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.

DR. STROBOS: That said, if you look at

the treatments rendered, a lot of them are empirical.

Some of the treatments, for instance, people will be

started on steroids, as you indicated, but they will

be simultaneously started on antibiotics as well.

That said, perhaps Dr. Leyden, I think who

has an interest in dermatology and allergy ‑‑

DR. LEYDEN: Dermatology I have an

interest in, yes.

DR. STROBOS: Yes.

DR. LEYDEN: That's true.

DR. STROBOS: Maybe you would want to

comment on the question.

DR. LEYDEN: Yes. Well, it's one of those

things that how do you get your hands on those

patients, number one? The situation where they had an

opportunity, where there actually was, as Dr. Adkinson

described, a paper and somebody did do some ELISA and

other tests trying to get at mechanisms, when they

redid it, they couldn't even reconfirm it.

So these kind of reports, occasionally I

get asked to look at reports. Drugs come out. And

the question is, is there something going on? It's

very hard to wade through that stuff. Personally when

you read through these cases, you end up often saying,

"How did this case get classified like this?"

Now, I have asked that question of Jur,

who has a lot or experience in that. He explained it

to me, and I didn't understand it. So there's

something about that classification that it gets

classified. And until you do something prospectively

or until you get your hands on people in a way that

you can actually fundamentally study them, I think you

have to just say, "Well, those are reports" and, as

described, are the worst case, if you will.

Based on what you heard Dr. Adkinson say

and what I think the experience of most people is, the

overwhelming majority of these "reactions" are not

immunologic. They're injection. Probably if you had

injected saline, you would have gotten a certain

amount of that.

As I tried to point out, if you look at

the persistent erythema, which I think is really an

interesting reaction, ‑‑ and Nick and I were talking

about, we have similar ideas, it turns out, on who

these people are ‑‑ a high percentage of them were

bilateral, which suggests it's the person more than

either agent, that if you inject something in certain

people, you are going to get erythema or you are going

to get reactions, some of which get classified as

hypersensitivity, implying immunologic

hypersensitivity, which is a big step until you have

shown it.

ACTING CHAIRPERSON CHANG: Dr. Leyden,

could you share with the panel at this time what are

your suppositions, your ideas of what kind of ‑‑

DR. LEYDEN: Who gets it?

ACTING CHAIRPERSON CHANG: Who gets it so

that perhaps this is a yellow light ‑‑

DR. LEYDEN: It's not a yellow light.

It's just like what's going on.

ACTING CHAIRPERSON CHANG: Yes, it is.

DR. LEYDEN: Yes, right.

ACTING CHAIRPERSON CHANG: One, two, three

reasons of why individuals ‑‑

DR. LEYDEN: Nick and I were talking about

that while Dr. Adkinson was making his presentation.

We think it's people like me, people who tend to flush

or blush easily, who have a richer microvasculature in

the superficial dermis. They're the people.

We have at Penn a Center for Human

Appearance. We work very closely with our plastic

surgery colleagues for more than 25 years. They have

patients that they operate on. They do laser

abrasions or they do facelifts or they do this and

that. And they stay red for a long period of time.

The people are unhappy because nobody told them that

was going to happen.

I think they're the same kind. They're

people with this what we call rosacea tendency of

flushing and blushing. I think they're probably the

ones who bruise more easily, too, because they have

more superficial dermal microvasculature.

They're the ones who react to

corticosteroids and blanche that are used in the

vasoconstrictor assay for developing topical

corticosteroids. I think they are the ones, and I

think it relates to the differences in vascular supply

to the superficial dermis.

DR. STROBOS: If I may perhaps have Dr.

Adkinson give his opinion on that?

DR. ADKINSON: Well, it is an opinion

because I don't know the answer to the question, but

it's interesting to speculate and to think about how

these reactions could occur. They seem to have a

random occurrence in the population. We don't know

how to pick out the people who are at risk. And even

those who are at risk don't have it at every injection

site, suggesting that there are local factors that

come into play.

The fact that these superficial rapidly

disappearing reactions went down drastically in

frequency when the protein content was reduced by

16‑fold in the current product suggests to me that

there may be some interaction between bacterial

components and the individuals' innate immune systems,

which in recent years we have learned can respond to

a wide variety of bacterial products with inflammatory

signals that lead to the production of cytokines that

draw inflammatory cells that could lead to the release

‑‑

DR. LEYDEN: The toll‑like receptor you're

talking about?

DR. ADKINSON: The toll‑like receptor

mechanism. But that's entirely speculative, and it

still wouldn't get at the idiosyncratic feature. That

is, if this was just an assault on the innate immune

system through these toll‑like receptors, we would

expect virtually everyone to react. And it seems to

have, however, a very strong host component, which to

my review has not been identified.

ACTING CHAIRPERSON CHANG: Dr. LoCicero?

MEMBER LoCICERO: I have four questions.

The first is, on the persistent erythema, sites 1 and

2 have quite a few more reactions than the other

sites. What is your analysis of that and your

speculation concerning that problem?

DR. LEYDEN: Yes. I noticed that, too.

Were they Manhattan experiments?

DR. STROBOS: One was I believe La Jolla.

It wasn't either one of these.

DR. LEYDEN: Good. I think technique is

important. I think the way you inject, how slowly you

do it, and how much experience you have is important.

I think that's an issue.

I have given you my sort of off‑the‑cuff

idea of who I think these people are. I am sure I am

right, but I could be wrong. I don't know the kind of

patients. I really would like to see that to see if

there is a correlation because it would be an

opportunity to test the hypothesis that Nick and I

have.

So I think technique and just who is in

that study at different centers is likely to be

responsible.

MEMBER LoCICERO: Second question, on your

proposed labeling, you have "facial wrinkles." Upon

what basis do you want that indication?

DR. STROBOS: Well, I think there are two

rationales. One is we think that the nasolabial fold

is a difficult wrinkle to treat. And so is the

experience in nasolabial folds, which is

generalizable.

We also have the Olenius study. And

although the efficacy data again is open label, in

that study, 285 sites were treated. And that was not

limited to nasolabial folds. So we think it's

basically generalizable based on the principles of

action of the product Olenius study.

MEMBER LoCICERO: Third question, you have

committed to a phase IV study, which means that you

pretty much agree that there is insufficient data

concerning African Americans.

If you were to get labeling, although it

hasn't happened in lower Alabama, the other L.A.,

there are many other parts of the country where

patients are multiethnic. How would you evaluate your

patients beforehand? What would you propose as a

method of eliminating those with multiethnic

backgrounds?

DR. LEYDEN: I don't know that you have to

think of it that way. I think what Susan said is

there is at least a theoretical reason why they should

be specifically prospectively looked at.

I think there is the extensive experience

worldwide in individuals who have multiple gene pools

who have much darker skin than I do. It doesn't

suggest anything different. I mean, there are lots of

African Americans who have been or people who are

ultimately descended from Africa who live in other

parts of the world who have been injected without any

signal, but there has not been a formal prospective

look. They're committed to doing that in American

African Americans.

DR. STROBOS: Let me just expand on that.

In the PMA, we were asked this question. And we did

provide a retrospective analysis of patients treated

in the Brazilian clinic, which included many patients

of the kind of mixed heritage that you might suspect.

We think that data suggests the product does not carry

any different risks in this patient population.

Just to clarify one thing, we're not

proposing the study because we have any concerns about

it. I think that's a mischaracterization. We just

think it's the right thing to do in today's world to

evaluate the demographics of the study.

I think you need to recognize that, at

least in the device guidance and in this protocol,

which was worked out with the agency, there was now a

preset demographic analysis. There was no discussion

of doing demographics.

At the time the study was set up, this

panel had not raised questions about demographic

subpopulations. And the way the study was designed,

the prospective study was unlikely. Had we known that

in advance, obviously, the demographics would be an

issue, we would have had a different design. But we

just think it's the right thing to do.

Let me have Dr. Taylor address this risk

issue.

DR. TAYLOR: I have two comments. I just

want to reiterate that in South America, in Brazil in

particular, there have been over 130,000 treatments of

Restylane, again without any increased adverse events

reported.

Additionally, there have been over 40,000

treatments in Japan and over 40,000 in Korea, again

without increase in adverse events being reported.

I think we need to understand clearly that

African Americans are relatively resistant to

wrinkling. Also, the depth of wrinkling is a lot

less. And if you look at the entry criteria in the

pivotal study, it required wrinkle depth of three or

four. That is moderate to severely deep folds.

Often, which is very nice for African

Americans, we did not meet that entry criteria in that

our folds, our wrinkles were not deep enough to be

included in the particular study.

I want to be clear that it wasn't as

though African Americans were excluded from the trial.

Fortunately in many respects, we didn't meet the entry

criteria. I think, however, we clearly would agree

that in many realms, African Americans have been

demonstrated to react differently.

That's why I think it's the right thing to

do and the appropriate thing to do for this to be

pursued in a phase IV clinical trial.

MEMBER BOYKIN: Dr. Taylor, were you one

of the sites in this study?

DR. TAYLOR: I was not.

MEMBER BOYKIN: Why? I mean, when were

you approached by the company about this?

DR. TAYLOR: I was approached by the

company when the issue was raised about African

Americans and to take a look at: a) why there wasn't

a larger number of African Americans enrolled; to also

review with the company the features of aging,

photoaging, in African Americans; and also to help

review and look at the potential problems that we

experience in terms of abnormal healing responses and

abnormal pigmentary responses.

MEMBER BOYKIN: With what you know about

the product, are you using similar fillers in your

operation right now?

DR. TAYLOR: Yes. I think it's very

important to point out that fillers are used,

particularly the collagen‑based fillers, in African

American patients.

As you well know, keloidal scars are

precipitated by a disruption in the integrity of the

skin. So the theory is that with the needle that is

used to implant the product in the dermis, that would

be the initiator of the disruption in the integrity of

the skin.

As a practical matter, as a dermatologist,

we inject a variety of substances, dermal fillers as

well as anesthetics, for example, corticosteroids into

the skin, again without an increased incidence of

keloidal scar formation.

MEMBER BOYKIN: Right. But you personally

have not had any experience with this product?

DR. TAYLOR: I have not personally had any

experience with this product, but let me say that my

particular feeling is that I would not necessarily

hesitate in using this particular product in patients

of all races and ethnicities.

MEMBER LoCICERO: One more question,

really for Dr. Taylor. And that is concerning the

design of this phase IV trial. The keloid formation

is out to 24 weeks, which is probably appropriate.

Pigmentation is only out to six weeks. And there may

be some pigmental changes that occur at that point,

but they may modify or one way or the other later. Is

six weeks too short?

DR. TAYLOR: Well, the six weeks was based

on the fact that most of the erythema that was seen

occurred at 14 days or less. So the feeling was that

if pigmentary disorders were going to be a response of

that inflammation, it would occur around the two‑week

period and we would definitely capture it in six

weeks.

DR. LEYDEN: And they would be followed

until it resolved. You know, if they had an adverse

event, it would be followed up until ‑‑

MEMBER LoCICERO: Okay. So that would be

part of the trial, that you would need to follow the

‑‑

DR. LEYDEN: Yes, right.

ACTING CHAIRPERSON CHANG: Dr. Miller and

then Dr. Newburger.

MEMBER MILLER: Yes. Thank you. I just

had a couple of questions. You know, you described an

extensive experience in Asia and Latin America. But

I haven't seen any publications, really, out of that

experience unless it's in other languages than

English. Have there been any publications out of

those areas?

DR. LEYDEN: I don't read those journals

either.

DR. STROBOS: There is one. In the PMA,

there is a report, Brazilian report, that I mentioned.

Go ahead.

DR. TAYLOR: There is a Brazilian report

in the literature of 2,241 subjects who received

injections, of whom 179 were characterized as having

skin phototypes V and VI. And 129 were characterized

as being of Asian descent. None of those patients had

adverse events reported.

MEMBER MILLER: One of the complications

listed in one of the presentations was a tic. What

exactly do you mean by a "tic"? Is this a neurologic

sort of tic you're talking about or ‑‑

DR. STROBOS: Well, this wasn't observed

in the pivotal study. Do you have any idea why these

tics are reported?

DR. LEYDEN: I have no idea what they're

talking about. It could be more of this reporting

stuff, you know. We didn't see anything like that.

DR. RENSFELDT: It was reported in the

supportive study, in the so‑called Olenius study. And

it was regarded as not related to the treatment.

I think one of the patients had tics on

the lip area. And the other case was tics around the

eye.

DR. LEYDEN: The coding would be an

involuntary muscle contraction.

MEMBER MILLER: Right. So these are just

reported.

DR. STROBOS: And judged to be unrelated.

MEMBER MILLER: And you have no idea what

those are. You can't envision any connection between

a patient developing a tic problem and injecting this

material.

DR. STROBOS: Well, there was a study. I

mean, we're not talking about the animal tick here.

We're talking about an involuntary ‑‑

MEMBER MILLER: No. I know. I

understand. I didn't expect ticks to begin. Thank

you for clarifying that, though.

(Laughter.)

MEMBER MILLER: Now, you feel that the

results in the nasolabial fold are pretty

generalizable, but in one of the papers I did run

across, there was a study looking at glabellar frown

lines. And the investigators in that study found a

return to baseline of the wrinkles in 18 weeks. That

seems to be a little bit of a shorter time than your

‑‑

DR. LEYDEN: Well, most people are above

the nose, it's Botox; below the nose it's fillers.

MEMBER MILLER: Right. This particular

study compared a combination of Botox and the

Restylane to Restylane alone and found that the

Restylane group returned to the baseline in 18 weeks.

DR. RENSFELDT: Could I comment?

MEMBER MILLER: Yes, please.

DR. RENSFELDT: In that study, since it

was a Botox study in the sense that Botox was

included, it's common in those studies to assess the

patient at maximum frown. That was when this

measurement was taken at 18 weeks.

The study is a bit, let's say, complicated

to realize what actually they found because this was

assessed at maximum frown for a static wrinkle. So

it's not the common way to assess people whom you have

injected with a filler substance to ask them to frown

maximally and see if the wrinkle is still there.

DR. LORENC: If I may, I have three

responses, one about the tic. I have seen in my

practice I do an awful lot of fillers. I am a plastic

surgeon, but I do an awful lot of fillers.

I have seen this involuntary muscle

contractors, especially with lip injection. I don't

know what the mechanism is. I don't think it's

related to the product. I think it's probably a

pressure phenomenon. So it could be related to that.

As far as the injection of Restylane in

patients who are classification V or VI, I have

extensive experience in that in my Montego Bay

practice with local patients. I have not seen any

pigment changes. I have not seen any hypertrophic

scars or keloids.

And that's just the personal experience.

I grant you that it's not published, but, again, it's

many, many patients.

MEMBER BOYKIN: In your list of

complications, you noted a couple of incidences

related to acne. Do you treat patients with acne with

this substance?

DR. LORENC: With active acne?

MEMBER BOYKIN: Well, I'm not sure exactly

what was going on here, but can you answer my

question? Do you treat patients with acne with this

substance?

DR. LORENC: I don't know. I don't quite

understand your question.

DR. LEYDEN: I can tell you I have treated

people with collagen injections, adults who have

various forms of acne vulgaris or acne rosacea. You

can certainly treat the nasolabial folds. It's not a

common place to get acne lesions.

I would assume that these acne lesions

were out on the cheek, the forehead, or the chin but

not in the nasolabial fold because that's an uncommon

place.

DR. STROBOS: There were two patients

reported to have acne at I believe six months after

the injection. Some were in a delayed relationship.

Those were classified as actually unrelated adverse

events that occurred later. That was in the study.

The exclusionary criteria in the study

were people with some active infectious process. And

I think the concept there, if I'm not mistaken, if

someone has an active infectious process on the face,

you wouldn't be injecting their wrinkles at the time

they have them.

DR. LEYDEN: The acne is not an active

infectious process. It's an inflammatory process.

MEMBER BOYKIN: So when you're excluding

people with skin diseases, you're not really talking

about acne? I mean, that's where I am a little

confused.

When I look at what your prospective

labeling is for this product, it says that you would

exclude people with skin diseases. And, of course,

that's a pretty broad, open thing. And then I see

some related. Acne is not here today, gone tomorrow.

This is a cycle of events that can take place over

many years. I'm sure you will agree with that.

How do you educate the clinician using

this about patients with histories of acne?

DR. LEYDEN: I don't think you have to.

Quite frankly, I don't understand why. In any

clinical study, there are always excluding patients

with significant diseases in the area you are going to

be evaluating that might confound the evaluation or

raise it. That's the main reason for excluding them.

Now, in practice, injecting collagen in

people with psoriasis that's stable because if you

traumatize their skin when they're unstable, you could

induce psoriasis. People with acne were on their

forehead and their cheeks. And injecting their

nasolabial fold, that's not an issue.

So I think that exclusion is for study

purposes, not implying that it would be risky or

unwise to use it in a person who happened to have acne

or some other condition, seborrheic dermatitis.

DR. STROBOS: Have we answered your

question?

MEMBER BOYKIN: Not really. We'll get

back to this.

ACTING CHAIRPERSON CHANG: We'll get back

to it later this afternoon.

MEMBER BOYKIN: It's just an issue of

labeling.

ACTING CHAIRPERSON CHANG: We have three

other questioners. Dr. Newburger, Dr. Doull, and Dr.

Olding have been waiting to ask questions.

DR. STROBOS: Okay. I just wanted to see

whether Dr. Lorenc wanted to address the issue of

differences in the glabella.

DR. LORENC: Just a comment about treating

patients. I wouldn't treat a patient clinically that

has active herpetic lesions with any injectable. I

think that's just an independent evaluation by the

physician at the time of treatment.

I have treated patients in the glabella,

of course, with Restylane with good results, no

reactions, no allergic reactions. Again, it's a

personal experience but on many patients.

ACTING CHAIRPERSON CHANG: Dr. Newburger?

MEMBER NEWBURGER: I have four short

questions, first one to Dr. Taylor. In your phase IV

study, are you planning to just introduce the

substance into the nasomalar folds or are you going to

use it for other wrinkles? And are you going to use

it for depressed scars?

DR. TAYLOR: The plan was to use it for

nasolabial fold wrinkling.

MEMBER NEWBURGER: Okay. Thank you.

DR. STROBOS: Let me clarify. One of the

problems we wanted to do is ensure adequate

enrollment. It's difficult to do that, as we pointed

out, in a prospective sort of narrow study. So we're

thinking of trying to have a more global experience.

I think we would be interested in your

comments or the panel's comments with regard to the

design of that study. That's to a certain extent why

we provided only a brief description because any

comment that you may have, we would appreciate,

understandably.

MEMBER NEWBURGER: Thank you.

The second question relates to labeling,

the proposed labeling. Under "Indications," you have

put "Restylane should only be administered by an

appropriately trained license practitioner." I

understand since this material has very different

physical characteristics than the collagen that has

been on the market for over 20 years.

How is someone going to be appropriately

trained, especially since there are differences in the

tutorial characteristics of this that a too

superficial injection is going to have a long‑lasting

cosmetic deficit? What is your plan to appropriately

train?

DR. STROBOS: Well, I believe that, in

fact, Medicis as part of its marketing efforts is

planning on engaging in such a program. Perhaps Dr.

Jonah Schaknai, who is the CEO of the company, could

address that.

DR. SCHAKNAI: Thank you, Dr. Newburger.

It's an excellent question, in fact, because we have,

among companies in this field, one of the strongest

commitments to continuing medical education, as you

know. Probably our largest promotional expenditure

involves supporting educational grant symposia.

Because of that commitment and because we

appreciate that there are subtle differences in

technique between Restylane injection and collagen and

other substances, we have hired one of the most

experienced continuing medical education firms to

provide live training probably in 50 cities, 2

dermatologists and plastic surgeons with hands‑on

experience among those who have injected Restylane,

have been trained specifically in Canada to do that.

Secondly, there will be a CD‑ROM tutorial

prepared by the same firm, ATS, that will educate

physicians at the time that they made purchase

arrangements of Restylane. We believe strongly that

an educational component is really the proper way to

ensure not only the success with individual patients

and good results from physicians with patients but

also to maximize the commercial success of the

product. It sells well if it works well.

To the degree that there is technique

dependence, you couldn't have a higher degree of

commitment.

MEMBER NEWBURGER: Next question, also

under "Labeling and Precautions," it says, "If laser

treatment, chemical peeling, or any other procedure

based on active dermal response is going to be

considered after treatment with Restylane, there is a

possible risk of eliciting an inflammatory reaction at

the implant site. This also applies if Restylane is

administered before the skin has healed completely

after such a procedure." What is the basis of such a

statement?

DR. STROBOS: Is there someone who can

answer that?

DR. LEYDEN: I don't know what you're

talking about. In the labeling, I think just as a

general sound of it, first of all, I don't think you

would do a procedure, if you were to inject somebody,

that you were then going to do a procedure in that

area. I mean, that wouldn't make any sense.

MEMBER NEWBURGER: It doesn't say anything

about how long ago the Restylane. It's right here

under the direct proposal for labeling.

DR. STROBOS: In the labeling ‑‑

ACTING CHAIRPERSON CHANG: Excuse me.

When the sponsor answers the question, could we

respectfully ask that one spokesperson reply to this,

rather than two or three rebuttals or clarification,

that one spokesperson clarify the issue so that we can

get to the other questions, please?

DR. STROBOS: I'm sorry. We were having

a little trouble understanding.

ACTING CHAIRPERSON CHANG: Dr. Newburger,

could you just clarify your question so that we can

have a succinct answer? Then we will have Dr. Doull

and Dr. Olding ask their questions. We need a

ten‑minute break, and we will return for other

questions.

MEMBER NEWBURGER: Under the proposed

insert with the product, one of the bullet points

under "Precautions" says, "If laser treatment,"is

going to be considered after treatment with Restylane,

there is a possible risk of eliciting an inflammatory

reaction at the implant site. This also applies if

Restylane is administered before the skin has healed

completely after such a procedure." I am asking, what

is the basis? What is the experience that led to this

precaution?

DR. RENSFELDT: I understand the question.

The primary basis is twofold. One is that the initial

experience that we had in Europe and elsewhere was

that we could see an association between some adverse

events that were reported and concomitant treatment

with this type of, for example, lasers and peeling and

also excessive use of sun beds. So, therefore, we as

a precaution added this sentence. And that has worked

very well since then.

And also from a purely theoretical

standpoint, there is a risk that you assume. When you

put the implant into the skin, at least initially

there is sort of a sensitive area when it's not

settled into the skin and has not been received by the

body completely.

Therefore, there is an area where we think

at least there is a theoretical basis for eliciting

such a reaction.

MEMBER NEWBURGER: But if Restylane in

some cases persists for nine months or so? I would

need more clarification of that time frame.

ACTING CHAIRPERSON CHANG: Dr. Doull?

MEMBER DOULL: Let me ask a quick tox

question. In the material that you provided, it says

that Restylane is not mutagenic. Can you describe the

tests that support that conclusion?

DR. STROBOS: Yes. Well, the FDA

presentation is going into that in a great deal of

detail, but the company was required to perform the

standard ICH battery of tests that are required of

medical devices by the Center for Devices and

Radiological Health. I believe the mutagenicity tests

included the Ames test, the microsomal nucleus test,

and the Chinese hamster ovary test.

Dr. Johns? Is he in the room? Were there

other tests?

MEMBER DOULL: Fruit flies?

DR. STROBOS: Fruit flies? No, we did not

do fruit flies.

ACTING CHAIRPERSON CHANG: Dr. Olding?

MEMBER OLDING: In your safety data

presentations, you reported decreased incidences of

complications, particularly or perhaps attributable to

the change in formulation in 1999, so that now it's

less than 6 parts per million of protein.

My patients are clambering, of course, for

any filler that lasts longer but with less

complication, the ideal one having none. If one

supposes that part of the problems are due to the six

part per million protein, is there a possibility that

that six part per million protein amount can be

reduced in the future or are you looking at that?

DR. STROBOS: Let me have Dr. Agerup

address it.

DR. AGERUP: I thank you for the question.

This is a continuous program inside Q‑Med to reduce

this protein. And we have a big plan, mainly also

because we have other indications that require higher

exposures of the NASHA gel. And we would like to be

absolutely out of any questions on safety.

ACTING CHAIRPERSON CHANG: Dr.

Blumenstein?

MEMBER BLUMENSTEIN: So I agree with the

sponsor that there is no concern over the McNemar test

reflecting the correct statistical significance.

However, it may be important in labeling to make sure

that the number of patients who had equivalent results

be displayed, just because that has an implication

with respect to clinical significance.

There are other concerns, however, with

respect to study design because I think the integrity

of the results depends a great deal on masking. And

I'm not sure I understand everything about the

masking.

Could somebody describe to me all of the

details of the masking; in particular, who it is that

actually looked at the photographs and whether they

were masked and the treating surgeon, what kind of

masking was going on there and so forth?

DR. STROBOS: Okay. Each site had two

investigators. The investigators were initially

evaluated for entry criteria by the treating

investigator. And that treating investigator would

then open a randomization and basically administer

Restylane or Zyplast according to the randomization.

That treating physician would do the

subsequent touch‑up evaluations. And that treating

physician would also do the adverse events evaluations

for both sides and make the determination about

severity and relatedness.

MEMBER BLUMENSTEIN: And this individual

was unmasked?

DR. STROBOS: That individual is unmasked,

right. And then the patient was not informed of which

side was getting which. And in the informed consent,

they were told that one site would be one and one site

would be the other but they wouldn't know which.

There was then at each site a second

investigator, who was identified as the evaluating

investigator. That investigator then reevaluated the

baseline as well as the post‑injection optimal

correction wrinkle skin severity score. And then the

evaluating physician was the individual who went and

evaluated the patients at the two‑month, four‑month,

and six‑month intervals in terms of identifying the

wrinkle severity score.

Wrinkle severity score was identified for

each side by that evaluating physician. And then once

that was documented in the record, a calculation was

made from the database as to whether there was an

improvement from the baseline, the baseline being the

post‑injection optimal correction to that evaluation

point.

The masking episode, the masking was done

after the physicians were asked to evaluate the

specific wrinkle severity score of patients at the

various time points that we're evaluating.

The evaluating physician was then asked to

guess which side was Restylane and which side was

Zyplast. They were not allowed to identify "Don't

know" or guessing as a choice. It was sort of a

forced choice between one or the other.

Have I answered your question?

MEMBER BLUMENSTEIN: Mostly. So the

evaluating investigator you're calling a person, they

were looking at the photographs or at the patient?

DR. STROBOS: They were looking at the

patient.

MEMBER BLUMENSTEIN: At each point in

time?

DR. STROBOS: Correct.

MEMBER BLUMENSTEIN: And, therefore, not

comparing to a baseline photograph?

DR. STROBOS: Correct.

MEMBER BLUMENSTEIN: Okay. That was a

little bit of a misunderstanding. Were there

photographs taken?

DR. STROBOS: Yes, photographs were taken.

MEMBER BLUMENSTEIN: Was there an external

panel or somebody who then looked at the photographs?

DR. STROBOS: No. Well, part of our

review is that the wrinkle severity score actually

requires you to touch the patient because the way the

wrinkle severity score works best is if you can spread

the wrinkle out.

In part of the discussions with the FDA,

there was no use of the photographs to set wrinkle

severity scores. The photographs were not used to

assess or to second‑guess, as it were, the evaluating

physician.

The validation study was specifically done

as an intra‑observer validation, precisely because of

that point, because the design of the study was such

that we were going to compare wrinkle severity scores

assigned by the same individual over a period of time.

MEMBER BLUMENSTEIN: Who is it that made

the decision that a satisfactory result had been

obtained to establish the baseline time point?

DR. STROBOS: I believe that would be the

injecting physician would ‑‑

DR. LEYDEN: And the patient together.

DR. STROBOS: The patient and the

injecting physician would conclude that optimal

correction had been reached and that no further

touch‑ups were needed. Sir?

DR. RENSFELDT: It was the evaluating

investigator who determined the optimal medical

correction.

DR. STROBOS: I'm sorry. I was mistaken.

MEMBER BLUMENSTEIN: So the decision at a

particular point in time that a satisfactory result

had been achieved on both sides was made by the

evaluating investigator?

DR. LORENC: I'm sorry. I just want to

make absolutely clear that I was the injector. I was

the treating physician. Another plastic surgeon was

the evaluator. He was completely blinded. He did not

know what was injected, which site. So they were

completely independent and unbiased in their

evaluation.

The decision that was made whether to

inject on what the baseline level was was made by the

evaluating physician and the patient.

MEMBER BLUMENSTEIN: Okay. But both sides

had to have a satisfactory result.

DR. STROBOS: Correct. And they could be

injected with different volumes.

MEMBER BLUMENSTEIN: So that if one side

were satisfactory at a given visit and the other side

was not, there was another treatment given by the

unmasked treating physician, which was subsequently

evaluated. Is that correct?

DR. STROBOS: My colleagues are nodding

yes, that that would be the case.

MEMBER BLUMENSTEIN: So if that were the

case, the other side was not treated. So there would

become a discrepancy in the follow‑up time for time

since last treatment.

DR. STROBOS: Well, yes, except this would

be at two weeks. In other words, the initial

injection would be at a time‑zero, let's say. And

then there would be a two‑week visit for a touch‑up.

And then there was another visit at two weeks

following for touch‑ups.

And I don't believe there were that many

patients who had a second touch‑up. about 35 percent

of the patients had a second touch‑up.

MEMBER BLUMENSTEIN: On one side but not

the other or both sides?

ACTING CHAIRPERSON CHANG: I think the

sponsor is making the point that time‑zero is not

established until both sides are satisfied. And that

is by the blinded evaluator.

MEMBER BLUMENSTEIN: But my point is that

there is some discrepancy in follow‑up introduced by

that procedure of judging one side versus the other.

DR. STROBOS: Not if time‑zero is set at

the time of optimal correction.

MEMBER BLUMENSTEIN: On both sides.

DR. STROBOS: Yes.

MEMBER BLUMENSTEIN: Right, but what it

amounts to is that the follow‑up time, time from the

last procedure for each side, may be different.

DR. LEYDEN: The answer is yes.

DR. STROBOS: I think the answer is yes.

DR. RENSFELDT: The answer is yes. And

the baseline is from when the last treatment was

counted.

MEMBER BLUMENSTEIN: In how many patients

would you guess for which this difference could be

four weeks, instead of two weeks?

DR. RENSFELDT: I can't answer that. I

don't have that. I can't even guess it.

MEMBER BLUMENSTEIN: You do concede,

though, that there could be a four‑week discrepancy?

DR. RENSFELDT: There could be in some

instances.

DR. STROBOS: I think the question is

looking just at the number of patients who had a

second injection or a third injection would not give

you the number of patients who only had an injection

on one side. Is that?

MEMBER BLUMENSTEIN: That's what I was

getting to. And then the follow‑up was six months

from the date of declaration of satisfactory results

on both sides.

DR. STROBOS: Correct.

MEMBER BLUMENSTEIN: That was a little bit

unclear in the materials that were given to me. It's

whether it was six months from that date or six months

from enrollment.

DR. STROBOS: It's six months from the

date of optimal correction.

MEMBER BLUMENSTEIN: And then 2 more

questions related to table 16.2.5.10 through 16. I

don't understand what statistical test was used to

evaluate the tendency to be correct on guessing.

DR. STROBOS: Is this the binomial

distribution?

DR. JANSSON: I think so.

DR. STROBOS: The statistician is Dr.

Jansson right here.

DR. JANSSON: I'm just looking through the

appendix there. Table 16.2.5.10 used chi‑squared

tests to test whether the portion of correct guesses

is different between sites.

MEMBER BLUMENSTEIN: And did this take

into account matching?

DR. JANSSON: Matching?

MEMBER BLUMENSTEIN: In other words, you

would have the correct result and then the guessed

result. And so that would be like a McNemar table.

DR. JANSSON: Yes. We would just identify

for each patient was the guess correct or not. So

it's a true binomial variable. And we tested whether

the portion of correct guesses in the six sites

differed from each other in that type of using a

chi‑squared test.

MEMBER BLUMENSTEIN: But you could also

see that as a McNemar type of table, right, with

matched pairs? In other words, you have truth, and

then you have the guess of truth. And you have both

kinds of discordance and you have concordance.

DR. JANSSON: Yes.

MEMBER BLUMENSTEIN: Did you take that

into account in the test?

DR. JANSSON: We did not do the McNemar

test for further masking data.

MEMBER BLUMENSTEIN: Right. Did the test

take into account the sites? In other words, there's

just a single p‑value given there, but there could

also be a test of homogeneity of results across sites;

in other words, an interaction between site and guess.

DR. STROBOS: Yes. We did do a site

analysis by site. And masking or incomplete masking

was, if I'm not mistaken, detected at different sites

at the different time points that were assessed when

you drill down into the individual sites. But perhaps

Dr. Jansson is better able to answer that question.

DR. JANSSON: Yes. We performed the exact

binomial test to test whether the portion of correct

guesses differed significantly from the hypothesized

50 percent. We did that for each center on the

baseline assessment.

We identified two centers there where the

p‑value was below 0.05. We could not reject if a

guess was truly random. We excluded those two sites

and did the primary efficacy analysis again and found

about the same results as in the overall analysis.

MEMBER BLUMENSTEIN: So you're saying that

there was heterogeneity across the sites with respect

to the ability to guess?

DR. STROBOS: Yes, but it changed. Yes.

The answer is yes, but it changed from baseline to ‑‑

I believe the masking analysis was done at baseline,

at two months, and at six months. So the

heterogeneity that you have identified there was

different at those three different time points.

MEMBER BLUMENSTEIN: Then did you do

statistical modeling to find out if the ability to

guess correctly influenced the result, the score that

was recorded by the evaluating investigator?

DR. JANSSON: Yes. We've done a number of

analyses to investigate that. For example, if we

looked at the patients where the improvement from

treatment was similar for Restylane and Zyplast, a

medial category, what we call the category B in our

report.

Those patients tended to have proportional

correct guesses, rather close to 50 percent; whereas,

the patients where a frequent benefit was seen at six

months were much better at guessing which treatment

was applied on which site.

MEMBER BLUMENSTEIN: Are those results

available to me here? I was not able to find them.

I'm not sure if I ‑‑

DR. JANSSON: They are available as

amendment 3 and amendment 5 to our responses to the

FDA questions we have received.

MEMBER BLUMENSTEIN: Well, I will go and

look for them, then, because it was rather hard to get

through all of this material without the indexing and

that sort of thing. Thank you.

ACTING CHAIRPERSON CHANG: Our last

question is from Dr. Doyle.

MEMBER DOYLE: This may seem somewhat

naive, but since I am not a plastic surgeon nor a

dermatologist but a wrinkled consumer, but I am

interested in the fact that the assumption I am making

that if I were a user of this is that in order to

maintain the cosmesis, I would have to be injected the

rest of my life, which in my case may be short but for

some, it may be a considerable amount of years. Is

that a correct assumption?

DR. STROBOS: Well, the answer is yes.

The reinjection rate with collagen, which is the

approved product in the United States, typically when

you look at studies, it's on the order of three to

four months. When you look at some of the episodic

studies that have been done on reinjection and in

Europe, it's a longer time period between reinjection.

There is also a certain demographic that

at a certain time period, people stop getting

reinjected. And the time period at which people start

varies, of course. And then some people are just

episodic injectors, but perhaps if you would like, I

would have Dr. Leyden ‑‑

MEMBER DOYLE: There are a couple of

things I would like to ask, then, with the assumption

that there is a long possible, very, very long‑term

usage of this, not necessarily with collagen but with

Restylane.

In the world literature because I realize

the trials here are quite short, is there any evidence

that if there is a longer time between injections or

a shorter time ‑‑ and the reason I ask, there seem to

be a number of adverse reactions that are transient

that occur in the first couple of weeks. If the time

period goes down, I am concerned that you would have

this repetition of these minor but irritating side

effects.

The other thing is, is there any evidence

of any sort of cumulative effect from the very small

parts of the protein that are in the six parts per

million?

DR. STROBOS: Perhaps I could have Dr.

Agerup address.

DR. AGERUP: Thank you. This is an

interesting question. My answer, though, is

anecdotal. I have been living with this for many

years, eight years about. So we have many patients

treated since then.

What we see is that after somewhat like

two or three injections, you need less of this

material. And because this material is degraded by

inflammatory reactions and other hydrolysis, our

interpretation is that the skin gets used to this

treatment and et cetera and, therefore, becomes a

friend with it, so to speak. The protein issue, this

is six ppm released over a time period of almost a

year. We are now down to enormous exposures.

ACTING CHAIRPERSON CHANG: Thank you. At

this time the panel is going to take a break for five

minutes. And we plan to reconvene at ‑‑ it is by my

watch 18 after ‑‑ shortly before 25 of.

(Whereupon, the foregoing matter went off

the record at 10:19 a.m. and went back on

the record at 10:32 a.m.)

ACTING CHAIRPERSON CHANG: I would like to

reconvene the advisory panel at this time. I would

like to introduce Anthony Watson, who will begin the

FDA's presentation for this PMA.

FDA PRESENTATION

INTRODUCTION AND PRECLINICAL

MR. WATSON: Some of this presentation may

seem repetitive based on what we have heard this

morning. So please bear with me.

First of all, I would like to thank

everybody for being here. I am Anthony Watson, the

lead reviewer for this PMA. As you know, we will be

discussing the PMA for Restylane injectable gel by

Q‑Med AB.

Today's FDA speakers will start with me.

As lead reviewer of the PMA, I will be discussing the

preclinical portion. Dr. Horbowyj will then discuss

the clinical aspects of the PMA. Dr. Telba Irony will

then discuss the statistical aspects of the PMA. I

would also like to point out that Dr. Amy Newburger,

a member of this advisory panel, provided a clinical

consult for this PMA.

So what is Restylane? Restylane is a

transparent, viscous, and sterile gel supplied in a

syringe. It consists of non‑animal, stabilized,

hyaluronic acid suspended in a physiologic buffer.

Restylane's proposed intended use, as you

can see there, is for the temporary correction,

moderate to severe facial wrinkles and folds, such as

nasolabial folds. The panel will be asked to comment

on these indications later.

The sponsor conducted a battery of

preclinical tests in the area of microbiology,

toxicology, immunology, biocompatibility, and shelf

life.

Microbiological preclinical testing

consisted of pyrogen and bacterial endotoxin testing.

The material passed both of these tests.

Toxicological testing consisted of acute

subchronic and chronic toxicity testing in rabbits as

well as two cytotoxicity tests. ISO elution and

colony formation methods were used. The material was

non‑cytotoxic, and there was no evidence of foreign

body reaction.

The sponsor also performed two Ames

mutagenicity tests and two genotoxicity tests, as

shown here. In these tests, the material was

non‑mutagenic and non‑genotoxic.

Now, Restylane contains 1,4 butanediol

diglycidyl ether, which is referred to as BDDE. BDDE

acts as a cross‑linker in the product. It has been

noted to be mutagenic in the Ames bacterial

mutagenicity assay, and diglycidyl ethers are known to

act also as sensitizers.

The sponsor has conducted an extensive

biocompatibility evaluation of the product and has

presented information that indicates the device to be

biocompatible, non‑mutagenic, and non‑sensitizing.

However, to further address the concern that BDDE

could act as a carcinogen, FDA requested the sponsor

to either provide the results of carcinogenicity

testing of BDDE or to provide information that

adequately addressed the safety issue.

The sponsor provided a study report of an

investigation of the potential for BDDE to cause

carcinogenesis in a mouse model. The study involved

a twice weekly topical application of BDDE at two

doses, .05 percent and .2 percent, over the course of

103 weeks, or approximately 2 years.

The finding of the study was that there

was no significant difference in the incidence of

tumor formation between treatment and control with the

exception of the induction of lymphoblastic

lymphosarcoma in female mice.

To address this observations, the sponsor

provided additional information indicating that the

method used for classification of mouse hematopoietic

neoplasms used in the study was outdated and that

using current methods for identifying and classifying

mouse hematopoietic tumors shows no difference between

treatment and control animals in this study.

The difference in categorization of tumor

types between when the study was conducted and today's

widely accepted approach is based upon whether

lymphoid neoplasms are separately identified, as was

done previously, or if they are lumped together under

the heading of lymphoid tumors, as is done today.

When tumors identified as of lymphoid origin are

combined in the study, there is no difference between

treatment and control.

The carcinogenicity information from the

mouse study and the sponsor's own preclinical

mutagenicity and genotoxicity evaluations indicate

that BDDE is not carcinogenic.

However, if we do assume that BDDE did

cause the induction of a specific tumor in the mouse

model at the high dose concentration, or .2 percent,

we can calculate the cancer risk posed to patients

using the product.

The calculated cancer risk of patients

receiving Restylane assuming the mouse study did

conclude that BDDE was carcinogenic is estimated to be

1.2 times 10‑7 divided by 10,000, or approximately one

in 100,000,000.

Based on modern evaluation techniques and

the anticipated dose level received by the patient,

FDA determined there to be no carcinogenic risk from

the BDDE in Restylane.

So, continuing with the preclinical

testing, Guinea pig maximization test was performed,

demonstrating that the material did not display

evidence of delayed hypersensitivity.

Two muscle implantation tests were

performed in rabbits: one for 4 weeks and the other

for 90 days. In the four‑week test, the material was

well‑tolerated. And in the 90‑day study, there was a

slight inflammatory response greater than observed in

the negative control, which we considered to be minor.

Shelf life stability studies demonstrate

that the device is stable at room temperature for up

to 12 months.

So the overall summary from the

preclinical testing indicated that Restylane was safe

to be evaluated in clinical studies. And now I would

like to introduce Dr. Roxi Horbowyj to discuss the

clinical portion of the PMA.

Roxi?

DR. HORBOWYJ: Thank you, Tony.

CLINICAL REVIEW

DR. HORBOWYJ: Good morning. As Tony

said, this presentation highlights the FDA clinical

review of this current Restylane application.

Specifically, as you have already heard,

the pivotal clinical study and open label extension

support this application.

The devices that have been studied are:

Restylane, which is a hyaluronic acid generated by at

least two Streptococcal species of bacteria,

stabilized and suspended in psychologic buffer at pH

7 and a concentration of 20 milligrams per cc.

The intended use of this study was to

correct contour deformities in wrinkles at the

nasolabial fold. During the study, the device was

delivered via a .7 cc syringe and using a 30‑gauge

half‑inch needle, maximum dose for treatment session

of 1.5 cc.

Zyplast was the control. And it is a

purified bovine dermal collagen cross‑linked with

glutaraldehyde dispersed in phosphate buffered saline.

And this device includes .3 percent lidocaine.

This device is indicated for the

correction of contour deficiencies of soft tissue. It

was delivered during the study via a one cc syringe

and a fine gauge needle to a maximum dose per year of

33 cc.

Pivotal study was designed as a one‑to‑one

randomized prospective study at six U.S. centers to

compare Restylane and Zyplast in a within‑patient

control model of augmentation of correction of

bilateral naso folds.

Effectiveness was followed for six months

after the post‑treatment baseline. Safety was

followed for 12 months after the post‑treatment

baseline.

Masking was attempted in several ways.

Patients were considered to be partially masked

because of prior history of exposure of some of these

patients to the control. Evaluating physicians were

independent. And masked treating physicians, as you

have heard, were unmasked.

As to effectiveness, the primary objective

was to evaluate differences in the effectiveness of

Restylane and Zyplast on the visual severity of the

nasolabial folds as were assessed by the evaluating

investigator at six months after the post‑treatment

baseline.

This baseline is defined, as we have

heard, to begin at the follow‑up, which demonstrated

that optimal correction had been sustained for two

weeks. And optimal correction was defined to be the

best cosmetic result obtainable as was determined by

the evaluating physician.

A specific objective score or goal for

correction was not defined in the protocol. Two

injectable implant sessions were expected to be needed

to achieve the goal, however.

The primary evaluating parameter was the

wrinkle severity rating scale, otherwise known as the

SRS score. This is a five‑point integer scale. A

change in the score of one was considered to be

clinically significant based on a review of 30

non‑study photos. This validation was not reconfirmed

using study photo evaluations.

As to safety, adverse events were reviewed

in two ways. A patient diary was kept, an allowed

record of intensity and duration of pain, tenderness,

swelling, redness, bruising, itching, and other events

for 14 days post‑treatment. Then there was also

follow‑up by the treating physician during follow‑up

that lasted through 12 months.

Hypersensitivity reaction was addressed

for both Restylane and control. Pre‑screening was

performed for sensitivity to collagen; however, not to

hyaluronic. Pre and post‑treatment antibody titers

were not monitored. However, a post‑treatment adverse

event skin testing protocol was planned for

sensitivity to hyalurone and to collagen in case

hypersensitivity was suspected by the investigator.

As to secondary objectives, there were

several. The number of treatment sessions required to

achieve optimal cosmesis, a global aesthetic

improvement score, which consisted of subjective

evaluation if the site was very much improved, much

improved, improved, had no change, or was worse. And

this was to be assessed at all follow‑up points by the

evaluating investigator and the subject.

Another secondary objective was to look at

the SRS score as assessed by the subject at two, four,

and six months as well as the evaluating investigator

at two and four months.

The study population consisted of

non‑pregnant, non‑lactating adults who were seeking

augmentation correction of bilateral naso folds.

Patients were enrolled if they met the criteria for

SRS 3 or 4 at pretreatment baseline. They needed to

be willing to abstain during the study from exclusion

procedures, such as laser or chemical resurfacing,

Botox injection, aesthetic facial surgery, concurrent

facial wrinkle treatments, immuno‑modulary therapy,

and desensitization injections to meat products.

They needed to have no active skin disease

or aesthetic facial therapy within six months of study

entry. And they needed to not have coagulopathy, any

known allergy or sensitivity to device components, or

to meat products.

As you have study, this pivotal study

procedure had two phases. There was a treatment

phase, in which the device dose was required to

achieve the optimum cosmetic result within the maximum

limits for device use. There was reevaluating every

two weeks with touch‑up if correction was suboptimal

on the follow‑up time.

Post‑treatment baseline began if the

optimal correction had been maintained for two weeks.

Follow‑up again for effectiveness was at 2, 8, 16, and

24 weeks after this baseline. And follow‑up for

safety was at 2, 8, 16, 24, 36, and 52 weeks after

this baseline.

Sample size was determined for this study

based on the hypothesis that three times as many

Restylane‑treated sites were to remain superior

compared to control at six months post‑treatment

baseline.

Superiority was defined in the protocol as

a difference of at least one unit in the SRS score in

favor of one of the treatments. The SRS score

difference, considered to be clinically significant,

was one unit. On the basis of this and accounting for

potential loss of follow‑up, the sample size was

calculated to be 130 patients.

Reviewing study outcomes: demographics,

as you have heard, for the cohort relayed a patient

population that was predominantly female, Caucasian,

nonsmokers, who had very little sun exposure or

minimal sun exposure. There were a few males, few

other ethnicities, and smokers involved in this study.

Demographics also show us that 65 percent

of the patients had had prior facial aesthetic

procedures, most commonly collagen injection, which

43.1 percent of the population had experienced, as

well as botulinum toxin injection, which was

experienced by 23.4 percent of the population.

Thirty‑five percent of the population had no prior

aesthetic procedures.

Patient disposition is summarized in this

slide. Pretreatment and at baseline, there were 138

patients who presented. By six months, there were 134

patients. And the study reports that 9 and 12‑month

follow‑up for safety included 125 patients.

There was a masking assessment that was

done evaluating both the evaluating investigator as

well as the patients. This slide shows the results

that were obtained at baseline, two months, and six

months. Usually, as the sponsor has also indicated,

a 50 percent guess is considered to be consistent with

masking.

What the study results showed was that at

baseline for both the evaluating investigators and for

patients, the correct guess was approximately 60

percent. This increased to approximately 70 percent

by 6 months. And a percentage greater than 50

percent, is associated with incomplete masking. It

was also noted that masking varied by center and this

variation was statistically significantly different.

As to pivotal study outcomes for primary

effectiveness, the incidence of the SRS score at six

months as determined by the evaluating physicians is

listed here. Seventy‑eight patients were found to

have a Restylane‑treated size score, which was better

than control. Forty‑six patients presented with

Restylane and control‑treated sites to be equal, and

13 patients presented with the Restylane‑treated sites

to be worse, had a higher SRS score than control.

This was from the per‑patient basis.

Looking on the overall basis of the study cohort, a

mean SRS score as determined by the evaluating

physician shows that when you look at the absolute

difference between Restylane and control at baseline

and pretreatment, the differences are very small, 0.02

and 0.01 units. However, at six months, the

difference is 0.58 units of SRS.

Another way of looking at this is depicted

in this slide, which shows time on the x‑axis and the

SRS score along the y‑axis. Each red line, fine red

line, is an indicator of a unit of SRS.

And what you can see here is that at

pretreatment. And at optimum treatment, the SRS score

changed or achieved was 1.5 for both Restylane and

control. The red line presenting the data represents

Restylane, the yellow line control. And the green

line shows the difference between the two. It simply

is the traction.

So what you see is that as time

progressed, the difference was 0.58, which is below

the unit of one, which was considered to be clinically

significant in superiority in the protocol per

patient.

The secondary pivotal study outcomes for

effectiveness from the patients' perspective of

evaluation of SRS trended along with the evaluating

physicians' assessment and is demonstrated here.

As you can see, both for the comparisons

of Restylane and control in the upper portion of this

slide, the trends are similar and in the overall mean

assessment and the absolute difference here, it is

also in line with what was found by evaluating the

evaluators' data.

Another secondary outcome was the mean

global aesthetic improvement score. This slide shows

Restylane being ‑‑ I will show this with this pointer.

Restylane is shown in this color, Restylane being

better than control. So it is in this color. I'm

pointing this out because I think sometimes the colors

are a little bit difficult to read, Restylane being

equal to control is shown in the blue. And Restylane

worse than control is shown in the gold. The

reference is here below.

And it did show that the trends were

similar to the evaluating investigators and patients.

And it did show an increase with time for Restylane

being judged better than control by SRS scale, which

was in the protocol.

As to the number of treatment sessions, to

achieve optimal cosmesis, optimal cosmesis required

one to two treatments. And for initial treatment

alone, there were 65 percent of patients from the

Restylane‑treated side that only needed one treatment

and 62 percent of patients who needed only one

treatment with control.

The distribution of patients requiring

three treatments was that seven patients receiving

Restylane needed three treatments and three patients

receiving control needed three treatments. Overall,

however, there were no statistically significant

differences in the number of treatments required for

optimal cosmesis.

Basic criteria for some of the more

frequent reactions after treatment with Restylane were

presented. Hypersensitivity was defined as an

inflammatory reaction with swelling, redness,

tenderness, induration, and rarely acneform papules at

the injection site with an onset of one to several

weeks after initial treatment in previously unexposed

individuals and in less than seven days following

treatment in patients known to have been previously

exposed. Average duration to systems were reported to

have a two‑week duration.

Injection site reactions were described to

be mainly shot‑term inflammatory symptoms starting

early after treatment and with less than seven days

duration. They were considered to be a mix of

different types of reactions that do not fit with

other classifications.

Looking at similar information for the

control as reported and the labeling for the control,

hypersensitivity is defined as erythema, swelling,

induration, and/or urticaria implant sites, often

following unrecognized or unreported positive collagen

skin tests. It is reported to occur in one to two

percent of treated patients, typically persists for

one to nine months, with an average duration of four

months.

Rarely, abscess formation is reported to

occur, in some cases associated with elevated

anti‑bovine collagen antibodies, weeks to months

following injections and may cause induration and/or

scarring.

Injection site reaction is defined to be

minimum swelling, redness, and discomfort immediately

following implantation. Temporary palpable lumpiness

or visible material, such as white papules or

milia‑like yellow, may occur.

As to safety, from the patient diary, this

slide shows the incidence of moderate or severe

symptoms at initial session and after touch‑ups. The

control is presented in the lighter color bar, and

Restylane is presented in the darker color, lower bar.

So for each one of these symptoms that we

look at, which is bruising, redness, swelling, pain,

tenderness, itching, and other, the two treatment

types are next to each other, the upper bar being

control, the lower bar being Restylane.

This data indicates that there was an

increased incidence of moderate or severe bruising,

redness, swelling, pain, tenderness, and itching after

the first treatment with Restylane compared to

control.

The difference for itching trended toward

statistical significance. The differences for

bruising, redness, swelling, pain, and tenderness,

were statistically significantly different. The data

indicates that this trend persists for swelling and

tenderness in patients who had touch‑ups. Of note,

the report of other for Restylane included two papulal

nodule lesions reported with onset at more than 40

days post‑treatment.

This side presents safety from the patient

diary for symptom duration. Again, this data is

presented after the initial session and after all of

the touch‑ups. The key here is a color code, which

shows that the green colored bar portion of the bar

represents one day symptomatology, the blue bar 2 to

7 days, the gold bar 8 to 13 days, and the orange bar

14 or more days. They are presented here in that time

order.

This chart shows that after first

treatments, while the symptom reports during the first

day were comparable, a greater percentage of

Restylane‑treated naso folds than control‑treated naso

folds were reported to have swelling, pain,

tenderness, itching, and other symptoms during the

second to seventh day post initial treatment. This

trend persisted for more than seven days, the golden

orange bands for bruising, redness, swelling, and

itching.

After all touch‑ups, there were more

presentations of redness, swelling, tenderness, and

other symptoms on the Restylane‑treated at two to

seven days. Bruising, redness, and swelling were

reported for Restylane as well as control at 14 or

more days.

The open label extension design allowed

study patients to receive unilateral or bilateral

re‑treatment with Restylane at the sixth or ninth

month visits. If re‑treated, the efficacy assessment

was performed before re‑treatment but not after

re‑treatment and if not re‑treated, efficacy

assessment was performed beyond six months. The

hypothesis here was that Restylane is superior to

Zyplast three times as frequently as Zyplast is

superior to Restylane.

For safety, the pivotal protocol

continued. However, it's important to note here that

these patients were evaluated at the 6th month, 9th

month, and 12th month follow‑ups, not every 2 weeks

post‑injection if they were injected as they were in

the initial phase of the study.

So there was no two‑week follow‑up after

reinjection during the open label extension design.

And there were also no patient diaries recorded. So

the opportunity for symptoms to be elicited after

reinjection at six months did not present itself until

nine months.

This represents the open label extension

disposition of patients as well, showing the number of

patients who were available for safety and for

effectiveness and the number of patients who were

re‑treated at six and nine months.

The assessment of pivotal study treatment

effectiveness at 9 or at 12 months is limited because

75 percent of pivotal study patients were re‑treated

at 6 months. Only 24.6 percent of pivotal study

patients presented for effectiveness at 9 months, and

only 5 percent of pivotal study patients presented for

effectiveness at 12 months.

In summary as to effectiveness, optimal

correction is achievable with both Restylane and

control by a mean change of 1.5 units SRS in a

comparable number of sessions. The wrinkle SRS

assessment that one unit is a clinically significant

change was not confirmed on study photos.

SRS for six months was one unit higher for

Restylane than control in 59.7 percent of treated

patients but less than one unit higher, specifically

at 0.8 units higher, on average for the overall

cohort. SRS interpretation at 9 and 12 months

post‑treatment is limited as most, specifically 72.5

percent of patients, were re‑treated at 6 months.

In summary as to safety, hypersensitivity

reaction to Restylane was reported to vary at onset of

symptom presentation in the protocol. During the U.S.

pivotal study, symptoms of inflammation within 14 days

post‑treatment were of statistically significantly

higher intensity after initial treatment with

Restylane compared to control.

There were two papulal nodule lesions

reported with onset at more than 40 days

post‑treatment. Antibody titers were not evaluated.

And so symptom profiles were not correlated to

immunologic status for change.

Hypersensitivity reaction may have been

underestimated as injection reaction and early

hypersensitivity symptom profiles overlap. This may

have confounded diagnosis of a hypersensitivity

reaction to a new product.

Now it is my pleasure to introduce Dr.

Telba Irony to present the FDA's statistical overview.

Thank you.

STATISTICAL REVIEW

DR. IRONY: Well, good morning. I am

Telba Irony, and I will provide the statistical

perspective of the Restylane pre‑market application.

My presentation will discuss the following

topics: the pivotal study design; the patient

disposition; the results provided by the evaluating

investigator; the open label study. And I will talk

about some important study characteristics that should

be taken into account when the study results are

analyzed; and, finally, some points to consider when

evaluating a superiority claim for this device.

The study had a split face design in the

sense that each patient received Restylane treatment

in one side of the face and Zyplast treatment that

served as a control in the other side of the face.

The treatments were randomly assigned to each side of

the face, and 138 subjects were randomized.

Only nasolabial folds were treated. The

study was double‑blind. The patients were masked.

And the evaluating investigators, who were different

than the treating investigators, were masked as well.

There were follow‑up visits at two, four,

and six months. At 6 months, 100 patients were

re‑treated. The remainder non‑re‑treated 34 patients

were also evaluated at 9 months. The study was

performed at six centers.

Each side of the face was evaluated before

treatment on the severity rating scale. The severity

rating scale goes from one ‑‑ that means no visible

fold ‑‑ to five, the extremely deep folds.

Then the sides were treated until both

became optimal. Sometimes that required more than one

application. After six months, each side of the face

was evaluated again.

The primary endpoint was the comparison of

both sides of the face with respect to the change from

pretreatment to six months post‑baseline. The

comparison was made by the evaluating investigator.

And one point different was considered clinically

significant.

The patient disposition was as follows.

One hundred, thirty‑eight patients were initially

randomized and constituted the intent‑to‑treat sample.

Out of those, 134 completed the study up to six

months. There were also 26 subjects with major

protocol violations. And, consequently, 108 subjects

constituted the per‑protocol sample. We analyzed the

results from the intent‑to‑treat sample that were

confirmed by the results of the per‑protocol sample.

The results for the primary endpoint

provided by the evaluating investigator follow.

Restylane was superior to control in about 57 percent

of the subjects. Restylane was equivalent to control

in 33.6 percent of the subjects. Restylane was

inferior to control in 9.5 percent of the subjects.

McNemar test provided statistical

significance, meaning that the hypothesis that

Restylane is inferior to control was rejected. Note,

however, that the McNemar test disregards the number

of cases for which the products were similar. This

would be true, even though there were much more cases

for which the products were similar.

This is a secondary endpoint. They are

the results from the measurements at two months, four,

and six months. They were all statistically

significant. Again, McNemar test was used. And the

equivalent cases were not taken into account, even

when they were 59 percent, as in the case of the

second month. No formal longitudinal analysis was

performed.

Here is another secondary endpoint, which

is the mean change from pretreatment in the SRS score,

which was computed for each side of the face at two,

four, six, and nine months. For 8 months, only 34

patients were included. Again, no formal statistical

longitudinal analysis was performed.

At all time points, the Restylane side had

lower ‑‑ that means better ‑‑ mean values than the

control side. The mean difference was always less

than one point.

Open label study. As I said before, at 6

months, 100 patients were re‑treated. The remaining

34 patients were not re‑treated and were evaluated at

9 months to provide an assessment of whether or not

the products last beyond 6 months.

The non‑re‑treated patients were mostly at

centers 1 and 2. Consequently, it is difficult to

assess whether the need for re‑treatment was due to

clinic effectiveness or treatment effectiveness.

The results of the open label study were

100 patients needed re‑treatment. And, consequently,

one can say that neither product lasted more than six

months. For 21 patients, which means 16 percent,

Restylane lasted more than control. For 13 patients,

10 percent, the control was equal to Restylane. Given

that information, it is problematic to state that

Restylane lasts beyond six months.

Important study characteristics, the

sponsor assessed the effectiveness of masking for the

evaluating investigators. Masking is important

because the measurements are quite subjective.

A statistical hypothesis test was

performed to assess the effectiveness of masking. The

effectiveness was rejected at all time points. At

baseline, the evaluating investigators could correctly

guess which side was treated with which product in 64

percent of the times. At two months, correct guesses

were made in 66 percent of the times. At six months,

correct guesses were made in 70 percent of the times.

The sponsor also performed a validation of

the severity rating scale. In that study, 30

photographs of wrinkles were shown to the evaluating

investigators at 2 time points separated by about 2

weeks. The proportion of agreement between the

evaluations was about 70 percent.

Treatment of missing values. There were

four withdrawn patients. The sponsor used the

pretreatment SRS score for all endpoints evaluated

after the patient's withdrawal. As a consequence,

both sides of the face should have the same score, and

the withdrawn patient was not considered by the

McNemar test.

Missing data for the secondary

effectiveness measures were handled according to the

last observation carried forward method, which is not

appropriate in this case because the endpoints tend to

get worse as time goes by. However, due to the split

face design, we do not think that this method favored

any treatment.

Results across centers: For all six

centers, the proportion of cases in which Restylane

was superior to control was larger than the proportion

of cases in which Restylane was inferior to control.

However, for half the centers, Restylane was

equivalent to control for most patients.

Points to consider: One of the questions

we have to the panel members concerns the superiority

claim. Could you say that Restylane is better than

control considering that for 43 percent of patients,

Restylane was not superior to control? In half the

centers, the proportion of patients for which

Restylane and control were equivalent was larger than

the proportion for which Restylane was superior.

There was a lack of a totally effective masking

procedure. And the evaluations are subjective.

More points to consider: Can we say that

Restylane lasts more than six months? The open label

had a small and biased sample. The non‑re‑treated

patients were mainly in two centers. And,

consequently, it is difficult to establish if

effectiveness was due to treatment or center. And,

finally, neither product lasted more than 6 months for

75 percent of the patients.

Thank you for your attention.

ACTING CHAIRPERSON CHANG: Thank you.

At this time, do any panel members have

questions to direct to the FDA? Dr. Newburger?

PANEL DELIBERATIONS AND ADDRESS FDA QUESTIONS

MEMBER NEWBURGER: For Dr. Irony, in

assessing the characteristics of this filler compared

to collagen, it's very, very different. Forty‑three

percent of the test population had previous treatment

with collagen.

DR. IRONY: Correct.

MEMBER NEWBURGER: And so these

individuals would recollect the characteristics of how

this filler vanished over time. So is that not an

unavoidable point in terms of looking at bias, how

they correctly guessed?

Second of all, for those who were

re‑treated, under "Results," you put a conclusion that

neither product lasted for more than six months.

Is that necessarily so? Couldn't it be

that these people were pleased with their results,

started to see it vanishing a bit, and wanted to have

more because, after all, why were they participating

in the study since they had abjured from other

cosmetic procedures?

DR. IRONY: I think your questions are yes

for both cases. One thing that I wanted to clarify is

that the masking that I pointed out was not the

patient, was the evaluating investigator, but I guess

the same conclusion that you made is valid to the

evaluating investigator.

They were dermatologists. And they

probably were familiar with the results by the

control. So maybe that could be a cause for the

correct guess that they guessed correctly which

product the patient had in each side.

So I agree with you. Masking is very,

very difficult, if not impossible, in this case.

MEMBER NEWBURGER: And then one last

question, the non‑re‑treated patients who were in the

two centers, did you happen to look? Were those the

two centers where they had more bruising and swelling

and these people just didn't want to go for a second

time?

DR. IRONY: I don't know. I didn't look.

So I'm not sure. I don't know if I answered your

other question, the second question, that you asked

about if it's possible that a patient, although not

optimal, was satisfied or maybe dissatisfied. I don't

know. That's possible, too.

MEMBER NEWBURGER: Thank you.

ACTING CHAIRPERSON CHANG: Okay. Dr.

Miller?

MEMBER MILLER: I just have a question

about nowhere in the data presented by FDA or by the

sponsor did I get a sense that there was any attempt

to track the absolute amount of the device which was

delivered to the patient and compare that to the

incidence of symptoms and side effects and that sort

of thing. Was there any tracking of that information?

ACTING CHAIRPERSON CHANG: If I can

rephrase the question, are you asking, was there any

attempt to correlate volume of injection and incidence

of adverse events?

MEMBER MILLER: Right, sort of a

dose‑response sort of thing, I guess.

DR. HORBOWYJ: We have not seen data that

correlates that.

ACTING CHAIRPERSON CHANG: Dr. Halsey?

MEMBER HALSEY: One quick technical

question. On the materials we have been provided, the

toxicity testing includes bacterial endotoxin. And it

says less than 0.5 used per ml. And then in the

summary, pre‑market summary draft, it says less than

.05. Is that a typo or has the endotoxin content

changed?

Do you see what I am looking at?

MR. WATSON: Actually, let me grab what I

have here. You are saying that there is a difference

between what is in the summary and what is actually in

the PMA?

MEMBER HALSEY: The preclinical summary

says it's 0.5. And here in this summary of laboratory

data, it says it is less than 0.05. So it's a tenfold

difference in endotoxin content. I just wonder if

that is a difference in a product or a typo?

MR. WATSON: I believe that is a typo, but

maybe the sponsor actually can answer that question,

what the actual level was.

DR. AGERUP: Soon. We are checking it.

MR. WATSON: Okay. They are checking it

as well. I don't know offhand, but I believe it's a

typo.

ACTING CHAIRPERSON CHANG: Whether it's a