UNITED STATES OF AMERICA
FOOD AND DRUG ADMINISTRATION
CENTER FOR DEVICES AND RADIOLOGICAL HEALTH
MEDICAL DEVICES ADVISORY COMMITTEE
GENERAL AND PLASTIC SURGERY DEVICES PANEL
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NOVEMBER 21, 2003
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The panel met at 8:00 a.m. in the
Walker/Whetstone Rooms of the Gaithersburg Holiday
Inn, Two Montgomery Village Avenue, Gaithersburg,
Maryland, DR. PHYLLIS CHANG, Acting Chairperson,
PHYLLIS CHANG, M.D. Acting Chairperson
GRACE T. BARTOO, Ph.D., R.A.C. Industry
BRENT A. BLUMENSTEIN, Ph.D. Voting Member
JOSEPH V. BOYKIN, JR., M.D. Temporary Voting
ROBERT F. DIEGELMANN, Ph.D. Temporary Voting
JOHN DOULL, Ph.D., M.D. Temporary Voting
LeeLEE DOYLE, Ph.D. Consumer
JOHN F. HALSEY, Ph.D. Temporary Voting
JOSEPH LoCICERO III, M.D. Voting Member
MICHAEL J. MILLER, M.D. Voting Member
AMY E. NEWBURGER, M.D. Voting Member
MICHAEL J. OLDING, M.D. Temporary Voting
ON BEHALF OF Q‑MED:
N. FRANKLIN ADKINSON, JR., M.D.
BENGT AGERUP, Ph.D.
GARY JANSSON, Ph.D.
JAMES LEMAN, M.D.
Z. PAUL LORENC, M.D., F.A.C.S.
KJELL RENSFELDT, M.D.
JUR STROBOS, M.D.
SUSAN C. TAYLOR
ROXOLANA HORBOWYJ, M.D.
TELBA IRONY, Ph.D.
DAVID KRAUSE, Ph.D.
CELIA WITTEN, Ph.D., M.D.
AGENDA ITEM PAGE
Call to Order 5
Conflict of Interest, Temporary Voting Member 6
Deputization and Opening Remarks
David Krause, Ph.D., Executive Secretary
Update Since Last Meeting 13
CDR Stephen Rhodes, Branch Chief, Plastic and
Reconstructive Surgery Devices Branch
Open Public Comments 16
Elizabeth Santoro 16
Dr. N. J. Lowe 20
Applicant Presentation, Q‑Med AB, Restylane 27
Jur Strobos, M.D., Council to Medicis 27
Bengt Agerup, CEO, Q‑Med AB 27
James Leyden, M.D., Professor of Dermatology, 30
University of Pennsylvania School of Medicine
Paul Lorenc, M.D., Assistant Professor of 52
Plastic Surgery, New York University Medical
Susan C. Taylor, M.D., Director, The Skin of 66
Color Center, St. Luke's‑Roosevelt Hospital
FDA Presentation 127
Introduction and Preclinical 127
Anthony D. Watson
Clinical Review 133
Roxolana Horbowyj, M.D.
Statistical Review 151
Telba Irony, Ph.D. 151
Panel Deliberations and Address FDA Questions 159
AGENDA ITEM (Continued) PAGE
Open Public Comments 188
Arnold W. Klein, M.D. 188
Jill Follows 196
Dr. Trevor Born 201
Concluding Panel Deliberations and Vote 214
CALL TO ORDER
EXECUTIVE SECRETARY KRAUSE: All right.
Good morning. We are going to be running on a fairly
tight schedule today. So I would like to try to get
the meeting started as soon as possible. If everybody
could please have a seat? Thank you.
Good morning, everyone. We're ready to
begin this, the 64th meeting of the General and
Plastic Surgery Devices Panel. My name is David
Krause. I am the Executive Secretary of this panel.
I'm also a biologist and a reviewer in the Plastic and
Reconstructive Surgery Devices Branch.
I would like to remind everyone that
you're requested to please sign in on the attendance
sheets, which are just outside the door. At that
table out there, you can also pick up an agenda, a
roster of the panel members, and information regarding
today's meeting. The information includes how to find
out about future meeting dates through the advisory
panel phone line and how to obtain meeting minutes or
I don't know if everybody knows, but the
FDA normally posts the transcript of these meetings
within about two or three weeks after the meeting on
our Web site. So you can get them there.
CONFLICT OF INTEREST, TEMPORARY VOTING MEMBER
DEPUTIZATION AND OPENING REMARKS
EXECUTIVE SECRETARY KRAUSE: Before
turning this meeting over to Dr. Chang, I am required
to read two statements into the record. The first
statement that I read is the deputization of temporary
voting members. And the second is the conflict of
I am going to read the deputization
statement first, "Pursuant to the authority granted
under the Medical Devices Advisory Committee charter
dated October 27, 1990 and as amended on August the
18th, 1999, I appoint Joseph Boykin, Robert
Diegelmann, John Doull, John Halsey, and Michael
Olding as voting members of the General and Plastic
Surgery Devices Panel for this meeting on November 21,
2003. In addition, I appoint Phyllis Chang, a voting
member, to act as temporary chair for the duration of
"For the record, these individuals are
special government employees and consultants to this
panel or other panels under the Medical Device
Advisory Committee. They have undergone the customary
conflict of interest review and have reviewed the
material to be considered at this meeting." This memo
is signed by Dr. David Feigal, who is the Director,
Center for Devices and Radiological Health.
The second statement that I read into the
record is the conflict of interest statement, "The
following announcement addresses conflict of interest
issues associated with this meeting and is made a part
of the record to preclude even the appearance of an
impropriety. To determine if any conflict existed,
the agency reviewed the submitted agenda for this
meeting and all financial interests reported by the
"The conflict of interest statutes
prohibit special government employees from
participating in matters that could affect their or
their employers' financial interests. However, the
agency has determined that participation of certain
members and consultants, the need for whose services
outweighs the potential conflict of interest involved,
is in the best interest of the government.
"We would like to note for the record that
the agency took into consideration certain matters
regarding Drs. Diegelmann, Halsey, and Miller. Each
of these panelists reported current and/or past
interest in firms at issue but in matters not related
to today's agenda. The agency has determined,
therefore, that they may participate fully in today's
"In the event that the discussion involves
any other products or firms not already on the agenda
for which an FDA participant has a financial interest,
the participants should excuse him or herself from
such involvement, and the exclusion will be noted for
"With respect to all other participants,
we ask in the interest of fairness that all persons
making statements or presentations disclose any
current or previous financial involvement with any
firm whose products they may wish to comment upon."
I would also like to remind anyone who has
a cell phone to please put that cell phone on some
kind of a silent mode so we don't hear phones ringing
At this point I would like to turn the
meeting over to Dr. Chang.
ACTING CHAIRPERSON CHANG: Good morning.
My name is Dr. Phyllis Chang, and I am the acting
panel chair for this session. I am an associate
professor in the Department of Surgery and staff
surgeon, plastic surgeon, and hand surgeon in the
Department of Surgery and Orthopedic Surgery at the
University of Iowa Carver College of Medicine.
Today the panel will be making
recommendations to the Food and Drug Administration on
two pre‑market approval applications. The next item
of business is to introduce the panel members who are
giving of their time to help the FDA in these matters
and the staff here at this table.
I am going to ask each person to introduce
him or herself, stating his or her area of expertise,
position, title, institution, and his or her status on
the panel, whether voting member, industry or consumer
representative, or deputized voting member. I would
like to begin with Dr. Witten on my far right. And
then let's please go around the table.
DR. WITTEN: I'm Dr. Celia Witten with
FDA. I'm the division director of the reviewing
division for these products.
MEMBER LoCICERO: I'm Joseph LoCicero.
I'm professor and chair of the Department of Surgery
at the University of South Alabama. I'm a thoracic
surgeon by training. And I'm a voting member of the
MEMBER MILLER: I'm Michael Miller. I'm
a professor of plastic surgery at the University of
Texas, M. D. Anderson Cancer Center. I do clinically
primarily cancer reconstructive surgery. And I am a
voting member of the panel.
MEMBER NEWBURGER: I'm Amy Newburger. I'm
director of Dermatology Consultants of Westchester,
which is a private practice in dermatology in
Scarsdale, New York. I teach at St. Luke's Roosevelt
Hospital Medical Consortium. I am a voting member of
MEMBER DIEGELMANN: I'm Robert Diegelmann.
I'm a professor of biochemistry at the Medical College
of Virginia, Virginia Commonwealth University in
Richmond, Virginia. My specialty is in the area of
tissue repair. And I'm a deputized member of the
MEMBER BOYKIN: Dr. Joseph Boykin,
clinical assistant professor of plastic surgery at the
Medical College of Virginia in Richmond and also the
medical director of the Wound Healing Center Retreat
Hospital. I'm a deputized voting member. And areas
of interest are wound healing, reconstructive and
cosmetic plastic surgery.
MEMBER HALSEY: John Halsey. I'm the
owner and director of IBT Reference Lab, a clinical
immunology laboratory and a contract research facility
in the areas of allergy and immunology. I'm also
chair of the Clinical Laboratory Immunology Committee
for the American Academy of Allergy, Asthma and
Immunology and a member of the Immunology Devices
MEMBER BLUMENSTEIN: I'm Brent
Blumenstein. I'm a biostatistician. I had my own
company, TriArc Consulting, out of Seattle. And I am
a voting member.
MEMBER DOULL: I'm John Doull. I'm a
clinical toxicologist from the University of Kansas.
I'm a deputized member.
MEMBER OLDING: Michael Olding. I'm chief
of the Division of Plastic Surgery, George Washington
University, associate professor at that institution.
And I am a deputized voting member.
MEMBER DOYLE: I'm LeeLee Doyle. I'm
professor emeritus of obstetrics and gynecology. I'm
the associate dean for continuing medical education
and faculty affairs at the University of Arkansas for
Medical Sciences College of Medicine. I am the
consumer representative, which is a nonvoting
position, on this board.
MEMBER BARTOO: Finally, I'm Grace Bartoo.
I'm the vice president of clinical and regulatory
affairs at a company called Instruments for Science
and Medicine, which is a small consulting firm to the
biomedical device industry. My expertise is in
biomedical engineering and software development. And
I'm the industrial representative, which is a
ACTING CHAIRPERSON CHANG: Thank you.
I would like to note for the record that
the voting members present constitute a quorum, as
required by 21 CFR Part 14.
Now I would like to introduce Commander
Stephen Rhodes, the branch chief of the Plastic and
Reconstructive Surgery Devices Branch, who will update
the panel since the last meeting.
CDR RHODES: Thank you, Dr. Chang.
UPDATE SINCE LAST MEETING
CDR RHODES: I am the branch chief here at
the Plastic and Reconstructive Surgery Devices Branch.
My update today will be brief since this panel last
met about five weeks ago to discuss a PMA for a
silicone gel‑filled breast implant, which the FDA is
still reviewing the recommendations from the panel for
Today we are going to be talking about two
wrinkle products. In the morning, we will be
discussing a product called Restylane from Q‑Med and
in the afternoon a product called Hylaform from
I want to extend my appreciation to you
for your participation. I also want to thank the
public speakers, who have chosen to elect to speak in
the public sessions and also the two companies who are
going to be presenting their safety and effectiveness
data in their PMAs.
That concludes my update. Thank you very
ACTING CHAIRPERSON CHANG: Thank you,
We will now proceed with the open public
hearing session of this meeting. All persons
addressing the panel are asked to speak clearly into
the microphone as the transcriptionist is dependent on
this means of providing an accurate record of this
Both the Food and Drug Administration and
the public believe in a transparent process for
information gathering and decision‑making to ensure
such transparency at the open public hearing session
of the advisory committee meeting.
FDA believes that it is important to
understand the context of an individual's
presentation. For this reason, the FDA encourages
you, the open public hearing speaker, at the beginning
of your written or oral statement to advise the
committee of any financial relationship that you may
have with the sponsor; its product; and, if known, its
For example, this financial information
may include the sponsor's payment of your travel,
lodging, or other expenses in connection with your
attendance at the meeting. Likewise, FDA encourages
you at the beginning of your statement to advise the
committee if you do not have any such financial
relationships. If you choose not to address this
issue of financial relationships at the beginning of
your statement, it will not preclude you from
We will start with those individuals who
have notified the FDA of their intent to testify
during the open public session. Is Elizabeth Santoro
present? Please come to the microphone and make any
disclosures that you wish.
OPEN PUBLIC COMMENTS
MS. SANTORO: Good morning. My name is
Elizabeth Santoro. I'm a registered nurse and also
have a Master of Public Health with a concentration in
health policy. In addition, I'm a health policy
fellow at the National Center for Policy Research for
Women and Families.
This morning I will be reading the
testimony of our president, Dr. Diana Zuckerman, who,
regretfully, could not be here today. Please note
that I am waiving my testimony for her. She has no
conflicts of interest. Neither do I.
Our center is a think tank that translates
research findings into meaningful information for the
public. We use that research information to advocate
for policies to benefit the health and safety of
women, children, and families.
It is clear that both women and men alike
search for the Fountain of Youth. We know that these
products are used widely. And that's why they should
be carefully studied. They should be approved if they
are safe and effective.
Of course, it's difficult to make this
statement before the data are presented, but based on
what was made available by the FDA yesterday on their
Web site, these are our concerns. Our main concern
about Restylane is the lack of data for African
Americans and Asian Americans. Only two of the
patients are African American, and only two are Asian
Research clearly shows that African
Americans are more likely to produce keloids and can
respond differently to procedures involving the skin.
In addition, African Americans are more likely to
develop autoimmune diseases than white women. The
company has not studied a reasonable number of African
Americans or Asian Americans to approve the product
for those populations.
Our center has joined with the National
Medical Association to express our very strong
concerns on this issue to the FDA commissioner. It is
a great concern for all of the products of this type,
not just the products under review today.
The FDA has suggested one solution:
post‑market studies. We strongly believe it is not
appropriate to require studies for minority
populations on a post‑market basis since the FDA has
no authority to enforce these requirements. The
company should be required to do the studies before
the product is approved.
It is also inappropriate to label the
product "For whites only." I am sure that I am not
the only person in the room who believes that it would
be inconsistent with the values of our country to
approve products only for white people unless there
was a compelling reason; for example, if a product was
found to be safe for whites but unsafe for other
racial or ethnic groups.
Such a label is not an appropriate way
around a sponsor's failure to conduct research on
people of color. Moreover, if there are no data on
people of color, it is likely that the product will be
used off label by them anyway. And that could be
potentially very dangerous. Research is needed. And
it won't take long to do it. And it should be done.
Another shortcoming on the research on
Restylane is the relatively small sample size. The
sample starts with only 138 people. And only 125 are
still in the study after 12 months. Since this is a
cosmetic procedure that is likely to be used by
hundreds of thousands, perhaps millions of people, the
product should be tested on a larger sample to
determine if there are rare adverse reactions that are
serious enough to be considered before approval.
Our final concern is a lack of long‑term
follow‑up and a lack of research on women who undergo
the procedure multiple times. It is clear from
published reports that women who have a good outcome
the first or second time they use this product may
have serious adverse reactions after the third or
later procedure. This needs to be studied before
approval since it is clear that their product will be
used more than once or twice.
We would like to make a final comment
about the risks and benefits of this product.
According to the company's own data, the product is
not necessarily better than the comparison product
Zyplast. For that reason, we believe rushing this
product to market without gathering the additional
data listed above is unwarranted.
ACTING CHAIRPERSON CHANG: Thank you, Ms.
And now is Dr. Lowe present?
DR. LOWE: Yes. Good morning. Thank you
to the FDA for allowing me to present some
I am clinical professor of dermatology at
UCLA, but I also have private practices in London and
Santa Monica and also research, clinical research,
I am presenting experience with the
Hylaform and Restylane products, particularly since
1996, in my London practice. It's that data that I
wish to present this morning.
Essentially in Europe, certainly in the
U.K., Restylane has become the most widely used
hyaluronic acid filler in the United Kingdom. And, as
we will shortly see, I think that I will show reasons
I wrote a publication published in the
Journal of the American Academy of Dermatology that
was published in the year 2001 in which we looked at
over 700 patients that had received both Hylaform and
Restylane. We found that there was an approximate .4
percent incidence of delayed nodular inflammatory
reactions in the skin. And we followed up by testing
some of those individuals with forearm skin test
challenge and finished up by getting positive results
in some of those patients.
Since the year 2000, here are my slides.
Actually, we can go through them a little bit quickly.
As I say, I'm a consultant dermatologist and faculty
member in London as well as at the University of
California in Los Angeles and have practices and
clinical research units in both places.
ACTING CHAIRPERSON CHANG: Dr. Lowe, would
you be willing to share with the panel whether or not
the sponsor has supported your travel?
DR. LOWE: Yes. This is my slide. And I
want to disclose conflicts of interest in two areas.
One is my research site in Santa Monica was one of the
research sites for the Hylaform product. And that was
funded by Genzyme.
And I have received educational grants
from both Medicis and Q‑Med. And Medicis has enabled
us to do some recent research studies on our U.K.
patients and has allowed me the funding to be here
this morning. So I make those disclosures.
This was a summary of our Journal of the
American Academy of Dermatology report, where we
found, as I said, with the old Restylane, which was
modified in the year 2000, and with Hylaform, we found
an incidence of about .4 percent delayed nodular
In a total of six patients, three of
others that were referred to me, we found that four
patients actually I was able to elicit positive
forearm testing. This is published in that article.
Since the year 2000, I have changed almost
entirely over to using Restylane products in the
United Kingdom for skin‑filling scar revision and
other deformity‑filling for the reason that it is a
non‑animal hyaluronic acid.
And there was considerable improvement in
the formulation in the year 2000 with a considerable
reduction in protein load. So the actual numbers of
patient treatments that we have been able to review in
a chart and case review from 2000 to 2003 is 1,537
I acknowledge my coworkers, my dermatology
colleague, Dr. Anne Maxwell; my plastic surgical
colleague, Mr. David Ross. So we have 1,537 patients
that we have been able to review charts and cases of,
1,537 treatments in a total of 558 patients. So, as
you can see, many of those patients received,
actually, at least three or more injections, some up
to five or six injections, some one or two injections.
The demographic grouping was preferences.
We got far more females than males. And I didn't have
the breakdown of racial or ethnic subsets, but
significant numbers of these patients were Asian and
some black patients as well.
Age range was 22 to 28. And with a review
of these 1,537 patient treatments, we found with the
new formulation of Restylane zero incidence of
This somewhat is reinforced. This is the
old data with the old Restylane and present Hylaform.
You can see the old data presented here again. This
is the new formulation Restylane, Perlane. And there
was a previous manuscript by Friedman, et al.,
published last year in one of the derm surgery
journals that showed an incidence of about one in a
thousand hypersensitivity reactions.
So the adverse reactions that we saw in
the 1,537 patients that we reviewed, 1,537 patient
treatments in 558 patients that we reviewed.
MEMBER OLDING: Excuse me. I hate to
interrupt you, but your slide said one in 5,000, I
believe, and you said one in 1,000.
DR. LOWE: I apologize. The correction is
one in 5,000. Thank you.
The adverse events in the group of
patients that we have recently looked at is that we
find common immediate erythema, which is clinically
not of great significance and usually results in a
matter of one to two days.
ACTING CHAIRPERSON CHANG: Dr. Lowe, could
you please summarize?
DR. LOWE: I will. This is my last slide.
Edema common with Perlane, which is the thicker one,
transient lumping, and one technique‑dependent
vascular occlusion in the forehand. This is the sort
of delayed reactions that we see, nodular painful
reactions in this instance with Hylaform.
My final slide is that the delayed allergy
risk with Restylane products is extremely rare. We
found no allergy in 1,537 patient patients in 558
Previous reactions observed with the old
form of Restylane was less severe than that observed
with Hylaform. All the hyaluronic acid reactions
observed were less severe than with the
And, in conclusion, Restylane, Perlane
products are the most frequently used hyaluronic acid
fillers in the United Kingdom.
Thank you for your attention. And I
apologize for the problems with the computer.
ACTING CHAIRPERSON CHANG: I would like to
thank all of you for taking time of your schedules to
testify to this panel.
I would like to remind public observers at
this meeting that while this portion of the meeting is
open to public observation, public attendees may not
participate except at the specific request of the
We are now ready to begin with the
APPLICANT PRESENTATION, Q‑MED AB, RESTYLANE
DR. STROBOS: Hi. My name is Jur Strobos.
I'm a physician. I change as a general surgeon. And
I am working as a consultant to the pharmaceutical
industry and today for Medicis and Q‑Med.
We are going to try and stick to pretty
much the schedule that you have laid out there. For
some reason, not all of our speakers got on the
agenda. We are going to have Dr. Agerup as the CEO of
the company and inventor of the product as well as
four physicians to the clinical investigators
discussing the product. And I will introduce them as
we go through.
We did time the talk yesterday, and I
think we are going to try and keep it to 45 minutes.
I understand that would be about 30 minutes for
That said, let me introduce Bengt Agerup,
who is the president, CEO, and inventor of the
DR. AGERUP: Good morning. It's a
pleasure and honor to be here. What we have designed
when we designed the Restylane is a product that would
reduce immunogenicity. That means it would not be
based on foreign proteins or have too much protein
contaminants. And they are also, of course, nontoxic.
And we would refrain from using animal‑origin
substances. So, for instance, rooster combs, bovine
collagen, et cetera, were not an origin. We also
wanted to decrease the esterase and protease‑mediated
degradation. That always happens in the skin.
So we used biotechnology to derive
hyaluronic acid, a non‑animal source. And we used the
purification process that we even increased in
efficacy in 1999 that you heard this morning to reduce
the protein contaminants. We are now down to less
than six parts per million, and we are still working
on this subject.
We don't have any animal nucleic acids.
And we think this is the first or it is the first
dermal filler that is not classified as a
Hyaluronic acid is completely useless as
an implant unless you modify it. We have chosen
modification products that are commonly used in
household articles and also in glues and other things,
We also use this BDDE in ether form of
binding that makes it very stable and less sensitive
to esterase. We also patented a way to use these BDDE
cross‑links at very, very low concentrations. So, for
instance, it's about one percent of the material used.
So that leaves very small amounts of BDDE in the final
So this is non‑animal. Then we call this
non‑animal stabilized hyaluronic acid. And we call it
stabilized because it's not really cross‑linked in a
way that you would normally find in modified products.
I thank you very much for your attention.
DR. STROBOS: Now I would like to
introduce Dr. James Leyden, who is a professor of
dermatology from the University of Pennsylvania. He
was one of the investigators in the pivotal study. He
is going to present the data from the pivotal study.
DR. LEYDEN: Thank you. Good morning. My
name is Jim Leyden. I am now professor emeritus,
actually, at the University of Pennsylvania. I've
been a member of the department since 1967, I guess,
had a wide range of interests. About 20 percent of my
research interest has been in appearance‑related
I have been asked by Medicis to present
the data from the multi‑centered clinical trial, of
which I was one of the investigators.
As far as my connections with Medicis, I
am not a consultant. I don't own any stock. I have
participated in some studies several years ago,
microbiologic studies. I have also served on advisory
Perhaps my major connection is that I am
a co‑chair of the clinical conference called the
Valley of the Sun, which preexists Medicis in how long
that meeting has been going on. But because Medicis
is in the Valley of the Sun, they have been a major
supporter of our annual conference.
So, with that introduction, I would like
to present to you the results of this randomized,
double‑blind, multi‑centered comparison of the safety
and efficacy of Restylane and Zyplast.
It was a six‑center study. There were
plastic surgeons and dermatologists involved. Each
center had a treating physician and then a blinded
This is the design of the protocol. As I
said, it's multi‑centered. It was a
patient‑controlled kind of study in which each patient
received both Restylane and Zyplast. It was
randomized by side and blinded to the patient as well
as to the evaluating dermatologist. And in the
evaluation, a validated wrinkle severity score that we
will discuss a little bit in a few minutes was used.
Patients were basically recruited and
tested with collagen and then randomized as far as
which eye got Zyplast and which eye got Restylane.
And then there was a period of time when both the
patient and the treating physician would decide when
optimal correction was achieved and there was the
opportunity for so‑called touch‑up injections to
whatever side seemed not to be optimally corrected.
Once that was stabilized for two weeks,
they were launched into the evaluation phase and seen
at two, four, and six months. At this point, patients
had the opportunity to enroll in an open label
extension, where they would receive Restylane. Most
of the patients, in fact, did enroll in that open
label portion of the study.
These are the demographics. As you can
see, as was pointed out in the open session, these
were predominantly white women, as you see here. You
will hear later about a study that Medicis is going to
do, will do in African Americans in America.
Contrary to what was said in the open
session, there actually is an extensive experience in
other populations. There is extensive experience in
Asia and in South America. But definitely a study in
African Americans is indicated and, as I say, will be
Now we get into the wrinkle severity
rating scale, as you can see here, is a one to five,
with one being basically the ideal situation with no
visible nasolabial fold or wrinkling, ranging up to a
very severe form, which even after stretching the
skin, you still had roughly a two to four‑millimeter
visible groove. This scale was developed in
cooperation with the FDA; validated; ‑‑ and we will
discuss that in a second ‑‑ and, in fact, has been
submitted for publication.
Just to give you some ideas of what these
scales look like, here on the one side, you can see
sort of a mild grade two. Here is another individual
and another. These are grade scores two, a little
more intense here with three, another three there,
another three, and then more severe forms here. You
can see that even when you stretch the skin back,
there is still a prominent groove in the nasolabial
area and another four and another.
Now, before the study began, there was a
validation study. There were five investigators who
looked in 2 sessions separated by I believe a week,
looked at 30 photographs of individuals ranging with
different severity of nasolabial grooving. We have
displayed it here this way, and we take a second to go
through this because the same kind of chart will
appear when we look at the six‑month primary efficacy
If you look here, you see the session two
with grades one through five and session one with
grades one through five. And if you go down this
diagonal, sort of light green, those are the times
when the scores were identical.
And you can see that for the left and the
right, there was a high degree of concordance, in the
range of 70 percent. And here is the kappa ratio,
kappa coefficient. The yellow represents where there
And you can see that basically all of the
scores were either equal or within one grade of each
other. There was no instance of a wider discrepancy.
MEMBER LoCICERO: Excuse me. Could you
define who the observers are?
DR. LEYDEN: They were five of the
investigators in the study.
MEMBER LoCICERO: Were they blinded to who
these patients were?
DR. LEYDEN: These weren't patients.
These were photographs. This was before the studies.
They were looking at photographs similar to the kinds
of photographs I showed you initially. So they didn't
know who they were if that's what you're getting at.
Now, here is the primary efficacy analysis
using the same kind of chart. This is the comparative
change in wrinkle severity score at the six‑month
period in the so‑called intent‑to‑treat population.
That means everybody who got launched. Those who were
lost to follow‑up were counted basically as no change
from baseline, which weighs against any effect for
So we have the change in severity rating
scale. A plus three would mean that a patient went,
for example, from a four to a one. Two would be, say,
from a three to a one or a four to a two. And this is
for Restylane. And this would be for Zyplast.
Now, again, if you look down the diagonal
in this sort of grayish zone, that's when there was
equivalent grade given on both sides. Anything above
this line, Restylane, had a better score that Zyplast.
And anything on the lower end of this diagonal,
Zyplast, had a better score, rating score, than
I think you can see a lot more numbers up
here than there are here. And down here we have
summarized that, the Restylane side, with one grade or
more improvement compared to the Zyplast side. There
were approximately whatever that is, 57 percent. And
equivalent grades were given in approximately a third
and then nine and a half percent on the Zyplast side.
There was a better score, a higher score, than was
seen on the Restylane side. These differences were
statistically significant by a variety of analysis, as
Now, in the information that was submitted
to the panel that I saw and in some of the slides from
the FDA that I saw, there are a few issues that I
would like to bring up and discuss. One of them is
that the wrinkle severity score may lack strength at
less than one plus change and that the scoring system
was not revalidated, that the McNemar analysis may
disregard patients with equivalent results and tends
to focus on those results that are discrepant from
equivalency that there wasn't a longitudinal analysis
performed, that there is no evidence of effect beyond
six months, and that incomplete masking raises a
possibility of unmasking and bias. So let's address
Actually, if you look at the data between
the treating physician and the evaluating physician as
far as grading, there is a very high degree of
concordance and correlation and grades given that
exceeds what was seen in the initial validation event.
I think that reflects the fact that this is with live
patients and you can actually stretch the skin and you
can get a better judgment of what is left after
stretching the skin; whereas, in the initial
validation, they were looking at photographs.
Now, as I understand it, the McNemar
analysis does actually account for non‑discrepant
cells in the denominator. The way that type of
analysis is done in the case of Restylane, there are
78 out of 137 that were superior and in the case of
Zyplast, 13 out of 137. So it does take into
consideration the individuals in which there was, in
fact, no difference.
In terms of the superiority, which
obviously is an important issue that you as a panel
have been asked to address as to whether or not the
data shows superiority of Restylane over Zyplast,
there are several things listed here. And then we
will go through an individual slide for each of them.
If you look at the responder rate of
patients with one‑plus or even a more conservative
analysis of a two‑plus improvement at six months after
that initial injection, Restylane is superior
The question has been asked of you if at
the end of 6 months you take all patients into
consideration and look at the difference between the
mean of those 2 groups, the difference is .56. And
the question is, is that mean difference significant,
particularly in consideration of the question that we
just discussed about the strength of the scale in
terms of less than one grade?
Using two types of analysis, both
parametric and non‑parametric, Restylane was superior
statistically to Zyplast. There was a longitudinal
assessment done. And it also showed Restylane
superior to Zyplast.
Then I think importantly, very
importantly, is that patient evaluation also gave
almost the same numbers as the evaluating
dermatologist. Then let's just look at those in a
Here we're looking at the responder rate
of those with a one‑plus or a two‑plus improvement
still present at six months. And you can see that for
the one‑plus, we have a 70 percent for Restylane
versus 32 percent for Zyplast and the much more
conservative, more significant clinical response of
two‑plus improvement still present. Again, there is
more than a three time improvement for Restylane
compared to Zyplast. And both of these are clearly
If you look at the means, as I said, that
mean difference at the end of 6 months was .56. Here
you can see for anybody who is interested the
confidence intervals. But the important point is that
with both parametric paired t‑tests and non‑parametric
signed rank tests, these means are significantly
Here is the longitudinal analysis over
two, four, and six months. You can see as early as
two months. It's not easily seen here, but there are
three crosses there, indicating a .001 significant
difference at this point, out here and here.
I would absolutely agree with the reviewer
that after six months, there is just not enough
information to say anything. So I think up to six
months, there's a lot of information that says that
Restylane is superior to Zyplast, but after six
months, I would agree there is not enough data.
Most of these people basically at the end
of six months said, "Yes, I would like the injection
on both sides." They got the injection, and they
said, "Aloha." And that was it. They really didn't
return. There was a very poor follow‑up.
Here is the patient assessment data using
two things, the relative improvement and wrinkle, as
well as the global improvement. And you can see that
here Restylane is superior to Zyplast, both of them in
the range of 50 to 55 percent and equivalency here and
much lower rate for Zyplast. So the patients agreed
that they got greater improvement with Restylane than
with Zyplast. I think that's important.
Let's get into this issue of masking.
Unmasking, of course, could serve as a signal of
possible unblinding. The evaluators who were involved
in this study tested in writing apparently that they
basically were guessing. They had no idea. They were
I don't think there's any reason to impute
bias. These people have no financial reasons or other
reasons to be biased one way or the other towards
Restylane or Zyplast.
I think an important point in this that is
different than what I have seen at least in one or two
of the slides from the FDA for your afternoon session,
is that, contrary to the study that you're going to be
discussing this afternoon, evaluators were required to
make a forced choice. They did not have the
opportunity to say, "I don't know. I really don't
know." They had to make a choice.
Incidentally, if you remove the
incompletely masked sites at different points, they
vary. It's not the same sites that are always
"potentially unmasked." If you do that and do an
analysis again, you get the same results. So take
that into consideration.
Now let's get into the adverse reactions.
First we'll talk about serious adverse reactions and
then briefly all the emergent events. We will
obviously concentrate mostly on the local events,
particularly the persistent erythema and whether or
not allergic or immunologically driven
hypersensitivity reactions took place.
There really were only two serious adverse
events. There was a patient who had a laminectomy,
another patient who got a pacemaker installed six
months after treatment. It's fairly clear that these
Here is the last of all the things that
come out in the usual studies. The way they're coded,
there are basically 142 that were for collagen and
Restylane that were judged to be related to the
treatment. So we'll be discussing them.
They were captured in two ways. There is
a patient diary during the first 14 days following
that initial injection and launched into the
evaluation period in which patients were encouraged to
write down anything and everything and to try as best
they could to make a judgment as to whether they
thought it was mild, moderate, or severe.
Then, of course, there's the case report
form, where the injecting physician captures
information and reports that historical information
from the patient to capture the entire event and
follow it to its completion. That, as we will be
discussing, is primarily this persistent erythema
So in terms of severe reactions, basically
in the case report form, there were four. And they
were one patient who reported severe events of redness
and swelling on two different days, who then got
followed by the treating investigator until that event
This is a photograph from that patient.
This photograph was taken on 4‑30. You can see that
there are about ten days after 4‑20 when it was judged
to be severe. This is the Zyplast side. We didn't
show you the Restylane side because you can't see
anything in it at 4‑30.
So this shows you how this patient looked
ten days after she personally judged what she saw in
terms of redness and swelling to be severe. I just
show that to show you that that was resolved fairly
quickly and appears to be one of those typical kinds
of things that all of us who have injected patients
over the years with collagen know that some people who
get erythema, just persistent. It's very interesting.
And this brings up that subject of this persistent
Now, here we have listed the sites, all
six sites. These are the number of patients who had
persistent erythema on the Restylane site alone, the
Zyplast site alone, or both. You can see that there
were more with Zyplast in terms of persistent erythema
beyond that 14‑day or 2‑week period following the
initial injection than there was with Restylane, where
there were 6. And there was persistent erythema in
both, which I think speaks to this persistent erythema
as probably more patient‑driven than what was
There are people who get this persistent
erythema. I have some ideas of who they are and why
they are, but perhaps that's for another day. Who
knows? I may be even right.
This is a busy slide, but I think it is an
interesting slide. It portrays all of the persistent
erythemas. The reds are Zyplast. The sort of
green/yellow is Restylane. I think, first of all, you
can see there are more reds. The longest ones are not
the lasting ones, turn out to be Zyplast. You can see
for the most part when it happens, it is somewhere in
the two to three‑month period for most. But then
there are these other ones that just last.
I am going to show you some photographs so
you get a feeling of the quality of these reactions.
First we'll look at this patient at that time point.
Then we'll look at this patient at three time points
and this patient at three time points with the lights
up. This one I guess is a little hard to see, but you
can see this is a two‑month period of this sort of
relatively mild and typical of these persistent
Here is a patient who looks like she could
use the help of some members on this panel. In
addition to being injected here, she could certainly
use some help down here.
Here you can see this reaction, persistent
for a relatively long period of time, several months
you can see here is being judged as moderate. And
then at this point, it's mild. By this point, it's
pretty much gone.
Here's another one that lasted two months.
You can see at this time point it's being judged as
moderate and then mild and gradually goes.
So I think they are fairly representative
of the quality of this persistent erythema that was
seen in these patients, with both, more with Zyplast
than with Restylane but clearly with both.
Now, one of the questions that has been
raised for your consideration is that there is a
significantly greater incidence of events in the
patient diary, moderate to severe, mostly moderate,
particularly for bruising, erythema, and swelling in
the first 14 days. I think that's probably true.
I think that is the experience with the
European studies and others in the literature that
there is a little more acute reaction in the skin
following injection of Restylane than with collagen.
But if you look at that data, you can see that within
five to seven days, it's over. These are events that
are short‑lived, not serious. And what persists is
this persistent erythema.
So personally I think ‑‑ and I have
discussed it with Nick Lowe, who has a lot more
experience because he is bi‑continental and has a
great experience in London. You treat someone who has
had collagen. You tell them, "You may experience a
little more bruising, in particular." Collagen I
think helps to minimize micro hemorrhaging into the
skin. "You may experience a little more bruising.
This is a gel. It may seem to you like it's a little
swollen for the first few days, but do not be alarmed.
This is not a sign of something going wrong." So I
think it is probably true that there was more of these
minor acute reactions in the first few days but not of
any clinical significance.
Now let's talk about allergic or
hypersensitivity reactions. There were no
immune‑driven allergic hypersensitivity reactions, no
antibody urticarial‑type reactions or t‑cell delayed
In this protocol, investigators had the
discretion as to decide as to whether or not they
thought an allergic hypersensitivity reaction was
occurring. Dr. Lowe showed you a picture of the way
allergic reactions look. I will show you one, too.
They are very, very different than this flat
persistent erythema. They are qualitatively very
easily distinguishable as well as allergic reactions
invariably have significant itching or pruritus
associated with them.
So most of what was seen was, as I said,
this persistent erythema. And it was often bilateral.
I think very, very important in trying to sort out
whether or not there could have been a subtle allergic
reaction that wasn't so obvious in that persistent
erythema is that all but one of these patients chose
at the end of the treatment, of the evaluation period
to be reinjected. They were reinjected bilaterally.
Now, when you have an allergic
immune‑driven reaction with subsequent reexposure, the
reaction is reproducible and often more intense. And
nothing happened with these individuals to suggest,
even remotely, that there was an allergic reaction on
reinjection. For that reason, I concluded that there
are no immune‑driven allergic reactions in this study.
You will hear more on this subject subsequently.
This is a typical allergic reaction. As
in the FDA, one of the FDA slides, it's qualitatively
indurated, edematous, itchy, lumpy. It's very, very
different. And this is similar to the reaction that
Nick lowe showed, where he had that patient with the
lumpy, indurated, erythematous, edematous reaction
around the mouth for injection of these vertical lines
that women tend to get. So this qualitatively is
very, very fundamentally different than these
persistent flat erythema, non‑immunologic events.
So, in summary, as far as the adverse
events go, these were usually seen with Restylane and
with Zyplast. For the most part, they were mild and
short‑lived with the exception of that persistent
erythema that we discussed in detail. No immunologic
hypersensitivity allergic events were seen. Actually,
the persistent erythema was seen with both agents and
was seen to a greater degree than with Zyplast.
And the type of thing that those of us who
have experienced with injecting collagen have come to
realize is something happens. When it happens, you
reassure the patient. You say, "You look terrific.
Keep using the makeup. It will go away." And it does
So, in summary, I think it's fairly clear
to me that from these data, Restylane is superior to
Zyplast at the six‑month period. It's also superior
at the two‑month and four‑month period. This is shown
both statistically. It's shown in terms of responder
rates, in terms of longitudinal assessment, and by
patient evaluation and was seen across centers. No
immunologic hypersensitivity, allergic reactions were
seen. And skin testing seems to be an irrelevant
issue in terms of this particular agent.
The local adverse events were
overwhelmingly self‑limited with the exception of
those patients with persistent erythema. And there
were no serious adverse events.
And I think that concludes my
presentation. I will now introduce another one, the
investigator site 5 plastic surgeon of New York
University, Dr. Paul Lorenc.
DR. LORENC: Thank you. Good morning.
First I would like to thank the panel for allowing me
to make this presentation to you this morning.
I am Paul Lorenc. I am an assistant
professor of plastic and reconstructive surgery at New
York University Medical School. I am also in private
practice in New York, in solo practice for the last 15
years. I was one of the clinical investigators in the
pivotal study, but I also have an extensive clinical
experience in Restylane injection in my other practice
in beautiful Montego Bay. I do have an extensive
experience in injections with patients from Montego
Bay, of course.
I would like to present to you the study,
a clinical study. We referred to it as the Olenius
study made in Sweden in 1995 to 1996, where it was a
single arm, open label study of 112 patients. The
eligibility of this study was patients that had
wrinkles or folds that were not deeper than four
millimeters and suitable for injection.
A hundred and one patients were followed
for 12 and 26 weeks in follow‑up. No skin test was
performed on these patients. The whole cohort was
naive to Restylane injection.
The protein levels in the Restylane
preparation at that time was 16 times higher than the
reformulated Restylane, which was involved in the
study that was discussed just before. So please keep
that in mind.
This is just the efficacy report, both
efficacy by the treating physician in four centers and
the patients. And you can see that it starts off very
close to 100 percent, the initial treatment, and then
it goes into the 60 percent range, a little bit higher
for the perception by the physician versus the
As far as the adverse events, the
unrelated ones were perceived to be unrelated. I'll
summarize. As you can see, they include tics,
telangiectasia, strings, and acne formation. The
numbers are on your right. They range from 2.7
percent to 0.9 percent.
The adverse events as assessed as possibly
being related to the injection procedure included red
spots, dark spots, and bumps. Total number of
injections were 285 and the percentage as far as
listed 5.4, 1.8, and 1.8 percent.
The results of the study showed that in
eight percent of the injected sites experience adverse
events with less than one week's duration. This was
mainly, as discussed before, redness and swelling.
there was no hypersensitivity reactions that were
observed, and no adverse events were assessed as
This is just a summary slide that looked
at the adverse events at 12 and 26 weeks. And it was
for a total of 16 percent or 16 out of 102. The ones
that were deemed related were 11 out of 101. And,
again, they include the minor redness and swelling.
As far as the acute events that were noted
in less than 14 days after the injection included 51
patients from 112. And they included redness,
swelling, hematoma, pain, and darker pigmentation, for
a total number of patients of 51.
In conclusion, based on the Olenius study,
reactions were minimal, even with higher protein
level. That was later on reformulated. And no skin
testing was involved. The product was very
well‑tolerated. And the efficacy supports the pivotal
study, in which I was involved.
Thank you very much.
DR. STROBOS: The next presentation I'm
going to do is fairly short. We just wanted to remind
the panel that the product was originally introduced
in Europe in 1996 and it's now marketed worldwide,
including Canada and Mexico. There's no requirement
for skin testing in any of these countries.
We did report to the FDA the spontaneous
adverse events that have been reported. I think many
of you are familiar with spontaneous adverse events
reporting. Basically the company receives calls from
health practitioners, reporting events, and those
events are typically a little bit more unusual, so
adverse events reporting that is frequently sort of a
signal as to the occurrence of some unexpected event
that may occur in a low percentage of patients.
This slide is a little bit difficult to
see from here, at least for me. What we have done
here is basically provide a duplicate of a listing
that you have probably already seen in the materials
provided. These are the reports for 1999, 2000, 2001,
and 2002. Now, these are coded according to an
international disease classification. And you can see
on this slide here these are injection site reactions.
And this would be hypersensitivity reactions.
We have also provided a little column here
just to provide a little bit of context. What this
represents is the number of syringes that have been
sold. To a certain extent discounted by the fact
that, as you noted from Dr. Lowe's presentation and
others, there are multiple injections per patient. So
we have discounted the number of syringes sold,
estimating that there may be somewhere between 1.7 and
2 syringes used per patient. So these provide those
numbers. And you can see that there is sort of a
gradually increasing usage.
Nineteen ninety‑nine was the year in which
there was a formulation change. I think you can see
in terms of the hypersensitivity reactions, even
though there is an increasing usage, there is actually
a decreasing incidence of reported hypersensitivity
reactions. So you can't read too much into that
because, of course, these are spontaneous reports.
However, we did do an analysis again using
the denominator of adjusting for increasing volume of
use. And I think you can see that there is a fairly
striking fall in the reported hypersensitivity
reactions, which you just saw on the table and
represented here graphically, no particular reason for
this fall. And, of course, it has continued at the
same level for those years. So I think it's
reasonable to suggest that the formulation change did,
in fact, reduce the incidence of hypersensitivity
What I have done here is a bit of a busy
slide, but I thought it would be important for you to
see. What we have done is taken the entire 27 reports
of hypersensitivity reports. And this, again, is in
your panel package.
In one of the later sections, we gave a
volume listing of all of the reports that were
received. And these were all ones that were coded as
hypersensitivity. Typically these occur at some delay
after the initial injection. They are coded largely
because they are reporting erythema and swelling.
There are obviously some reactions here.
The investigator may also have thought that the
reaction was an infection because of the expression of
pus, so forth. If you go back to that slide, the
previous two slides, infections are reported as well
in this database.
That said, I think the incidence of the
reports, especially the hypersensitivity and
inflammatory reaction, appear to decrease following
decrease in the protein level, 1999.
There are delayed, rare delayed, erythema
and swelling reactions. They tend to be self‑limited,
tend to be treated with topical steroids, sometimes
oral steroids. However, it's not been proven that
these reactions are immunologically mediated.
We just thought that would be a thorough
way of making sure that you're aware of the fact that
there is international experience and there is a
database to look at these reactions.
That said, we had asked Dr. Franklin
Adkinson, who is a professor of allergy and immunology
at Johns Hopkins, to basically review the entire world
of literature as well as our database on allergy and
immunology and briefly render his opinion on the
likelihood of an immunologic mediation of any of
DR. ADKINSON: Good morning. My name is
Franklin Adkinson. I am a professor of allergy and
immunology at Johns Hopkins, just up the road. I have
enjoyed a 30‑year academic career at that institution,
where I have taken a longstanding interest in
immunologic and idiosyncratic reactions to drugs, both
marketed and in development.
I was pleased to have been asked by the
sponsor a number of months ago to take a comprehensive
and independent look at their own safety database and
what may have been published in the literature with
regard to the possibility that high molecular weight
hyaluronates can or do induce hypersensitivity
I have done so. What I have looked at is
the entire safety data set that has been reviewed for
you this morning from the two clinical trials and the
spontaneously reported adverse reactions.
I have also reviewed the literature, both
with regard to facially injectable hyaluronics but
also with regard to other high molecular weight forms
that are used for intra‑articular injections, for
example, looking for evidence of immunogenicity and
demonstrably allergic reactions and at any published
reports in the literature that might suggest evidence
for immune responses to these materials. I would like
to just review with you some observations I made
during that review and the conclusions that I have
The first observation I think is important
is that all of the reactions have been labeled by
various investigators and reports is hypersensitivity
were local at the injection site only. This would be
very unexpected were true immunological
hypersensitivity being manifest.
Almost all of them required days or weeks
to be manifested and included, as you have heard,
erythema, red spots, local swelling, pain, and
tenderness, some of which has an inflammatory
component but none of which are accompanied by the
hallmarks of true allergic disease.
The pattern, the temporal pattern, under
which these reactions emerged, is also not suggestive
of any particular form of immunopathology. And high
variability among the patterns suggests that something
else is going on that must be a function of either the
host or the technical properties of the administration
of the agent.
All the reactions that were observed in
the clinical trials resolved without treatment. The
most unexpected result if you were dealing with true
hypersensitivity was immunologically mediated.
And almost all of the local reactions
occurred at some time but not at all injection sites.
That is, I was impressed that over half of the
reactions occurred at one but not at other sites
injected with the same material, again, a most
unexpected if one were dealing with immune‑mediated or
Finally, when patients were re‑treated
after a seminal event that was labeled as
hypersensitivity and were observed thereafter, if
anything, there are fewer reports, spontaneous
reports, of adverse events following re‑treatment
after an initial reaction that is labeled as
hypersensitivity, rather than more, as we would
Some of this may be due to reduced
surveillance in an open follow‑up, but the fact that
there are not more or more severe reactions I think
supports my own conclusion in reviewing all of these
features of the reactions that an immunological basis
for them is most unlikely.
I also looked at case reports in the
literature that examine some of these nodular, late
appearing reactions. One involved an excisional
biopsy, which showed a granulomatous reaction with a
mild inflammatory infiltrate. This had all of the
features of a foreign body granulomatous reaction,
rather than one that had an immune pathogenesis, and
suggests the possibility that failure of the material
to resorb entirely in certain susceptible individuals
may lead to this type of granulomatous inflammation,
which is again entirely local and not likely to be a
Almost all of the patients, as I
mentioned, who were repeatedly challenged after an
incident labeled as hypersensitivity, had no further
problems with the second injection. Those who did
reported a second episode. It was usually not like
the first. It was temporally at a time point very
difficult to explain by any known immune mechanism.
There is one case series in the literature
accompanied by reported lymphocyte stimulation studies
and ELISA measurements done in a reputable laboratory
in Paris. However, looking at the technical
description of these assays in the paper as it's
reported, I was unable to come to any firm conclusion
about the validity of these studies.
There was no dose‑response curve
demonstrated with the lymphocyte transformation
studies. No controls were included in the studies.
And the highest titer of IgG antibody, if I
interpreted the paper correctly, was observed in a
patient who was a non‑treated control, raising serious
questions about the specificity of the assays.
Now, when this report occurred, the
sponsor, I think quite commendably, attempted to
pursue this and asked Dr. Michel, who published this
series, to make available these patients for
Two of his most sensitive patients were
again restudied at the same Paris laboratory that did
the original studies in lymphocyte transformation.
And ELISA studies were repeated. This time they were
So not only were these poorly documented
to begin with, but they appear not to be reproducible.
To my knowledge, this is the only reported
immune‑specific activity to these products that's
available in the literature.
So, in conclusion, I find no convincing
evidence that the high molecular weight, hyaluronic
products are immunogenic. There is the occasional
granulomatous reaction, which appears to resemble a
foreign body reaction, which appears to be random and
idiosyncratic and not reproducible.
The common reactions that we have heard
about today, including the redness and erythema, all
seem transient. And they're exclusively local and in
my judgment do not suggest the participation of
DR. STROBOS: Finally, the company has
proposed a phase IV study in the African Americans.
I would like to introduce Dr. Taylor from Columbia
University to describe that.
DR. TAYLOR: Good morning. My name is Dr.
Susan Taylor. I am the director of the Skin of Color
Center at St. Luke's‑Roosevelt Hospital Center in New
York and assistant clinical professor of dermatology
at Columbia. I will discuss with you a planned phase
IV study of Restylane therapy in African Americans.
Dermal fillers have been used successfully
in patients with skin of color, including African
Americans. Restylane has been used extensively in
South America as well as Asia and has not been
associated with a different safety profile.
Clearly safety profiles for African
Americans may be different. Abnormal healing
responses and pigmentary responses are theoretical
adverse clinical outcomes in this subpopulation of
In specific post‑inflammatory pigmentary
changes, either post‑inflammatory hyperpigmentation or
hypopigmentation is a theoretical adverse clinical
outcome. Keloidal scar formation is another
theoretical adverse clinical outcome. And we do know
that in African Americans, in particular, there is a
higher incidence of keloidal scar formation.
We plan a phase IV multi‑center
observational safety study of Restylane treatment in
African Americans. Eligibility requirements include
self‑identified African Americans. The age range is
between 35 and 75. Patients will have Fitzpatrick
skin types V or VI.
We propose ten sites, which will be
selected based upon prior demographics. Sample size
will include 100 patients as our target. The
enrollment, however, will close six months after the
first patient is enrolled to ensure FDA reporting
within one year.
Our endpoints include keloidal scar
formation, which will be examined at weeks 12 and 24
as well as pigmentation changes, which will be
examined at weeks 2 and 6. We feel that a phase IV
study is indeed an appropriate study to observe
possible safety issues in this subpopulation.
Thank you very much.
DR. STROBOS: That pretty much concludes
our presentation. We do have a few just summary
slides. If I could have Dr. Leyden and Dr. Gary
Jansson perhaps sit up here because I know you
probably will have some questions to ask? And then I
can just briefly review my summary slides.
We believe in terms of the clinical
efficacy that the study satisfied the mutually agreed
predefined criteria for establishing superiority.
It's my personal view ‑‑ you may differ, but it's my
personal view as a physician that a superiority or a
statement about superiority is appropriate and that
not all patients have to do better.
The principles underlying superiority I
think are that more than half should do better and
most of the rest should do the same. That's my view.
You may differ, but we do have a superiority statement
in the proposed labeling, which I am going to show on
the last slide. I believe a question has been
directed to you about that.
In terms of clinical safety, overall
clinical safety, we think there is a low rate of
clinically significant adverse events from the three
data sources that have been put into the PMA, the
pivotal study, the Olenius study, the spontaneous
reports in the medical literature. We think most of
the adverse events are self‑limited, last less than
two weeks after injection.
There are, as has been noted, rare serious
dermal sequelae, but those are almost uniformly
reported on in the medical literature, which obviously
has a selection bias in terms of reporting.
We have proposed as the indication for the
product that Restylane is indicated for the correction
of moderate to severe facial wrinkles and folds, such
as nasolabial folds. We believe that this is
principally supported by the pivotal study. We do
need not to remind you that the Olenius study was an
open label study. And we're using it principally as
support for the safety. However, there is some also
in the medical literature and international
The superiority claim that we're talking
about is not in the indication. Rather, it's in the
description of the clinical study.
We have committed to performing a phase IV
study in African American patients. We believe that's
appropriate as a phase IV study. The study design
when we were initially discussing the study with the
agency, they wanted to ensure that the study was
performed in the United States.
The product is used in Brazil, and we have
submitted some data about usage in Brazil. However,
because of the demographics of treatment of wrinkles
in the United States, the likelihood of enrolling a
lot of African American patients in sort of a
broad‑ranging efficacy study is limited. And that's
why we would like to do this as a phase IV study.
We do have proposed a statement about use
in African Americans to add to the proposed labeling.
And that statement is "Limited controlled clinical
study data are available regarding the use of
Restylane in patients with skin types V and VI on the
Fitzpatrick scale." And we would certainly like your
views if that's possible as to if that is an
appropriate statement or whether it should be
In terms of hypersensitivity, another
question you have been asked to addressed, we think
the redness and erythema that you see in these cases
is not clinically allergic. The clinical studies
suggest there is low risk. Spontaneous AB suggests
there is low risk. And the medical literature has
suggested there is low risk.
We have, however, also proposed to do a
surveillance study. The way this has worked is, as I
described, we would be setting up a spontaneous
reporting system, under which we would propose that
any patient who has a reaction coded as
hypersensitivity, that we would attempt to contact the
health care provider and evaluate the patient with
intradermal skin testing. The likelihood is that we
would use some sort of a control population as well,
but it would be difficult to do the control population
as part of that study itself.
The superiority statement that you have
been asked to render an opinion on is the following.
I've written it up here. It says, "In the randomized
study Restylane was shown to be statistically
significantly superior to an approved cross‑linked
collagen dermal implant as regards persistence of
augmentation of nasolabial folds." That's the
statement. We believe, as I pointed out before and I
think Dr. Leyden pointed out, that we have support for
That said, that's the end of our
presentation. And we would appreciate being able to
answer any questions you might have.
ACTING CHAIRPERSON CHANG: Thank you very
This time period is now open for panel
members to ask questions for the sponsor. Dr. Halsey?
MEMBER HALSEY: In the exclusion criteria
for the study, you have eliminated all patients with
a history of severe allergies or multiple severe
allergies, including like histology. Is it possible
or should we be concerned that the reason we have not
seen what appears to be typical immune reactions is
that they have been excluded from the study group?
And if that's the case, should we require this allergy
testing of some kind or allergy evaluation prior to
getting patients on this treatment?
DR. STROBOS: Well, let me ask Dr. Leyden
to answer that, but just to remind the panel, all the
patients in the study received both collagen and
Restylane. So the concern in the study and reason for
that exclusion was because there is a known reaction
The Olenius study, which was submitted to
the PMA and is experienced in 101 patients
longitudinally open label, in that study, there was no
exclusion for people with prior atopic reactions. And
there was no skin testing performed in that study at
all. And those were people all of whom were naive to
DR. LEYDEN: I think that two things are
maybe important. One is those people with severe
chronic, recurrent allergic reactions tend to get on
drugs that could interfere or influence any reaction.
That was the reason for excluding, not trying to
exclude people, leaving aside whether or not those
people who react to pollens, et cetera, would be more
likely to react to this. They may.
But I think the wide experience in Asia,
Europe, South America were all comers, including those
with significant atopic backgrounds, exist, doesn't
show a signal that that subgroup may be more likely to
get these, what appear to be non‑immunologic
reactions. To date, we don't think they are
MEMBER HALSEY: Certainly the clinical
characteristics, as pointed out. Dr. Jansson would
Now, you have in this product bacterial
protein. It's six parts per million. That's not
zero. And it is potentially a problem. Is there any
way to test for that? And what do you think that that
should be lowered?
DR. STROBOS: Excuse me. Could you
clarify your question in terms of the testing?
MEMBER HALSEY: The product has six parts
per million of protein. I assume that's
DR. STROBOS: Correct. I believe that's
MEMBER HALSEY: Was there any specific
attempt to look for an immune response to this
DR. STROBOS: In these clinical studies,
there were no immunologic studies performed on the
ACTING CHAIRPERSON CHANG: Dr. Newburger?
MEMBER NEWBURGER: I reviewed the
worldwide safety data that you provided. I just
looked at the numbers of adverse events from 1999 to
2001. During that time frame, ‑‑ and, admittedly,
it's a very sketchy kind of reporting database ‑‑ 201
hypersensitivity reactions were reported.
Now, we know that reporting worldwide is
very different than it is in the United States. And
very often if there is an adverse event, it will be
dealt with with the physician, rather than being
reported to a governmental agency.
But if we just limit that to the 2001 and
2002 years, which was after the more purified material
was available, in those years, there were 62 reports
of so‑called hypersensitivity reaction, delayed onset,
and 10 reports of granulomata.
Why was there no concerted effort made to
clarify what was the mechanism with these patients?
Furthermore, I see in that database that there were
some individuals who had to be treated with systemic
medications. So that to me just signals this is a
substantial number of people who got quite sick.
Now, in terms of the total doses given,
that's very small, but I would like to know what
efforts there would be to characterize those who would
be at risk for such severe reactions. It's a long
period of time without having really a handle on
what's provoking this reaction.
So as a clinician, although I could say
statistically there's likely a very small incidence of
an adverse event, I would like to have more
information so we could truly give an informed
DR. STROBOS: Right. Well, just to
clarify, two points. One is most of the reports in
that database arise from northern Europe. Reporting
I can't agree with you more that you can't draw too
many conclusions from that. Reporting from Europe in
the studies that I would do, spontaneous reporting
tends to be a little better in the United States, not
a whole lot.
That said, we also, as I have pointed out,
are intending in the United States to try and study
those patients prospectively and more or less in the
exact manner that you said.
Let me have Dr. Rensfeldt from Q‑Med, who
is in charge of this spontaneous reporting, speak to
the activities that the company has engaged in
heretofore, which I think have been relatively
aggressive in trying to address these issues and find
out the problem.
DR. RENSFELDT: First of all, a
clarification. Regarding the classification of the
adverse events, they are done on a worst case basis.
And the data that we have, the information that we
usually have on spontaneous adverse events reports
varies considerably from case to case when it comes to
the quality of the data and the amount of information,
which makes the classification rather difficult. So
that's important to have in mind that it's certainly
worst case classification.
So when it comes to the cases classified
as hypersensitivity, these have not been confirmed in
any way. So the classification is only based upon
certain clinical data that has been received in the
report that might imply that it could be some sort of
hypersensitivity reaction involved. So that's
important to have in mind when you consider the data.
It also is important to have in mind that
the great numbers or the majority of these cases are
self‑limited. They don't require treatment. And the
symptoms are usually gone by about two weeks.
Therefore, we have not felt compelled to do any
further research on each case since they have in
general been mild to moderate symptoms and
DR. STROBOS: That said, if you look at
the treatments rendered, a lot of them are empirical.
Some of the treatments, for instance, people will be
started on steroids, as you indicated, but they will
be simultaneously started on antibiotics as well.
That said, perhaps Dr. Leyden, I think who
has an interest in dermatology and allergy ‑‑
DR. LEYDEN: Dermatology I have an
interest in, yes.
DR. STROBOS: Yes.
DR. LEYDEN: That's true.
DR. STROBOS: Maybe you would want to
comment on the question.
DR. LEYDEN: Yes. Well, it's one of those
things that how do you get your hands on those
patients, number one? The situation where they had an
opportunity, where there actually was, as Dr. Adkinson
described, a paper and somebody did do some ELISA and
other tests trying to get at mechanisms, when they
redid it, they couldn't even reconfirm it.
So these kind of reports, occasionally I
get asked to look at reports. Drugs come out. And
the question is, is there something going on? It's
very hard to wade through that stuff. Personally when
you read through these cases, you end up often saying,
"How did this case get classified like this?"
Now, I have asked that question of Jur,
who has a lot or experience in that. He explained it
to me, and I didn't understand it. So there's
something about that classification that it gets
classified. And until you do something prospectively
or until you get your hands on people in a way that
you can actually fundamentally study them, I think you
have to just say, "Well, those are reports" and, as
described, are the worst case, if you will.
Based on what you heard Dr. Adkinson say
and what I think the experience of most people is, the
overwhelming majority of these "reactions" are not
immunologic. They're injection. Probably if you had
injected saline, you would have gotten a certain
amount of that.
As I tried to point out, if you look at
the persistent erythema, which I think is really an
interesting reaction, ‑‑ and Nick and I were talking
about, we have similar ideas, it turns out, on who
these people are ‑‑ a high percentage of them were
bilateral, which suggests it's the person more than
either agent, that if you inject something in certain
people, you are going to get erythema or you are going
to get reactions, some of which get classified as
hypersensitivity, implying immunologic
hypersensitivity, which is a big step until you have
ACTING CHAIRPERSON CHANG: Dr. Leyden,
could you share with the panel at this time what are
your suppositions, your ideas of what kind of ‑‑
DR. LEYDEN: Who gets it?
ACTING CHAIRPERSON CHANG: Who gets it so
that perhaps this is a yellow light ‑‑
DR. LEYDEN: It's not a yellow light.
It's just like what's going on.
ACTING CHAIRPERSON CHANG: Yes, it is.
DR. LEYDEN: Yes, right.
ACTING CHAIRPERSON CHANG: One, two, three
reasons of why individuals ‑‑
DR. LEYDEN: Nick and I were talking about
that while Dr. Adkinson was making his presentation.
We think it's people like me, people who tend to flush
or blush easily, who have a richer microvasculature in
the superficial dermis. They're the people.
We have at Penn a Center for Human
Appearance. We work very closely with our plastic
surgery colleagues for more than 25 years. They have
patients that they operate on. They do laser
abrasions or they do facelifts or they do this and
that. And they stay red for a long period of time.
The people are unhappy because nobody told them that
was going to happen.
I think they're the same kind. They're
people with this what we call rosacea tendency of
flushing and blushing. I think they're probably the
ones who bruise more easily, too, because they have
more superficial dermal microvasculature.
They're the ones who react to
corticosteroids and blanche that are used in the
vasoconstrictor assay for developing topical
corticosteroids. I think they are the ones, and I
think it relates to the differences in vascular supply
to the superficial dermis.
DR. STROBOS: If I may perhaps have Dr.
Adkinson give his opinion on that?
DR. ADKINSON: Well, it is an opinion
because I don't know the answer to the question, but
it's interesting to speculate and to think about how
these reactions could occur. They seem to have a
random occurrence in the population. We don't know
how to pick out the people who are at risk. And even
those who are at risk don't have it at every injection
site, suggesting that there are local factors that
come into play.
The fact that these superficial rapidly
disappearing reactions went down drastically in
frequency when the protein content was reduced by
16‑fold in the current product suggests to me that
there may be some interaction between bacterial
components and the individuals' innate immune systems,
which in recent years we have learned can respond to
a wide variety of bacterial products with inflammatory
signals that lead to the production of cytokines that
draw inflammatory cells that could lead to the release
DR. LEYDEN: The toll‑like receptor you're
DR. ADKINSON: The toll‑like receptor
mechanism. But that's entirely speculative, and it
still wouldn't get at the idiosyncratic feature. That
is, if this was just an assault on the innate immune
system through these toll‑like receptors, we would
expect virtually everyone to react. And it seems to
have, however, a very strong host component, which to
my review has not been identified.
ACTING CHAIRPERSON CHANG: Dr. LoCicero?
MEMBER LoCICERO: I have four questions.
The first is, on the persistent erythema, sites 1 and
2 have quite a few more reactions than the other
sites. What is your analysis of that and your
speculation concerning that problem?
DR. LEYDEN: Yes. I noticed that, too.
Were they Manhattan experiments?
DR. STROBOS: One was I believe La Jolla.
It wasn't either one of these.
DR. LEYDEN: Good. I think technique is
important. I think the way you inject, how slowly you
do it, and how much experience you have is important.
I think that's an issue.
I have given you my sort of off‑the‑cuff
idea of who I think these people are. I am sure I am
right, but I could be wrong. I don't know the kind of
patients. I really would like to see that to see if
there is a correlation because it would be an
opportunity to test the hypothesis that Nick and I
So I think technique and just who is in
that study at different centers is likely to be
MEMBER LoCICERO: Second question, on your
proposed labeling, you have "facial wrinkles." Upon
what basis do you want that indication?
DR. STROBOS: Well, I think there are two
rationales. One is we think that the nasolabial fold
is a difficult wrinkle to treat. And so is the
experience in nasolabial folds, which is
We also have the Olenius study. And
although the efficacy data again is open label, in
that study, 285 sites were treated. And that was not
limited to nasolabial folds. So we think it's
basically generalizable based on the principles of
action of the product Olenius study.
MEMBER LoCICERO: Third question, you have
committed to a phase IV study, which means that you
pretty much agree that there is insufficient data
concerning African Americans.
If you were to get labeling, although it
hasn't happened in lower Alabama, the other L.A.,
there are many other parts of the country where
patients are multiethnic. How would you evaluate your
patients beforehand? What would you propose as a
method of eliminating those with multiethnic
DR. LEYDEN: I don't know that you have to
think of it that way. I think what Susan said is
there is at least a theoretical reason why they should
be specifically prospectively looked at.
I think there is the extensive experience
worldwide in individuals who have multiple gene pools
who have much darker skin than I do. It doesn't
suggest anything different. I mean, there are lots of
African Americans who have been or people who are
ultimately descended from Africa who live in other
parts of the world who have been injected without any
signal, but there has not been a formal prospective
look. They're committed to doing that in American
DR. STROBOS: Let me just expand on that.
In the PMA, we were asked this question. And we did
provide a retrospective analysis of patients treated
in the Brazilian clinic, which included many patients
of the kind of mixed heritage that you might suspect.
We think that data suggests the product does not carry
any different risks in this patient population.
Just to clarify one thing, we're not
proposing the study because we have any concerns about
it. I think that's a mischaracterization. We just
think it's the right thing to do in today's world to
evaluate the demographics of the study.
I think you need to recognize that, at
least in the device guidance and in this protocol,
which was worked out with the agency, there was now a
preset demographic analysis. There was no discussion
of doing demographics.
At the time the study was set up, this
panel had not raised questions about demographic
subpopulations. And the way the study was designed,
the prospective study was unlikely. Had we known that
in advance, obviously, the demographics would be an
issue, we would have had a different design. But we
just think it's the right thing to do.
Let me have Dr. Taylor address this risk
DR. TAYLOR: I have two comments. I just
want to reiterate that in South America, in Brazil in
particular, there have been over 130,000 treatments of
Restylane, again without any increased adverse events
Additionally, there have been over 40,000
treatments in Japan and over 40,000 in Korea, again
without increase in adverse events being reported.
I think we need to understand clearly that
African Americans are relatively resistant to
wrinkling. Also, the depth of wrinkling is a lot
less. And if you look at the entry criteria in the
pivotal study, it required wrinkle depth of three or
four. That is moderate to severely deep folds.
Often, which is very nice for African
Americans, we did not meet that entry criteria in that
our folds, our wrinkles were not deep enough to be
included in the particular study.
I want to be clear that it wasn't as
though African Americans were excluded from the trial.
Fortunately in many respects, we didn't meet the entry
criteria. I think, however, we clearly would agree
that in many realms, African Americans have been
demonstrated to react differently.
That's why I think it's the right thing to
do and the appropriate thing to do for this to be
pursued in a phase IV clinical trial.
MEMBER BOYKIN: Dr. Taylor, were you one
of the sites in this study?
DR. TAYLOR: I was not.
MEMBER BOYKIN: Why? I mean, when were
you approached by the company about this?
DR. TAYLOR: I was approached by the
company when the issue was raised about African
Americans and to take a look at: a) why there wasn't
a larger number of African Americans enrolled; to also
review with the company the features of aging,
photoaging, in African Americans; and also to help
review and look at the potential problems that we
experience in terms of abnormal healing responses and
abnormal pigmentary responses.
MEMBER BOYKIN: With what you know about
the product, are you using similar fillers in your
operation right now?
DR. TAYLOR: Yes. I think it's very
important to point out that fillers are used,
particularly the collagen‑based fillers, in African
As you well know, keloidal scars are
precipitated by a disruption in the integrity of the
skin. So the theory is that with the needle that is
used to implant the product in the dermis, that would
be the initiator of the disruption in the integrity of
As a practical matter, as a dermatologist,
we inject a variety of substances, dermal fillers as
well as anesthetics, for example, corticosteroids into
the skin, again without an increased incidence of
keloidal scar formation.
MEMBER BOYKIN: Right. But you personally
have not had any experience with this product?
DR. TAYLOR: I have not personally had any
experience with this product, but let me say that my
particular feeling is that I would not necessarily
hesitate in using this particular product in patients
of all races and ethnicities.
MEMBER LoCICERO: One more question,
really for Dr. Taylor. And that is concerning the
design of this phase IV trial. The keloid formation
is out to 24 weeks, which is probably appropriate.
Pigmentation is only out to six weeks. And there may
be some pigmental changes that occur at that point,
but they may modify or one way or the other later. Is
six weeks too short?
DR. TAYLOR: Well, the six weeks was based
on the fact that most of the erythema that was seen
occurred at 14 days or less. So the feeling was that
if pigmentary disorders were going to be a response of
that inflammation, it would occur around the two‑week
period and we would definitely capture it in six
DR. LEYDEN: And they would be followed
until it resolved. You know, if they had an adverse
event, it would be followed up until ‑‑
MEMBER LoCICERO: Okay. So that would be
part of the trial, that you would need to follow the
DR. LEYDEN: Yes, right.
ACTING CHAIRPERSON CHANG: Dr. Miller and
then Dr. Newburger.
MEMBER MILLER: Yes. Thank you. I just
had a couple of questions. You know, you described an
extensive experience in Asia and Latin America. But
I haven't seen any publications, really, out of that
experience unless it's in other languages than
English. Have there been any publications out of
DR. LEYDEN: I don't read those journals
DR. STROBOS: There is one. In the PMA,
there is a report, Brazilian report, that I mentioned.
DR. TAYLOR: There is a Brazilian report
in the literature of 2,241 subjects who received
injections, of whom 179 were characterized as having
skin phototypes V and VI. And 129 were characterized
as being of Asian descent. None of those patients had
adverse events reported.
MEMBER MILLER: One of the complications
listed in one of the presentations was a tic. What
exactly do you mean by a "tic"? Is this a neurologic
sort of tic you're talking about or ‑‑
DR. STROBOS: Well, this wasn't observed
in the pivotal study. Do you have any idea why these
tics are reported?
DR. LEYDEN: I have no idea what they're
talking about. It could be more of this reporting
stuff, you know. We didn't see anything like that.
DR. RENSFELDT: It was reported in the
supportive study, in the so‑called Olenius study. And
it was regarded as not related to the treatment.
I think one of the patients had tics on
the lip area. And the other case was tics around the
DR. LEYDEN: The coding would be an
involuntary muscle contraction.
MEMBER MILLER: Right. So these are just
DR. STROBOS: And judged to be unrelated.
MEMBER MILLER: And you have no idea what
those are. You can't envision any connection between
a patient developing a tic problem and injecting this
DR. STROBOS: Well, there was a study. I
mean, we're not talking about the animal tick here.
We're talking about an involuntary ‑‑
MEMBER MILLER: No. I know. I
understand. I didn't expect ticks to begin. Thank
you for clarifying that, though.
MEMBER MILLER: Now, you feel that the
results in the nasolabial fold are pretty
generalizable, but in one of the papers I did run
across, there was a study looking at glabellar frown
lines. And the investigators in that study found a
return to baseline of the wrinkles in 18 weeks. That
seems to be a little bit of a shorter time than your
DR. LEYDEN: Well, most people are above
the nose, it's Botox; below the nose it's fillers.
MEMBER MILLER: Right. This particular
study compared a combination of Botox and the
Restylane to Restylane alone and found that the
Restylane group returned to the baseline in 18 weeks.
DR. RENSFELDT: Could I comment?
MEMBER MILLER: Yes, please.
DR. RENSFELDT: In that study, since it
was a Botox study in the sense that Botox was
included, it's common in those studies to assess the
patient at maximum frown. That was when this
measurement was taken at 18 weeks.
The study is a bit, let's say, complicated
to realize what actually they found because this was
assessed at maximum frown for a static wrinkle. So
it's not the common way to assess people whom you have
injected with a filler substance to ask them to frown
maximally and see if the wrinkle is still there.
DR. LORENC: If I may, I have three
responses, one about the tic. I have seen in my
practice I do an awful lot of fillers. I am a plastic
surgeon, but I do an awful lot of fillers.
I have seen this involuntary muscle
contractors, especially with lip injection. I don't
know what the mechanism is. I don't think it's
related to the product. I think it's probably a
pressure phenomenon. So it could be related to that.
As far as the injection of Restylane in
patients who are classification V or VI, I have
extensive experience in that in my Montego Bay
practice with local patients. I have not seen any
pigment changes. I have not seen any hypertrophic
scars or keloids.
And that's just the personal experience.
I grant you that it's not published, but, again, it's
many, many patients.
MEMBER BOYKIN: In your list of
complications, you noted a couple of incidences
related to acne. Do you treat patients with acne with
DR. LORENC: With active acne?
MEMBER BOYKIN: Well, I'm not sure exactly
what was going on here, but can you answer my
question? Do you treat patients with acne with this
DR. LORENC: I don't know. I don't quite
understand your question.
DR. LEYDEN: I can tell you I have treated
people with collagen injections, adults who have
various forms of acne vulgaris or acne rosacea. You
can certainly treat the nasolabial folds. It's not a
common place to get acne lesions.
I would assume that these acne lesions
were out on the cheek, the forehead, or the chin but
not in the nasolabial fold because that's an uncommon
DR. STROBOS: There were two patients
reported to have acne at I believe six months after
the injection. Some were in a delayed relationship.
Those were classified as actually unrelated adverse
events that occurred later. That was in the study.
The exclusionary criteria in the study
were people with some active infectious process. And
I think the concept there, if I'm not mistaken, if
someone has an active infectious process on the face,
you wouldn't be injecting their wrinkles at the time
they have them.
DR. LEYDEN: The acne is not an active
infectious process. It's an inflammatory process.
MEMBER BOYKIN: So when you're excluding
people with skin diseases, you're not really talking
about acne? I mean, that's where I am a little
When I look at what your prospective
labeling is for this product, it says that you would
exclude people with skin diseases. And, of course,
that's a pretty broad, open thing. And then I see
some related. Acne is not here today, gone tomorrow.
This is a cycle of events that can take place over
many years. I'm sure you will agree with that.
How do you educate the clinician using
this about patients with histories of acne?
DR. LEYDEN: I don't think you have to.
Quite frankly, I don't understand why. In any
clinical study, there are always excluding patients
with significant diseases in the area you are going to
be evaluating that might confound the evaluation or
raise it. That's the main reason for excluding them.
Now, in practice, injecting collagen in
people with psoriasis that's stable because if you
traumatize their skin when they're unstable, you could
induce psoriasis. People with acne were on their
forehead and their cheeks. And injecting their
nasolabial fold, that's not an issue.
So I think that exclusion is for study
purposes, not implying that it would be risky or
unwise to use it in a person who happened to have acne
or some other condition, seborrheic dermatitis.
DR. STROBOS: Have we answered your
MEMBER BOYKIN: Not really. We'll get
back to this.
ACTING CHAIRPERSON CHANG: We'll get back
to it later this afternoon.
MEMBER BOYKIN: It's just an issue of
ACTING CHAIRPERSON CHANG: We have three
other questioners. Dr. Newburger, Dr. Doull, and Dr.
Olding have been waiting to ask questions.
DR. STROBOS: Okay. I just wanted to see
whether Dr. Lorenc wanted to address the issue of
differences in the glabella.
DR. LORENC: Just a comment about treating
patients. I wouldn't treat a patient clinically that
has active herpetic lesions with any injectable. I
think that's just an independent evaluation by the
physician at the time of treatment.
I have treated patients in the glabella,
of course, with Restylane with good results, no
reactions, no allergic reactions. Again, it's a
personal experience but on many patients.
ACTING CHAIRPERSON CHANG: Dr. Newburger?
MEMBER NEWBURGER: I have four short
questions, first one to Dr. Taylor. In your phase IV
study, are you planning to just introduce the
substance into the nasomalar folds or are you going to
use it for other wrinkles? And are you going to use
it for depressed scars?
DR. TAYLOR: The plan was to use it for
nasolabial fold wrinkling.
MEMBER NEWBURGER: Okay. Thank you.
DR. STROBOS: Let me clarify. One of the
problems we wanted to do is ensure adequate
enrollment. It's difficult to do that, as we pointed
out, in a prospective sort of narrow study. So we're
thinking of trying to have a more global experience.
I think we would be interested in your
comments or the panel's comments with regard to the
design of that study. That's to a certain extent why
we provided only a brief description because any
comment that you may have, we would appreciate,
MEMBER NEWBURGER: Thank you.
The second question relates to labeling,
the proposed labeling. Under "Indications," you have
put "Restylane should only be administered by an
appropriately trained license practitioner." I
understand since this material has very different
physical characteristics than the collagen that has
been on the market for over 20 years.
How is someone going to be appropriately
trained, especially since there are differences in the
tutorial characteristics of this that a too
superficial injection is going to have a long‑lasting
cosmetic deficit? What is your plan to appropriately
DR. STROBOS: Well, I believe that, in
fact, Medicis as part of its marketing efforts is
planning on engaging in such a program. Perhaps Dr.
Jonah Schaknai, who is the CEO of the company, could
DR. SCHAKNAI: Thank you, Dr. Newburger.
It's an excellent question, in fact, because we have,
among companies in this field, one of the strongest
commitments to continuing medical education, as you
know. Probably our largest promotional expenditure
involves supporting educational grant symposia.
Because of that commitment and because we
appreciate that there are subtle differences in
technique between Restylane injection and collagen and
other substances, we have hired one of the most
experienced continuing medical education firms to
provide live training probably in 50 cities, 2
dermatologists and plastic surgeons with hands‑on
experience among those who have injected Restylane,
have been trained specifically in Canada to do that.
Secondly, there will be a CD‑ROM tutorial
prepared by the same firm, ATS, that will educate
physicians at the time that they made purchase
arrangements of Restylane. We believe strongly that
an educational component is really the proper way to
ensure not only the success with individual patients
and good results from physicians with patients but
also to maximize the commercial success of the
product. It sells well if it works well.
To the degree that there is technique
dependence, you couldn't have a higher degree of
MEMBER NEWBURGER: Next question, also
under "Labeling and Precautions," it says, "If laser
treatment, chemical peeling, or any other procedure
based on active dermal response is going to be
considered after treatment with Restylane, there is a
possible risk of eliciting an inflammatory reaction at
the implant site. This also applies if Restylane is
administered before the skin has healed completely
after such a procedure." What is the basis of such a
DR. STROBOS: Is there someone who can
DR. LEYDEN: I don't know what you're
talking about. In the labeling, I think just as a
general sound of it, first of all, I don't think you
would do a procedure, if you were to inject somebody,
that you were then going to do a procedure in that
area. I mean, that wouldn't make any sense.
MEMBER NEWBURGER: It doesn't say anything
about how long ago the Restylane. It's right here
under the direct proposal for labeling.
DR. STROBOS: In the labeling ‑‑
ACTING CHAIRPERSON CHANG: Excuse me.
When the sponsor answers the question, could we
respectfully ask that one spokesperson reply to this,
rather than two or three rebuttals or clarification,
that one spokesperson clarify the issue so that we can
get to the other questions, please?
DR. STROBOS: I'm sorry. We were having
a little trouble understanding.
ACTING CHAIRPERSON CHANG: Dr. Newburger,
could you just clarify your question so that we can
have a succinct answer? Then we will have Dr. Doull
and Dr. Olding ask their questions. We need a
ten‑minute break, and we will return for other
MEMBER NEWBURGER: Under the proposed
insert with the product, one of the bullet points
under "Precautions" says, "If laser treatment,"is
going to be considered after treatment with Restylane,
there is a possible risk of eliciting an inflammatory
reaction at the implant site. This also applies if
Restylane is administered before the skin has healed
completely after such a procedure." I am asking, what
is the basis? What is the experience that led to this
DR. RENSFELDT: I understand the question.
The primary basis is twofold. One is that the initial
experience that we had in Europe and elsewhere was
that we could see an association between some adverse
events that were reported and concomitant treatment
with this type of, for example, lasers and peeling and
also excessive use of sun beds. So, therefore, we as
a precaution added this sentence. And that has worked
very well since then.
And also from a purely theoretical
standpoint, there is a risk that you assume. When you
put the implant into the skin, at least initially
there is sort of a sensitive area when it's not
settled into the skin and has not been received by the
Therefore, there is an area where we think
at least there is a theoretical basis for eliciting
such a reaction.
MEMBER NEWBURGER: But if Restylane in
some cases persists for nine months or so? I would
need more clarification of that time frame.
ACTING CHAIRPERSON CHANG: Dr. Doull?
MEMBER DOULL: Let me ask a quick tox
question. In the material that you provided, it says
that Restylane is not mutagenic. Can you describe the
tests that support that conclusion?
DR. STROBOS: Yes. Well, the FDA
presentation is going into that in a great deal of
detail, but the company was required to perform the
standard ICH battery of tests that are required of
medical devices by the Center for Devices and
Radiological Health. I believe the mutagenicity tests
included the Ames test, the microsomal nucleus test,
and the Chinese hamster ovary test.
Dr. Johns? Is he in the room? Were there
MEMBER DOULL: Fruit flies?
DR. STROBOS: Fruit flies? No, we did not
do fruit flies.
ACTING CHAIRPERSON CHANG: Dr. Olding?
MEMBER OLDING: In your safety data
presentations, you reported decreased incidences of
complications, particularly or perhaps attributable to
the change in formulation in 1999, so that now it's
less than 6 parts per million of protein.
My patients are clambering, of course, for
any filler that lasts longer but with less
complication, the ideal one having none. If one
supposes that part of the problems are due to the six
part per million protein, is there a possibility that
that six part per million protein amount can be
reduced in the future or are you looking at that?
DR. STROBOS: Let me have Dr. Agerup
DR. AGERUP: I thank you for the question.
This is a continuous program inside Q‑Med to reduce
this protein. And we have a big plan, mainly also
because we have other indications that require higher
exposures of the NASHA gel. And we would like to be
absolutely out of any questions on safety.
ACTING CHAIRPERSON CHANG: Dr.
MEMBER BLUMENSTEIN: So I agree with the
sponsor that there is no concern over the McNemar test
reflecting the correct statistical significance.
However, it may be important in labeling to make sure
that the number of patients who had equivalent results
be displayed, just because that has an implication
with respect to clinical significance.
There are other concerns, however, with
respect to study design because I think the integrity
of the results depends a great deal on masking. And
I'm not sure I understand everything about the
Could somebody describe to me all of the
details of the masking; in particular, who it is that
actually looked at the photographs and whether they
were masked and the treating surgeon, what kind of
masking was going on there and so forth?
DR. STROBOS: Okay. Each site had two
investigators. The investigators were initially
evaluated for entry criteria by the treating
investigator. And that treating investigator would
then open a randomization and basically administer
Restylane or Zyplast according to the randomization.
That treating physician would do the
subsequent touch‑up evaluations. And that treating
physician would also do the adverse events evaluations
for both sides and make the determination about
severity and relatedness.
MEMBER BLUMENSTEIN: And this individual
DR. STROBOS: That individual is unmasked,
right. And then the patient was not informed of which
side was getting which. And in the informed consent,
they were told that one site would be one and one site
would be the other but they wouldn't know which.
There was then at each site a second
investigator, who was identified as the evaluating
investigator. That investigator then reevaluated the
baseline as well as the post‑injection optimal
correction wrinkle skin severity score. And then the
evaluating physician was the individual who went and
evaluated the patients at the two‑month, four‑month,
and six‑month intervals in terms of identifying the
wrinkle severity score.
Wrinkle severity score was identified for
each side by that evaluating physician. And then once
that was documented in the record, a calculation was
made from the database as to whether there was an
improvement from the baseline, the baseline being the
post‑injection optimal correction to that evaluation
The masking episode, the masking was done
after the physicians were asked to evaluate the
specific wrinkle severity score of patients at the
various time points that we're evaluating.
The evaluating physician was then asked to
guess which side was Restylane and which side was
Zyplast. They were not allowed to identify "Don't
know" or guessing as a choice. It was sort of a
forced choice between one or the other.
Have I answered your question?
MEMBER BLUMENSTEIN: Mostly. So the
evaluating investigator you're calling a person, they
were looking at the photographs or at the patient?
DR. STROBOS: They were looking at the
MEMBER BLUMENSTEIN: At each point in
DR. STROBOS: Correct.
MEMBER BLUMENSTEIN: And, therefore, not
comparing to a baseline photograph?
DR. STROBOS: Correct.
MEMBER BLUMENSTEIN: Okay. That was a
little bit of a misunderstanding. Were there
DR. STROBOS: Yes, photographs were taken.
MEMBER BLUMENSTEIN: Was there an external
panel or somebody who then looked at the photographs?
DR. STROBOS: No. Well, part of our
review is that the wrinkle severity score actually
requires you to touch the patient because the way the
wrinkle severity score works best is if you can spread
the wrinkle out.
In part of the discussions with the FDA,
there was no use of the photographs to set wrinkle
severity scores. The photographs were not used to
assess or to second‑guess, as it were, the evaluating
The validation study was specifically done
as an intra‑observer validation, precisely because of
that point, because the design of the study was such
that we were going to compare wrinkle severity scores
assigned by the same individual over a period of time.
MEMBER BLUMENSTEIN: Who is it that made
the decision that a satisfactory result had been
obtained to establish the baseline time point?
DR. STROBOS: I believe that would be the
injecting physician would ‑‑
DR. LEYDEN: And the patient together.
DR. STROBOS: The patient and the
injecting physician would conclude that optimal
correction had been reached and that no further
touch‑ups were needed. Sir?
DR. RENSFELDT: It was the evaluating
investigator who determined the optimal medical
DR. STROBOS: I'm sorry. I was mistaken.
MEMBER BLUMENSTEIN: So the decision at a
particular point in time that a satisfactory result
had been achieved on both sides was made by the
DR. LORENC: I'm sorry. I just want to
make absolutely clear that I was the injector. I was
the treating physician. Another plastic surgeon was
the evaluator. He was completely blinded. He did not
know what was injected, which site. So they were
completely independent and unbiased in their
The decision that was made whether to
inject on what the baseline level was was made by the
evaluating physician and the patient.
MEMBER BLUMENSTEIN: Okay. But both sides
had to have a satisfactory result.
DR. STROBOS: Correct. And they could be
injected with different volumes.
MEMBER BLUMENSTEIN: So that if one side
were satisfactory at a given visit and the other side
was not, there was another treatment given by the
unmasked treating physician, which was subsequently
evaluated. Is that correct?
DR. STROBOS: My colleagues are nodding
yes, that that would be the case.
MEMBER BLUMENSTEIN: So if that were the
case, the other side was not treated. So there would
become a discrepancy in the follow‑up time for time
since last treatment.
DR. STROBOS: Well, yes, except this would
be at two weeks. In other words, the initial
injection would be at a time‑zero, let's say. And
then there would be a two‑week visit for a touch‑up.
And then there was another visit at two weeks
following for touch‑ups.
And I don't believe there were that many
patients who had a second touch‑up. about 35 percent
of the patients had a second touch‑up.
MEMBER BLUMENSTEIN: On one side but not
the other or both sides?
ACTING CHAIRPERSON CHANG: I think the
sponsor is making the point that time‑zero is not
established until both sides are satisfied. And that
is by the blinded evaluator.
MEMBER BLUMENSTEIN: But my point is that
there is some discrepancy in follow‑up introduced by
that procedure of judging one side versus the other.
DR. STROBOS: Not if time‑zero is set at
the time of optimal correction.
MEMBER BLUMENSTEIN: On both sides.
DR. STROBOS: Yes.
MEMBER BLUMENSTEIN: Right, but what it
amounts to is that the follow‑up time, time from the
last procedure for each side, may be different.
DR. LEYDEN: The answer is yes.
DR. STROBOS: I think the answer is yes.
DR. RENSFELDT: The answer is yes. And
the baseline is from when the last treatment was
MEMBER BLUMENSTEIN: In how many patients
would you guess for which this difference could be
four weeks, instead of two weeks?
DR. RENSFELDT: I can't answer that. I
don't have that. I can't even guess it.
MEMBER BLUMENSTEIN: You do concede,
though, that there could be a four‑week discrepancy?
DR. RENSFELDT: There could be in some
DR. STROBOS: I think the question is
looking just at the number of patients who had a
second injection or a third injection would not give
you the number of patients who only had an injection
on one side. Is that?
MEMBER BLUMENSTEIN: That's what I was
getting to. And then the follow‑up was six months
from the date of declaration of satisfactory results
on both sides.
DR. STROBOS: Correct.
MEMBER BLUMENSTEIN: That was a little bit
unclear in the materials that were given to me. It's
whether it was six months from that date or six months
DR. STROBOS: It's six months from the
date of optimal correction.
MEMBER BLUMENSTEIN: And then 2 more
questions related to table 126.96.36.199 through 16. I
don't understand what statistical test was used to
evaluate the tendency to be correct on guessing.
DR. STROBOS: Is this the binomial
DR. JANSSON: I think so.
DR. STROBOS: The statistician is Dr.
Jansson right here.
DR. JANSSON: I'm just looking through the
appendix there. Table 188.8.131.52 used chi‑squared
tests to test whether the portion of correct guesses
is different between sites.
MEMBER BLUMENSTEIN: And did this take
into account matching?
DR. JANSSON: Matching?
MEMBER BLUMENSTEIN: In other words, you
would have the correct result and then the guessed
result. And so that would be like a McNemar table.
DR. JANSSON: Yes. We would just identify
for each patient was the guess correct or not. So
it's a true binomial variable. And we tested whether
the portion of correct guesses in the six sites
differed from each other in that type of using a
MEMBER BLUMENSTEIN: But you could also
see that as a McNemar type of table, right, with
matched pairs? In other words, you have truth, and
then you have the guess of truth. And you have both
kinds of discordance and you have concordance.
DR. JANSSON: Yes.
MEMBER BLUMENSTEIN: Did you take that
into account in the test?
DR. JANSSON: We did not do the McNemar
test for further masking data.
MEMBER BLUMENSTEIN: Right. Did the test
take into account the sites? In other words, there's
just a single p‑value given there, but there could
also be a test of homogeneity of results across sites;
in other words, an interaction between site and guess.
DR. STROBOS: Yes. We did do a site
analysis by site. And masking or incomplete masking
was, if I'm not mistaken, detected at different sites
at the different time points that were assessed when
you drill down into the individual sites. But perhaps
Dr. Jansson is better able to answer that question.
DR. JANSSON: Yes. We performed the exact
binomial test to test whether the portion of correct
guesses differed significantly from the hypothesized
50 percent. We did that for each center on the
We identified two centers there where the
p‑value was below 0.05. We could not reject if a
guess was truly random. We excluded those two sites
and did the primary efficacy analysis again and found
about the same results as in the overall analysis.
MEMBER BLUMENSTEIN: So you're saying that
there was heterogeneity across the sites with respect
to the ability to guess?
DR. STROBOS: Yes, but it changed. Yes.
The answer is yes, but it changed from baseline to ‑‑
I believe the masking analysis was done at baseline,
at two months, and at six months. So the
heterogeneity that you have identified there was
different at those three different time points.
MEMBER BLUMENSTEIN: Then did you do
statistical modeling to find out if the ability to
guess correctly influenced the result, the score that
was recorded by the evaluating investigator?
DR. JANSSON: Yes. We've done a number of
analyses to investigate that. For example, if we
looked at the patients where the improvement from
treatment was similar for Restylane and Zyplast, a
medial category, what we call the category B in our
Those patients tended to have proportional
correct guesses, rather close to 50 percent; whereas,
the patients where a frequent benefit was seen at six
months were much better at guessing which treatment
was applied on which site.
MEMBER BLUMENSTEIN: Are those results
available to me here? I was not able to find them.
I'm not sure if I ‑‑
DR. JANSSON: They are available as
amendment 3 and amendment 5 to our responses to the
FDA questions we have received.
MEMBER BLUMENSTEIN: Well, I will go and
look for them, then, because it was rather hard to get
through all of this material without the indexing and
that sort of thing. Thank you.
ACTING CHAIRPERSON CHANG: Our last
question is from Dr. Doyle.
MEMBER DOYLE: This may seem somewhat
naive, but since I am not a plastic surgeon nor a
dermatologist but a wrinkled consumer, but I am
interested in the fact that the assumption I am making
that if I were a user of this is that in order to
maintain the cosmesis, I would have to be injected the
rest of my life, which in my case may be short but for
some, it may be a considerable amount of years. Is
that a correct assumption?
DR. STROBOS: Well, the answer is yes.
The reinjection rate with collagen, which is the
approved product in the United States, typically when
you look at studies, it's on the order of three to
four months. When you look at some of the episodic
studies that have been done on reinjection and in
Europe, it's a longer time period between reinjection.
There is also a certain demographic that
at a certain time period, people stop getting
reinjected. And the time period at which people start
varies, of course. And then some people are just
episodic injectors, but perhaps if you would like, I
would have Dr. Leyden ‑‑
MEMBER DOYLE: There are a couple of
things I would like to ask, then, with the assumption
that there is a long possible, very, very long‑term
usage of this, not necessarily with collagen but with
In the world literature because I realize
the trials here are quite short, is there any evidence
that if there is a longer time between injections or
a shorter time ‑‑ and the reason I ask, there seem to
be a number of adverse reactions that are transient
that occur in the first couple of weeks. If the time
period goes down, I am concerned that you would have
this repetition of these minor but irritating side
The other thing is, is there any evidence
of any sort of cumulative effect from the very small
parts of the protein that are in the six parts per
DR. STROBOS: Perhaps I could have Dr.
DR. AGERUP: Thank you. This is an
interesting question. My answer, though, is
anecdotal. I have been living with this for many
years, eight years about. So we have many patients
treated since then.
What we see is that after somewhat like
two or three injections, you need less of this
material. And because this material is degraded by
inflammatory reactions and other hydrolysis, our
interpretation is that the skin gets used to this
treatment and et cetera and, therefore, becomes a
friend with it, so to speak. The protein issue, this
is six ppm released over a time period of almost a
year. We are now down to enormous exposures.
ACTING CHAIRPERSON CHANG: Thank you. At
this time the panel is going to take a break for five
minutes. And we plan to reconvene at ‑‑ it is by my
watch 18 after ‑‑ shortly before 25 of.
(Whereupon, the foregoing matter went off
the record at 10:19 a.m. and went back on
the record at 10:32 a.m.)
ACTING CHAIRPERSON CHANG: I would like to
reconvene the advisory panel at this time. I would
like to introduce Anthony Watson, who will begin the
FDA's presentation for this PMA.
INTRODUCTION AND PRECLINICAL
MR. WATSON: Some of this presentation may
seem repetitive based on what we have heard this
morning. So please bear with me.
First of all, I would like to thank
everybody for being here. I am Anthony Watson, the
lead reviewer for this PMA. As you know, we will be
discussing the PMA for Restylane injectable gel by
Today's FDA speakers will start with me.
As lead reviewer of the PMA, I will be discussing the
preclinical portion. Dr. Horbowyj will then discuss
the clinical aspects of the PMA. Dr. Telba Irony will
then discuss the statistical aspects of the PMA. I
would also like to point out that Dr. Amy Newburger,
a member of this advisory panel, provided a clinical
consult for this PMA.
So what is Restylane? Restylane is a
transparent, viscous, and sterile gel supplied in a
syringe. It consists of non‑animal, stabilized,
hyaluronic acid suspended in a physiologic buffer.
Restylane's proposed intended use, as you
can see there, is for the temporary correction,
moderate to severe facial wrinkles and folds, such as
nasolabial folds. The panel will be asked to comment
on these indications later.
The sponsor conducted a battery of
preclinical tests in the area of microbiology,
toxicology, immunology, biocompatibility, and shelf
Microbiological preclinical testing
consisted of pyrogen and bacterial endotoxin testing.
The material passed both of these tests.
Toxicological testing consisted of acute
subchronic and chronic toxicity testing in rabbits as
well as two cytotoxicity tests. ISO elution and
colony formation methods were used. The material was
non‑cytotoxic, and there was no evidence of foreign
The sponsor also performed two Ames
mutagenicity tests and two genotoxicity tests, as
shown here. In these tests, the material was
non‑mutagenic and non‑genotoxic.
Now, Restylane contains 1,4 butanediol
diglycidyl ether, which is referred to as BDDE. BDDE
acts as a cross‑linker in the product. It has been
noted to be mutagenic in the Ames bacterial
mutagenicity assay, and diglycidyl ethers are known to
act also as sensitizers.
The sponsor has conducted an extensive
biocompatibility evaluation of the product and has
presented information that indicates the device to be
biocompatible, non‑mutagenic, and non‑sensitizing.
However, to further address the concern that BDDE
could act as a carcinogen, FDA requested the sponsor
to either provide the results of carcinogenicity
testing of BDDE or to provide information that
adequately addressed the safety issue.
The sponsor provided a study report of an
investigation of the potential for BDDE to cause
carcinogenesis in a mouse model. The study involved
a twice weekly topical application of BDDE at two
doses, .05 percent and .2 percent, over the course of
103 weeks, or approximately 2 years.
The finding of the study was that there
was no significant difference in the incidence of
tumor formation between treatment and control with the
exception of the induction of lymphoblastic
lymphosarcoma in female mice.
To address this observations, the sponsor
provided additional information indicating that the
method used for classification of mouse hematopoietic
neoplasms used in the study was outdated and that
using current methods for identifying and classifying
mouse hematopoietic tumors shows no difference between
treatment and control animals in this study.
The difference in categorization of tumor
types between when the study was conducted and today's
widely accepted approach is based upon whether
lymphoid neoplasms are separately identified, as was
done previously, or if they are lumped together under
the heading of lymphoid tumors, as is done today.
When tumors identified as of lymphoid origin are
combined in the study, there is no difference between
treatment and control.
The carcinogenicity information from the
mouse study and the sponsor's own preclinical
mutagenicity and genotoxicity evaluations indicate
that BDDE is not carcinogenic.
However, if we do assume that BDDE did
cause the induction of a specific tumor in the mouse
model at the high dose concentration, or .2 percent,
we can calculate the cancer risk posed to patients
using the product.
The calculated cancer risk of patients
receiving Restylane assuming the mouse study did
conclude that BDDE was carcinogenic is estimated to be
1.2 times 10‑7 divided by 10,000, or approximately one
Based on modern evaluation techniques and
the anticipated dose level received by the patient,
FDA determined there to be no carcinogenic risk from
the BDDE in Restylane.
So, continuing with the preclinical
testing, Guinea pig maximization test was performed,
demonstrating that the material did not display
evidence of delayed hypersensitivity.
Two muscle implantation tests were
performed in rabbits: one for 4 weeks and the other
for 90 days. In the four‑week test, the material was
well‑tolerated. And in the 90‑day study, there was a
slight inflammatory response greater than observed in
the negative control, which we considered to be minor.
Shelf life stability studies demonstrate
that the device is stable at room temperature for up
to 12 months.
So the overall summary from the
preclinical testing indicated that Restylane was safe
to be evaluated in clinical studies. And now I would
like to introduce Dr. Roxi Horbowyj to discuss the
clinical portion of the PMA.
DR. HORBOWYJ: Thank you, Tony.
DR. HORBOWYJ: Good morning. As Tony
said, this presentation highlights the FDA clinical
review of this current Restylane application.
Specifically, as you have already heard,
the pivotal clinical study and open label extension
support this application.
The devices that have been studied are:
Restylane, which is a hyaluronic acid generated by at
least two Streptococcal species of bacteria,
stabilized and suspended in psychologic buffer at pH
7 and a concentration of 20 milligrams per cc.
The intended use of this study was to
correct contour deformities in wrinkles at the
nasolabial fold. During the study, the device was
delivered via a .7 cc syringe and using a 30‑gauge
half‑inch needle, maximum dose for treatment session
of 1.5 cc.
Zyplast was the control. And it is a
purified bovine dermal collagen cross‑linked with
glutaraldehyde dispersed in phosphate buffered saline.
And this device includes .3 percent lidocaine.
This device is indicated for the
correction of contour deficiencies of soft tissue. It
was delivered during the study via a one cc syringe
and a fine gauge needle to a maximum dose per year of
Pivotal study was designed as a one‑to‑one
randomized prospective study at six U.S. centers to
compare Restylane and Zyplast in a within‑patient
control model of augmentation of correction of
bilateral naso folds.
Effectiveness was followed for six months
after the post‑treatment baseline. Safety was
followed for 12 months after the post‑treatment
Masking was attempted in several ways.
Patients were considered to be partially masked
because of prior history of exposure of some of these
patients to the control. Evaluating physicians were
independent. And masked treating physicians, as you
have heard, were unmasked.
As to effectiveness, the primary objective
was to evaluate differences in the effectiveness of
Restylane and Zyplast on the visual severity of the
nasolabial folds as were assessed by the evaluating
investigator at six months after the post‑treatment
This baseline is defined, as we have
heard, to begin at the follow‑up, which demonstrated
that optimal correction had been sustained for two
weeks. And optimal correction was defined to be the
best cosmetic result obtainable as was determined by
the evaluating physician.
A specific objective score or goal for
correction was not defined in the protocol. Two
injectable implant sessions were expected to be needed
to achieve the goal, however.
The primary evaluating parameter was the
wrinkle severity rating scale, otherwise known as the
SRS score. This is a five‑point integer scale. A
change in the score of one was considered to be
clinically significant based on a review of 30
non‑study photos. This validation was not reconfirmed
using study photo evaluations.
As to safety, adverse events were reviewed
in two ways. A patient diary was kept, an allowed
record of intensity and duration of pain, tenderness,
swelling, redness, bruising, itching, and other events
for 14 days post‑treatment. Then there was also
follow‑up by the treating physician during follow‑up
that lasted through 12 months.
Hypersensitivity reaction was addressed
for both Restylane and control. Pre‑screening was
performed for sensitivity to collagen; however, not to
hyaluronic. Pre and post‑treatment antibody titers
were not monitored. However, a post‑treatment adverse
event skin testing protocol was planned for
sensitivity to hyalurone and to collagen in case
hypersensitivity was suspected by the investigator.
As to secondary objectives, there were
several. The number of treatment sessions required to
achieve optimal cosmesis, a global aesthetic
improvement score, which consisted of subjective
evaluation if the site was very much improved, much
improved, improved, had no change, or was worse. And
this was to be assessed at all follow‑up points by the
evaluating investigator and the subject.
Another secondary objective was to look at
the SRS score as assessed by the subject at two, four,
and six months as well as the evaluating investigator
at two and four months.
The study population consisted of
non‑pregnant, non‑lactating adults who were seeking
augmentation correction of bilateral naso folds.
Patients were enrolled if they met the criteria for
SRS 3 or 4 at pretreatment baseline. They needed to
be willing to abstain during the study from exclusion
procedures, such as laser or chemical resurfacing,
Botox injection, aesthetic facial surgery, concurrent
facial wrinkle treatments, immuno‑modulary therapy,
and desensitization injections to meat products.
They needed to have no active skin disease
or aesthetic facial therapy within six months of study
entry. And they needed to not have coagulopathy, any
known allergy or sensitivity to device components, or
to meat products.
As you have study, this pivotal study
procedure had two phases. There was a treatment
phase, in which the device dose was required to
achieve the optimum cosmetic result within the maximum
limits for device use. There was reevaluating every
two weeks with touch‑up if correction was suboptimal
on the follow‑up time.
Post‑treatment baseline began if the
optimal correction had been maintained for two weeks.
Follow‑up again for effectiveness was at 2, 8, 16, and
24 weeks after this baseline. And follow‑up for
safety was at 2, 8, 16, 24, 36, and 52 weeks after
Sample size was determined for this study
based on the hypothesis that three times as many
Restylane‑treated sites were to remain superior
compared to control at six months post‑treatment
Superiority was defined in the protocol as
a difference of at least one unit in the SRS score in
favor of one of the treatments. The SRS score
difference, considered to be clinically significant,
was one unit. On the basis of this and accounting for
potential loss of follow‑up, the sample size was
calculated to be 130 patients.
Reviewing study outcomes: demographics,
as you have heard, for the cohort relayed a patient
population that was predominantly female, Caucasian,
nonsmokers, who had very little sun exposure or
minimal sun exposure. There were a few males, few
other ethnicities, and smokers involved in this study.
Demographics also show us that 65 percent
of the patients had had prior facial aesthetic
procedures, most commonly collagen injection, which
43.1 percent of the population had experienced, as
well as botulinum toxin injection, which was
experienced by 23.4 percent of the population.
Thirty‑five percent of the population had no prior
Patient disposition is summarized in this
slide. Pretreatment and at baseline, there were 138
patients who presented. By six months, there were 134
patients. And the study reports that 9 and 12‑month
follow‑up for safety included 125 patients.
There was a masking assessment that was
done evaluating both the evaluating investigator as
well as the patients. This slide shows the results
that were obtained at baseline, two months, and six
months. Usually, as the sponsor has also indicated,
a 50 percent guess is considered to be consistent with
What the study results showed was that at
baseline for both the evaluating investigators and for
patients, the correct guess was approximately 60
percent. This increased to approximately 70 percent
by 6 months. And a percentage greater than 50
percent, is associated with incomplete masking. It
was also noted that masking varied by center and this
variation was statistically significantly different.
As to pivotal study outcomes for primary
effectiveness, the incidence of the SRS score at six
months as determined by the evaluating physicians is
listed here. Seventy‑eight patients were found to
have a Restylane‑treated size score, which was better
than control. Forty‑six patients presented with
Restylane and control‑treated sites to be equal, and
13 patients presented with the Restylane‑treated sites
to be worse, had a higher SRS score than control.
This was from the per‑patient basis.
Looking on the overall basis of the study cohort, a
mean SRS score as determined by the evaluating
physician shows that when you look at the absolute
difference between Restylane and control at baseline
and pretreatment, the differences are very small, 0.02
and 0.01 units. However, at six months, the
difference is 0.58 units of SRS.
Another way of looking at this is depicted
in this slide, which shows time on the x‑axis and the
SRS score along the y‑axis. Each red line, fine red
line, is an indicator of a unit of SRS.
And what you can see here is that at
pretreatment. And at optimum treatment, the SRS score
changed or achieved was 1.5 for both Restylane and
control. The red line presenting the data represents
Restylane, the yellow line control. And the green
line shows the difference between the two. It simply
is the traction.
So what you see is that as time
progressed, the difference was 0.58, which is below
the unit of one, which was considered to be clinically
significant in superiority in the protocol per
The secondary pivotal study outcomes for
effectiveness from the patients' perspective of
evaluation of SRS trended along with the evaluating
physicians' assessment and is demonstrated here.
As you can see, both for the comparisons
of Restylane and control in the upper portion of this
slide, the trends are similar and in the overall mean
assessment and the absolute difference here, it is
also in line with what was found by evaluating the
Another secondary outcome was the mean
global aesthetic improvement score. This slide shows
Restylane being ‑‑ I will show this with this pointer.
Restylane is shown in this color, Restylane being
better than control. So it is in this color. I'm
pointing this out because I think sometimes the colors
are a little bit difficult to read, Restylane being
equal to control is shown in the blue. And Restylane
worse than control is shown in the gold. The
reference is here below.
And it did show that the trends were
similar to the evaluating investigators and patients.
And it did show an increase with time for Restylane
being judged better than control by SRS scale, which
was in the protocol.
As to the number of treatment sessions, to
achieve optimal cosmesis, optimal cosmesis required
one to two treatments. And for initial treatment
alone, there were 65 percent of patients from the
Restylane‑treated side that only needed one treatment
and 62 percent of patients who needed only one
treatment with control.
The distribution of patients requiring
three treatments was that seven patients receiving
Restylane needed three treatments and three patients
receiving control needed three treatments. Overall,
however, there were no statistically significant
differences in the number of treatments required for
Basic criteria for some of the more
frequent reactions after treatment with Restylane were
presented. Hypersensitivity was defined as an
inflammatory reaction with swelling, redness,
tenderness, induration, and rarely acneform papules at
the injection site with an onset of one to several
weeks after initial treatment in previously unexposed
individuals and in less than seven days following
treatment in patients known to have been previously
exposed. Average duration to systems were reported to
have a two‑week duration.
Injection site reactions were described to
be mainly shot‑term inflammatory symptoms starting
early after treatment and with less than seven days
duration. They were considered to be a mix of
different types of reactions that do not fit with
Looking at similar information for the
control as reported and the labeling for the control,
hypersensitivity is defined as erythema, swelling,
induration, and/or urticaria implant sites, often
following unrecognized or unreported positive collagen
skin tests. It is reported to occur in one to two
percent of treated patients, typically persists for
one to nine months, with an average duration of four
Rarely, abscess formation is reported to
occur, in some cases associated with elevated
anti‑bovine collagen antibodies, weeks to months
following injections and may cause induration and/or
Injection site reaction is defined to be
minimum swelling, redness, and discomfort immediately
following implantation. Temporary palpable lumpiness
or visible material, such as white papules or
milia‑like yellow, may occur.
As to safety, from the patient diary, this
slide shows the incidence of moderate or severe
symptoms at initial session and after touch‑ups. The
control is presented in the lighter color bar, and
Restylane is presented in the darker color, lower bar.
So for each one of these symptoms that we
look at, which is bruising, redness, swelling, pain,
tenderness, itching, and other, the two treatment
types are next to each other, the upper bar being
control, the lower bar being Restylane.
This data indicates that there was an
increased incidence of moderate or severe bruising,
redness, swelling, pain, tenderness, and itching after
the first treatment with Restylane compared to
The difference for itching trended toward
statistical significance. The differences for
bruising, redness, swelling, pain, and tenderness,
were statistically significantly different. The data
indicates that this trend persists for swelling and
tenderness in patients who had touch‑ups. Of note,
the report of other for Restylane included two papulal
nodule lesions reported with onset at more than 40
This side presents safety from the patient
diary for symptom duration. Again, this data is
presented after the initial session and after all of
the touch‑ups. The key here is a color code, which
shows that the green colored bar portion of the bar
represents one day symptomatology, the blue bar 2 to
7 days, the gold bar 8 to 13 days, and the orange bar
14 or more days. They are presented here in that time
This chart shows that after first
treatments, while the symptom reports during the first
day were comparable, a greater percentage of
Restylane‑treated naso folds than control‑treated naso
folds were reported to have swelling, pain,
tenderness, itching, and other symptoms during the
second to seventh day post initial treatment. This
trend persisted for more than seven days, the golden
orange bands for bruising, redness, swelling, and
After all touch‑ups, there were more
presentations of redness, swelling, tenderness, and
other symptoms on the Restylane‑treated at two to
seven days. Bruising, redness, and swelling were
reported for Restylane as well as control at 14 or
The open label extension design allowed
study patients to receive unilateral or bilateral
re‑treatment with Restylane at the sixth or ninth
month visits. If re‑treated, the efficacy assessment
was performed before re‑treatment but not after
re‑treatment and if not re‑treated, efficacy
assessment was performed beyond six months. The
hypothesis here was that Restylane is superior to
Zyplast three times as frequently as Zyplast is
superior to Restylane.
For safety, the pivotal protocol
continued. However, it's important to note here that
these patients were evaluated at the 6th month, 9th
month, and 12th month follow‑ups, not every 2 weeks
post‑injection if they were injected as they were in
the initial phase of the study.
So there was no two‑week follow‑up after
reinjection during the open label extension design.
And there were also no patient diaries recorded. So
the opportunity for symptoms to be elicited after
reinjection at six months did not present itself until
This represents the open label extension
disposition of patients as well, showing the number of
patients who were available for safety and for
effectiveness and the number of patients who were
re‑treated at six and nine months.
The assessment of pivotal study treatment
effectiveness at 9 or at 12 months is limited because
75 percent of pivotal study patients were re‑treated
at 6 months. Only 24.6 percent of pivotal study
patients presented for effectiveness at 9 months, and
only 5 percent of pivotal study patients presented for
effectiveness at 12 months.
In summary as to effectiveness, optimal
correction is achievable with both Restylane and
control by a mean change of 1.5 units SRS in a
comparable number of sessions. The wrinkle SRS
assessment that one unit is a clinically significant
change was not confirmed on study photos.
SRS for six months was one unit higher for
Restylane than control in 59.7 percent of treated
patients but less than one unit higher, specifically
at 0.8 units higher, on average for the overall
cohort. SRS interpretation at 9 and 12 months
post‑treatment is limited as most, specifically 72.5
percent of patients, were re‑treated at 6 months.
In summary as to safety, hypersensitivity
reaction to Restylane was reported to vary at onset of
symptom presentation in the protocol. During the U.S.
pivotal study, symptoms of inflammation within 14 days
post‑treatment were of statistically significantly
higher intensity after initial treatment with
Restylane compared to control.
There were two papulal nodule lesions
reported with onset at more than 40 days
post‑treatment. Antibody titers were not evaluated.
And so symptom profiles were not correlated to
immunologic status for change.
Hypersensitivity reaction may have been
underestimated as injection reaction and early
hypersensitivity symptom profiles overlap. This may
have confounded diagnosis of a hypersensitivity
reaction to a new product.
Now it is my pleasure to introduce Dr.
Telba Irony to present the FDA's statistical overview.
DR. IRONY: Well, good morning. I am
Telba Irony, and I will provide the statistical
perspective of the Restylane pre‑market application.
My presentation will discuss the following
topics: the pivotal study design; the patient
disposition; the results provided by the evaluating
investigator; the open label study. And I will talk
about some important study characteristics that should
be taken into account when the study results are
analyzed; and, finally, some points to consider when
evaluating a superiority claim for this device.
The study had a split face design in the
sense that each patient received Restylane treatment
in one side of the face and Zyplast treatment that
served as a control in the other side of the face.
The treatments were randomly assigned to each side of
the face, and 138 subjects were randomized.
Only nasolabial folds were treated. The
study was double‑blind. The patients were masked.
And the evaluating investigators, who were different
than the treating investigators, were masked as well.
There were follow‑up visits at two, four,
and six months. At 6 months, 100 patients were
re‑treated. The remainder non‑re‑treated 34 patients
were also evaluated at 9 months. The study was
performed at six centers.
Each side of the face was evaluated before
treatment on the severity rating scale. The severity
rating scale goes from one ‑‑ that means no visible
fold ‑‑ to five, the extremely deep folds.
Then the sides were treated until both
became optimal. Sometimes that required more than one
application. After six months, each side of the face
was evaluated again.
The primary endpoint was the comparison of
both sides of the face with respect to the change from
pretreatment to six months post‑baseline. The
comparison was made by the evaluating investigator.
And one point different was considered clinically
The patient disposition was as follows.
One hundred, thirty‑eight patients were initially
randomized and constituted the intent‑to‑treat sample.
Out of those, 134 completed the study up to six
months. There were also 26 subjects with major
protocol violations. And, consequently, 108 subjects
constituted the per‑protocol sample. We analyzed the
results from the intent‑to‑treat sample that were
confirmed by the results of the per‑protocol sample.
The results for the primary endpoint
provided by the evaluating investigator follow.
Restylane was superior to control in about 57 percent
of the subjects. Restylane was equivalent to control
in 33.6 percent of the subjects. Restylane was
inferior to control in 9.5 percent of the subjects.
McNemar test provided statistical
significance, meaning that the hypothesis that
Restylane is inferior to control was rejected. Note,
however, that the McNemar test disregards the number
of cases for which the products were similar. This
would be true, even though there were much more cases
for which the products were similar.
This is a secondary endpoint. They are
the results from the measurements at two months, four,
and six months. They were all statistically
significant. Again, McNemar test was used. And the
equivalent cases were not taken into account, even
when they were 59 percent, as in the case of the
second month. No formal longitudinal analysis was
Here is another secondary endpoint, which
is the mean change from pretreatment in the SRS score,
which was computed for each side of the face at two,
four, six, and nine months. For 8 months, only 34
patients were included. Again, no formal statistical
longitudinal analysis was performed.
At all time points, the Restylane side had
lower ‑‑ that means better ‑‑ mean values than the
control side. The mean difference was always less
than one point.
Open label study. As I said before, at 6
months, 100 patients were re‑treated. The remaining
34 patients were not re‑treated and were evaluated at
9 months to provide an assessment of whether or not
the products last beyond 6 months.
The non‑re‑treated patients were mostly at
centers 1 and 2. Consequently, it is difficult to
assess whether the need for re‑treatment was due to
clinic effectiveness or treatment effectiveness.
The results of the open label study were
100 patients needed re‑treatment. And, consequently,
one can say that neither product lasted more than six
months. For 21 patients, which means 16 percent,
Restylane lasted more than control. For 13 patients,
10 percent, the control was equal to Restylane. Given
that information, it is problematic to state that
Restylane lasts beyond six months.
Important study characteristics, the
sponsor assessed the effectiveness of masking for the
evaluating investigators. Masking is important
because the measurements are quite subjective.
A statistical hypothesis test was
performed to assess the effectiveness of masking. The
effectiveness was rejected at all time points. At
baseline, the evaluating investigators could correctly
guess which side was treated with which product in 64
percent of the times. At two months, correct guesses
were made in 66 percent of the times. At six months,
correct guesses were made in 70 percent of the times.
The sponsor also performed a validation of
the severity rating scale. In that study, 30
photographs of wrinkles were shown to the evaluating
investigators at 2 time points separated by about 2
weeks. The proportion of agreement between the
evaluations was about 70 percent.
Treatment of missing values. There were
four withdrawn patients. The sponsor used the
pretreatment SRS score for all endpoints evaluated
after the patient's withdrawal. As a consequence,
both sides of the face should have the same score, and
the withdrawn patient was not considered by the
Missing data for the secondary
effectiveness measures were handled according to the
last observation carried forward method, which is not
appropriate in this case because the endpoints tend to
get worse as time goes by. However, due to the split
face design, we do not think that this method favored
Results across centers: For all six
centers, the proportion of cases in which Restylane
was superior to control was larger than the proportion
of cases in which Restylane was inferior to control.
However, for half the centers, Restylane was
equivalent to control for most patients.
Points to consider: One of the questions
we have to the panel members concerns the superiority
claim. Could you say that Restylane is better than
control considering that for 43 percent of patients,
Restylane was not superior to control? In half the
centers, the proportion of patients for which
Restylane and control were equivalent was larger than
the proportion for which Restylane was superior.
There was a lack of a totally effective masking
procedure. And the evaluations are subjective.
More points to consider: Can we say that
Restylane lasts more than six months? The open label
had a small and biased sample. The non‑re‑treated
patients were mainly in two centers. And,
consequently, it is difficult to establish if
effectiveness was due to treatment or center. And,
finally, neither product lasted more than 6 months for
75 percent of the patients.
Thank you for your attention.
ACTING CHAIRPERSON CHANG: Thank you.
At this time, do any panel members have
questions to direct to the FDA? Dr. Newburger?
PANEL DELIBERATIONS AND ADDRESS FDA QUESTIONS
MEMBER NEWBURGER: For Dr. Irony, in
assessing the characteristics of this filler compared
to collagen, it's very, very different. Forty‑three
percent of the test population had previous treatment
DR. IRONY: Correct.
MEMBER NEWBURGER: And so these
individuals would recollect the characteristics of how
this filler vanished over time. So is that not an
unavoidable point in terms of looking at bias, how
they correctly guessed?
Second of all, for those who were
re‑treated, under "Results," you put a conclusion that
neither product lasted for more than six months.
Is that necessarily so? Couldn't it be
that these people were pleased with their results,
started to see it vanishing a bit, and wanted to have
more because, after all, why were they participating
in the study since they had abjured from other
DR. IRONY: I think your questions are yes
for both cases. One thing that I wanted to clarify is
that the masking that I pointed out was not the
patient, was the evaluating investigator, but I guess
the same conclusion that you made is valid to the
They were dermatologists. And they
probably were familiar with the results by the
control. So maybe that could be a cause for the
correct guess that they guessed correctly which
product the patient had in each side.
So I agree with you. Masking is very,
very difficult, if not impossible, in this case.
MEMBER NEWBURGER: And then one last
question, the non‑re‑treated patients who were in the
two centers, did you happen to look? Were those the
two centers where they had more bruising and swelling
and these people just didn't want to go for a second
DR. IRONY: I don't know. I didn't look.
So I'm not sure. I don't know if I answered your
other question, the second question, that you asked
about if it's possible that a patient, although not
optimal, was satisfied or maybe dissatisfied. I don't
know. That's possible, too.
MEMBER NEWBURGER: Thank you.
ACTING CHAIRPERSON CHANG: Okay. Dr.
MEMBER MILLER: I just have a question
about nowhere in the data presented by FDA or by the
sponsor did I get a sense that there was any attempt
to track the absolute amount of the device which was
delivered to the patient and compare that to the
incidence of symptoms and side effects and that sort
of thing. Was there any tracking of that information?
ACTING CHAIRPERSON CHANG: If I can
rephrase the question, are you asking, was there any
attempt to correlate volume of injection and incidence
of adverse events?
MEMBER MILLER: Right, sort of a
dose‑response sort of thing, I guess.
DR. HORBOWYJ: We have not seen data that
ACTING CHAIRPERSON CHANG: Dr. Halsey?
MEMBER HALSEY: One quick technical
question. On the materials we have been provided, the
toxicity testing includes bacterial endotoxin. And it
says less than 0.5 used per ml. And then in the
summary, pre‑market summary draft, it says less than
.05. Is that a typo or has the endotoxin content
Do you see what I am looking at?
MR. WATSON: Actually, let me grab what I
have here. You are saying that there is a difference
between what is in the summary and what is actually in
MEMBER HALSEY: The preclinical summary
says it's 0.5. And here in this summary of laboratory
data, it says it is less than 0.05. So it's a tenfold
difference in endotoxin content. I just wonder if
that is a difference in a product or a typo?
MR. WATSON: I believe that is a typo, but
maybe the sponsor actually can answer that question,
what the actual level was.
DR. AGERUP: Soon. We are checking it.
MR. WATSON: Okay. They are checking it
as well. I don't know offhand, but I believe it's a
ACTING CHAIRPERSON CHANG: Whether it's a