UNITED STATES OF AMERICA

P‑R‑O‑C‑E‑E‑D‑I‑N‑G‑S

(1:35 p.m.)

CALL TO ORDER

EXECUTIVE SECRETARY KRAUSE: We are ready

to begin the afternoon portion of the General and

Plastic Surgery Devices meeting. Before I turn the

meeting back over to Dr. Chang, I would just like to

remind everybody here that you are requested to sign

in on the attendance sheets, which are outside the

door, if you didn't do so this morning.

Also, there is information out at that

table that is right outside the door, such as an

agenda or a roster of the panel. There is also

information regarding today's meeting. There is also

information out there that you can obtain on methods

of finding out how to find out about future meetings

and things like that.

Now that we all seem settled, I am going

to turn the meeting back over to Dr. Chang. Wait. We

do have a public testimony session before you start.

So could you just clear that table until the public

testifiers are done? Thank you. I appreciate that.

Okay. Now let's start the afternoon and

go back to Dr. Chang. Thank you.

ACTING CHAIRPERSON CHANG: Good afternoon.

We will now proceed with the next 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.

As mentioned this morning, both the Food

and Drug Administration and public believe in a

transparent process for information gathering and

decision‑making to ensure such transparency at the

open public hearing 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, our 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. This may include sponsor's payment of

your travel, lodging, or other expenses in connection

with your attendance at this meeting.

Likewise, FDA encourages you at the

beginning of your statement to advise the committee if

you do not have such financial relationships. If you

choose not to address this issue, it will not preclude

you from speaking.

We have one individual who has notified

the FDA of their intent to testify during this open

public session. Is Dr. Diana Zuckerman or her

representative available to speak this afternoon?

OPEN PUBLIC COMMENTS

MS. SANTORO: Good afternoon. My name is

Elizabeth Santoro. I'm a health policy fellow at the

National Center for Policy Research for Women and

Families.

I will be reading the testimony of our

president, Dr. Diana Zuckerman, who, regretfully,

could not be here today. Our center is a think tank

that translates scientific research findings into

meaningful information for the public. We use that

research information to advocate for policies that

benefit the health and safety of children, women, and

families. We have several concerns about Hylaform.

As I stated at this morning's session, it

is difficult for us to testify before the data are

presented. We are basing this testimony on the

information that was made available on the FDA Web

site yesterday. Our concern about Hylaform is the

lack of data for African Americans and Asian

Americans. Only three of the patients are African

American, and only five are Asian Americans.

Our concerns were addressed with the

National Medical Association and to the FDA

commissioner a few months ago. 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.

It is not appropriate to require studies

of minority populations on a post‑market basis since

the FDA does not have the authority to enforce such

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." This would be acceptable

if a product were found to be safe for whites but

unsafe for other racial or ethnic groups, but such a

label is not an appropriate way around a sponsor's

failure to conduct research on people of color.

And, of course, if the product were

approved, it would probably be used off label for

people of color. And that could potentially be

dangerous. Research is needed. It won't take long to

do it. And it should be done.

We are also concerned about the sample

size. The sample starts with only 133 people, and

only 123 are still in the study after 12 weeks. 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 consider before approval.

The study only lasted for 12 weeks, which

is a major concern. According to the FDA slides,

safety data, immunological responses were at four

weeks. This obviously is too short a time to prove

whether this product is safe.

Since this product doesn't last long,

women would need to 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.

The sponsor also excluded women who had

procedures in the previous six months. This is not

how the product will be used in the real world. And,

again, it raises safety concerns.

A major shortcoming of this research is

the high adverse reaction rate. I don't consider this

necessarily a problem of the product but, rather, of

the study design.

It is not helpful for the sponsor to

evaluate adverse reactions in a way that almost all

the women using this product or Zyplast all have

adverse reactions.

The additions of serious or severe adverse

reactions is helpful, but it seems likely that there

is a continuum of problems between what is listed as

an adverse reaction, which almost everybody

experiences, and what is listed as a serious adverse

reaction, which almost nobody experiences.

The standard needs to be set in a way that

is more meaningful. For example, it should measure

adverse reactions lasting more than a day or two.

That would enable the FDA to determine how safe this

product is compared to other products.

I don't think the FDA should be approving

a cosmetic product where 88 percent of the patients

have adverse reactions. Either the FDA should reject

this product or require the company to provide a more

meaningful measure of adverse reactions.

In conclusion, I have even more concerns

about this product than about Restylane. According to

the company's own data, this product is not

necessarily better than the comparison product Zyplast

and apparently may not last as long. For that reason,

I believe rushing this product to market without

gathering the additional data listed above is

unwarranted.

Thank you.

ACTING CHAIRPERSON CHANG: Thank you.

Is there anyone from the general public

who wishes to make a public comment limited to five

minutes?

(No response.)

ACTING CHAIRPERSON CHANG: Hearing none,

we would like to at this time invite Genzyme

Corporation to present their PMA information.

APPLICANT PRESENTATION, GENZYME CORPORATION,

HYLAFORM

INTRODUCTION

MS. STEWART: Good afternoon, Dr. Chang,

members of the panel and FDA. My name is Susan

Stewart. I'm a vice president of regulatory affairs

at Genzyme Corporation. We are happy to be here today

to present Hylaform to you. And I would like to start

with a brief introduction and overview.

Dr. Burns will begin our presentations

with a description of our device and a presentation on

the preclinical studies in support of the safety of

Hylaform.

Dr. Polisson will then summarize our

rationale, clinical history, and discuss and describe

the study that we are later going to present results

on with Dr. Holmdahl that shows we are comparable to

Zyplast, the standard of care.

We also have with us a number of

colleagues and invited experts that are available to

assist us in answering questions as they arise.

They're listed here on these two slides. I

specifically would like to point out that we have with

us today principal investigator for the study Dr.

Ellen Gendler as well as Dr. Gary Monheit and Dr.

Leslie Baumann, also investigators in our study.

Now I would like to give some background

on Hylaform. Hylaform is a clear, colorless hylan B

gel. Hylan B is composed of cross‑linked HA, which is

a naturally occurring polysaccharide found in all

human tissue, including skin, and is found to be

identical across all species.

Hylan B used in Hylaform is also used in

our product Synvisc, which is a visco supplement used

to treat osteoarthritis. We sold approximately nine

million doses of Synvisc around the world.

This is the indication that we are seeking

for Hylaform. I would like to point out it is also

the indication for which we have been granted approval

in about 30 countries around the world. I would like

to read it for you now, "Hylaform is injected into the

mid to deep dermis for correction of soft tissue

contour deficiencies, such as wrinkles or acne scars."

Outside the U.S., Hylaform is sold as a

product family. They include Hylaform, Hylaform Plus,

and Hylaform Fineline. Hylan B is the main component

to these three products. The only difference in these

dermal fillers is that they have been processed to

optimize delivery through a range of needle sizes.

These were produced in reaction 2 position preference

and surgical practice.

I would like to be clear that although the

subject of the PMA is Hylaform, we do refer to

Hylaform Plus later in the presentation. The

commercial history of Hylaform begins with our CE mark

in 1995, which allowed us to begin launching product

in all the European Union countries in 1996. Since

then, Hylaform has been used to treat a variety of

wrinkles, including the nasolabial fold, those around

the lip and periorbital areas.

No pre‑implant skin test has been required

when using this product. And we report a worldwide

overall post‑market adverse event rate of about 0.1

percent.

This time line illustrates our current

status in the United States. Please note that the

sponsor of this PMA is Genzyme and that our worldwide

marketing partner is Inamed Corporation.

Initial clinical studies in the U.S. were

conducted under an IDE sponsored by Biomatrix,

Incorporated of Ridgefield, New Jersey. Safety and

efficacy of Hylaform were evaluated in a 216‑patient

open label single arm study. A PMA was later

submitted, which was then withdrawn by Biomatrix due

to issues concerning the clinical design. Please note

that this study did form the basis of our approvals

outside the United States.

In 2000, Genzyme Corporation acquired

Biomatrix. And by 2000, we had begun new studies with

Hylaform using a protocol that we believe addressed

the issues raised in the original PMA.

Our PMA was then submitted and has been

reviewed as a modular PMA. We have been submitting

sections over the past year, with our final clinical

module submitted in August of 2003.

Now I would like to ask Dr. Burns to begin

the preclinical presentation. Thank you.

DR. BURNS: Thank you and good afternoon.

PRECLINICAL REVIEW

DR. BURNS: I am Jim Burns. I am senior

vice president for biomaterials research at Genzyme.

I am going to provide some brief background on

Hylaform and a brief description of our preclinical

studies that preceded the clinical trials that you

will be hearing about.

As you have heard, Hylaform is a

hyaluronan‑based gel that is injected into the dermal

tissue to provide space‑occupying augmentation of the

extracellular matrix, thereby providing a temporary

correction of skin contour deficiencies, such as

folds, wrinkles, as well as acne scars.

By the way, during this presentation and

subsequent presentations, you will hear hyaluronate,

hyaluronic acid, hyaluronan. And for simplicity's

sake, we will very often just call it HA.

HA is particularly well‑suited for this

application of dermal augmentation because it is

already an important component of extracellular

matrix. And within the extracellular matrix, it is in

a proteoglycan complex called aggrecan.

You can see on this slide the HA molecule,

which is a slender ribbon here, which is associated

with protein as well as other glycocyamine glycans,

chondroitin sulfate, and keratin sulfate. If you

looked at an electron micrograph of this complex, you

would see a ribbon of HA that is decorated with

comb‑like structures shown here.

This structure is very important for wound

repair. It is important for allowing cells to migrate

into a dermal wound. In this hylan‑rich milieu, it

also helps regulate the fluid retention. And it keeps

the tissue hydrated.

When it is not associated with this

proteoglycan complex, relatively dilute solutions, it

can form fairly slippery or lubricous solutions, such

as occur in synovial fluid for joint protection. In

high concentrations, it will form a gel‑like structure

that is useful for mechanical support to occupy space

as in a vitreous humor of the eye.

Not surprisingly, it's found its way into

a number of products that are available in the U.S. as

well as throughout the world. Here are some examples

of those.

HA is a primary component of a product for

adhesion prevention and gynecologic as well as

abdominal surgery. It's also in a class of products

shown here for prevention or dealing with the pain of

osteoarthritis.

In this case, the viscoelastic solutions

are injected intra‑articularly in the knee. They also

have found their way into viscoelastic solutions that

are used in cataract and intraocular lens surgery.

Actually, an important point of this slide

I want to point out is that HA is a very interesting

molecule in the sense that it is biogenetically

conserved, that structurally and chemically, it is

identical, whether it comes from the protective cell

coat of a bacterium from an avian source or from our

own synovial fluid. The differences among HA

preparations come from purification processes from the

source, from low molecular weight or low‑level

contaminants or molecular weight of the HA.

So let me briefly describe some of the

design characteristics that we wanted to have in a

dermal filler. First, we want to balance durability

with safety. Any biomaterial that you implant in the

body is going to elicit a reaction. And we wanted to

ensure that we could provide temporary augmentation

without generating an untoward response.

So we feel we have done that with this

particular formulation. So our material provides

temporary correction and biorebsorbs with minimal

tissue reaction. We feel that it possesses acceptable

viscoelastic properties so that it can withstand some

of the forces that would be present at the site of

injection that will remain at the injection site for

an appropriate period of time and also be easily

injectable.

Natural HA will not meet these criteria

because it will resorb and clear from the site fairly

quickly. So we get to this product by starting with

avian tissue and treating that tissue in situ to

increase the molecular weight of the HA through a

formaldehyde treatment.

This is still water‑soluble HA of high

molecular weight of about four to six million. We

then cross‑link that further to form a gel. So we

have hylan A, which comes from the avian tissue

through out modification process, and then hylan B gel

is the component that goes into Hylaform.

This is just going to illustrate the

cross‑linking with hyalanosulphone. So we see two

parallel chains of hyaluronic acid on the left in

yellow. We see the basic monomeric unit of HA, which

is glucuronic acid or neutral pH sodium glucouron and

acetyl glycocyamine. Under basic conditions and only

under basic conditions divinyl sulphone will react

with free hydroxyl groups on the HA chains to form a

gel.

We have conducted a number of preclinical

studies to characterize the safety of this material.

These studies were consistent with the ISO 10993

standards as well as the FDA guidance document for an

implant that will reside for greater than 30 days.

We conducted 20 GLP and 7 non‑GLP

preclinical studies, which included cytotoxicity,

irritation, intercutaneous as well as subcutaneous,

acute systemic toxicity, subchronic as well as chronic

toxicity going out to one year, a number of

genotoxicity studies, sensitization and immunogenicity

implantation in the rabbit muscle implant test,

pyrogenicity, hemocompatibility, reproduction, as well

as clearance.

We found in these studies that Hylan B was

safe and nontoxic at amounts that were equivalent to

or in great excess to that which was studied in the

human clinical trial that you will be hearing about.

So, in summary, we had developed an

HA‑based formulation that we feel is consistent with

our design inputs for a temporary dermal filler. Our

preclinical studies show that Hylan B did not elicit

a significant biological response, indicating that it

made sense to go ahead and evaluate this material in

human clinical trials.

I would now like to ask Dr. Dick Polisson

to describe the design of our trial.

DR. POLISSON: Thank you, Jim.

CLINICAL STUDY DESIGN

DR. POLISSON: Ladies and gentlemen, my

name is Richard Polisson. I am senior vice president

of clinical research at Genzyme Corporation. My

charge in the next 14 minutes or so is to go over

three major areas: first, to provide a very brief

background regarding the biology of aging skin and how

dermal fillers are used in this condition; second, to

refresh for you a prior clinical experience with

Hylaform, which exists from two open label, single arm

studies, one in the U.S., one in Sweden; and, finally,

to spend most of my time going over three distinct

clinical research activities involving the clinical

endpoint development, which I will discuss in the

context of what we were calling our control material

characterization study.

I will try to explain to you our

non‑inferiority approach in the context of describing

our pivotal trial design and then finally end up

describing our repeat treatment study, which was

designed primarily to look at the safety of Hylaform

after repeat treatment.

Okay. So this is the condition under

study, if you will. It's not really a disease per se.

It's really a process of life. Most of us already

have some of this and if not now, then very near in

the future.

If you can't tell, this is old skin. I

will just point out to you the fact that there are

amorphous collections of eosinophilic material in the

dermis that has been termed by dermatopathologists

"elastosis." I would like to focus our discussion

here on the dermis because I think that is very

important for this particular discussion.

So the dermis has cells, of course. But,

in addition, it has extracellular matrix molecules.

Three I think deserve mention. One is collagen, which

by virtue of its triple helical structure provides a

structural scaffold to the dermis.

Elastin by virtue of its elasticity

provides resiliency to the dermis such that the skin

would snap back into place after being retracted.

And, finally, glycocyaminic glycans,

particularly hyaluronic acid, which has a unique

physicochemical state and relationship with water,

provides an osmotic force that gives the dermis its

turgidity. The bad news is that with aging, all of

these molecules become deficient to one degree or

another.

So that's the biology. The clinical

problem is this, and that is wrinkles. There are many

different types of wrinkles. I have been learning

about all of these types of wrinkles. We have

marionette lines. We have the forehead wrinkles,

glabellar lines. And the nasolabial fold is the one

that we have chosen to focus on for the purposes of

our clinical trial.

We have done this primarily because we

feel it's the most challenging in terms of filler. It

exists in a very high‑motion area and because of its

sheer length and depth requires a significant volume

of dermal filler in order to correct.

I think the idea is really quite simple in

that in the dermis, which has deficient extracellular

matrix, we are really injecting into that space a

material that primarily is manufactured extracellular

matrix molecules in the form of collagen or hyaluronic

acid in an attempt to fill out the wrinkle from below

to give you a more pleasing visual contour.

And then this in the bottom is sort of an

idealized great treatment response, patient before and

after. For me as a clinical trialist, however, these

two panels are very important. The question is, how

do we quantify the degree of correction? I will get

into that when I describe our clinical endpoint.

Now to go over some of the prior studies

that we have. Again, these are single arm, open label

trials. One of them was performed in Sweden. It

involved 63 patients from 8 centers, followed for up

to 24 weeks. Multiple defects, not just the

nasolabial fold but other defects in the face, were

corrected, but only one touch‑up was allowed, which

doesn't really reflect practice at this point in time.

The endpoint was assessed by the

investigator, a 100‑millimeter visual analog scale,

and expressed as percent improvement from baseline.

The top‑level results are that 49 percent

of the defects had a greater than 50 percent

improvement at 12 weeks, 39 percent of the defects had

greater than a 50 percent improvement out to 24 weeks,

and there were no concerning safety trends in this

study.

The U.S. study was a bit different in a

number of areas. It was larger, certainly, involving

216 patients, 6 centers. These individuals were

followed up for up to 12 months, primarily for safety.

Multiple defects were treated, again

similar to the Swedish study. But in this particular

case, greater than one touch‑up was allowed, which

reflects more of the standard practice that we see

nowadays.

Again, the endpoint was assessed in

similar fashion. Top‑line results, greater than 60

percent of the defects that were treated in this study

had greater than or equal to a 33 percent improvement

out to 18 weeks. And, again, as with the Swedish

study, there were no concerning safety trends.

This is the list of the different types of

defects that were treated in those two studies. I

believe, as you can see, there were many different

types of wrinkles, many locations, including the

nasolabial fold but also including the lips, the

forehead. And, in particular, scars are treated.

These are for the most part acneiform or post‑viral

scars.

Our clinical strategy really drives our

clinical trial design. This is very important. We

wanted to develop a non‑bovine, non‑collagen source

dermal filler that was clear, not opaque, and it did

not require a pre‑implantation skin test. We wanted

this dermal filler to be comparable to, not superior

to, but comparable to, the current standard of care,

which is Zyplast.

We recognized that in order to do that, in

order to get this approved, that we have to perform a

well‑designed, well‑controlled clinical trial that

meets regulatory standards.

Let me now talk a little bit about our

clinical endpoint development. Lemperle published his

scale in 2001. That group designed the scale

specifically to look at efficacy of dermal fillers.

They evaluated this in three domains: the visual

assessment, live assessment; a photographic

assessment; and a profilometric assessment, in which

one takes a negative silicon impression of the wrinkle

and actually gets a depth. That then provides the

gold standard to which the other two domains are

compared and validated.

Now, this is a great scale, six‑point

scale. One I think would agree that that going from

here to there goes from almost no nasolabial fold

wrinkle to a very severe one. The problem is that

there are other visual signals in this scale that are

distracting to the individual who might be scaling

these wrinkles. Those include different lighting;

different pigments; and, indeed, different wrinkles on

other parts of the face.

So for our particular trial, we were very

keyed on the nasolabial fold, as I mentioned before.

So what we decided to do was to take photographic

images of nasolabial folds of varying degrees of

severity and digitize them and morph them onto a

standardized face. Again, the whole idea here is to

focus the individual who is scoring this on the scale.

Now, this is an animation showing how this

was done. We are aging this person's face 40 years in

5 seconds. And so what we see here is a very, very

severe nasolabial fold at the end with redundant

tissue. Although you may not remember the first one,

it was a perfectly normal face with no nasolabial

fold.

Now, the second part of this whole process

that we think is incredibly important is that we

establish an independent panel review. We recognize

that when investigators evaluate wrinkles in the live

situation, that there is a potential for variability

in measurement and a potential for unblinding because

oftentimes there is a team of individuals where one

would be the injector and the other would be the

evaluator.

In order to get over that, we elect to

establish this independent panel review and to have

the photographs of the patients evaluated outside of

the site at a central location.

So the IPR consisted of two groups of

three board‑certified dermatologists. They were

trained to the scale. They were tested and retested

to establish high intra and inter‑rater correlation.

At the time of the patient visit,

standardized photographic stereotactic methodology and

standardized letting was used to take the picture.

These pictures were then compared to the photographs

independently by each IPR member, who reviewed them in

random order. We have no idea whether this was the

first or the last treatment. They were blinded to

subject, treatment, to site, and to time.

This was the data collection form that

they used, sort of annotating the previous comments

about the systematic nature of how one collects the

data in this particular situation. This data

collection form then goes on to data management and

then is analyzed.

Okay. Now, what do we do with that?

Well, we wanted to evaluate this in our control

material characterization study. We wanted to get

experience with this scale and experience with the

process of the IPR review.

We also needed to evaluate intra and

inter‑rater correlations using the Genzyme scale.

Remember, this is almost exactly like the Lemperle

scale, even to the degree that the written descriptors

of the wrinkles were the same; and, finally, to

confirm the patient to patient variation so we could

convince ourselves that the sample size that we

calculated for the pivotal trial was accurate.

This was an open label trial involving

Zyplast only, 32 patients. They had to have a grade

three or four on our six‑point scale nasolabial fold.

They were touched up at two weeks if less than a

one‑point improvement. And then a final assessment

was made at 12 weeks.

What we found was that this new way of

evaluating wrinkles, this photographic review process,

was logistically feasible, that the standard deviation

of 1.28 confirmed the appropriateness of the sample

size of 108 in each treatment group, and that the IPR

group showed good inter and intra‑rater correlations.

So now on to our pivotal trial. What did

that look like? The primary objective, very simply,

was to evaluate the safety and efficacy, but the key

thing here is we wanted to do so in a non‑inferiority

type of approach. And we're comparing ourselves to

the 20‑year gold standard of Zyplast; and,

secondarily, wanted to measure other clinical

effectiveness measures, including the investigator

live assessment at the site face to face with the

patient as well as patient and physician global

assessments.

A couple of comments about the two fillers

under study. Many of you may know this, but I'll just

review it for you. Zyplast is cross‑linked bovine

collagen and has 0.3 percent lidocaine in it.

Hylaform is cross‑linked avian hyaluronic acid. It

does not contain lidocaine. Zyplast is opaque.

Hylaform is clear. Zyplast has a higher concentration

of 35 milligrams per ml; whereas, Hylaform is 5.5

milligrams per ml. Skin testing is required for

Zyplast, and skin testing is not for Hylaform.

Our methodology is as follows. It was a

double‑blinded, randomized multi‑center study against

an active comparator. And patients were followed up

and observed for 12 weeks. Both nasolabial folds were

corrected with the same material with one touch‑up

allowed at two weeks but only if less than one‑point

improvement was noted by the investigator at the site.

The key point here, patients were

blindfolded at the site, blindfolded before the

injector and the investigator entered the room and

before any material was visible to the patient. They

remained blinded to the treatment arm throughout the

study.

Finally, patients in order to really

evaluate whether or not blinding was appropriate and

good were queried about treatment allocation at the

conclusion of the study. Dr. Holmdahl will review

that data for you.

Major inclusion/exclusion criteria:

healthy men and women between 30 and 55 years of age,

‑‑ ethnicity was not an exclusion in this trial ‑‑ a

negative double skin test to collagen before

randomization, two visible nasolabial folds with a

live score of three or four, no exposure to

potentially confounding cosmetic therapy or procedures

for six months, ‑‑ the reason for this was to evaluate

confounding measurement of the endpoint ‑‑ and no

history of scar‑related diseases, delayed wound

healing, or keloid formation.

This is a schematic of the trial. Again,

patients were skin tested here about six weeks before

randomization. Two weeks later if they were clean,

they were randomized to Hylaform or Zyplast, followed

at three days for safety and efficacy.

A key point here is that two weeks after

the first implantation, they were touched up if the

degree of improvement was less than one in the

investigator's eye. And then again, they were

followed up for three days, two weeks. If they were

not touched up, they went on to 4, 8, and 12 weeks for

both safety and efficacy.

I will parenthetically state that the

proportion of patients touched up was actually quite

small in this study. It is a very important point.

Now I will try to explain non‑inferiority.

Clinically interpreted, it really implies that if one

is non‑inferior, the test device in this case is

comparable to the control. If you remember, that is

compatible with our development strategy in which we

wanted to develop a dermal filler that was comparable

to the effect that has been seen in Zyplast but had

different other characteristics that we think were

important.

Now, when one does non‑inferiority, one

has to define a margin or window of difference between

the treatment and control arm that is small enough or

smaller than a clinically meaningful treatment

benefit.

Remember that we used a six‑point scale

here. A one‑point difference was considered

clinically meaningful. A one‑point difference was

used as the decision note to touch up or not touch in

the pivotal study. And so 50 percent of that, or .5,

was considered to be the window that was most

appropriate.

Now, by convention, when one does a

non‑inferiority study, ‑‑ the reason I am going into

this in great detail is that most of us have done

trials where we are looking at superiority or drug A

is greater or better than drug B. But in a

non‑inferiority type of approach, one really does it

by virtue of confidence intervals, which are

constructed around the difference between the

treatment and the control mean.

In this case, if the 97.5 percent lower

confidence interval falls within the margin that I

have just described, the .5, then one is considered

non‑inferior.

I think Dr. Holmdahl will show you that in

our trial, we actually met this particular endpoint.

On the other hand, if one falls outside of that range,

if the treatment differences are significantly

different, then one is not considered non‑inferior.

Finally, the repeat treatment phase, very

simply, to evaluate safety of repeat treatment with

Hylan B products and to measure rates of adverse

events associated with re‑treatment and, very

importantly, to measure Hylan B anti‑IgG antibodies

and, even more importantly, to determine whether or

not there is an association of those particularly

laboratory tests with adverse events.

The schematic at that trial, again,

remember, Hylaform‑treated patients only. So they

have already been in the trial 12 weeks. If they

agreed to go into this study, they were re‑randomized

to receive Hylaform or Hylaform Plus in either the

right or the left nasolabial fold. They were followed

three days, two weeks, and four weeks for safety.

So I conclude. It is our opinion that

this study design just described meets the principles

of a well‑controlled clinical investigation as

outlined in 21 CFR 860 in that we identified and

recruited and randomized appropriate subjects, who

will receive this product in practice if it is

approved. We used an active control, which is the

gold standard. And we did so in a double‑blinded,

randomized fashion.

Our photographic endpoint provides a

systematic method of observation that we feel

minimizes bias and maximizes the blind at the site.

And a non‑inferiority statistical approach matches our

clinical development strategy.

Thank you for your attention. I am now

going to turn the podium over to Dr. Lena Holmdahl,

who will discuss for you the results of safety and

efficacy.

Thank you.

CLINICAL STUDY RESULTS

DR. HOLMDAHL: Good afternoon. My name is

Lena Holmdahl. I am a senior director in clinical

research at Genzyme. I am also professor of surgery

with about 20 years of clinical experience. I will

present the results to you from the trial that has

been introduced to you by Dr. Polisson.

This is an overview of what I will

present: first, that the two populations were

comparable at baseline; that the use of Hylaform

produces a cosmetic correction that is comparable to

the active comparator, Zyplast; and that the primary

efficacy endpoint was thereby met; that Hylaform does

so with the use of less material, leading to less

exposure of patients to implanted material; that

treatment and repeat treatment are safe, at least

after four weeks after treatment; that the overall

patients; tolerability to Hylaform is excellent; and

that this leads to an overall favorable risk‑benefit

ratio with Hylaform over standard of care.

This slide summarizes important

information about this study population. Three

hundred, thirty‑nine patients were consented, of which

23 percent were screen failures, most of which because

they didn't meet the wrinkle criteria.

Eleven tested positive for bovine collagen

skin tests. So they were not randomized. Please keep

this in mind when you compare the safety results that

patients with positive skin tests to bovine collagen

were already sorted out and did not participate in the

study.

In total, 261 patients were randomized,

133 to the Hylaform arm and 128 to the Zyplast arm.

And, as you can see in the table, there were three

discontinuations in both groups. In the Hylaform

treatment group, one subject requested to withdraw and

two were lost to follow‑up. And then in the Zyplast

group, there were two discontinuations due to adverse

events that were unrelated to the use of the product

and one patient that requested to withdraw.

This slide summarizes important baseline

characteristics that potentially could affect outcome

for the two populations that are compared. All of

these factors were the same in the two groups, which

shows that randomization worked and that the two

groups were comparable at baseline.

Ethnic background was not an exclusion

criteria in the study. This graph shows the ethnic

background of subjects seeking cosmetic improvement,

as published on the internet by the American Society

of Plastic Surgeons and American Society of Aesthetic

Plastic Surgery pertaining to 2002. The ethnic

distribution of patients in the trial is shown in

yellow.

The population in the trial is similar to

what has been published. We, therefore, believe that

the trial population accurately reflects the target

population.

I want to draw your attention to that 80

percent of the patients were Caucasian. So that means

that 20 percent were subjects with skin of color.

Wrinkles were scored at baseline using the

scoring scale that has been described to you by Dr.

Polisson. This graph illustrates that the two groups

were comparable at baseline. It also shows that the

investigators scored at baseline the wrinkles within

the range specified in the protocol for inclusion into

the study.

As degree of cosmetic correction is by

virtue of its nature challenging to quantify and at

the same time is one of the very few endpoints of a

trial that easily lends itself to illustration, I

thought it could be helpful to show some pictures of

patients in the study before and after treatment. As

a side note, the patients have consented to having

their pictures used.

On the left‑hand side is shown Hylaform

patients before treatment and at two weeks after the

last treatment. This area here is a nasolabial fold.

Here you can see the results after treatment.

On the right‑hand side is shown a Zyplast

patient at the same time points. As you can see,

there was an improvement in both cases. In fact,

two‑thirds of the patients in both treatment groups

assessed themselves as better at the conclusion of the

study.

The FDA has specifically asked us to

present examples of various cosmetic outcomes. Here

is shown a good outcome of treatment. In the middle,

we see an average outcome of treatment. And to the

right we can see is an example of a poor outcome of

the treatment.

The primary efficacy endpoint was met.

This diagram again illustrates the results of the

primary efficacy endpoint, showing that the lower

bound of the one‑sided confidence interval was within

the specified non‑inferiority margin. The reason that

I am showing this diagram is to avoid confusion about

the difference, or the delta.

The results from the model were based on

the adjusted score, taking into consideration baseline

factors, including treatment group, study center,

baseline median IPR score, and nasolabial fold. That

difference, or delta, was ‑.2. What I will show in

the following graphs is the raw score.

This difference, or delta, is ‑.1. This

graph illustrates the primary efficacy endpoint, IPR

score, at 12 weeks after the last treatment. The bars

illustrate the mean values of wrinkles of the error

bars, one standard deviation.

The majority of wrinkles did not have any

touch‑ups. As shown in the graph to the left, the IPR

score was the same in the two groups. This group

consisted of 111 of the 133 Hylaform‑treated patients

and 119 of the 128 Zyplast‑treated patients.

The middle bar shows the IPR scores in the

subset of wrinkles that had a touch‑up. That was 22

patients, or 42 wrinkles, in the Hylaform group and 9

patients, or 14 wrinkles, in the Zyplast group.

The bars to the right show combined

results. As illustrated in the graph, the numerical

difference that exists at 12 weeks is being driven by

the subset of wrinkles that had an initial correction

that was less than one score and, thus, qualified for

a touch‑up.

The difference, or delta, between the two

groups is ‑.1. That difference is located in the

range between IPR scores two and three.

The cosmetic appearance of wrinkles grades

two and three is shown in this picture. The numerical

difference at 12 weeks, thus, translates into a tenth

of the difference between these 2 wrinkles, something

that is not discernible by the eye.

To be clinically meaningful, any

difference needed to be at least one point, 50 percent

of which was used as the non‑inferiority limit.

According to these predefined criteria, Hylaform is

statistically and clinically comparable to Zyplast.

As dermal fillers operate through a

mechanism that is depending on occupational space to

be efficacious, the volume administered needs to be

taken into consideration.

The purpose of this slide is to illustrate

and emphasize that Hylaform exhibited a comparable

efficacy to Zyplast with a smaller volume of material

used.

This graph is showing the volume

administered to achieve the results. From this

comparison, it is evident that Hylaform can achieve a

similar result as the comparator with less volume.

This is particularly apparent in the majority of

wrinkles, that they are not qualified for a touch‑up.

In this subset, the volume of Zyplast needed to

achieve the same correction was 1.4 times greater.

This graph illustrates the live assessment

of wrinkles at 12 weeks after the last treatment.

That was the secondary endpoint in the study. This

assessment was done by the investigator in a

face‑to‑face meeting enabling a three‑dimensional

perception of the contour defect, as opposed to the

IPR scores that were assessed from standardized

photographs. The bars illustrate the mean values and

the error bars one standard deviation.

Again, the difference, or delta, between

the two groups is ‑.1. And that difference is located

in the range between live scores two and three. The

same grading template was used for the live scores as

for the IPR scores. And the cosmetic appearance or

wrinkles live scores two and three is shown in this

picture.

The numerical difference at 12 weeks,

thus, translates into a tenth of the difference

between these 2 wrinkles, a difference that is not

visible.

The patients were blinded to their

treatment assignment, as described here earlier by Dr.

Polisson. They were, actually, as a part of the study

asked if they knew their treatment assignment.

As shown in this graph, some of them

thought that they knew the treatment assignment. Some

were right; some were wrong. But, most importantly,

the majority did not know. A proper blinding of the

patients makes patient assessment of outcome valid.

Given the IPR scores I just presented to

you, one might ask if either of the two dermal fillers

had any effect at the conclusion of the study with a

strict treatment regimen that was employed. The

answer to that question is yes, they both had an

effect.

To a certain degree, cosmetic outcome is

in the eye of the beholder. And, therefore, patient

assessment of patient satisfaction must be considered

as this drives the need for additional treatments.

Global assessment is the qualitative

composite outcome measure consisting of positive and

negative effects produced by the use of the product.

This was a secondary endpoint in the study. Global

assessment was done by both the investigators and the

patients.

The bars illustrate the mean values of

patients' assessment at 12 weeks and the error bars

one standard deviation. At the last visit, the

difference in patients' global assessment was ‑.1 on

a 5‑point scale. Both the treatment and the control

group were on average about one, which means that they

assessed the outcome as better than before treatment.

None of the Hylaform patients considered themselves

worse or much worse.

This is important in patient satisfaction

or dissatisfaction with cosmetic correction, governs

the timing of repeat treatment. This is what for a

cosmetic product one might call a clinical benefit.

This notion of improvement from baseline

was confirmed by the investigators. The investigators

were also asked to qualitatively assess outcome. The

bars illustrate the mean values of investigators'

global assessment at 12 weeks and the error bars one

standard deviation.

The difference was, again, ‑.1 on a

5‑point scale. Both the treatment and the control

group were on average about one, which means that the

investigator assessed the outcome as better than

before treatment.

The next section of the presentation will

summarize results pertaining to the safety of the

product. Based on the mechanism of action of

Hylaform, our expectation was that the patients would

come back for repeat treatment and would, therefore,

have an interim safety assessment in the repeat

treatment phase.

At one percent, adverse events were

captured both during the initial phase and after four

weeks of the repeat treatment phase. That was a time

point that was considered by us and by the FDA to be

sufficient to evaluate safety of repeat treatment.

And the data that we have from the initial phase

support that. Lastly, immunogenicity results will be

presented.

This diagram shows the definition of

adverse events as stated in the protocol.

Treatment‑emergent adverse events could be either

procedure‑related or not procedure‑related.

Adverse events with an onset of up to

three days could be deemed by the investigator to be

procedure‑related. Regardless of onset, adverse

events could be deemed as not procedure‑related. In

this case, the investigator was asked for a

relationship with the device and anesthetic procedure

or if the adverse event was unrelated to the

treatment.

This slide shows the treatment‑emergent

adverse events during the initial phase. The overall

incidence of adverse events was the same in the two

groups. The incidence of procedure‑related adverse

events was also similar. The incidence of

device‑related adverse events was two percent for

Hylaform‑treated and seven percent for Zyplast‑treated

patients.

There was one serious adverse event that

was in the Hylaform group. That adverse event was

seen by the investigator to be unrelated to the

product.

There were three patients experiencing

severe adverse events in the Hylaform group and seven

in the Zyplast group. Finally, there was no

discontinuation because of adverse events in the

Hylaform group, but two patients chose to discontinue

because of adverse events in the Zyplast group.

There is no news here. This table shows

the procedure‑related adverse events. They are in

agreement with what has been reported with the use of

dermal fillers. That's what one would expect.

The overall incidence between the two

treatment groups was similar. The most common adverse

events were erythema, bruising, swelling, pain, and

pruritus.

As a side note, the adverse event profile

was the same in subjects with skin of color. And we

have no occurrence of scarring or keloid formation or

pigmentation disorders in patients with skin of color

in the Hylaform group.

These are the device‑related adverse

events in the two treatment groups. Two Hylaform

patients experienced device‑related adverse events.

They were erythema, induration, and pruritus. Nine

Zyplast patients experienced deice‑related adverse

events listed here: erythema, bruising, pain, nodule,

necrosis, and stomatitis.

Duration of adverse events is another

factor that needs to be considered in the evaluation

of the overall safety profile. Using a conservative

approach, the adverse events that could be

attributable to the treatment are the procedure and

the device‑related adverse events. Most of them had

a short duration and had resolved within a week in

both treatment groups, as shown in this table. None

of the adverse events in the Hylaform group had an

onset after one month. This is, of course, evaluating

safety after two weeks after repeat treatment was

reasonable.

Blood sampling for antibodies to Hylan B

was done in all randomized patients prior to

treatment, 2 weeks after last treatment, and at 12

weeks and measured with an ELISA test. Most

importantly, we looked specifically if titer levels

were associated with adverse events. And they were

not.

One of the 261 patients tested developed

a significant increase in Hylan B IgG. That patient

had been treated with a single injection of Hylaform.

The increase in titer was detected at the four‑week

visit. Keep this in mind when assessing repeat

treatment results.

The adverse events that that specific

patient had were injection site bruising and headache,

none of them consistent with an immune‑mediated

response.

In this context, it might be appropriate

to mention that the incidence of bovine collagen skin

tests was 3.2 percent of the screened population and

that screening for potential hyperreactivity to

Hylaform was not done.

Finally, a brief summary of the interim

safety data from the repeat treatment phase. These

results pertain to data collected up to four weeks

after the repeat treatment. Ninety‑six of the 133

patients who were treated with Hylaform opted to enter

into the repeat treatment phase. Overall, the types

of adverse events that did develop were the same as in

the initial phase.

One patient developed an abscess at the

treatment site that needed intervention and, thus, was

classified as serious. It did resolve without

sequelae and was of moderate intensity. There were no

severe adverse events in the repeat treatment phase

and there were no discontinuations because of adverse

events.

The patients who enrolled in the repeat

treatment phase were again tested for Hylan B

antibodies in blood samples. All of these patients

had previously been exposed to Hylaform, some of them

twice. None of the 92 or the 96 patients from which

antibody results are available developed a significant

increase in Hylan B IgG during the first four weeks of

repeat treatment.

So, to conclude, we believe that these

results demonstrate that Hylaform exhibits the same

degree of cosmetic correction, that Hylaform is

well‑tolerated without the skin test, that Hylaform

has a similar safety profile after repeat treatment.

And we believe that this translates into a favorable

overall risk‑benefit ratio.

Thank you.

CONCLUSION

MS. STEWART: I would just like to present

some of the key points that we have provided today:

the fact that Hylaform has been available worldwide

and in Europe beginning in 1996, we have shown in

extensive preclinical testing that Hylaform is safe,

we have demonstrated in a robust clinical trial that

it is comparable to Zyplast in both safety and

efficacy, and we truly believe it is safe to use in

repeat use and that our results support its use in

correction of soft tissue contour deficiencies.

Thank you. Now we are available to answer

any questions the panel may have.

ACTING CHAIRPERSON CHANG: Questions from

the panel? Dr. Blumenstein, do you have any specific

questions regarding the study design?

MEMBER BLUMENSTEIN: I might have missed

it, but did you show just changed scores, just changed

scores?

DR. HOLMDAHL: No. What I showed was the

scores at 12 weeks. I didn't show any changes in

scores.

MEMBER BLUMENSTEIN: What I'm trying to do

is get the magnitude of change that happened in the

Zyplast group, for example.

DR. LARHOLT: I'm Kay Larholt from Genzyme

Corporation, the biostatistics group.

We had established that the efficacy

parameter that we were measuring was the week 12

score. and, therefore, that's what we looked at. We

did not look at changes from baseline.

MEMBER BLUMENSTEIN: Do you have baseline

scores?

DR. LARHOLT: We have baseline scores that

we have shown. Those are the IPR median scores that

were at baseline, the live score as well.

Lena had showed the IPR scores at

baseline. She had shown that they were 3.5 in the

Hylaform group and 3.6. The mean was 3.5 in the

Hylaform group and 3.6 in the Zyplast group, which

shows the means at baseline for using the live score.

This was what was used for enrollment into the study.

MEMBER BLUMENSTEIN: I may have questions

later.

ACTING CHAIRPERSON CHANG: Dr. Newburger?

MEMBER NEWBURGER: I have a question. In

the population of people who were treated a second

time, where you say that the incidence of adverse

events is similar between the two groups, in the

people who were treated de novo in your study the

first time, very few people are reported to have

nodules. I think it was at a zero or one.

In the repeat study, individuals who had

Hylaform the second time, I count 12 people who had a

3 or more days induration. Now, I understand there's

a difference in that there is a diary the second time

around and there wasn't. However, since the protocol,

I think, didn't it show investigator observation the

first time at three days? Why is there such a

disparity? Because 12 out of 96 is a tremendous

proportion.

DR. HOLMDAHL: I would like to call on Dr.

Kingma to answer that question.

DR. KINGMA: Hi. My name is Wytske Kingma.

I am heading up the safety department at Genzyme.

With regard to the nodules we find in the

study, it's important to note that in the initial

phase, the nodules as such were assessed by the

physician. We did not have any in the Hylaform group,

and we have three in the Zyplast group.

In the repeat treatment phase, as you

pointed out, the patients used a diary. It was

actually anything that were lumps or bumps that were

coded. In order to collect adverse events, you need

to code them in the dictionary. So they code to

nodules.

As we are, of course, concerned about

whether or not that nodule is a true nodule in the

immunological sense, we actually looked at those. The

majority of the mean onset for all those 22 patients

who had reported lumps and bumps was 1.2 days, with

the majority of them starting right at the time of

injection and actually some commenting that they felt

that the material under their skin and noting that as

a lump or bump.

In addition, the mean duration of the

entire group was only 12 days. There were no nodules

that actually had the delayed onset, which is what you

would otherwise expect with regards to a possible

immunological reaction.

Does that answer your question?

MEMBER NEWBURGER: Yes, sort of.

ACTING CHAIRPERSON CHANG: Dr. Halsey?

MEMBER HALSEY: I have a question about

the exclusion criteria. Reading the documents, it

seemed that patients were excluded from the study if

they had allergies to avian proteins as well as bovine

proteins. Is that correct?

How was that determined? Was that

patients' reported history of allergy or was there

some test, either a skin test or a blood test of

atopic status?

DR. POLISSON: Those exclusions were by

history.

MEMBER HALSEY: Reported history from the

patient, not a physician's evaluation?

DR. POLISSON: I would like actually to

get some clarification from that. May I ask Laura

Fleming to come forward and specifically address that?

MS. FLEMING: Hi. I'm Laura Fleming from

Genzyme clinical research.

The history is avian source protein

histories. The patients were asked if they were

allergic to eggs. It was patient‑reported. Patients

were only excluded for bovine if they had positive

skin tests.

MEMBER HALSEY: You did not exclude

patients with other allergies, seasonal allergies,

perennial rhinitis, or anything like that?

MS. FLEMING: No, we did not.

MEMBER HALSEY: Not even if it was severe?

MS. FLEMING: That's correct.

MEMBER HALSEY: I would also like to ask

a little bit of detail about the IgG ELISA that you

used. How was that standardized and quantified? Are

these titer units, this 50, or is that nanograms per

ml of IgG or what?

MS. RICHARDS: I'm Sue Richards, Genzyme

immunology department.

The immunologic assay that was used was an

indirect ELISA. So basically Hylaform was coded into

the microtiter plate well. It was then blocked using

nonfat dry milk. Patient sera was then added using a

twofold serial dilution series. And then any bound

antibody was detected using an HRP anti‑human IgG

conjugate. Certain colorometric reaction was then

determined.

Now, the titer was assessed using the

negative control, which was a normal human serum

sample that was tetanus‑positive because we also used

tetanus as a positive control for coding in the assay.

In that particular sample from the

validation, it was determined that an ODE value

greater than .5 was what was considered as negative

reactivity of normal human serum because we did

discover that we had a human serum effect in the

assay.

So the titer values are the reciprocal of

the highest dilution that gave that particular cut

point value.

MEMBER HALSEY: Then you used a fourfold

rule. So it would have to be four times the titer of

that to have been concluded what you concluded?

MS. RICHARDS: No. Since we do have

background reactivity of normal human serum in this

particular assay, the fourfold rule was based on each

patient's own baseline. So we had a true baseline

value of that particular individual. So a sera sample

was drawn before treatment and then a titer determined

on that if there was background reactivity. And then

a fourfold or greater increase above that patient's

own baseline was what was determined as showing

positivity in the assay.

MEMBER HALSEY: Just to address one

further technical detail, the IgG ELISA, did you show

inhibition with soluble forms of hyaluronic acid to

show that what we're really measuring is antibody to

HA, rather than something else?

MS. RICHARDS: What we had looked at

subsequently, we did not do inhibition analysis. What

we had looked upon subsequently in the positive

patient was we had looked at alternative avian sources

and alternative bacterial sources of HA and had

ascertained that the reactivity was specific to

Hylaform B, the cross‑linked avian material.

MEMBER HALSEY: So these patients didn't

have antibody that you could measure to other avian

proteins?

MS. RICHARDS: Correct.

MEMBER HALSEY: Did you measure IgE to any

of these?

MS. RICHARDS: The initial conjugate that

was used in the screening assay, although the vendor

did specify it was anti‑IgG, we did do

cross‑reactivity analysis and ascertained that it is

cross‑reactive to IgM and also IgE.

So the positivity at the beginning would

show cross‑reactivity to IgE if it was present. So if

we did see an increase, we would have seen it also for

IgE.

ACTING CHAIRPERSON CHANG: Dr. Bartoo?

MEMBER BARTOO: You've presented data

outside the U.S. in 30‑plus countries with over

500,000 units distributed. My first question is, what

is the ethnic diversity within those treatments

outside the U.S. that you have presented here?

The second question I have is that I

understand that in the U.S. pivotal study, your

representation of ethnic groups is in proportion to

what typically is treated. However, you still have

very small numbers of certain groups, especially

African Americans. There's only three subjects in

that group.

So I would like to hear your justification

for why you feel that is enough in terms of safety

data in this group.

DR. POLISSON: With respect to the two

clinical trials that I reviewed and presented to you,

most of those patients were Caucasian, but I can

actually get those numbers for you and present to you

later in the panel. I don't have them on the tip of

my tongue.

Now, with respect to other worldwide use,

I, quite frankly, don't think we actually track that

data. But, again, if that's a mistaken or misspoken

comment, then we'll correct that later.

ACTING CHAIRPERSON CHANG: And the second

question was, do you as a sponsor have a feel that the

study is adequate, even though there are three

patients who are of African American descent?

DR. HOLMDAHL: I would like to call on one

of our investigators, Dr. Monheit, who has experience

with patients with skin of color from his practice.

DR. MONHEIT: Hi. I'm Dr. Gary Monheit.

I'm a dermatologist from Birmingham, Alabama

associated with the Department of Dermatology in the

University of Alabama Medical Center.

I have a 20‑plus‑year history of using

injectables in a diverse population in Birmingham and

through a portion of Alabama. First, I'll address the

fact that in our study group, we have the three

African American patients, whom I took care of and

treated. Their efficacy was the same and as good as

all of the other patients treated, and there were no

adverse events in those three particular patients.

In addition to that, I've got many years

of experience injecting patients of color, including

African Americans, with Zyderm, Zyplast injectable

fillers. I have found that there is very little in

the way of adverse events among the populations I've

treated with Zyplast and Zyderm of African American

descent as I have found among Caucasians.

The things that we have always worried

about have been keloid scars, the possibilities of

pigmentary dischromias, hyper and hypopigmentation.

I found that we get probably the same degree of

pigmentation problems as we get in people who have

prolonged erythema, who then may get pigmentation.

That's probably the derivation of it. It's an

inflammatory response that can lead to

post‑inflammatory hyperpigmentation.

When we have seen this with Zyderm and

Zyplast, it is treated in the same way we have treated

hyperpigmentation of other causes. And that's with

bleaching agents and skin creams and exfoliating

agents.

I have never seen a keloid in my 20 years

of experience treating African American patients. I

think part of the reason why is we're treating mainly

the mid‑face area and keloids are very rare in all

diverse populations of people.

Thank you.

ACTING CHAIRPERSON CHANG: Dr. Newburger?

MEMBER NEWBURGER: Obviously you have

given a great deal of thought and care in the design

of the study and have considered immunologic

compatibility. I am wondering since in the

literature, the reports of reactions, adverse

reactions, to Hylaform have been what appear to be of

the delayed hypersensitivity type, have you looked at

all that t‑cell response to the material?

DR. DeLUSTRO: My name is Dr. Frank

DeLustro. I'm with Global Biodevice Development. I

am here as a consultant for Inamed. I have no

financial involvement with either of those companies.

I would like to address that question a

little bit. Perhaps you could put on slide H010. The

company did look at the data and sorted out reactions

which could potentially be ascribed or immunological

in nature.

What we did was to take a look at any

incidences of erythema, redness, induration, swelling,

pruritus in any combination which occurred in patients

in the absence of bruising at those sites and which

occurred at a duration of greater than 14 days.

MEMBER NEWBURGER: Excuse me. Is it

occurred at greater than 14 days or ‑‑

DR. DeLUSTRO: Excuse me. No, no. Had a

duration of grater than 14 days. We also did a cut at

greater than seven days with the same results.

What I will show you is a cut at greater

than 14 days since our experiences with other

injectables demonstrates that those reactions

typically last four weeks at a time. And we're real

happy when they go away.

You can see from this table that, in fact,

what we saw in the initial phase of the study was that

there were only two patients in the Hylaform group

that fit any of this criteria. They were typical

erythema and in a second patient some pruritus and

induration, I suppose, to nine subjects that

demonstrated this type of erythema or pruritus in the

Zyplast group.

These reactions, as you have heard

probably too extensively by now, are not truly

indicative of immunologically mediated events but are

events of reaction within the dermis to the material.

You can see that with removal of

hypersensitive patients from the Zyplast group with

the double skin testing procedure which resulted in

3.2 percent of the population being eliminated prior

to treatment ‑‑ and that is consistent with the

literature of allergic reaction rates to injectable

collagen.

With that elimination, one still sees

approximately a 7 percent rate of these nonspecific

indicators, as opposed to the 1.5 percent seen with

Hylaform. So it's clearly far less.

That little tiny footnote in the bottom is

also important. What that states down there is that

in the second group, which received not only the

primary treatment but went on into the repeat phase

and were retreated, of that 96 patients, none of these

symptomologies were seen. No conditions that fit this

inflammatory categorization were seen at all.

Could I have the next slide? I think this

data specifically on the Hylaform study in conjunction

with what we know about Hylaform from a worldwide

study demonstrates that, in fact, it does not have

significant incidence of immunologically mediated

hypersensitivity.

As you can see in the first point, the

published studies of hypersensitivity to hyaluronic

acid dermal fillers is approximately .42 percent, but,

in fact, if you look specifically at Hylaform within

those numbers, it actually is about .2 percent. That

is clearly a logarithmic level lower than what is seen

with the injectable collagens in the dermal area. In

addition, the adverse event rate seen with Hylaform on

a worldwide basis is approximately 0.1 percent, a

very, very low level.

So I think in terms of your question, I

think the incidence, potential incidence, of

immunological reactions to Hylaform is exceedingly

unlikely based on what we have seen.

MEMBER NEWBURGER: I'm sorry. That wasn't

my question. My question was, have you looked at

t‑cell recognition?

DR. DeLUSTRO: T‑cell recognition, as we

know from bovine collagen, would occur with the same

symptomology. So if you look at the capture of

clinical symptoms, one sees, in fact, the same

clinical picture of reaction.

When you look at a delayed type

hypersensitivity reaction in a bovine

collagen‑mediated reaction, one sees the same

symptomologies occurring. And that we have studied

for quite some time.

So by looking at the clinical

symptomology, one captures the potential reactions

that are going to occur without looking at the

specific etiology, whether it's t‑cell or

antibody‑mediated.

ACTING CHAIRPERSON CHANG: Dr. Miller?

MEMBER MILLER: In your study, you

excluded people who skin‑tested positive against

collagen and also I guess avian proteins. That was

done by skin test or by history only that they exclude

them?

DR. DeLUSTRO: No. That was by history.

And that history of allergy or sensitivity to avian

proteins or bovine proteins is consistent with the

existing package labeling for Zyplastic control

material.

MEMBER MILLER: So what do you think would

happen if you took a group of patients who were

positive in their reaction to bovine collagen and you

gave them your product?

DR. DeLUSTRO: I think our worldwide

experience actually speaks to that. In Europe,

outside the United States, where Hylaform has been in

use since '96, the first population to be treated with

Hylaform, in fact, was the built‑up population of

subjects who had bovine collagen sensitivity. We know

from the literature and experience with Hylaform in

Europe that, in fact, those patients were treated very

successfully with the material.

MEMBER MILLER: Do you still recommend or

are you recommending for the product that if it is

approved, that it not be administered to people who

have a history of reactivity to avian proteins?

DR. DeLUSTRO: We would suggest that as a

precautionary statement in the package insert.

MEMBER MILLER: Just one other question.

Is there some avian protein present in the Hylaform

preparation, some minimal amount?

DR. BURNS: There's about 0.01 percent

avian protein per ml in Hylaform.

MEMBER HALSEY: My understanding is that

there was .45 percent of the mass in the product.

DR. BURNS: Absolutely not.

MEMBER HALSEY: That's what was here.

Okay.

DR. BURNS: 0.01 percent protein.

ACTING CHAIRPERSON CHANG: Dr.

Blumenstein? Dr. Doull next.

MEMBER BLUMENSTEIN: Was Zyplast effective

in this study?

DR. LARHOLT: We chose Zyplast as a

comparator because of this data.

ACTING CHAIRPERSON CHANG: Please speak

into the microphone. Identify yourself.

DR. LARHOLT: I'm Kay Larhout from

biostatistics from Genzyme.

We chose Zyplast as the comparator because

it is the gold standard. It has been used 20 years.

We show that at the end of the study, as Dr. Holmdahl

has shown, the life scores were on average one point

better than they had been at baseline, that the

investigator and patient‑level assessments were both

positive at 12 weeks. And those were significantly

different from zero. So we thought that yes, Zyplast

was effective in this study.

I will let Dr. Holmdahl talk a little bit

about the differences in this study compared to how

Zyplast is used in practice.

MEMBER BLUMENSTEIN: All I'm asking is,

was there a statistical test done to show that Zyplast

was effective in this study?

DR. LARHOLT: No, there was not.

MEMBER BLUMENSTEIN: Well, then can I

conclude from that that it wasn't or that you didn't

do the statistical test? That's what I'm trying to

get to because if you demonstrate non‑inferiority to

something that is not effective, then you haven't done

anything.

DR. LARHOLT: We did not test

statistically whether Zyplast was effective. However,

we feel that the result we have shown shows that

Zyplast still was effective at 12 weeks in the study

and, therefore, shown comparability to it shows that

we are non‑inferior to an active comparator.

MEMBER BLUMENSTEIN: I am convinced that

you have shown non‑inferiority to Zyplast, but I am

concerned about whether Zyplast was effective.

DR. LARHOLT: I think that maybe Dr.

Holmdahl can talk about the actual use of Zyplast in

the study that may be different from how it's used and

how it's been shown in different studies.

DR. HOLMDAHL: Well, if you recall the

graphs that I showed, both the live scores show that

both Zyplast and Hylaform had an average of about one

point improvement at 12 weeks and also the global

assessment, both investigator and patients' global

assessment, were about average of whether it shows or

it translates into that they rated themselves as

better.

So I think from a clinical perspective,

there is no doubt in the study that there was an

effect at 12 weeks. I would also like to call on Dr.

Monheit, who was one of the investigators, to give his

view of this.

MEMBER BLUMENSTEIN: Well, the problem is

I don't have the standard deviation. I have no idea

of the variability for the patients in this study. So

I don't know whether Zyplast was truly effective in

this study.

ACTING CHAIRPERSON CHANG: Do you have

data to show about the efficacy, sir, of Zyplast to

answer that question?

DR. MONHEIT: No. I'm not talking about

data. I'm talking about clinical experience.

MEMBER BLUMENSTEIN: That doesn't matter.

ACTING CHAIRPERSON CHANG: Thank you.

MEMBER BLUMENSTEIN: My next question is,

in your statement of the primary analysis that you

were going to do, you said that you were going to have

a combination of a two‑sided test of superiority and

a one‑sided test of non‑inferiority that was used for

the primary efficacy endpoint. The test of

non‑inferiority was considered to be the primary

analysis. So you presented that. And I believe it,

for a change.

(Laughter.)

MEMBER BLUMENSTEIN: And then you said if

the non‑inferiority test was demonstrated, the test of

superiority was to be performed as a secondary

analysis.

So you demonstrated non‑inferiority.

Where is your test of superiority?

DR. LARHOLT: We did not present the test

for superiority because it was obvious from the

results that said that the Hylaform because of the

negative difference, the ‑.2, would not show

superiority to Zyplast.

MEMBER BLUMENSTEIN: I just wanted to say

it. You're not superior, right?

DR. LARHOLT: No, no.

MEMBER BLUMENSTEIN: Okay. Thank you.

DR. LARHOLT: We're not, but that was not

the primary endpoint. The primary endpoint was

non‑inferiority.

ACTING CHAIRPERSON CHANG: Dr. Doull has

a question and then Dr. Halsey.

MEMBER DOULL: I may have missed it in

your material, but can you tell me how much divinyl

sulphone and formaldehyde are in your product?

DR. BURNS: There's approximately 2.3

parts per million total formaldehyde in the product.

About one part per million is actually free. And for

divinyl sulphone, it's about two parts per million

divinyl sulphone free cross‑linker.

There's also a hydrated form of that

product, which is about ten, less than ten parts per

million.

MEMBER DOULL: That's the amount in there?

DR. BURNS: Those are actually our

specifications. So the amount of material in there is

actually less than that. I think typically we'll be

able to measure about one part per million divinyl

sulphone.

ACTING CHAIRPERSON CHANG: Dr. Halsey and

then one other.

MEMBER HALSEY: I wanted to follow up on

the protein contamination. I am looking at the

documents we were presented. The protein was

determined by Lowry on 42 batches. The protein

content ranged from .12 to .85 percent with an average

of .83. Is that wrong? Did I read that wrong?

That's different than .01 percent.

DR. BURNS: Absolutely. Let me check on

that and get back to you. Obviously you have the data

in front of you, but I will get back and check on

that.

MEMBER HALSEY: Has anybody done any skin

testing or patch testing with this vinyl sulphone? Is

this something we should consider, too?

DR. BURNS: We haven't done any skin

testing with it per se. We have done sensitization

studies with Hylaform and immunogenicity studies, the

typical sensitization studies, Ames or the Guinea pig

maximization tests. We have done repeat injections in

a rabbit intramuscular test and then looking for

sensitization following a challenge.

MEMBER HALSEY: Those are all preclinical.

DR. BURNS: Those are preclinical, but we

haven't done any work specifically looking at vinyl

sulphone itself.

MEMBER HALSEY: Has anybody done skin

tests or patch tests with this product in humans?

DR. KINGMA: Hi. Wytske Kingma, Genzyme.

As part of the skin testing, as you know,

any hyaluronic acid has been widely available. In

general, there is no skin testing.

In the literature, as you may be aware,

there are some reports where subsequent to a reaction

patients were skin tested. One of those series is

actually from Dr. Lowe, who presented in 709 patients

that 2 Restylane and one Hylaform patients actually

were having reactions.

He added another three patients to that

with a total of six. Five of those were skin tested.

One of those was actually negative to everything,

despite the reaction. And the other four were

positive. That's a mix of Hylaform with Restylane.

In post‑marketing settings, we found both.

We found that patients will actually skin test

negative and had a reaction; the other, reverse, as

well, that if you had patients positive, for example,

to other dermal fillers or there was a delayed

sensitivity, that they have been continued to be

receiving it well. So we don't think that the skin

testing itself is a very predictive measure of seeing

who will have a reaction as a means of detection.

ACTING CHAIRPERSON CHANG: Last question.

Dr. Diegelmann?

MEMBER DIEGELMANN: Dr. Burns, you

mentioned that the average molecular weight is between

four and six million. What percent are the small

molecular weight products in the ‑‑

DR. BURNS: That molecular weight, by the

way, is the Hylan A. And then that gets cross‑linked.

Once it's cross‑linked, you basically have an infinite

network.

But we have analyzed for any lower

molecular weight oligomers that may be in the product.

It looks like about less than probably five percent of

it by mass would be less than about three or four

hundred thousand in terms of molecular weight.

I don't know how low you want to go. If

you want to go to about a 20,000, the percentage goes

down accordingly in terms of the amount of material

that is there. So not very much there, maybe some but

not much.

MEMBER DIEGELMANN: Do these low molecular

weight products increase with aging, with storage?

DR. BURNS: The proportion that is free

and not modified does not change in a significant way,

but you will see a decrease over a period of 2 years

from about 500,000 molecular weight in terms of the

initial material that might be free to about 300‑350.

MEMBER DIEGELMANN: I am just concerned

about the small, real small, molecular weight

compounds that can cause angiogenesis and increased

inflammatory or fibrotic responses.

DR. BURNS: Yes. And it's a good

question. Whenever I look at that data, I always am

cautioned by the fact that most of that work is in

vitro. There's a lot of work that shows that

exogenously added low molecular weight material in the

setting that we are using it has certainly a potent

type of biological activity.

We also have a lot of animal data in vivo

biological work with these materials that indicate

that the site where it's injected appears to be

healing in a fairly normal way.

ACTING CHAIRPERSON CHANG: Unless there

are any very pressing questions from the panel, we're

going to take a five to seven‑minute break so that the

FDA may do their presentation. Let's reconvene at ‑‑

MS. STEWART: Dr. Chang?

ACTING CHAIRPERSON CHANG: Yes?

MS. STEWART: May we answer two questions

that we weren't quick enough on one to Dr.

Blumenstein?

ACTING CHAIRPERSON CHANG: Yes. On ones

previously asked, yes, please.

MS. STEWART: And one to Dr. Bartoo.

DR. POLISSON: This is the question

relating to the ethnicity of the patients who enrolled

in the two trials. One was done in the United States

and was 216 patients. Only three percent were

patients of color. Ninety‑seven percent were

Caucasian. In the Swedish study, 95 percent of

patients were Caucasian; 5 percent were patients of

color.

DR. LARHOLT: I'm Kay Larholt from the

biostatistics department at Genzyme.

To answer your question, Dr. Blumenstein,

about the standard deviation, we do feel that in the

clinical study report, table 11.5, the standard

deviation for the Zyplast group at 12 weeks is 1.1.

The standard deviation for the change between the two

groups is approximately .8. That comes out of the

model.

So they're approximately in that range

between .8 and 1.1 depending on what score you're

looking at.

MEMBER BLUMENSTEIN: The change?

DR. LARHOLT: Not the change, the

difference between the 2 scores at 12 weeks, the

different score. The standard deviation on that is

about .8.

MEMBER BLUMENSTEIN: .8?

DR. LARHOLT: Yes. The standard error is

.8.

MEMBER BLUMENSTEIN: Standard error or ‑‑

DR. LARHOLT: Is .08. Therefore, the

standard deviation is approximately .8.

MEMBER BLUMENSTEIN: So you're saying the

standard deviation at 12 weeks for Zyplast was 1.1.

DR. LARHOLT: Yes.

MEMBER BLUMENSTEIN: And the standard

deviation for the difference in the mean, standard

deviation was .8?

DR. LARHOLT: Yes.

MEMBER BLUMENSTEIN: Thank you.

ACTING CHAIRPERSON CHANG: Thank you very

much. We are going to take a short break, reconvene

at ten after. Thank you.

(Whereupon, the foregoing matter went off

the record at 3:06 p.m. and went back on

the record at 3:15 p.m.)

ACTING CHAIRPERSON CHANG: Good afternoon.

We're reconvening. And we invite the FDA to begin its

review with Dr. Herbert Lerner.

DR. LERNER: Thank you.

FDA PRESENTATION

INTRODUCTION AND CLINICAL REVIEW

DR. LERNER: Good afternoon. Dr. Chang,

Dr. Krause, members of the panel, and guests, I am Dr.

Herbert Lerner, a reviewer in the Plastic and

Reconstructive Devices Branch of the ODE and team

leader for this PMA. That's PMA number 030032,

Hylaform viscoelastic gel sponsored by Genzyme

Corporation.

I would just like to mention the others on

our team who had input into this presentation. Dr.

David Krause will follow me immediately and present

the preclinical data. I will then present the

clinical summary. Ms. Phyllis Silverman will come up

and provide the statistical analysis.

Others on the team included David Kaplan

reviewing some of the preclinical data, Peggy Mayo

from Office of Compliance, Linda Godfrey from the

Office of Compliance, and Jack McCracken and Mary Lou

Pijar of the labeling issues on the PMA.

Dr. Krause?

PRECLINICAL REVIEW

EXECUTIVE SECRETARY KRAUSE: Good

afternoon. I'm donning the other hat now. Besides

being the executive secretary of the panel, I

occasionally get to review stuff.

I just wanted to say that the company did

extensive preclinical testing, which included

biocompatibility as well as proof of concept and many

different studies. It would take hours for me to get

up here and try to go through it all.

I am kind of just focusing on the studies

that I think are appropriate to mention. The company

successfully passed irritation testing, which was

performed via intracutaneous and subcutaneous.

Sensitization and immunogenicity were studied via

immunization subchronic toxicity, Guinea pig dermal

sensitization, delayed contact sensitization. Again,

these are animal tests.

Cytotoxicity was assessed, acute systemic

toxicity, hemocompatibility, implantation via muscle

implantation studies in rabbits for 7 and 30 days.

Mutagenicity was assessed using the Ames

mutagenicity test and three mammalian cell tests, the

induction for HGPRT mutation, chromosome aberrations,

and also the test for morphological cell

transformation.

Subchronic tox was looked at via

subchronic intraperitoneal toxicity, immunization, and

subchronic toxicity. Chronic toxicity,

carcinogenicity were assessed via the one‑year

subcutaneous toxicity study. Also, the company looked

for reproductive effects. They studied

pharmacokinetics and pharmacodynamics.

One thing that has come up ‑‑ and a

question was asked about this ‑‑ that was of interest

to us is that in the manufacture of the product, there

is a question about formaldehyde and the fact that as

patients get reinjected, is there going to be a fairly

large amount of formaldehyde or could that be a

problem?

The information that we received is that

the product contains a specification for 2.3 ppm but

usually has less, of which about one ppm is what we

would call free. So you would expect that if this

material were to come out of the product, it would do

so at a fairly slow rate.

What we thought was a critical factor was

that if you look at the level of formaldehyde, which

is a normal body metabolite, you would find that the

normal serum and tissue levels for formaldehyde are

between 3 and 12 micrograms per gram, which is about

the equivalent of 3 to 12 parts per million.

So, in actuality, the product would be

adding a negative amount of formaldehyde. In other

words, formaldehyde from the body would seep into the

product, rather than the other way around. So

formaldehyde really is not an issue as far as we have

concluded.

That is really all I have. Thank you.

DR. LERNER: The object of my clinical

presentation today is to provide a summary of

Genzyme's Hylaform clinical study and to highlight the

issues pertaining to the safety and effectiveness of

the study device.

The sponsor's study purpose is to evaluate

the safety and effectiveness of Hylaform viscoelastic

gel when used for cosmetic correction of contour

deformities of the dermis of the face.

The study I am about to present corrected

only nasolabial folds. I will be asking you a

question at the end of my presentation regarding the

study and the indications cited above.

As outlined previously by the sponsor,

this was a prospective, multi‑center, randomized,

double‑blinded, parallel group study comparing

Hylaform and Zyplast in the nasolabial fold during the

initial 12‑week treatment and Hylaform and Hylaform

Plus during the extended treatment period.

The sponsor has not included any efficacy

data for the extended treatment phase of the study,

and only four weeks of safety data for possible

immunologic responses were presented in the PMA. The

sponsor at this time does not seek approval for

Hylaform Plus.

The sponsor has carefully gone over all of

the inclusion and exclusion criteria. And I will

highlight just a few, again, a wrinkle severity score

of three or four on the six‑point grading scale, a

negative skin test to collagen implant, and two fixed

facial sites, fully visible nasolabial folds, which

were both candidates for correction. Again, patients

could not be pregnant and had to agree to use of

contraception.

Exclusion criteria included a known prior

or present positive skin test to the collagen test

implant; have received prior therapy, including

dermabrasion or facelift during the previous six

months; and previous tissue augmentation or other

wrinkle/fold therapies within the past six months.

The treatment protocol, as outlined by the

sponsor, included a screening period, collagen skin

testing times two per patient, randomization, and

treatment. Patients could have a touch‑up at two

weeks.

It should be noted that all patients were

skin tested. Randomization took place after the skin

testing. And touch‑up was indicated if there was not

a greater than one‑point improvement in the grading

scale. Also note that standard photography was taken

at each visit time.

During the initial phase of the study,

both nasolabial folds were treated. As I mentioned,

photographs were taken. An investigator wrinkle

assessment was performed. Touch‑up for the patients

was for 12 weeks starting after the touch‑up if one

was needed.

In the repeat phase, the treatment was

offered to patients who had only received Hylaform in

the initial phase. They must have finished the

initial phase. They were randomized on a side‑to‑side

basis and offered a treatment of Hylaform or Hylaform

Plus.

Of the 133 patients who finished the

initial phase of the study, 37 did not re‑enroll in

this phase. The main reasons for not re‑enrolling

were scheduling conflicts, prior restricted therapies,

dissatisfaction, or no interest, patients lost to

follow‑up, and two people were trying to get pregnant.

In the repeat phase, Hylaform and Hylaform

Plus were randomized. There was an investigator

assessment. Again, photographs were taken at each

visit.

And there was a patient global assessment

at each visit. Again note that the patients were

studied for 12 weeks, but only 4 weeks of safety data

was presented for this PMA.

The wrinkle assessment scale, as you have

seen, was a validated six‑point reference scale with

reference photographs that classified the deep facial

wrinkles, zero representing no lines or folds and five

representing severe lines or fold.

The clinical endpoints of the study, the

primary phase was to evaluate the efficacy or

non‑inferiority of Hylaform for the correction of

nasolabial folds as compared to Zyplast. This was

done using serial photographic documentation and

blinded IPR scores at 12 weeks. The second was to

evaluate the safety of Hylaform as compared to Zyplast

determined by the rates of adverse events associated

with the use of each product.

A secondary objective was to evaluate the

clinical utility of Hylaform with respect to physician

assessment and patient self‑assessment.

For the repeat phase, the endpoint was to

evaluate the safety of repeat treatment with Hylan B

gel products. In particular, the sponsor added this

phase to assess the safety of the device after repeat

maintenance doses by determining the presence or

absence of an immunologic response by measuring serum

Hylan B, IgG, antibodies and, again, to evaluate the

efficacy or non‑inferiority of Hylaform Plus versus

Hylaform for the correction of nasolabial fold contour

defects. The same secondary endpoint was for this

part of the study.

As you have already heard, both groups

were comparable with respect to age, gender,

ethnicity, smoking history, sun exposure, height, and

weight. Approximately 80 percent of the enrolled

patients were Caucasian females, with only 3 African

Americans and 16 Hispanics in the Hylaform group.

Patient accountability, at the end of 12

weeks, of the original 133 patients, 123 patients were

evaluated. It should be noted that there were 130

patients who completed the 12 weeks. However, 7 of

the Hylaform patients did not have their IPR scores

available at 12 weeks, and they were excluded.

Therefore, the actual follow‑up rate for Hylaform was

92.4 percent and for Zyplast was 91.4 percent.

Of the patients who withdrew from this

part of the study and for the Hylaform group, two

patients were lost to follow‑up. One patient simply

wished to withdraw. In the Zyplast group, there were

two adverse events, and one patient just simply wished

to withdraw.

Baseline wrinkle severity, the

investigators' live assessment at day zero showed a

mean for the Hylaform of 3.5 and Zyplast of 3.6.

Remember, the inclusion criteria was a score of three

or four on the six‑point scale. And the minimum and

maximum scores that were presented by the live

investigators were three to four.

The independent panel reviewers who looked

at the photographs taken at day zero had a mean for

the Hylaform of 2.2. Zyplast was 2.3. And based on

their scoring, patients from zero to five were

enrolled in the study.

The endpoint wrinkle severity, which was

at 12 weeks. The mean for the Hylaform was 2.4, the

Zyplast 2.3. Again, the minimum, maximum numbers are

at the bottom and the independent panel reviewers'

scores at 12 weeks 2.3, 2.2 with the same ranges.

Adverse events, in the initial phase of

the study, we were presented 117 patients with at

least one adverse event, representing 88 percent of

those patients enrolled in the Hylaform arm and a

similar percentage in the Zyplast arm.

It should be noted that there were 342

adverse events in those 117 patients and 322 adverse

events in the 112 Zyplast patients. The majority, as

you can see here, were procedure‑related.

If you look at the procedure‑related

adverse events, most of them fell within the injection

site erythema or bruising, swelling, pain, and

pruritus. And I think this was outlined nicely by the

sponsor in their presentation.

For the repeat phase, the same 96 patients

were enrolled on each side. Again, for the Hylaform

side, there were 269 adverse events in 87 patients,

286 adverse events in the 92 Hylaform Plus patients

who had at least one adverse event. And, similar to

the initial phase, the adverse events were generally

in the mild category of injection site difficulties.

On the second repeat phase of the study,

the majority of the adverse events were noted on

patient diaries. On the initial phase, it was by the

investigator during his office observations.

For the immunological response, serum IgG

levels during the repeat phase were determined to

evaluate the response to repeat treatments with

Hylaform.

There was no immunologic response

demonstrates. That is, no patient had a fourfold

increase in the IgG levels during the repeat treatment

phase. Only one patient had an elevated serum IgG

level to four times the standard. And this was before

treatment. At the end of this presentation, you will

be asked about the appropriateness of this evaluation

to determine long‑term safety.

Duration of effect. This is the 12‑week

IPR baseline analysis of the percent of the number of

patients who returned to baseline during this study.

At two weeks, 38.2 percent of the Hylaform‑treated

patients returned to baseline; 2.9 percent of the

controls, the Zyplast group, did. At 4 weeks, 8

weeks, and at 12 weeks, 73.3 percent of the patients

returned to baseline; 65.1 percent of the patients

returned to baseline.

For the analysis of masking, this was

presented by the sponsor. Approximately 75 percent in

each group did not know to which treatment arm they

were assigned.

The conclusions were that adverse events

were similar in both groups. And improvement of

wrinkle severity at 12 weeks was comparable.

At this point Ms. Phyllis Silverman will

come and review the statistical analysis.

STATISTICAL REVIEW

MS. SILVERMAN: Good afternoon. I'm

Phyllis Silverman, the statistical reviewer for this

PMA.

You have already been familiarized with

the sponsor's clinical study, claims, and multi‑phase

nature of this study. My task is to evaluate the

validity of the data presentation as well as point out

the strengths and weaknesses of the study design and

analyses.

Since claims for efficacy of repeat

treatments or of Hylaform Plus have been deferred,

this review will focus on the initial phase only. The

following is an outline of what I will discuss. You

can glance at that quickly.

The sponsor's clinical study was

well‑designed and the PMA clearly written and

comprehensive. The use of the concurrent control and

multiple evaluators made for a strong study design.

The study was designed as both a non‑inferiority and

a superiority study with separate criteria for each

one.

The six‑point Genzyme grading scale was

specifically created and validated for this study. A

validation study performed on 46 photographs rated

once and then again two weeks later by the same

three‑member independent review panel resulted in an

inter‑rater correlation of .91 as measured by the

kappa statistic and an intra‑rater agreement between

the first and second readings of approximately 80

percent.

The use of photographic evaluations for

the independent review panel, hereafter referred to as

the IPR, assisted in maintaining the blind. Patient

masking was also successful as determined by querying

patients as to which treatment group they believed

they had been assigned. And you have seen some of the

results of that from our clinical reviewer.

The two treatment groups were

well‑balanced on all demographic features, which

included age, weight, height, gender, ethnicity,

smoking history, and sun exposure. Therefore, I

consider the randomization and the masking to have

been effective.

Patient accountability was very good. Of

the 261 patients randomized and treated, 255 completed

the 12 weeks of the initial study phase. Three

patients in each treatment group withdrew from the

study and an additional 7 Hylaform and 8 Zyplast

patients did not have 12‑week IPR scores and were

excluded from the primary efficacy analysis. Thus, it

was not a true intent‑to‑treat analysis but close.

I have examined these 15 cases that did

not have 12‑week IPR scores. And these patients

appear to be missing at random. Thus, there is no

reason to suspect that any bias was introduced by

their exclusion.

The sponsor did not estimate any missing

values. And there was no data imputation. All

patients were included in the safety analysis. The

per‑protocol subgroup consisted of 115 Hylaform and

109 Zyplast subjects.

The study was sized to test both

non‑inferiority and superiority. The sponsor

confirmed their estimate of the standard deviation

from an external data collection on 32 Zyplast‑treated

patients over 12 weeks. This estimate was used to

calculate the sample size for the pivotal study.

It was calculated that 108 completed

patients for group would afford more than 80 percent

power for a non‑inferiority test with a delta of

one‑half point on a 6‑point scale and 95 percent power

for a superiority test of one full point. Thus, the

study was sized adequately for efficacy.

The primary efficacy variable, which was

the mean of the median IPR scores ‑‑ and that was the

median of 3 evaluators ‑‑ at 12 weeks was 2.3 for

Hylaform patients and 2.2 for Zyplast.

The lower bound of the one‑sided 97.5

percent confidence interval for the adjusted

difference was ‑.38, indicating that Hylaform was less

than one‑half point inferior, thus satisfying the

non‑inferiority criteria with a significance level

equivalent to 2 and a half percent. The analysis was

done on the intent‑to‑treat population and on a

per‑wrinkle basis.

To construct the confidence intervals, the

sponsor used a repeated measures analysis of

co‑variance model with the co‑variates being treatment

group, site, patient within treatment group, and

baseline IPR score.

The patient scores for the right and left

nasolabial folds served as the repeated measure. This

analysis was appropriate because it adjusted for any

differences in baseline values and accounted for the

within‑patient correlation between the two sides of

the face.

Adjustment for baseline differences was

particularly important because patients were entered

into the study based on a live wrinkle score of three

or four, but the analysis was based on the more

variable IPR scores assessed from photographs. The

superiority claim held to a higher threshold was not

met.

The sponsor also performed a categorical

analysis comparing the proportion of patients who

maintained at least a one‑point improvement in both

nasolabial folds at 12 weeks by the blinded

assessment. This proportion was higher for Zyplast

than Hylaform, although not statistically significant.

The investigator live wrinkle severity

score and the investigator and patient global

assessments were extremely close between Hylaform and

Zyplast, generally within one‑tenth of a point with,

again, no statistical difference.

As an aside, I would also like to point

out that results at earlier follow‑ups. That is, the

2, 4, and 8‑week follow‑up also showed the same

consistent pattern as any of the 12‑week endpoints.

The sponsor performed subgroup analyses

for the primary endpoint for the subgroups defined by

smoking history and sun exposure. No significant

difference in median IPR scores between treatment

groups were noted based on smoking history or sun

exposure using a confidence interval analysis. Thus,

it is acceptable to pool these subgroups for the

analysis.

As for pooling across the sites, the

sponsor provided a site‑by‑site analysis of the

primary efficacy endpoint. The direction of the

difference, Zyplast minus Hylaform, was always

negative, indicating Zyplast did just a little better

at each center. However, what is important here is

that there was no treatment by site interaction and

the data are poolable.

The analysis of the primary endpoint,

which was the median IPR score at 12 weeks, was also

performed on the per‑protocol population. Eighteen

Hylaform and 19 Zyplast patients were excluded from

the per‑protocol analysis due to major protocol

deviations, leaving 115 Hylaform and 109 Zyplast

subjects.

The mean of the median IPR scores were

identical to the intent‑to‑treat population. And the

lower bound of the confidence interval for the

difference was ‑.36, a hair tighter than the

intent‑to‑treat analysis. Thus, the non‑inferiority

criteria were met for the per‑protocol population.

As far as safety is concerned, the

incidence of overall adverse events was identical in

each treatment group and most were mild. The

occurrence of individual events appears to be

comparable in both groups.

Given the sample size, large differences

would have been required between the treatment groups

for any individual rate to be statistically increased.

The study was not sized for this purpose. The safety

profile has been discussed by the clinical reviewer

and should be evaluated from the clinical perspective.

One area of concern is the fact that 94

percent of the subjects were women and 80 percent of

the subjects were Caucasian. Although this

distribution is likely representative of the target

population of people who would seek this treatment in

real life, the 26 non‑Caucasian subjects may not have

been sufficient to assess how Hylaform performs in all

skin types, which can differ with respect to scarring,

for example. Therefore, this issue should be

evaluated from a clinical perspective.

My other concern is the longevity of the

treatment. A comparison of duration of effect between

Hylaform and Zyplast was never a primary or second

endpoint of this study. And no testing for

statistical significance was performed. However, I

think it is important to point out that over half of

the Hylaform folds returned to their IPR baseline by

four weeks and almost three‑quarters by 12 weeks.

Zyplast wrinkles did a little better,

particularly at the earlier time points. I will give

you a moment to study these numbers.

(Pause.)

MS. SILVERMAN: In summary, I find that

the sponsor conducted a well‑designed and analyzed

clinical study and that the data support the

non‑inferiority of Hylaform to Zyplast for treatment

of nasolabial folds. The superiority of Hylaform was

not demonstrated. And the longevity of this treatment

should be evaluated from the clinical perspective.

Thank you.

ACTING CHAIRPERSON CHANG: At this time I

would like to ask panel members, are there any

questions that need to be directed to the FDA

presentation? Dr. Blumenstein?

PANEL DELIBERATIONS AND ADDRESS FDA QUESTIONS

MEMBER BLUMENSTEIN: I would like to ask

the FDA if they believe that Zyplast was effective in

this study.

DR. WITTEN: Yes. Well, I would just say

that we picked a control on the basis that we could do

a comparison to an effective product at 12 weeks.

So our selection wasn't based on a

demonstration within this study or let's say working

with the sponsor and accepting the control they

proposed wasn't based on a demonstration in the study.

It was based on our understanding of the performance

of the product use for the control. And its

performance is generally accepted in the clinical

community. So it's not based on the study but based

on what we know about the control treatment.

MEMBER BLUMENSTEIN: Well, there were two

slides presented by Dr. Lerner. One of them was the

baseline wrinkle severity table with the independent

panel review. The other was the endpoint wrinkle

severity by the independent panel review.

If I look in the Zyplast results there,

the mean baseline score for Zyplast is 2.3 by the

independent panel review and the mean score at 12

weeks by the independent panel review is 2.2. So that

the difference is .1.

DR. WITTEN: Well, can I just clarify that

or perhaps I will ask Dr. Lerner to clarify my

clarification if I'm wrong. There is a baseline

assessment. I'm just looking at the handouts, on page

4, which has the slides on it.

The independent panel review, day zero, is

that the post‑treatment assessment or the pretreatment

assessment? Is that the baseline post‑treatment

assessment?

DR. LERNER: That's the number that was

given to the patients for inclusion into the study.

So if you look at the investigators' live assessment

at day zero, the 3.5 and 3.6 were the mean of all of

the patients included into the study. That fell

within the inclusion criteria.

DR. WITTEN: And then the independent

panel review assessment is?

DR. LERNER: That's the panel's review of

the photographs taken at time‑zero before treatment.

And then at 12 weeks, that's the endpoint.

MEMBER BLUMENSTEIN: So the question is,

was Zyplast effective in this study for the patients

treated with Zyplast? And the mean of 2.3 at baseline

and 2.2 at 12 weeks using comparable methodology for

assessing the endpoint is a difference of .1 with a

standard deviation of 1.04 and 1.12 for the second.

I just happen to have a little computer program that

lets me put this stuff in, which is not significant.

MEMBER BARTOO: Excuse me. I am taking a

look at the slides. And baseline wrinkle severity

shows here 3.5 Hylaform at baseline.

MEMBER BLUMENSTEIN: That's a different

methodology. Live assessment is the investigator at

the clinical site. The next slide is independent

panel review.

MEMBER BARTOO: Right.

MEMBER BLUMENSTEIN: You might also ask

the question why there is such a difference between

the investigator at the clinical site and the panel.

That is another issue. What I am trying to get at,

was Zyplast effective in this study?

DR. LERNER: The simple without trying to

be funny answer is .1.

MEMBER BLUMENSTEIN: My conclusion is that

it was not. Therefore, the demonstration of

non‑inferiority is non‑inferiority to something that

didn't work.

ACTING CHAIRPERSON CHANG: Dr. LoCicero?

MEMBER LoCICERO: Again, not to be trite,

but one of these four is not like the other. If one

looks at the initial live assessment, you get 3.5 and

3.6. The validated from a previous study independent

panel review is 2.2 and 2.3.

The reason for entry was the live

assessment. And the evaluation of efficacy was

independent assessment. The post‑study independent

assessment is 2.3 and 2.2, which is not different from

the investigators' live assessment of 2.4 and 2.3.

So looking at those four panels, I would

have to assume that the investigators were

overaggressive in entry criteria. And if I'm wrong,

I'd like ‑‑

MEMBER BLUMENSTEIN: That would be one

possible interpretation of why the investigators'

scores, the clinical site investigators' scores, are

higher, was that they were ‑‑ the word "fudging"

doesn't really ‑‑ that they were inflating those

scores to be able to get the patients on the study.

That would be one possible explanation.

The point is that I think the efficacy of

Zyplast in this study needs to be assessed using

comparable rating. And the sponsor went to a great

deal of trouble to set up the independent panel

review. And they did take the photographs at

baseline, and they did get the scores at baseline.

And they also looked at the scores at 12 weeks.

So my conclusion is that Zyplast was not

effective.

MEMBER BLUMENSTEIN: But the point is

ACTING CHAIRPERSON CHANG: Dr. Miller?

MEMBER MILLER: I guess I'm a little

confused because I thought the baseline wrinkle

severity was the starting point after the treatment

and that they don't like ‑‑ the baseline wrinkle

severity is at pretreatment. And so at time‑zero,

immediately after treatment, we have no data on that,

on what they looked like at the outset of the trial

here?

MEMBER BLUMENSTEIN: Well, you had some

two‑week data and some four‑week. I don't remember

the time. I don't remember the time points.

MEMBER MILLER: Okay. I'll have to look

back at the data here.

ACTING CHAIRPERSON CHANG: I have a

question to the sponsor, then, to try to clarify this.

Dr. Blumenstein is saying that a live examination of

the numbers does not match a pictorial evaluation of

these same patients. Is that true or is the picture

at baseline after injection of these materials? That

is the key question.

Pictures were taken of the patient at

point zero. Was that after filler was injected to

start off a study or was that before any treatment was

done?

DR. POLISSON: The pictures were taken at

baseline before the patients were treated. Again,

that was the primary endpoint that we were hanging our

hat on because we felt it was better with respect to

blinding at the site, was much more systematic and

objective to do so.

The live scores were done live with a

patient in the room at the time of randomization. So

the two scores made. A couple of things I would like

to bring out about the live scores that have been

introduced to me by my colleagues.

If the panel allows, I am going to

actually ask that person to comment, but, first of

all, the live scores we don't believe were a way to

get patients randomized into this trial in an

overzealous manner because if you look at the rate of

enrollment, this was a very, very popular study.

Patients were randomized in a very, very short period

of time. So it wasn't a gimmick to kind of get

patients in.

The other thing is that live scores

clearly represent different information. A live

score, I'm a rheumatologist. So I can take a look at

an X‑ray. And I know that the information that you

get is much different than when it's digitized on a

screen. So it's a 3D, versus a 2D, effect.

We would like to say that the live scores

really changed and there was no difference between the

two treatment groups throughout the course of the

study. So I would like to clarify that.

Dr. Witten, would it be possible for me to

ask Dr. Monheit to amplify those or, Dr. Chang, could

I ask one of our investigators to amplify that or have

I answered your question?

ACTING CHAIRPERSON CHANG: This does

answer that question that was posed and amplifies what

Dr. Blumenstein is saying, that the data presented

using the IPR shows change from 2.3 to 2.2. Thank you

very much.

MEMBER BARTOO: Can I ask another question

regarding that?

ACTING CHAIRPERSON CHANG: Yes.

MEMBER BARTOO: For the live scores, was

that blinded or unblinded in terms of the person who

assessed that score?

MS. SILVERMAN: They were unblinded.

MEMBER BARTOO: Unblinded.

ACTING CHAIRPERSON CHANG: Any other

questions for FDA? Dr. LoCicero?

MEMBER LoCICERO: I just want to clarify

from Dr. Lerner. The entry criteria was the live

score and the evaluation after 12 weeks was the

independent panel?

DR. LERNER: Yes, that's correct.

ACTING CHAIRPERSON CHANG: It's time to

move on to the FDA questions. May we have the

questions on the screen, please? Question, Dr.

Halsey?

MEMBER HALSEY: I'm still concerned about

the avian protein dose and that it might be

significant and want to be sure that I haven't made an

error in my calculations.

The data that I have in this submission

says that that's .4 percent, which would be if this is

correct, 4 parts per thousand. So it's possible that

the avian dose that the patient gets could be

significant.

DR. BURNS: Can I?

ACTING CHAIRPERSON CHANG: Dr. Burns?

DR. BURNS: Yes.

MEMBER HALSEY: Go ahead and answer that.

DR. BURNS: I want to make sure I am

looking at the same thing that you are. This is .4

percent with a range of .12 to .85 weight percent?

MEMBER HALSEY: That's correct.

DR. BURNS: That's for Hylan A, which is

an intermediate for the final production of Hylan B.

MEMBER HALSEY: Okay.

DR. BURNS: The final product, Hylaform,

has a product spec of .052 milligrams per ml. And

over a series of 89 lots, the actual number comes out

to approximately 10 milligrams per ml, which I believe

is about 10 parts per million.

MEMBER HALSEY: .05 milligrams per ml.

DR. BURNS: That's the spec. And over a

series of approximately 89 lots, it comes out to .01

mgs per ml.

MEMBER HALSEY: So we're down to micrograms

of dose.

DR. BURNS: Right, approximately ten parts

per million.

MEMBER HALSEY: That is a step forward.

And that may be good enough, but I think that still

was a question.

The other question I have on safety is

that the duration of the study was fairly short, as I

recall, for both antibody measurements and any other

assay for delayed type hypersensitivity, which was not

done.

In view of the fact that, as I could

determine it from what was presented, we didn't know

if the assay measured IgG because it seemed to measure

other isotypes of immunoglobulins and there was no

inhibition done, so we don't know if we were measuring

antibody to what we were measuring antibody to. So I

think we don't know enough about the immune response.

Finally, I would ask, what are the

exclusion criteria that are used for the treatment

with the collagen? Is a skin test or is an allergy to

bovine protein a requirement for the use of that drug?

Can somebody tell me?

ACTING CHAIRPERSON CHANG: Dr. Olding,

you're nodding?

MEMBER OLDING: Yes, it is one test one

time. Although I believe it is suggested to have two,

it is a requirement to have a skin test and then that

be evaluated for a full month.

MEMBER HALSEY: Then I think we should

discuss whether that would be a requirement here for

avian protein sensitivity since one study interval for

sensitization was relatively short and even though

there's less than what we were concerned with before,

there's still a significant dose of avian protein.

DR. KINGMA: Wytske Kingma. I would like

to address the concern that you have with regards to

duration of adverse events and sensitivity.

We really specifically looked at local

reactions in order to see whether there was prolonged

effect. When you look at the patient, entire patient

population, treatment emergence, not going into

whether they were procedure‑related or whatever, to

look at everything, in effect, the majority of the

events actually occurred within the first week and

resolved within the first week.

That is equally the case in the first

initial phase of the study as well as in the repeat.

In fact, there were only two patients in the initial

phase that continued to have an event after 30 days,

which were induration and erythema, and the other one

patient in the repeat treatment, which continued to

have one event after 30 days.

So the delayed hypersensitivity is really

not in issue. However, of course, as with any

thorough follow‑up with all adverse events, we

continue to follow anything that may be ongoing.

In effect, if you look at the design of

the trial, you have the 12 weeks of the initial phase.

Then you have a break where anything ongoing would be

requirement of study design continue to be followed.

In patients, the interval between initial

phase and repeat phase varies between 6 days and 152

days. Then they went into the repeat, which continues

to be followed for another 12 weeks.

So if you look at it from the safety side,

you probably have a good expansion of about six months

to eight months at least of safety data.

MEMBER HALSEY: For the patients included

in this trial. And you excluded those that might have

allergy to egg protein, correct? You've shown the

safety in this population, which is good, but we

haven't tested those. You have eliminated those from

the study population. So I am wondering if we

shouldn't require somehow that patients be tested

before they're treated.

DR. KINGMA: If you look at the worldwide

experience, we have treated a lot of patients, more

than 500,000 patients, with this product specifically.

And there's no exclusion of such. And it has not been

a link. There is no skin test that would tell you

whether or not an avian sensitivity will actually

predict a reaction.

MEMBER HALSEY: I hadn't seen that data.

ACTING CHAIRPERSON CHANG: Do we want to

have a discussion again about whether there is

reasonable ‑‑

DR. KINGMA: I think ‑‑

ACTING CHAIRPERSON CHANG: Excuse me.

This is a discussion among the panel. I am asking for

a discussion among panel members to answer the FDA

question of available data presented in this PMA,

whether there is reasonable assurance that the device

is safe. Dr. Miller?

MEMBER MILLER: I think it's a little

difficult, especially because of the questions raised

about the avian protein issue. I think if you look at

the data that's been presented and compare it to

Zyplast, all the complications appear local.

And I can't I guess speak as competently

about the IgG levels after just four weeks if that's

adequate. It doesn't seem to be any significant

immune responses to the material, but it is a select

population. This population is a selected group to

exclude those who have a history of reacting to

foreign proteins.

So this just raises a question in my mind,

which it would be helpful to know worldwide data

perhaps or to look at what happens if you have

somebody you know has an allergy to avian protein in

whom you inject this or perhaps to know what happens

with that.

This is very similar I think to another

product for treating arthritis, I think. So what is

the experience in that group? Is there a restriction

in arthritis patients for those who have allergies who

have avian proteins? And do they get this material

and not have a problem?

ACTING CHAIRPERSON CHANG: The question

that you ask, Dr. Miller, may also be addressed as a

query to FDA regarding labeling issues, warning as an

example of trying to find some answers.

So FDA is asking at this time based on the

presentation given by the sponsor and by FDA's

evaluation and summation, based on examining this data

today, opinions regarding reasonable assurance that

this product is safe. So panel members are asked to

speak up in part of this discussion. Dr. Newburger?

MEMBER NEWBURGER: I think the data show

that the product is safe, but I think it only shows

that it's safe for one treatment. I don't see

anything else to speak to that to see that there is

safety established for multiple treatments over time.

But for the data presented, I think that it's safe.

ACTING CHAIRPERSON CHANG: Yes?

MEMBER OLDING: I just want to clarify

something. You said there is no test for avian

allergy, no skin test? Is that correct?

MEMBER HALSEY: There is.

MEMBER OLDING: I thought I heard her say

there was not.

ACTING CHAIRPERSON CHANG: Dr. Halsey?

MEMBER HALSEY: Most definitely there is.

Allergists do it all the time.

MEMBER DOULL: I might just comment about

the tox part of the safety. The tox studies did

include, of course, subchronic. And they included

carcinogenicity studies.

So there was a repeated evaluation of the

hazard associated with toxicity. It's the immunology

part where they don't really have that well‑done.

But, as Dr. Krause told us, the full

battery of protocols required by the agency were

carried out. And there were no toxicity alerts in any

of those studies which would raise serious concerns

about the safety of the product from a tox point of

view.

MEMBER HALSEY: Can I comment?

ACTING CHAIRPERSON CHANG: Yes.

MEMBER HALSEY: I think the question of

egg allergy is a difficult one and the agency is going

to have to decide if they're going to let a primary

care physician and a patient decide if they are

allergic to egg protein or they're going to require a

skin test.

There are reagents, licensed products for

doing that or there is a blood test that's available

that people use throughout the world for such

determinations.

ACTING CHAIRPERSON CHANG: Dr. Witten,

finally, the discussion of question 1 regarding the

safety issue, one panel member stated the belief that

comparing short‑term and local reactions that this

product as a result of the PMA is deemed safe. The

remaining issue is longer‑term study and whether or

not because the PMA specifically excluded by history

those who may have avian product hypersensitivity that

the issue raised and question raised for labeling

perhaps is whether or not skin testing should be

recommended, suggested, or required as a condition for

use of this product.

Does this answer the FDA's question to the

panel?

DR. WITTEN: Yes. Thank you.

ACTING CHAIRPERSON CHANG: May we have

question 2, please? Question 2 is asking the panel to

discuss whether on the basis of this PMA the device is

effective.

And we're open to comments. Dr. LoCicero?

MEMBER LoCICERO: I think if we work

backwards, the investigators at the endpoint found,

both on live and independent panel, that there was no

difference between the two groups following completion

of treatment and 12 weeks of observation.

Another fact is that looking at the IPR

scores at the end of 12 weeks among patients who

received touch‑up had scores that were within .5 of

the initial evaluation by the live group so that

touch‑up appears not to be affected in changing from

baseline, nor are they different from one another.

There is some difference in the initial

evaluation of patients between independent panel

review and the live review. I think the only way to

solve that is to know is there a statistical

difference between the live assessment and the

independent panel review. We don't have that data.

Finally, there is no data on African

Americans that is sufficient in any amount for us to

assess its efficacy in that group.

ACTING CHAIRPERSON CHANG: Dr.

Blumenstein?

MEMBER BLUMENSTEIN: The sponsor has shown

non‑inferiority to Zyplast based on the 12‑week

measurement. Unfortunately, Zyplast based on the

sponsor's own independent panel review has not been

shown to be effective in this study based on the data

that were shown to us here unless there is some reason

to believe that Zyplast is effective in this study and

one can conclude that the sponsor has shown

non‑inferiority to something that isn't effective and,

therefore, as a result, this product is not effective.

ACTING CHAIRPERSON CHANG: Any further

comments? Dr. Miller?

MEMBER MILLER: I guess I agree with what

you say. I mean, you're exactly logically correct in

what we have seen in the data today. However, I am

not sure how to factor in just the years of experience

where Zyplast has been used to correct these problems

with an effectiveness that is sufficient to warrant

its continued use, maybe not demonstrated in a

rigorous fashion like we would like.

But certainly I guess I came into this

assuming Zyplast was effective because of the

experience of many years of its use in observing how

it helped some patients. So to question the validity

of Zyplast is a sudden sort of a question to raise.

I guess I am just having some trouble with that.

I know based on the data, you're exactly

right; the data we see here, you're exactly correct.

I can't argue with you. But this data isn't really

exhaustive for what the experience has been with

Zyplast.

ACTING CHAIRPERSON CHANG: Dr. Bartoo? I

would like to ask Dr. Olding also since it has been

established that he has been a user of some of these

products.

MEMBER BARTOO: I have to echo some of the

comments from Dr. Miller. In addition, I know that

the sponsor has worked with FDA, as Dr. Witten said,

to determine what is the appropriate control. They

were told that Zyplast would be an appropriate

control.

I feel that to be fair to the sponsor,

they followed the directions from FDA as to what they

should use for their control. So I think we need to

take that into consideration, in addition to the fact

that Zyplast has already been shown to be effective in

other studies and in its long‑term use.

ACTING CHAIRPERSON CHANG: Dr Olding,

comment for the FDA regarding efficacy?

MEMBER OLDING: Certainly. I cannot fault

the statistical analysis of the data. However, two

comments. Number one, I agree with Dr. Miller.

Certainly having utilized the products, there is an

efficacy associated with them. The length of that

efficacy has certainly been long enough to have been

approved by the FDA at some point in the past.

However, as in the last panel on

Restylane, when we discussed the superiority of

Restylane over the Zyplast, there was no scientific

evidence that, in fact, it was better. And so the

panel has voted not to allow inclusion of material in

the handout that says that it's superior in the same

fashion. This does not show any effect ultimately.

So based on a gut reaction, I think it has

to, but based on science, it apparently does not.

ACTING CHAIRPERSON CHANG: Not to pick on

plastic surgeons, but I will ask Dr. Boykin to weigh

in to ask about efficacy.

MEMBER BOYKIN: I think the numbers just

underscore the difficulty of doing these types of

tests or demonstrating valid clinical results in terms

of mathematical models. I think what is obvious is

that we have shown that there is quite a bit of

similarity between these two products. The efficacy,

of course, is different to different people. It

certainly isn't superior.

I do question the follow‑up evaluation.

It's hard to believe that it's unchanged

significantly. But we have to deal with the data that

we have in order to make these decisions.

And without pulling in a lot of other

outside bias, I think it's safe to say that perhaps

only half of the indications have been met and that we

are lacking in some firm objective data to make more

statements than that.

ACTING CHAIRPERSON CHANG: Dr. Newburger,

is this an efficacious product?

MEMBER NEWBURGER: If it's equivalent, if

this product performs essentially the same as Zyplast,

my experience with several thousand times injecting,

that product has efficacy.

ACTING CHAIRPERSON CHANG: Any other panel

members with an opinion?

(No response.)

ACTING CHAIRPERSON CHANG: Dr. Witten,

after discussion for question number 2 regarding the

efficacy of the device proposed by sponsor, there is

a divided opinion in terms of the data that has been

presented. There is a question in terms of efficacy

of primarily the control. The sponsor has shown that

there is no difference between the two, but the

question again is raised regarding the presumed gold

standard of using collagen.

So looking at data, some members feel very

strongly that data has not shown the efficacy of the

control itself; whereas, it is a different mindset of

having that presumption of a gold standard being

efficacious having been approved and used for many

years of not showing a change by the data presented

today.

On the other hand, there is a strength of

clinical experience, including clinical experience by

members of the panel, that yes, long‑term clinical use

has shown its efficacy and, therefore, we have a

divided opinion regarding the efficacy of the device.

Does this adequately answer your question?

DR. WITTEN: Yes. Thank you.

ACTING CHAIRPERSON CHANG: Question number

three, please? Due to the low numbers of African

American patients that were enrolled in this PMA, FDA

would like the panel members to consider this

question, should the device be approved? Should

sponsor be required to conduct a post‑approval study

to collect safety data on specific minorities? Is

there specific labeling that is needed to address the

potential use in minorities or, I will say, patients

of color? Dr. Boykin?

MEMBER BOYKIN: Yes. I believe that a

post‑approval study would definitely be indicated.

And safety data is certainly needed in this particular

area.

I believe that the patients of color

present with issues that would require that they be

looked at perhaps with some other outlines and in

respect to the safety of the device.

The labeling, of course, needs to be

reflective as well.

ACTING CHAIRPERSON CHANG: Dr. Miller?

MEMBER MILLER: I agree with that. I

would suggest that the exact same concerns arise over

this as did this morning over the Restylane and should

have sort of a parallel approach.

ACTING CHAIRPERSON CHANG: Dr. Witten, in

answer to question 3, it's yes to both for the

previous discussions.

Does this adequately answer?

DR. WITTEN: Yes. Thank you.

ACTING CHAIRPERSON CHANG: Question number

4 is sponsor proposes indications that "Hylaform is

intended for the correction of soft tissue contour

deficiencies, such as wrinkles and acne scars." Based

on the fact that only nasolabial folds were treated in

this PMA, has the information presented today been

adequate to accept the scope as proposed by the

sponsor, to include acne scars? Dr. Newburger?

MEMBER NEWBURGER: I believe that the

indications should hold as they're written. It's a

fairly short‑lived correction, so my concern about if

there is cosmetic mistake in injection, that it's not

going to have a long‑term adverse impact on the

individual. Also, there's the worldwide experience as

well where it has been used in this regard.

ACTING CHAIRPERSON CHANG: Further

comment? Dr. Olding?

MEMBER OLDING: Since we didn't show that

Restylane theoretically lasts longer than Zyplast from

the other panel, then to me your comments are not

consistent because this one only lasts a short period

of time theoretically; i.e., the same as the Zyplast.

And the other study did not show, the Restylane did

not show, that it lasted longer. Therefore, it's hard

for me to understand that rationale.

In fact, there was one patient that

developed an aseptic abscess with this particular. So

I'm trying to bring all of this so that it's equal and

understandable?

MEMBER NEWBURGER: May I respond? Your

point is well‑taken, but this, the consistency of this

material, is different and the injection technique is

different than the other material, I believe because

there's a difference in the cohesiveness of the

substance, at least as I can glean from the

literature. It's not going to have quite the same

visibility.

ACTING CHAIRPERSON CHANG: Dr. Witten?

DR. WITTEN: Yes. I just want to comment

that we really need to stay away from discussing the

product that was discussed this morning and focus on

this application and this product and what we are

doing with this product.

ACTING CHAIRPERSON CHANG: Thank you.

Comments that would relate to the use,

indications? I would say the analogy would be soft

tissue defects, to say soft tissue defects. And would

acne scars be categorized as a soft tissue defect?

MEMBER NEWBURGER: Sure.

ACTING CHAIRPERSON CHANG: Dr. Newburger

says yes. Any other comments? Dr. Witten?

MEMBER OLDING: Excuse me.

ACTING CHAIRPERSON CHANG: Yes?

MEMBER OLDING: I have one other

suggestion or question about this. Many of my

patients want to have augmentation of the lips. The

lips I think if not new, it's one of the most

frequently requested areas for augmentation. There's

nothing in this particular guidelines that they're

planning to distribute about its efficacy for lips.

I would like to see in the guidelines for

their use that it has not been officially tested for

lip augmentation. There's no clinical evidence of its

efficacy or its safety in lip augmentation.

ACTING CHAIRPERSON CHANG: Please keep

that in mind. That would be certainly an item that

would need to be brought up regarding potential

conditions for approval.

Dr. Witten, based on the discussion, panel

members believe that the indications are for soft

tissue defects, that acne scars would be rated under

the category of soft tissue defects.

DR. WITTEN: Thank you.

ACTING CHAIRPERSON CHANG: Question number

5. This is the last question posed to the panel. No

significant changes in adverse events were noted.

Does this data support the safety of the device for

repeated use or do you believe that a post‑approval

study is needed to address this issue?

MEMBER HALSEY: I think we discussed that

at the top in immunology earlier.

ACTING CHAIRPERSON CHANG: Can you restate

your opinion, then?

MEMBER HALSEY: We discussed this earlier

and felt that it is possible that the avian protein

dose might be significant, even though it's in the 10

to 20 microgram range, and that the duration of the

immunology studies was limited. And the question of

an exclusion criteria for patients that receive this

treatment is something I think the agency needs to

consider since the studies were short‑term and not

complete.

ACTING CHAIRPERSON CHANG: Any other

discussion?

(No response.)

ACTING CHAIRPERSON CHANG: Dr. Witten, as

previously discussed in conjunction with the first

question, it is felt that there has been limited

12‑week study for immunological reactions. And,

therefore, post‑approval studies should be considered

to address this issue.

DR. WITTEN: Thank you.

ACTING CHAIRPERSON CHANG: We're going to

proceed now with the next open comment session. At

this time no one has notified the FDA that they wish

to address the panel with open public comment, but I

will ask the audience if there is anyone who wishes to

address the panel for approximately five minutes

regarding the issues that have been discussed this

afternoon.

(No response.)

ACTING CHAIRPERSON CHANG: I see no

raising of hands. At this time, is there any FDA

summation?

DR. WITTEN: FDA has no further

discussion.

ACTING CHAIRPERSON CHANG: Thank you, Dr.

Witten.

Is there an applicant summation by Genzyme

Corporation?

DR. POLISSON: Thank you, Dr. Witten.

SPONSOR SUMMATION, CONCLUDING PANEL DELIBERATIONS

AND VOTE

DR. POLISSON: Dr. Witten and panel

members, thank you for the chance to provide a summary

and to provide some rebuttal to some of the points

that were made in the last period of discussion.

The first thing I would like to talk about

is the safety issue. I would just like to remind the

panel that Hylan B, of course, which is made from

hyaluronic acid in preclinical studies, has been shown

in our application to be safe, nontoxic, and

non‑immunogenic and that we feel in our study that the

safety of Hylaform was comparable to that that was

observed in Zyplast and, in addition, in the repeat

treatment phase that Hylaform appears to be safe and

particular for that one patient. There was no

association between IgG titers and adverse events.

I think I would like to focus now on the

last two bullets. And that is the worldwide

post‑market adverse event rate is about .11 percent.

We all recognize how these figures are obtained in a

pharmacovigilance post‑marketing setting, but I would

also like to add a few other points.

In our worldwide label for both Hylaform

and Synvisc, which is used for the treatment of

osteoarthritis, we do have a cautionary phrase for

patients who have allergies to avian proteins. We

would clearly expect to see this in our label in the

U.S.

I just also would like to remind people in

terms of volume of exposure that nine million units of

Synvisc have been sold worldwide to date and, finally,

that there has been no skin test that has been

required for use pre‑exposure to this particular

treatment.

A lot has been made of efficacy. And we

have heard questions about, does this really work. It

actually resonates with me, the comment that Zyplast

really does work because it's been out for two

decades. I would like to remind the panel that the

Zyplast has never been tested like we have tested it

in this trial. It's never been tested in an IPR type

of review.

So I think that I believe that for the

purposes of this study, that we have met our primary

endpoint as agreed to with the colleagues at FDA.

Really, finally, to really fully evaluate

in my opinion Zyplast, does it really work, one would

have to add a placebo control group to this, which we

would obviously be unable to do because of efficacy

issues.

The point under there I have beaten to

death is that we feel that we have really developed a

robust endpoint and that, again, Zyplast has never

been tested to that.

A couple of other points here that I want

to make are that we have met our primary endpoint, but

if there is an insecurity about the primary endpoint,

what I have always been taught ‑‑ and my clinical

trial, of course, as one looks to the totality of the

evidence and one looks to secondary efficacy

endpoints, I will remind the panel that the patient

and physical live and the globals were all better at

12 weeks and were comparable to that seen with the

Zyplast.

On average, patients and physicians

continued to assess response to treatments as better

or much better at 12 weeks. And I believe the figures

are 66 percent for patients and 83 percent for

physicians. And, again, that is comparable to

Zyplast.

So I really do feel that not only from a

statistical point of view but from a clinical point of

view, that we have met our endpoint and this is, in

fact, effective.

A few of the things that Dr. Monheit

wanted to get to the podium to describe for you is

that we really limited touch‑ups in this study. And

this does not necessarily reflect practice. Touch‑ups

in other studies and in practice really are done to

produce optimum correction.

We reduced or limited touch‑ups to one

touch‑up only. And the reason that we did that was

that we wanted to reduce the variability in the study.

We didn't want to have three or four touch‑ups in one

treatment group and have to try to answer that in our

analysis at the end.

Again, the final thing is and I am sure

that it has not escaped you is that Hylaform was

similar to Zyplast in this trial with less volume

injected.

Next. I just want to point out one thing

here. Most of the stuff I have already alluded to.

But in terms of duration of effect, I've heard some

talk about the treatment worked, and then it lost its

effect early on.

This study again was not designed to be a

study in which we evaluate duration of effect of time

to treatment failure. This was designed to look at

the comparability between Zyplast and Hylaform at 12

weeks in a non‑inferiority paragon. And we met that

endpoint.

And so, again, in the last bullet there,

I think most of the people who have taught me

statistics tell me that multiple post hoc looks at

this at four weeks and eight weeks really are

statistically problematic.

Next. A final point about this, not so

much the duration of effect, but it works back to the

efficacy issue, is the nasolabial fold, as I

mentioned, I believe, is the worst case, as my

colleagues have been teaching me, and that the

duration of correction might be expected to be shorter

than in other locations with previously studied

fillers.

I think there are a lot of caveats. There

is a lot of stuff around this trial that just goes

beyond the statistical that I believe should be taken

into consideration, the least of which is previously

clinical studies and post‑market experience.

Next. Now with respect to skin types, we

have heard a lot this afternoon regarding the lack of

exposure of patients of color to this particular

intervention. I will remind the group that 20 percent

of the study population was people of color. It was

comparable efficacy between those two groups,

comparable safety profile, and no occurrences of

hypertrophic scars, or keloid formation and no hyper

or hypopigmentation.

Dr. Holmdahl pointed up that the ethnic

makeup reflected the target population. And, finally,

I believe that Inamed, who is our partner in this

regard, has 20 years of successful experience in

dealing with dermal fillers in diverse populations.

Finally, Hylaform is a clear gel. It's

not opaque. And it might be expected to be neutral

with respect to implantation in people of color.

Next slide. Many different types of

wrinkles have been tested in the U.S. and the Swedish

study that I presented in my part of the presentation.

We have focused on the nasolabial fold.

Again, we did that for a particular

reason. And so if we think that we're not inferior to

Zyplast, we would expect that the degree of correction

would be equivalent in other areas and equivalent to

how Zyplast works in practice.

Finally, with repeat treatment, our

feeling is that we did this primarily to look at

repeat exposure. So, again, patients who had been

randomized to the Hylaform arm at 12 weeks were asked

whether or not they wanted to re‑enroll in the repeat

treatment phase. And we have significant safety data

at four weeks after repeat treatment.

Again, the majority of these adverse

events are likely to occur in the first week. And,

therefore, no further study is indicated at this time

in our opinion. And with repeat treatment, we saw no

increased safety issues and, most importantly to me,

I believe that we have defined no association between

IgG antibody titers to Hylan B and the adverse event.

Then I think my final slide has to do with

the skin tests and that I believe that there have been

a number of people who were at the podium today, Dr.

DeLustro in particular, who have suggested that skin

testing is not predictive of clinical reaction.

HA, again, is biogenetically conserved.

It's not a different protein across all species.

Going back to our Synvisc experience, it's been used

worldwide without a skin test. We don't think it's

immunogenic. Based on this data and the literature,

we do not believe that a skin test pre‑exposure for

Hylaform is indicated.

Thank you for your attention.

ACTING CHAIRPERSON CHANG: Thank you.

At this time I am going to ask Dr. Krause

to read the voting instructions for the panel.

EXECUTIVE SECRETARY KRAUSE: "The medical

device amendments to the Food, Drug, and Cosmetic Act

as amended by the Safe Medical Devices Act of 1990

allows for the Food and Drug Administration to obtain

a recommendation from an expert advisory panel on

designated medical device pre‑market approval

applications that are filed with the agency.

"The PMA must stand on its own merits.

And your recommendation must be supported by safety

and effectiveness data in the application or by

applicable publicly available information.

"Safety is defined in the act as

reasonable assurance based on valid scientific

evidence that the probable benefits to health under

conditions on intended use outweigh any probable

risks.

"Effectiveness is defined as reasonable

assurance that in a significant portion of the

population, the use of the device for its intended use

and conditions of use when labeled will provide

clinically significant results.

"Your recommendation options for the vote

are as follows. Number one, approval. This is if

there are no conditions attached. Number two,

approvable with conditions. The panel may recommend

that the PMA be found approvable subject to specified

conditions, such as physician or patient education,

labeling changes, or a further analysis of the

existing data. Prior to voting, all of the conditions

should be discussed by the panel.

"Number three is not approvable. The

panel may recommend that the PMA is not approvable if

the data do not provide a reasonable assurance that

the device is safe or if a reasonable assurance has

not been given that the device is effective under the

conditions of use prescribed, recommended, or

suggested in the proposed labeling.

"Following the voting, the Chair will ask

each panel member to present a brief statement

outlining the reasons for their vote."

ACTING CHAIRPERSON CHANG: I will

entertain a motion. Dr. LoCicero?

MEMBER LoCICERO: I move non‑approval

until the FDA can clarify issues within the PMA,

specifically this issue concerning the variability

between the live evaluation and independent

evaluation.

MEMBER BLUMENSTEIN: I second it.

ACTING CHAIRPERSON CHANG: Discussion?

(No response.)

ACTING CHAIRPERSON CHANG: Hearing no

discussion, I am going to ask the panel members to

raise their hand if they vote yea, non‑approval. Call

for any years?

(Whereupon, there was a show of hands.)

ACTING CHAIRPERSON CHANG: Dr.

Blumenstein, Dr. LoCicero, Dr. Boykin, Dr. Diegelmann.

No to the motion?

(Whereupon, there was a show of hands.)

ACTING CHAIRPERSON CHANG: Dr. Halsey, Dr.

Miller, Dr. Newburger, Dr. Olding, Dr. Doull.

The motion is defeated. I will entertain

another motion. There were no abstentions. The

motion for non‑approval has been defeated. And I will

entertain another motion. Dr. Halsey?

MEMBER HALSEY: I move that the product be

approved with conditions.

MEMBER OLDING: Second.

ACTING CHAIRPERSON CHANG: Second by Dr.

Olding. Open the floor to discuss and the

recommendation for such possible PMA approval with

conditions. Dr. Halsey?

MEMBER HALSEY: I would ask the agency to

require some assessment of avian protein allergy in

patients before they are treated. And I am not

specifying what that need be. It could be decided

later with the agency's consultants.

ACTING CHAIRPERSON CHANG: Again, just to

repeat that again, you would ask as a condition that

the sponsor ask or ‑‑

MEMBER HALSEY: That the directions for the

use of the treatment be limited to those that pass an

assessment of allergy; in other words, that are not

allergic to the drug.

ACTING CHAIRPERSON CHANG: Could I suggest

an assessment of possible hypersensitivity to avian

products? Is that your intent?

MEMBER HALSEY: To avian products, yes.

ACTING CHAIRPERSON CHANG: Is there a

second to this condition?

MEMBER MILLER: I just have a question

about your proposal. Are you suggesting that we

require a test or as a simple screening people for

those who deny a history of sensitivity to avian

products? Is that adequate?

MEMBER HALSEY: I decided we should give

the FDA some latitude to develop a policy on that. It

could be historical, as was done in the clinical

trial, or it could be a blood test or it could be a

skin test of avian proteins. I would like to not have

to specify at this time.

MEMBER MILLER: I'll second that.

ACTING CHAIRPERSON CHANG: Seconded by Dr.

Miller. Comments, please?

(No response.)

ACTING CHAIRPERSON CHANG: I would like a

show of hands. The proposed condition states that the

sponsor as a condition of approval of this PMA, that

there be some assessment of potential of

hypersensitivity reaction to avian products. May I

have a show of hands for those who would vote yes for

this proposed condition?

(Whereupon, there was a show of hands.)

ACTING CHAIRPERSON CHANG: Dr. Halsey, Dr.

Diegelmann, Dr. Newburger, Dr. Miller.

May I have by a show of hands those who

would say no to imposing this condition? All votes

for no?

(No response.)

ACTING CHAIRPERSON CHANG: May I ask those

who have abstained to please raise your hand?

(Whereupon, there was a show of hands.)

ACTING CHAIRPERSON CHANG: Dr. Olding, Dr.

Doull, Dr. Blumenstein, Dr. Boykin, Dr. LoCicero.

Motion passes. So this one condition is

an assessment for hypersensitivity to avian products.

Dr. Miller?

MEMBER MILLER: I would like to move for

three additional conditions.

ACTING CHAIRPERSON CHANG: Can we just do

one at a time, please? You are certainly welcome to

bring one up. And we will discuss and move on, then.

MEMBER MILLER: I would propose that we

have an assurance of a physician qualification and

education prior to use of this product as a condition.

ACTING CHAIRPERSON CHANG: The motion is

that physician education be incorporated as a

condition for approval. Is there a second?

MEMBER NEWBURGER: Seconded.

ACTING CHAIRPERSON CHANG: Seconded by Dr.

Newburger. Comments?

(No response.)

ACTING CHAIRPERSON CHANG: May I have a

show of hands, please, for those who would accept this

proposal as a condition?

(Whereupon, there was a show of hands.)

ACTING CHAIRPERSON CHANG: Dr. Olding, Dr.

Doull, Dr. Halsey, Dr. Newburger, Dr. Miller.

By show of hands, those who would vote no

for this condition?

(No response.)

ACTING CHAIRPERSON CHANG: Please by a

show of hands, those who would abstain from this

condition?

(Whereupon, there was a show of hands.)

ACTING CHAIRPERSON CHANG: Dr.

Blumenstein, Dr. Boykin, Dr. Diegelmann, Dr. LoCicero.

Five.

The motion passes to incorporate physician

education as a potential condition for PMA approval.

Further comments or recommendations? Dr.

Miller, did you have a second condition you had in

mind?

MEMBER MILLER: Yes. I think that the

labeling needs to state that its use in people of

color if I could just say similar to the one we

suggested this morning. I don't remember the words,

but I liked the words.

MEMBER OLDING: I could read it if you

want it.

MEMBER MILLER: Could you, please? Thank

you.

MEMBER OLDING: "Limited controlled

clinical study data are available regarding the use of

Hylaform in patients with skin types V and VI on the

Fitzpatrick scale and individuals of color" or "people

of color."

ACTING CHAIRPERSON CHANG: Do I have a

second to this motion?

MEMBER OLDING: I'll second it.

ACTING CHAIRPERSON CHANG: Dr. Olding

seconds. Is there a discussion?

(No response.)

ACTING CHAIRPERSON CHANG: Hearing none,

I would like those who would be in favor of this

proposed condition to state in the labeling that there

is limited controlled clinical data available for use

of this device for persons of color or those in the

Fitzpatrick V or VI category. All of those in favor,

please raise your hands.

(Whereupon, there was a show of hands.)

ACTING CHAIRPERSON CHANG: Dr. Olding, Dr.

Doull, Dr. Halsey, Dr. Diegelmann, Dr. Newburger, Dr.

Miller.

Opposed?

(No response.)

ACTING CHAIRPERSON CHANG: Those

abstaining, please raise your hands?

(Whereupon, there was a show of hands.)

ACTING CHAIRPERSON CHANG: Dr.

Blumenstein, Dr. Boykin, Dr. LoCicero.

Motion passes.

Dr. Miller?

MEMBER MILLER: I would like to move that

there also be a post‑approval study involving people

of color to assess the efficacy and safety in that

population.

MEMBER NEWBURGER: I second that.

ACTING CHAIRPERSON CHANG: And again?

Just repeat it one more time.

MEMBER MILLER: Yes. I would like to

propose that there be a post‑approval study in people

of color to determine safety and efficacy of this

product in that population.

ACTING CHAIRPERSON CHANG: Seconded by Dr.

Newburger. Open to discussion or comment by the

panel?

(No response.)

ACTING CHAIRPERSON CHANG: We will take a

vote. All of those in favor of the proposed condition

requesting the sponsor to conduct a post‑approval

study for determining and demonstrating efficacy and

safety for persons of color, please raise your hands.

(Whereupon, there was a show of hands.)

ACTING CHAIRPERSON CHANG: Dr. Olding, Dr.

Doull, Dr. Boykin, Dr. Diegelmann, Dr. Newburger, Dr.

Miller.

All of those opposed?

(No response.)

ACTING CHAIRPERSON CHANG: All of those

abstaining, please raise your hands?

(Whereupon, there was a show of hands.)

ACTING CHAIRPERSON CHANG: Dr.

Blumenstein, Dr. Halsey, Dr. LoCicero.

The motion passes.

Dr. Miller, any further recommendation?

(No response.)

ACTING CHAIRPERSON CHANG: Dr. Newburger?

MEMBER NEWBURGER: I move that there be a

post‑marketing requirement for a study to document the

safety of repeated use with this device and that ‑‑

well, I guess that's separate ‑‑ that the labeling

show that this device is approved on the basis of data

from one use.

Does that have to be two separate motions?

ACTING CHAIRPERSON CHANG: No. May I

paraphrase that you were suggesting that the labeling

suggest that clinical prospective studies have

demonstrated the safety and efficacy for one‑time use?

MEMBER NEWBURGER: Okay.

ACTING CHAIRPERSON CHANG: With no mention

of repeated uses?

MEMBER NEWBURGER: If that's how the FDA

would phrase it.

ACTING CHAIRPERSON CHANG: I think they

can work with the sponsor with that. The concern is

that the 12‑week data reflects safety issues regarding

one‑time use. Is that correct?

MEMBER NEWBURGER: And I would like to

request that there be a post‑approval study showing