice. It's that data that I

wish to present this morning.

Essentially in Europe, certainly in the

U.K., Restylane has become the most widely used

hyaluronic acid filler in the United Kingdom. And, as

we will shortly see, I think that I will show reasons

for that.

I wrote a publication published in the

Journal of the American Academy of Dermatology that

was published in the year 2001 in which we looked at

over 700 patients that had received both Hylaform and

Restylane. We found that there was an approximate .4

percent incidence of delayed nodular inflammatory

reactions in the skin. And we followed up by testing

some of those individuals with forearm skin test

challenge and finished up by getting positive results

in some of those patients.

Since the year 2000, here are my slides.

Actually, we can go through them a little bit quickly.

As I say, I'm a consultant dermatologist and faculty

member in London as well as at the University of

California in Los Angeles and have practices and

clinical research units in both places.

ACTING CHAIRPERSON CHANG: Dr. Lowe, would

you be willing to share with the panel whether or not

the sponsor has supported your travel?

DR. LOWE: Yes. This is my slide. And I

want to disclose conflicts of interest in two areas.

One is my research site in Santa Monica was one of the

research sites for the Hylaform product. And that was

funded by Genzyme.

And I have received educational grants

from both Medicis and Q‑Med. And Medicis has enabled

us to do some recent research studies on our U.K.

patients and has allowed me the funding to be here

this morning. So I make those disclosures.

This was a summary of our Journal of the

American Academy of Dermatology report, where we

found, as I said, with the old Restylane, which was

modified in the year 2000, and with Hylaform, we found

an incidence of about .4 percent delayed nodular

reactions.

In a total of six patients, three of

others that were referred to me, we found that four

patients actually I was able to elicit positive

forearm testing. This is published in that article.

Since the year 2000, I have changed almost

entirely over to using Restylane products in the

United Kingdom for skin‑filling scar revision and

other deformity‑filling for the reason that it is a

non‑animal hyaluronic acid.

And there was considerable improvement in

the formulation in the year 2000 with a considerable

reduction in protein load. So the actual numbers of

patient treatments that we have been able to review in

a chart and case review from 2000 to 2003 is 1,537

patients.

I acknowledge my coworkers, my dermatology

colleague, Dr. Anne Maxwell; my plastic surgical

colleague, Mr. David Ross. So we have 1,537 patients

that we have been able to review charts and cases of,

1,537 treatments in a total of 558 patients. So, as

you can see, many of those patients received,

actually, at least three or more injections, some up

to five or six injections, some one or two injections.

The demographic grouping was preferences.

We got far more females than males. And I didn't have

the breakdown of racial or ethnic subsets, but

significant numbers of these patients were Asian and

some black patients as well.

Age range was 22 to 28. And with a review

of these 1,537 patient treatments, we found with the

new formulation of Restylane zero incidence of

hypersensitivity reactions.

This somewhat is reinforced. This is the

old data with the old Restylane and present Hylaform.

You can see the old data presented here again. This

is the new formulation Restylane, Perlane. And there

was a previous manuscript by Friedman, et al.,

published last year in one of the derm surgery

journals that showed an incidence of about one in a

thousand hypersensitivity reactions.

So the adverse reactions that we saw in

the 1,537 patients that we reviewed, 1,537 patient

treatments in 558 patients that we reviewed.

MEMBER OLDING: Excuse me. I hate to

interrupt you, but your slide said one in 5,000, I

believe, and you said one in 1,000.

DR. LOWE: I apologize. The correction is

one in 5,000. Thank you.

The adverse events in the group of

patients that we have recently looked at is that we

find common immediate erythema, which is clinically

not of great significance and usually results in a

matter of one to two days.

ACTING CHAIRPERSON CHANG: Dr. Lowe, could

you please summarize?

DR. LOWE: I will. This is my last slide.

Edema common with Perlane, which is the thicker one,

transient lumping, and one technique‑dependent

vascular occlusion in the forehand. This is the sort

of delayed reactions that we see, nodular painful

reactions in this instance with Hylaform.

My final slide is that the delayed allergy

risk with Restylane products is extremely rare. We

found no allergy in 1,537 patient patients in 558

patients.

Previous reactions observed with the old

form of Restylane was less severe than that observed

with Hylaform. All the hyaluronic acid reactions

observed were less severe than with the

Zyderm/Zyplast.

And, in conclusion, Restylane, Perlane

products are the most frequently used hyaluronic acid

fillers in the United Kingdom.

Thank you for your attention. And I

apologize for the problems with the computer.

ACTING CHAIRPERSON CHANG: I would like to

thank all of you for taking time of your schedules to

testify to this panel.

I would like to remind public observers at

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 are now ready to begin with the

applicant's presentation.

APPLICANT PRESENTATION, Q‑MED AB, RESTYLANE

DR. STROBOS: Hi. My name is Jur Strobos.

I'm a physician. I change as a general surgeon. And

I am working as a consultant to the pharmaceutical

industry and today for Medicis and Q‑Med.

We are going to try and stick to pretty

much the schedule that you have laid out there. For

some reason, not all of our speakers got on the

agenda. We are going to have Dr. Agerup as the CEO of

the company and inventor of the product as well as

four physicians to the clinical investigators

discussing the product. And I will introduce them as

we go through.

We did time the talk yesterday, and I

think we are going to try and keep it to 45 minutes.

I understand that would be about 30 minutes for

questions.

That said, let me introduce Bengt Agerup,

who is the president, CEO, and inventor of the

Restylane product.

DR. AGERUP: Good morning. It's a

pleasure and honor to be here. What we have designed

when we designed the Restylane is a product that would

reduce immunogenicity. That means it would not be

based on foreign proteins or have too much protein

contaminants. And they are also, of course, nontoxic.

And we would refrain from using animal‑origin

substances. So, for instance, rooster combs, bovine

collagen, et cetera, were not an origin. We also

wanted to decrease the esterase and protease‑mediated

degradation. That always happens in the skin.

So we used biotechnology to derive

hyaluronic acid, a non‑animal source. And we used the

purification process that we even increased in

efficacy in 1999 that you heard this morning to reduce

the protein contaminants. We are now down to less

than six parts per million, and we are still working

on this subject.

We don't have any animal nucleic acids.

And we think this is the first or it is the first

dermal filler that is not classified as a

xenotransplantation product.

Hyaluronic acid is completely useless as

an implant unless you modify it. We have chosen

modification products that are commonly used in

household articles and also in glues and other things,

other products.

We also use this BDDE in ether form of

binding that makes it very stable and less sensitive

to esterase. We also patented a way to use these BDDE

cross‑links at very, very low concentrations. So, for

instance, it's about one percent of the material used.

So that leaves very small amounts of BDDE in the final

product.

So this is non‑animal. Then we call this

non‑animal stabilized hyaluronic acid. And we call it

stabilized because it's not really cross‑linked in a

way that you would normally find in modified products.

I thank you very much for your attention.

DR. STROBOS: Now I would like to

introduce Dr. James Leyden, who is a professor of

dermatology from the University of Pennsylvania. He

was one of the investigators in the pivotal study. He

is going to present the data from the pivotal study.

DR. LEYDEN: Thank you. Good morning. My

name is Jim Leyden. I am now professor emeritus,

actually, at the University of Pennsylvania. I've

been a member of the department since 1967, I guess,

had a wide range of interests. About 20 percent of my

research interest has been in appearance‑related

issues.

I have been asked by Medicis to present

the data from the multi‑centered clinical trial, of

which I was one of the investigators.

As far as my connections with Medicis, I

am not a consultant. I don't own any stock. I have

participated in some studies several years ago,

microbiologic studies. I have also served on advisory

panels.

Perhaps my major connection is that I am

a co‑chair of the clinical conference called the

Valley of the Sun, which preexists Medicis in how long

that meeting has been going on. But because Medicis

is in the Valley of the Sun, they have been a major

supporter of our annual conference.

So, with that introduction, I would like

to present to you the results of this randomized,

double‑blind, multi‑centered comparison of the safety

and efficacy of Restylane and Zyplast.

It was a six‑center study. There were

plastic surgeons and dermatologists involved. Each

center had a treating physician and then a blinded

evaluating physician.

This is the design of the protocol. As I

said, it's multi‑centered. It was a

patient‑controlled kind of study in which each patient

received both Restylane and Zyplast. It was

randomized by side and blinded to the patient as well

as to the evaluating dermatologist. And in the

evaluation, a validated wrinkle severity score that we

will discuss a little bit in a few minutes was used.

Patients were basically recruited and

tested with collagen and then randomized as far as

which eye got Zyplast and which eye got Restylane.

And then there was a period of time when both the

patient and the treating physician would decide when

optimal correction was achieved and there was the

opportunity for so‑called touch‑up injections to

whatever side seemed not to be optimally corrected.

Once that was stabilized for two weeks,

they were launched into the evaluation phase and seen

at two, four, and six months. At this point, patients

had the opportunity to enroll in an open label

extension, where they would receive Restylane. Most

of the patients, in fact, did enroll in that open

label portion of the study.

These are the demographics. As you can

see, as was pointed out in the open session, these

were predominantly white women, as you see here. You

will hear later about a study that Medicis is going to

do, will do in African Americans in America.

Contrary to what was said in the open

session, there actually is an extensive experience in

other populations. There is extensive experience in

Asia and in South America. But definitely a study in

African Americans is indicated and, as I say, will be

done.

Now we get into the wrinkle severity

rating scale, as you can see here, is a one to five,

with one being basically the ideal situation with no

visible nasolabial fold or wrinkling, ranging up to a

very severe form, which even after stretching the

skin, you still had roughly a two to four‑millimeter

visible groove. This scale was developed in

cooperation with the FDA; validated; ‑‑ and we will

discuss that in a second ‑‑ and, in fact, has been

submitted for publication.

Just to give you some ideas of what these

scales look like, here on the one side, you can see

sort of a mild grade two. Here is another individual

and another. These are grade scores two, a little

more intense here with three, another three there,

another three, and then more severe forms here. You

can see that even when you stretch the skin back,

there is still a prominent groove in the nasolabial

area and another four and another.

Now, before the study began, there was a

validation study. There were five investigators who

looked in 2 sessions separated by I believe a week,

looked at 30 photographs of individuals ranging with

different severity of nasolabial grooving. We have

displayed it here this way, and we take a second to go

through this because the same kind of chart will

appear when we look at the six‑month primary efficacy

data.

If you look here, you see the session two

with grades one through five and session one with

grades one through five. And if you go down this

diagonal, sort of light green, those are the times

when the scores were identical.

And you can see that for the left and the

right, there was a high degree of concordance, in the

range of 70 percent. And here is the kappa ratio,

kappa coefficient. The yellow represents where there

was discordance.

And you can see that basically all of the

scores were either equal or within one grade of each

other. There was no instance of a wider discrepancy.

MEMBER LoCICERO: Excuse me. Could you

define who the observers are?

DR. LEYDEN: They were five of the

investigators in the study.

MEMBER LoCICERO: Were they blinded to who

these patients were?

DR. LEYDEN: These weren't patients.

These were photographs. This was before the studies.

They were looking at photographs similar to the kinds

of photographs I showed you initially. So they didn't

know who they were if that's what you're getting at.

Now, here is the primary efficacy analysis

using the same kind of chart. This is the comparative

change in wrinkle severity score at the six‑month

period in the so‑called intent‑to‑treat population.

That means everybody who got launched. Those who were

lost to follow‑up were counted basically as no change

from baseline, which weighs against any effect for

either treatment.

So we have the change in severity rating

scale. A plus three would mean that a patient went,

for example, from a four to a one. Two would be, say,

from a three to a one or a four to a two. And this is

for Restylane. And this would be for Zyplast.

Now, again, if you look down the diagonal

in this sort of grayish zone, that's when there was

equivalent grade given on both sides. Anything above

this line, Restylane, had a better score that Zyplast.

And anything on the lower end of this diagonal,

Zyplast, had a better score, rating score, than

Restylane.

I think you can see a lot more numbers up

here than there are here. And down here we have

summarized that, the Restylane side, with one grade or

more improvement compared to the Zyplast side. There

were approximately whatever that is, 57 percent. And

equivalent grades were given in approximately a third

and then nine and a half percent on the Zyplast side.

There was a better score, a higher score, than was

seen on the Restylane side. These differences were

statistically significant by a variety of analysis, as

listed here.

Now, in the information that was submitted

to the panel that I saw and in some of the slides from

the FDA that I saw, there are a few issues that I

would like to bring up and discuss. One of them is

that the wrinkle severity score may lack strength at

less than one plus change and that the scoring system

was not revalidated, that the McNemar analysis may

disregard patients with equivalent results and tends

to focus on those results that are discrepant from

equivalency that there wasn't a longitudinal analysis

performed, that there is no evidence of effect beyond

six months, and that incomplete masking raises a

possibility of unmasking and bias. So let's address

those issues.

Actually, if you look at the data between

the treating physician and the evaluating physician as

far as grading, there is a very high degree of

concordance and correlation and grades given that

exceeds what was seen in the initial validation event.

I think that reflects the fact that this is with live

patients and you can actually stretch the skin and you

can get a better judgment of what is left after

stretching the skin; whereas, in the initial

validation, they were looking at photographs.

Now, as I understand it, the McNemar

analysis does actually account for non‑discrepant

cells in the denominator. The way that type of

analysis is done in the case of Restylane, there are

78 out of 137 that were superior and in the case of

Zyplast, 13 out of 137. So it does take into

consideration the individuals in which there was, in

fact, no difference.

In terms of the superiority, which

obviously is an important issue that you as a panel

have been asked to address as to whether or not the

data shows superiority of Restylane over Zyplast,

there are several things listed here. And then we

will go through an individual slide for each of them.

If you look at the responder rate of

patients with one‑plus or even a more conservative

analysis of a two‑plus improvement at six months after

that initial injection, Restylane is superior

statistically.

The question has been asked of you if at

the end of 6 months you take all patients into

consideration and look at the difference between the

mean of those 2 groups, the difference is .56. And

the question is, is that mean difference significant,

particularly in consideration of the question that we

just discussed about the strength of the scale in

terms of less than one grade?

Using two types of analysis, both

parametric and non‑parametric, Restylane was superior

statistically to Zyplast. There was a longitudinal

assessment done. And it also showed Restylane

superior to Zyplast.

Then I think importantly, very

importantly, is that patient evaluation also gave

almost the same numbers as the evaluating

dermatologist. Then let's just look at those in a

little detail.

Here we're looking at the responder rate

of those with a one‑plus or a two‑plus improvement

still present at six months. And you can see that for

the one‑plus, we have a 70 percent for Restylane

versus 32 percent for Zyplast and the much more

conservative, more significant clinical response of

two‑plus improvement still present. Again, there is

more than a three time improvement for Restylane

compared to Zyplast. And both of these are clearly

statistically different.

If you look at the means, as I said, that

mean difference at the end of 6 months was .56. Here

you can see for anybody who is interested the

confidence intervals. But the important point is that

with both parametric paired t‑tests and non‑parametric

signed rank tests, these means are significantly

different statistically.

Here is the longitudinal analysis over

two, four, and six months. You can see as early as

two months. It's not easily seen here, but there are

three crosses there, indicating a .001 significant

difference at this point, out here and here.

I would absolutely agree with the reviewer

that after six months, there is just not enough

information to say anything. So I think up to six

months, there's a lot of information that says that

Restylane is superior to Zyplast, but after six

months, I would agree there is not enough data.

Most of these people basically at the end

of six months said, "Yes, I would like the injection

on both sides." They got the injection, and they

said, "Aloha." And that was it. They really didn't

return. There was a very poor follow‑up.

Here is the patient assessment data using

two things, the relative improvement and wrinkle, as

well as the global improvement. And you can see that

here Restylane is superior to Zyplast, both of them in

the range of 50 to 55 percent and equivalency here and

much lower rate for Zyplast. So the patients agreed

that they got greater improvement with Restylane than

with Zyplast. I think that's important.

Let's get into this issue of masking.

Unmasking, of course, could serve as a signal of

possible unblinding. The evaluators who were involved

in this study tested in writing apparently that they

basically were guessing. They had no idea. They were

just guessing.

I don't think there's any reason to impute

bias. These people have no financial reasons or other

reasons to be biased one way or the other towards

Restylane or Zyplast.

I think an important point in this that is

different than what I have seen at least in one or two

of the slides from the FDA for your afternoon session,

is that, contrary to the study that you're going to be

discussing this afternoon, evaluators were required to

make a forced choice. They did not have the

opportunity to say, "I don't know. I really don't

know." They had to make a choice.

Incidentally, if you remove the

incompletely masked sites at different points, they

vary. It's not the same sites that are always

"potentially unmasked." If you do that and do an

analysis again, you get the same results. So take

that into consideration.

Now let's get into the adverse reactions.

First we'll talk about serious adverse reactions and

then briefly all the emergent events. We will

obviously concentrate mostly on the local events,

particularly the persistent erythema and whether or

not allergic or immunologically driven

hypersensitivity reactions took place.

There really were only two serious adverse

events. There was a patient who had a laminectomy,

another patient who got a pacemaker installed six

months after treatment. It's fairly clear that these

are unrelated.

Here is the last of all the things that

come out in the usual studies. The way they're coded,

there are basically 142 that were for collagen and

Restylane that were judged to be related to the

treatment. So we'll be discussing them.

They were captured in two ways. There is

a patient diary during the first 14 days following

that initial injection and launched into the

evaluation period in which patients were encouraged to

write down anything and everything and to try as best

they could to make a judgment as to whether they

thought it was mild, moderate, or severe.

Then, of course, there's the case report

form, where the injecting physician captures

information and reports that historical information

from the patient to capture the entire event and

follow it to its completion. That, as we will be

discussing, is primarily this persistent erythema

issue.

So in terms of severe reactions, basically

in the case report form, there were four. And they

were one patient who reported severe events of redness

and swelling on two different days, who then got

followed by the treating investigator until that event

was over.

This is a photograph from that patient.

This photograph was taken on 4‑30. You can see that

there are about ten days after 4‑20 when it was judged

to be severe. This is the Zyplast side. We didn't

show you the Restylane side because you can't see

anything in it at 4‑30.

So this shows you how this patient looked

ten days after she personally judged what she saw in

terms of redness and swelling to be severe. I just

show that to show you that that was resolved fairly

quickly and appears to be one of those typical kinds

of things that all of us who have injected patients

over the years with collagen know that some people who

get erythema, just persistent. It's very interesting.

And this brings up that subject of this persistent

erythema.

Now, here we have listed the sites, all

six sites. These are the number of patients who had

persistent erythema on the Restylane site alone, the

Zyplast site alone, or both. You can see that there

were more with Zyplast in terms of persistent erythema

beyond that 14‑day or 2‑week period following the

initial injection than there was with Restylane, where

there were 6. And there was persistent erythema in

both, which I think speaks to this persistent erythema

as probably more patient‑driven than what was

injected.

There are people who get this persistent

erythema. I have some ideas of who they are and why

they are, but perhaps that's for another day. Who

knows? I may be even right.

This is a busy slide, but I think it is an

interesting slide. It portrays all of the persistent

erythemas. The reds are Zyplast. The sort of

green/yellow is Restylane. I think, first of all, you

can see there are more reds. The longest ones are not

the lasting ones, turn out to be Zyplast. You can see

for the most part when it happens, it is somewhere in

the two to three‑month period for most. But then

there are these other ones that just last.

I am going to show you some photographs so

you get a feeling of the quality of these reactions.

First we'll look at this patient at that time point.

Then we'll look at this patient at three time points

and this patient at three time points with the lights

up. This one I guess is a little hard to see, but you

can see this is a two‑month period of this sort of

relatively mild and typical of these persistent

erythema reactions.

Here is a patient who looks like she could

use the help of some members on this panel. In

addition to being injected here, she could certainly

use some help down here.

Here you can see this reaction, persistent

for a relatively long period of time, several months

you can see here is being judged as moderate. And

then at this point, it's mild. By this point, it's

pretty much gone.

Here's another one that lasted two months.

You can see at this time point it's being judged as

moderate and then mild and gradually goes.

So I think they are fairly representative

of the quality of this persistent erythema that was

seen in these patients, with both, more with Zyplast

than with Restylane but clearly with both.

Now, one of the questions that has been

raised for your consideration is that there is a

significantly greater incidence of events in the

patient diary, moderate to severe, mostly moderate,

particularly for bruising, erythema, and swelling in

the first 14 days. I think that's probably true.

I think that is the experience with the

European studies and others in the literature that

there is a little more acute reaction in the skin

following injection of Restylane than with collagen.

But if you look at that data, you can see that within

five to seven days, it's over. These are events that

are short‑lived, not serious. And what persists is

this persistent erythema.

So personally I think ‑‑ and I have

discussed it with Nick Lowe, who has a lot more

experience because he is bi‑continental and has a

great experience in London. You treat someone who has

had collagen. You tell them, "You may experience a

little more bruising, in particular." Collagen I

think helps to minimize micro hemorrhaging into the

skin. "You may experience a little more bruising.

This is a gel. It may seem to you like it's a little

swollen for the first few days, but do not be alarmed.

This is not a sign of something going wrong." So I

think it is probably true that there was more of these

minor acute reactions in the first few days but not of

any clinical significance.

Now let's talk about allergic or

hypersensitivity reactions. There were no

immune‑driven allergic hypersensitivity reactions, no

antibody urticarial‑type reactions or t‑cell delayed

hypersensitivity reactions.

In this protocol, investigators had the

discretion as to decide as to whether or not they

thought an allergic hypersensitivity reaction was

occurring. Dr. Lowe showed you a picture of the way

allergic reactions look. I will show you one, too.

They are very, very different than this flat

persistent erythema. They are qualitatively very

easily distinguishable as well as allergic reactions

invariably have significant itching or pruritus

associated with them.

So most of what was seen was, as I said,

this persistent erythema. And it was often bilateral.

I think very, very important in trying to sort out

whether or not there could have been a subtle allergic

reaction that wasn't so obvious in that persistent

erythema is that all but one of these patients chose

at the end of the treatment, of the evaluation period

to be reinjected. They were reinjected bilaterally.

Now, when you have an allergic

immune‑driven reaction with subsequent reexposure, the

reaction is reproducible and often more intense. And

nothing happened with these individuals to suggest,

even remotely, that there was an allergic reaction on

reinjection. For that reason, I concluded that there

are no immune‑driven allergic reactions in this study.

You will hear more on this subject subsequently.

This is a typical allergic reaction. As

in the FDA, one of the FDA slides, it's qualitatively

indurated, edematous, itchy, lumpy. It's very, very

different. And this is similar to the reaction that

Nick lowe showed, where he had that patient with the

lumpy, indurated, erythematous, edematous reaction

around the mouth for injection of these vertical lines

that women tend to get. So this qualitatively is

very, very fundamentally different than these

persistent flat erythema, non‑immunologic events.

So, in summary, as far as the adverse

events go, these were usually seen with Restylane and

with Zyplast. For the most part, they were mild and

short‑lived with the exception of that persistent

erythema that we discussed in detail. No immunologic

hypersensitivity allergic events were seen. Actually,

the persistent erythema was seen with both agents and

was seen to a greater degree than with Zyplast.

And the type of thing that those of us who

have experienced with injecting collagen have come to

realize is something happens. When it happens, you

reassure the patient. You say, "You look terrific.

Keep using the makeup. It will go away." And it does

go away.

So, in summary, I think it's fairly clear

to me that from these data, Restylane is superior to

Zyplast at the six‑month period. It's also superior

at the two‑month and four‑month period. This is shown

both statistically. It's shown in terms of responder

rates, in terms of longitudinal assessment, and by

patient evaluation and was seen across centers. No

immunologic hypersensitivity, allergic reactions were

seen. And skin testing seems to be an irrelevant

issue in terms of this particular agent.

The local adverse events were

overwhelmingly self‑limited with the exception of

those patients with persistent erythema. And there

were no serious adverse events.

And I think that concludes my

presentation. I will now introduce another one, the

investigator site 5 plastic surgeon of New York

University, Dr. Paul Lorenc.

DR. LORENC: Thank you. Good morning.

First I would like to thank the panel for allowing me

to make this presentation to you this morning.

I am Paul Lorenc. I am an assistant

professor of plastic and reconstructive surgery at New

York University Medical School. I am also in private

practice in New York, in solo practice for the last 15

years. I was one of the clinical investigators in the

pivotal study, but I also have an extensive clinical

experience in Restylane injection in my other practice

in beautiful Montego Bay. I do have an extensive

experience in injections with patients from Montego

Bay, of course.

I would like to present to you the study,

a clinical study. We referred to it as the Olenius

study made in Sweden in 1995 to 1996, where it was a

single arm, open label study of 112 patients. The

eligibility of this study was patients that had

wrinkles or folds that were not deeper than four

millimeters and suitable for injection.

A hundred and one patients were followed

for 12 and 26 weeks in follow‑up. No skin test was

performed on these patients. The whole cohort was

naive to Restylane injection.

The protein levels in the Restylane

preparation at that time was 16 times higher than the

reformulated Restylane, which was involved in the

study that was discussed just before. So please keep

that in mind.

This is just the efficacy report, both

efficacy by the treating physician in four centers and

the patients. And you can see that it starts off very

close to 100 percent, the initial treatment, and then

it goes into the 60 percent range, a little bit higher

for the perception by the physician versus the

patient.

As far as the adverse events, the

unrelated ones were perceived to be unrelated. I'll

summarize. As you can see, they include tics,

telangiectasia, strings, and acne formation. The

numbers are on your right. They range from 2.7

percent to 0.9 percent.

The adverse events as assessed as possibly

being related to the injection procedure included red

spots, dark spots, and bumps. Total number of

injections were 285 and the percentage as far as

listed 5.4, 1.8, and 1.8 percent.

The results of the study showed that in

eight percent of the injected sites experience adverse

events with less than one week's duration. This was

mainly, as discussed before, redness and swelling.

there was no hypersensitivity reactions that were

observed, and no adverse events were assessed as

device‑related.

This is just a summary slide that looked

at the adverse events at 12 and 26 weeks. And it was

for a total of 16 percent or 16 out of 102. The ones

that were deemed related were 11 out of 101. And,

again, they include the minor redness and swelling.

As far as the acute events that were noted

in less than 14 days after the injection included 51

patients from 112. And they included redness,

swelling, hematoma, pain, and darker pigmentation, for

a total number of patients of 51.

In conclusion, based on the Olenius study,

reactions were minimal, even with higher protein

level. That was later on reformulated. And no skin

testing was involved. The product was very

well‑tolerated. And the efficacy supports the pivotal

study, in which I was involved.

Thank you very much.

DR. STROBOS: The next presentation I'm

going to do is fairly short. We just wanted to remind

the panel that the product was originally introduced

in Europe in 1996 and it's now marketed worldwide,

including Canada and Mexico. There's no requirement

for skin testing in any of these countries.

We did report to the FDA the spontaneous

adverse events that have been reported. I think many

of you are familiar with spontaneous adverse events

reporting. Basically the company receives calls from

health practitioners, reporting events, and those

events are typically a little bit more unusual, so

adverse events reporting that is frequently sort of a

signal as to the occurrence of some unexpected event

that may occur in a low percentage of patients.

This slide is a little bit difficult to

see from here, at least for me. What we have done

here is basically provide a duplicate of a listing

that you have probably already seen in the materials

provided. These are the reports for 1999, 2000, 2001,

and 2002. Now, these are coded according to an

international disease classification. And you can see

on this slide here these are injection site reactions.

And this would be hypersensitivity reactions.

We have also provided a little column here

just to provide a little bit of context. What this

represents is the number of syringes that have been

sold. To a certain extent discounted by the fact

that, as you noted from Dr. Lowe's presentation and

others, there are multiple injections per patient. So

we have discounted the number of syringes sold,

estimating that there may be somewhere between 1.7 and

2 syringes used per patient. So these provide those

numbers. And you can see that there is sort of a

gradually increasing usage.

Nineteen ninety‑nine was the year in which

there was a formulation change. I think you can see

in terms of the hypersensitivity reactions, even

though there is an increasing usage, there is actually

a decreasing incidence of reported hypersensitivity

reactions. So you can't read too much into that

because, of course, these are spontaneous reports.

However, we did do an analysis again using

the denominator of adjusting for increasing volume of

use. And I think you can see that there is a fairly

striking fall in the reported hypersensitivity

reactions, which you just saw on the table and

represented here graphically, no particular reason for

this fall. And, of course, it has continued at the

same level for those years. So I think it's

reasonable to suggest that the formulation change did,

in fact, reduce the incidence of hypersensitivity

reactions.

What I have done here is a bit of a busy

slide, but I thought it would be important for you to

see. What we have done is taken the entire 27 reports

of hypersensitivity reports. And this, again, is in

your panel package.

In one of the later sections, we gave a

volume listing of all of the reports that were

received. And these were all ones that were coded as

hypersensitivity. Typically these occur at some delay

after the initial injection. They are coded largely

because they are reporting erythema and swelling.

There are obviously some reactions here.

The investigator may also have thought that the

reaction was an infection because of the expression of

pus, so forth. If you go back to that slide, the

previous two slides, infections are reported as well

in this database.

That said, I think the incidence of the

reports, especially the hypersensitivity and

inflammatory reaction, appear to decrease following

decrease in the protein level, 1999.

There are delayed, rare delayed, erythema

and swelling reactions. They tend to be self‑limited,

tend to be treated with topical steroids, sometimes

oral steroids. However, it's not been proven that

these reactions are immunologically mediated.

We just thought that would be a thorough

way of making sure that you're aware of the fact that

there is international experience and there is a

database to look at these reactions.

That said, we had asked Dr. Franklin

Adkinson, who is a professor of allergy and immunology

at Johns Hopkins, to basically review the entire world

of literature as well as our database on allergy and

immunology and briefly render his opinion on the

likelihood of an immunologic mediation of any of

these.

DR. ADKINSON: Good morning. My name is

Franklin Adkinson. I am a professor of allergy and

immunology at Johns Hopkins, just up the road. I have

enjoyed a 30‑year academic career at that institution,

where I have taken a longstanding interest in

immunologic and idiosyncratic reactions to drugs, both

marketed and in development.

I was pleased to have been asked by the

sponsor a number of months ago to take a comprehensive

and independent look at their own safety database and

what may have been published in the literature with

regard to the possibility that high molecular weight

hyaluronates can or do induce hypersensitivity

reactions.

I have done so. What I have looked at is

the entire safety data set that has been reviewed for

you this morning from the two clinical trials and the

spontaneously reported adverse reactions.

I have also reviewed the literature, both

with regard to facially injectable hyaluronics but

also with regard to other high molecular weight forms

that are used for intra‑articular injections, for

example, looking for evidence of immunogenicity and

demonstrably allergic reactions and at any published

reports in the literature that might suggest evidence

for immune responses to these materials. I would like

to just review with you some observations I made

during that review and the conclusions that I have

come to.

The first observation I think is important

is that all of the reactions have been labeled by

various investigators and reports is hypersensitivity

were local at the injection site only. This would be

very unexpected were true immunological

hypersensitivity being manifest.

Almost all of them required days or weeks

to be manifested and included, as you have heard,

erythema, red spots, local swelling, pain, and

tenderness, some of which has an inflammatory

component but none of which are accompanied by the

hallmarks of true allergic disease.

The pattern, the temporal pattern, under

which these reactions emerged, is also not suggestive

of any particular form of immunopathology. And high

variability among the patterns suggests that something

else is going on that must be a function of either the

host or the technical properties of the administration

of the agent.

All the reactions that were observed in

the clinical trials resolved without treatment. The

most unexpected result if you were dealing with true

hypersensitivity was immunologically mediated.

And almost all of the local reactions

occurred at some time but not at all injection sites.

That is, I was impressed that over half of the

reactions occurred at one but not at other sites

injected with the same material, again, a most

unexpected if one were dealing with immune‑mediated or

driven reaction.

Finally, when patients were re‑treated

after a seminal event that was labeled as

hypersensitivity and were observed thereafter, if

anything, there are fewer reports, spontaneous

reports, of adverse events following re‑treatment

after an initial reaction that is labeled as

hypersensitivity, rather than more, as we would

expect.

Some of this may be due to reduced

surveillance in an open follow‑up, but the fact that

there are not more or more severe reactions I think

supports my own conclusion in reviewing all of these

features of the reactions that an immunological basis

for them is most unlikely.

I also looked at case reports in the

literature that examine some of these nodular, late

appearing reactions. One involved an excisional

biopsy, which showed a granulomatous reaction with a

mild inflammatory infiltrate. This had all of the

features of a foreign body granulomatous reaction,

rather than one that had an immune pathogenesis, and

suggests the possibility that failure of the material

to resorb entirely in certain susceptible individuals

may lead to this type of granulomatous inflammation,

which is again entirely local and not likely to be a

systemic problem.

Almost all of the patients, as I

mentioned, who were repeatedly challenged after an

incident labeled as hypersensitivity, had no further

problems with the second injection. Those who did

reported a second episode. It was usually not like

the first. It was temporally at a time point very

difficult to explain by any known immune mechanism.

There is one case series in the literature

accompanied by reported lymphocyte stimulation studies

and ELISA measurements done in a reputable laboratory

in Paris. However, looking at the technical

description of these assays in the paper as it's

reported, I was unable to come to any firm conclusion

about the validity of these studies.

There was no dose‑response curve

demonstrated with the lymphocyte transformation

studies. No controls were included in the studies.

And the highest titer of IgG antibody, if I

interpreted the paper correctly, was observed in a

patient who was a non‑treated control, raising serious

questions about the specificity of the assays.

Now, when this report occurred, the

sponsor, I think quite commendably, attempted to

pursue this and asked Dr. Michel, who published this

series, to make available these patients for

additional studies.

Two of his most sensitive patients were

again restudied at the same Paris laboratory that did

the original studies in lymphocyte transformation.

And ELISA studies were repeated. This time they were

entirely negative.

So not only were these poorly documented

to begin with, but they appear not to be reproducible.

To my knowledge, this is the only reported

immune‑specific activity to these products that's

available in the literature.

So, in conclusion, I find no convincing

evidence that the high molecular weight, hyaluronic

products are immunogenic. There is the occasional

granulomatous reaction, which appears to resemble a

foreign body reaction, which appears to be random and

idiosyncratic and not reproducible.

The common reactions that we have heard

about today, including the redness and erythema, all

seem transient. And they're exclusively local and in

my judgment do not suggest the participation of

hypersensitivity mechanisms.

Thank you.

DR. STROBOS: Finally, the company has

proposed a phase IV study in the African Americans.

I would like to introduce Dr. Taylor from Columbia

University to describe that.

DR. TAYLOR: Good morning. My name is Dr.

Susan Taylor. I am the director of the Skin of Color

Center at St. Luke's‑Roosevelt Hospital Center in New

York and assistant clinical professor of dermatology

at Columbia. I will discuss with you a planned phase

IV study of Restylane therapy in African Americans.

Dermal fillers have been used successfully

in patients with skin of color, including African

Americans. Restylane has been used extensively in

South America as well as Asia and has not been

associated with a different safety profile.

Clearly safety profiles for African

Americans may be different. Abnormal healing

responses and pigmentary responses are theoretical

adverse clinical outcomes in this subpopulation of

patients.

In specific post‑inflammatory pigmentary

changes, either post‑inflammatory hyperpigmentation or

hypopigmentation is a theoretical adverse clinical

outcome. Keloidal scar formation is another

theoretical adverse clinical outcome. And we do know

that in African Americans, in particular, there is a

higher incidence of keloidal scar formation.

We plan a phase IV multi‑center

observational safety study of Restylane treatment in

African Americans. Eligibility requirements include

self‑identified African Americans. The age range is

between 35 and 75. Patients will have Fitzpatrick

skin types V or VI.

We propose ten sites, which will be

selected based upon prior demographics. Sample size

will include 100 patients as our target. The

enrollment, however, will close six months after the

first patient is enrolled to ensure FDA reporting

within one year.

Our endpoints include keloidal scar

formation, which will be examined at weeks 12 and 24

as well as pigmentation changes, which will be

examined at weeks 2 and 6. We feel that a phase IV

study is indeed an appropriate study to observe

possible safety issues in this subpopulation.

Thank you very much.

DR. STROBOS: That pretty much concludes

our presentation. We do have a few just summary

slides. If I could have Dr. Leyden and Dr. Gary

Jansson perhaps sit up here because I know you

probably will have some questions to ask? And then I

can just briefly review my summary slides.

We believe in terms of the clinical

efficacy that the study satisfied the mutually agreed

predefined criteria for establishing superiority.

It's my personal view ‑‑ you may differ, but it's my

personal view as a physician that a superiority or a

statement about superiority is appropriate and that

not all patients have to do better.

The principles underlying superiority I

think are that more than half should do better and

most of the rest should do the same. That's my view.

You may differ, but we do have a superiority statement

in the proposed labeling, which I am going to show on

the last slide. I believe a question has been

directed to you about that.

In terms of clinical safety, overall

clinical safety, we think there is a low rate of

clinically significant adverse events from the three

data sources that have been put into the PMA, the

pivotal study, the Olenius study, the spontaneous

reports in the medical literature. We think most of

the adverse events are self‑limited, last less than

two weeks after injection.

There are, as has been noted, rare serious

dermal sequelae, but those are almost uniformly

reported on in the medical literature, which obviously

has a selection bias in terms of reporting.

We have proposed as the indication for the

product that Restylane is indicated for the correction

of moderate to severe facial wrinkles and folds, such

as nasolabial folds. We believe that this is

principally supported by the pivotal study. We do

need not to remind you that the Olenius study was an

open label study. And we're using it principally as

support for the safety. However, there is some also

in the medical literature and international

experience.

The superiority claim that we're talking

about is not in the indication. Rather, it's in the

description of the clinical study.

We have committed to performing a phase IV

study in African American patients. We believe that's

appropriate as a phase IV study. The study design

when we were initially discussing the study with the

agency, they wanted to ensure that the study was

performed in the United States.

The product is used in Brazil, and we have

submitted some data about usage in Brazil. However,

because of the demographics of treatment of wrinkles

in the United States, the likelihood of enrolling a

lot of African American patients in sort of a

broad‑ranging efficacy study is limited. And that's

why we would like to do this as a phase IV study.

We do have proposed a statement about use

in African Americans to add to the proposed labeling.

And that statement is "Limited controlled clinical

study data are available regarding the use of

Restylane in patients with skin types V and VI on the

Fitzpatrick scale." And we would certainly like your

views if that's possible as to if that is an

appropriate statement or whether it should be

modified.

In terms of hypersensitivity, another

question you have been asked to addressed, we think

the redness and erythema that you see in these cases

is not clinically allergic. The clinical studies

suggest there is low risk. Spontaneous AB suggests

there is low risk. And the medical literature has

suggested there is low risk.

We have, however, also proposed to do a

surveillance study. The way this has worked is, as I

described, we would be setting up a spontaneous

reporting system, under which we would propose that

any patient who has a reaction coded as

hypersensitivity, that we would attempt to contact the

health care provider and evaluate the patient with

intradermal skin testing. The likelihood is that we

would use some sort of a control population as well,

but it would be difficult to do the control population

as part of that study itself.

The superiority statement that you have

been asked to render an opinion on is the following.

I've written it up here. It says, "In the randomized

study Restylane was shown to be statistically

significantly superior to an approved cross‑linked

collagen dermal implant as regards persistence of

augmentation of nasolabial folds." That's the

statement. We believe, as I pointed out before and I

think Dr. Leyden pointed out, that we have support for

that.

That said, that's the end of our

presentation. And we would appreciate being able to

answer any questions you might have.

ACTING CHAIRPERSON CHANG: Thank you very

much.

This time period is now open for panel

members to ask questions for the sponsor. Dr. Halsey?

MEMBER HALSEY: In the exclusion criteria

for the study, you have eliminated all patients with

a history of severe allergies or multiple severe

allergies, including like histology. Is it possible

or should we be concerned that the reason we have not

seen what appears to be typical immune reactions is

that they have been excluded from the study group?

And if that's the case, should we require this allergy

testing of some kind or allergy evaluation prior to

getting patients on this treatment?

DR. STROBOS: Well, let me ask Dr. Leyden

to answer that, but just to remind the panel, all the

patients in the study received both collagen and

Restylane. So the concern in the study and reason for

that exclusion was because there is a known reaction

to collagen.

The Olenius study, which was submitted to

the PMA and is experienced in 101 patients

longitudinally open label, in that study, there was no

exclusion for people with prior atopic reactions. And

there was no skin testing performed in that study at

all. And those were people all of whom were naive to

Restylane therapy.

DR. LEYDEN: I think that two things are

maybe important. One is those people with severe

chronic, recurrent allergic reactions tend to get on

drugs that could interfere or influence any reaction.

That was the reason for excluding, not trying to

exclude people, leaving aside whether or not those

people who react to pollens, et cetera, would be more

likely to react to this. They may.

But I think the wide experience in Asia,

Europe, South America were all comers, including those

with significant atopic backgrounds, exist, doesn't

show a signal that that subgroup may be more likely to

get these, what appear to be non‑immunologic

reactions. To date, we don't think they are

immunologic.

MEMBER HALSEY: Certainly the clinical

characteristics, as pointed out. Dr. Jansson would

indicate.

Now, you have in this product bacterial

protein. It's six parts per million. That's not

zero. And it is potentially a problem. Is there any

way to test for that? And what do you think that that

should be lowered?

DR. STROBOS: Excuse me. Could you

clarify your question in terms of the testing?

MEMBER HALSEY: The product has six parts

per million of protein. I assume that's

Streptococcus‑derived.

DR. STROBOS: Correct. I believe that's

correct, yes.

MEMBER HALSEY: Was there any specific

attempt to look for an immune response to this

contaminating protein?

DR. STROBOS: In these clinical studies,

there were no immunologic studies performed on the

patients.

ACTING CHAIRPERSON CHANG: Dr. Newburger?

MEMBER NEWBURGER: I reviewed the

worldwide safety data that you provided. I just

looked at the numbers of adverse events from 1999 to

2001. During that time frame, ‑‑ and, admittedly,

it's a very sketchy kind of reporting database ‑‑ 201

hypersensitivity reactions were reported.

Now, we know that reporting worldwide is

very different than it is in the United States. And

very often if there is an adverse event, it will be

dealt with with the physician, rather than being

reported to a governmental agency.

But if we just limit that to the 2001 and

2002 years, which was after the more purified material

was available, in those years, there were 62 reports

of so‑called hypersensitivity reaction, delayed onset,

and 10 reports of granulomata.

Why was there no concerted effort made to

clarify what was the mechanism with these patients?

Furthermore, I see in that database that there were

some individuals who had to be treated with systemic

medications. So that to me just signals this is a

substantial number of people who got quite sick.

Now, in terms of the total doses given,

that's very small, but I would like to know what

efforts there would be to characterize those who would

be at risk for such severe reactions. It's a long

period of time without having really a handle on

what's provoking this reaction.

So as a clinician, although I could say

statistically there's likely a very small incidence of

an adverse event, I would like to have more

information so we could truly give an informed

consent.

DR. STROBOS: Right. Well, just to

clarify, two points. One is most of the reports in

that database arise from northern Europe. Reporting

I can't agree with you more that you can't draw too

many conclusions from that. Reporting from Europe in

the studies that I would do, spontaneous reporting

tends to be a little better in the United States, not

a whole lot.

That said, we also, as I have pointed out,

are intending in the United States to try and study

those patients prospectively and more or less in the

exact manner that you said.

Let me have Dr. Rensfeldt from Q‑Med, who

is in charge of this spontaneous reporting, speak to

the activities that the company has engaged in

heretofore, which I think have been relatively

aggressive in trying to address these issues and find

out the problem.

DR. RENSFELDT: First of all, a

clarification. Regarding the classification of the

adverse events, they are done on a worst case basis.

And the data that we have, the information that we

usually have on spontaneous adverse events reports

varies considerably from case to case when it comes to

the quality of the data and the amount of information,

which makes the classification rather difficult. So

that's important to have in mind that it's certainly

worst case classification.

So when it comes to the cases classified

as hypersensitivity, these have not been confirmed in

any way. So the classification is only based upon

certain clinical data that has been received in the

report that might imply that it could be some sort of

hypersensitivity reaction involved. So that's

important to have in mind when you consider the data.

It also is important to have in mind that

the great numbers or the majority of these cases are

self‑limited. They don't require treatment. And the

symptoms are usually gone by about two weeks.

Therefore, we have not felt compelled to do any

further research on each case since they have in

general been mild to moderate symptoms and

self‑limiting.