UNITED STATES OF
AMERICA
FOOD AND DRUG
ADMINISTRATION
CENTER FOR DEVICES AND
RADIOLOGICAL HEALTH
MEDICAL DEVICES ADVISORY
COMMITTEE
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GENERAL AND PLASTIC SURGERY
DEVICES PANEL
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65TH
MEETING
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THURSDAY,
MARCH 25, 2004
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The
panel met at 8:00 a.m. in Salons A-D of the Gaithersburg Hilton Hotel, 620
Perry Parkway, Gaithersburg, Maryland, Dr. Michael Choti, Chairman, presiding.
PRESENT:
MICHAEL A. CHOTI, M.D., Chairman
GRACE T. BARTOO, Ph.D., RAC, Industry
Representative
BRENT A. BLUMENSTEIN, Ph.D., Voting Member
PHYLLIS CHANG, M.D., Voting Member
LEELEE DOYLE, Ph.D., Consumer Representative
DOUGLAS G. FISH, M.D., Temporary Voting Member
MICHAEL J. MILLER, M.D., Voting Member
ROBERT J. MUNK, Ph.D., Patient Advocate
AMY E. NEWBURGER, M.D., Voting Member
MICHAEL J. OLDING, M.D., Temporary Voting Member
NEAL S. PENNEYS, M.D.,
Ph.D.,
M.B.A., Temporary Voting Member
DAVID KRAUSE, Ph.D., Executive Secretary
FDA REPRESENTATIVES:
CELIA WITTEN, Ph.D., Division Director
CDR STEPHEN RHODES, Branch Chief
DAVID BERKOWITZ, V.M.D., Ph.D.
CHARLES DURFOR, Ph.D.
HERBERT LERNER, M.D.
SPONSOR REPRESENTATIVES:
MARCUS A. CONANT, M.D.
PETER ENGELHARD, D.O.
KIMBERLEY FORBES-McKEAN, Ph.D.
SHARON LEVY, M.D.
DOUGLAS MEST, M.D.
DANNY VLEGGAAR, M.D.
A G E N D A
Call to Order: ................................. 5
Conflict of Interest, Temporary Voting
Member Deputization and Opening Remarks
........................................ 5
David
Krause, Ph.D., Executive Secretary
Panel Introductions ............................ 9
Michael
Choti, M.D., Chairman
Update Since Last Meeting...................... 13
CDR
Stephen Rhodes, Branch Chief
Plastic
and Reconstructive Surgery
Devices
Branch
Open Public Comment ........................... 16
Applicant Presentation, Dermik Laboratories,
Sculptra ...................................... 36
Product
History ......................... 41
Kimberley
Forbes-McKean, Ph.D., Senior Director,
Product
Development and Commercialization
Dermik
Laboratories
Lipoatrophy
Condition ................... 46
Marcus
A. Conant, M.D., Medical Director
Dermatology/HIV
Consultations
Non-clinical
Data ....................... 54
Jeffrey
Handler, Ph.D., DABT, Director
Drug
Safety Assessment and Evaluation
Dermik
Laboratories
Clinical
Data ........................... 57
Sharon
Levy, M.D., Senior Medical Director
Scientific
and Medical Affairs
Dermik
Laboratories
Sponsor-Investigator
Studies ............ 77
Peter
Engelhard, D.O., Medical Director
Apex
South Beach
A G E N D A
Conclusions
............................. 85
Kimberley
Forbes-McKean, Ph.D., Senior Director
Product
Development and Commercialization
Dermik
Laboratories
BREAK ........................................ 132
FDA Presentation ............................. 133
Office
of Device Evaluation/Division
of
General, Restorative, and Neurological
Devices
Introduction
........................... 133
Herbert
P. Lerner, M.D.
Toxicology
David
B. Berkowitz, Ph.D., VMD.......... 134
Clinical
Herbert
P. Lerner, M.D.................. 138
Panel Deliberations and Address FDA Questions 152
Lunch ........................................ 204
Continue Panel Deliberations and FDA Question
Discussion
............................. 205
Break ........................................ 254
FDA and Sponsor Summations, Concluding Panel
Deliberations and Vote .............................................. 254
Adjournment .................................. 303
P-R-O-C-E-E-D-I-N-G-S
(8:06
a.m.)
DR.
KRAUSE: Good morning. Glad to see
everybody could make it today. Were
ready to begin this, the 65th Meeting of the General and Plastic
Surgery Devices Panel. My name is David Krause. I'm the Executive Secretary of the panel. I'm also a biologist and a reviewer in the
Plastic and Reconstructive Surgery Devices Branch, and the Division of General,
Restorative and Neurological Devices. I
would like to remind everybody that you are requested to sign in on the
attendance sheets which are available at the tables just outside the door. You may also pick up an agenda, panel roster
and information about today's meeting on that table. The information includes how to find out about future meeting
dates through the advisory panel phone line, and how to obtain meeting Minutes
or transcripts.
Before
I turn the meeting over to Dr. Choti, I'm required to read a number of
statements into the record. These are
the Deputization of Temporary Voting Members and Conflict of interest. I'm going to start with the appointment to temporary
voting status. Today we have a number
of panel members who are from Center for Drug Panels, and I need to read a
different statement for them. That's
this statement here.
Pursuant
to the authority granted under the Medical Device Advisory Committee Charter of
the Center for Devices and Radiological Health dated October 27, 1990, and
amended August the 18th, 1999, I appoint the following individuals
as voting members of the General and Plastic Surgery Devices Panel for the
meeting on March the 25th, 2004; Dr. Douglas Fish and Dr. Neal S.
Penneys. For the record, Dr. Fish is a
voting member of the Anti-Viral Drug Advisory Committee, and Dr. Penneys is a
consultant to the Dermatologic and Opthamologic Drugs Advisory Committee of the
Center for Drug Evaluation and Research.
They are special government employees who have undergone the customary
conflict of interest review, and have reviewed the material to be considered at
this meeting. This is signed by Mr.
Peter Pitts, who is the Associate Commissioner for External Relations.
The
second appointment to temporary voting s status is for individuals who are
consultants to Center for Device Panels.
Pursuant to the authority granted under the Medical Device Advisory
Committee Charter dated October 27, 1990, and as amended August the 18th,
1999, I appoint Steven Lee and Michael Olding as Voting Members of the General
and Plastic Surgery Devices Panel for this meeting on March 25th,
2004.
For
the record, these individuals are special government employee 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 is signed by Dr. David
Feigel, who is the Director for the Center for Devices and Radiological Health.
The
final statement which I will read into the record is the conflict of interest
statement. The following announcement
addresses conflict of interest issues associated with this meeting, and is made
a part of the record to preclude even the appearance of an impropriety.
To
determine if any conflict existed, the agency reviewed the submitted agenda for
this meeting, and all financial
interests reported by the committee participants. The conflict of interest statute prohibits special government
employees from participating in matters that could affect their or their
employer's 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 Dr. Leach and
Dr. Miller. Each of these panelists
reported current and/or past interest in a firm at issue, but in matters not
related to today's agenda.
The
agency has determined, therefore, that they may participate fully in today's
deliberations. In the event that the
discussions involve any other products or firms not already on the agenda for
which an FDA participant has a financial interest, the participant should
excuse him or herself from such involvement and the exclusion will be noted for
the record.
With
respect to all other participants we ask in the interest of fairness that all
persons making statements or presentations disclose any current or previous
financial involvement with any firm whose products they may wish to comment
upon.
Okay. Now that I've read the statements into the
record, I'd like to turn the meeting over to Dr. Choti.
CHAIRMAN
CHOTI: Thank you, Dr. Krause, and good morning. My name is Michael Choti.
I'm an Associate Professor in the Department of Surgery, with an
interest in Surgical Oncology at Johns-Hopkins. Today this panel will be making recommendations to the Food and
Drug Administration on the pre-market approval application. The next item of business is to introduce
the panel members who are giving time to help the FDA in these matters, and FDA
Staff as well at the table.
I'm
going to ask each person to introduce him or herself stating his or her area of
expertise, position title, institution, and his or her status on the panel,
whether they're a voting member, industry or consumer representative, or
deputized voting member. Why don't we start
with Dr. Lee.
DR.
LEE: Good morning. My name is
Steven Lee. I'm President of Medical
Device Testing Innovations in Sarasota, Florida, independent research and
testing lab. My areas of interest are
biomaterials and biomechanics, and I'm a deputized voting member.
DR.
OLDING: Michael Olding. I'm Chief
of Plastic Surgery at George Washington University. I'm a deputized voting member, and David didn't mention it, but I
do have stock investment in what might be a competing company, which is Medisys,
which produces Restylane, which is a filler.
It's less than 5 percent of my income from stock.
DR.
PENNEYS: Good morning. My name is
Neil Penneys. I'm a voting member. I'm a dermatologist/dermatopathologist and
I'm working at Ameripath.
DR.
FISH: Good morning. I'm Douglas
Fish, a deputized voting member. I'm
the Division Head of the Division of HIV Medicine at Albany Medical College in
Albany, New York, and Assistant Professor of Medicine there.
DR.
MILLER: I'm Michael Miller. I'm a
Professor of Plastic Surgery at the University of Texas MD Anderson Cancer
Center. I do cancer-related
reconstructive surgery as a clinician primarily, and I am a voting member.
DR.
LEITCH: I'm Marilyn Leitch. I'm a
Professor of Surgery at the University of Texas Southwestern Medical Center in
Dallas. I deal primarily with cancer
surgery, and I am a voting panel member.
DR.
KRAUSE: I'm Dave Krause.
DR.
CHANG: Good morning. I'm Phyllis
Chang. I'm an Associate Professor at
the University of Iowa, Carver College of Medicine. I am a Plastic Surgeon with joint appointments in the Division of
Plastic Surgery, Department of Surgery, and the Division of Hand and
Microsurgery in the Department of Orthopedic Surgery. I am a voting member.
DR.
BLUMENSTEIN: I'm Brent Blumenstein, Biostatistician, Seattle,
Washington. I'm a voting member.
DR.
NEWBURGER: I'm Amy Newburger. I'm
a Dermatologist in private practice in New York. I teach at Roosevelt-St. Luke's Medical Center Consortium. I'm a voting member.
DR.
MONK: I'm Robert Monk with the Department of Internal Medicine at
University of New Mexico, where I'm the coordinator of the New Mexico AIDS
Infonet. I am a patient representative,
non-voting member.
DR.
BARTEAU: Good morning. My name is
Grace Barteau and I'm the General Manager of Decus Biomedical. We are a medical device consulting firm
where my expertise is in regulatory affairs, designing and executing clinical
trials and quality systems. I am an
industry representative which is a non-voting position.
DR.
DOYLE: I'm LeeLee Doyle. I'm a
Professor Emeritus of Obstetrics and Gynecology, and currently the Assistant
Dean for Faculty Development at the University of Arkansas for Medical
Sciences, College of Medicine. I'm a
consumer representative and non-voting member.
DR.
WITTEN: Celia Witten, FDA Division Director of the Reviewing Division for
these products.
CHAIRMAN
CHOTI: Thank you. I'd like to
note for the record that the voting members present constitute a forum as
required by 21 CFR Part 14.
Now
I'd like to introduce Commander Stephen Rhodes, the Branch Chief of Plastics
and Reconstructive Surgery Devices Panel, who will update the panel since the
last meeting. Steve.
CDR
RHODES: Thank you, Dr. Choti, and good morning. I am Stephen Rhodes. I am
the Branch Chief here at the Plastic and Reconstructive Surgery Devices Branch
at the FDA. I want to welcome the
members of the panel, members of the public, and the medical device industry to
this one-day meeting of the General Plastic Surgery Panel.
This
panel last met on November 21st of last year, at which time you
recommended that two premarket approval applications for facial augmentation
devices, Restylane and Hylaform, be approved with conditions.
In
December, FDA approved the PMA for Restylane and the firm Q-Med agreed to
conduct a post approval study in people of color to gain more safety data for
this population.
In
January, FDA issued a draft revision of the breast implant guidance document,
which updated a previous version issued in February, 2003. The substantive new recommendations in this
guidance document involve mechanical testing, modes and causes of rupture,
clinical study information, post approval studies and labeling.
Also
in January, FDA determined that Inamed's PMA application for their silicone
gel-filled breast implants was not approvable.
The panel reviewed the PMA during the October 14th and 15th
panel meeting last year and recommended that it be found approvable with
conditions.
Today
you will make recommendations on a premarket approval application from Dermik
Laboratories for their Sculptra Augmentation Device. Because of public interest in this application, the agenda today
includes two one-hour periods for public comment, one in the morning, and one
in the afternoon. Panel Members, we
appreciate your commitment to members of the public who have requested time to
address the panel. We appreciate your
comments. And to the sponsor of this
application, we appreciate your participation in presenting the information you
have to the panel, and answering any questions that the panel may have. Thank you.
CHAIRMAN
CHOTI: Thank you, Commander Rhodes.
We'll now proceed with the open public hearing session of this meeting,
or the first one. All persons
addressing the panel are asked to speak clearly into the microphone as the
transcriptionist is dependent on this in order to provide an accurate record of
the meeting.
I
would like to have the attention of all the individuals who are registered to
speak to the panel this morning and today.
We have given you a number corresponding to the order of
appearance. Please come to the podium
area in advance so that we are not spending a great deal of time during the
transition period between speakers. The
FDA panel will direct you to the appropriate podium.
Please
remain within your time constraints as we have a timer going to help you follow
this. And also, let me address the
issue regarding financial disclosure.
Both the Food and Drug Administration and the public believe in a
transparent process for information gathering and decision-making. To ensure such a transparency at an open
public hearing session of the advisory committee meeting, the FDA believes it
is important to understand the context of an individual's presentation.
For
this reason, the FDA encourages you, the open public hearing speaker, to advise
the committee of any financial relationship that you may have with the sponsor,
its product, and if known, its direct competitors. For example, this financial information may include the sponsor's
payment for travel, lodging or other expenses in connection with your
attendance at this meeting.
Likewise,
the FDA encourages you at the beginning of your statement to advise the
committee if you have any such financial relationships, or if you have
none. If you choose not to address this
issue, you will not be precluded from speaking.
Why
don't we begin with speaker number one.
These are individuals who have notified the FDA of their intent to
testify during the open public session.
Remember to state your name clearly for the record if you feel
comfortable doing so.
MR.
VIRGIL: Hello. Good morning. My name is Nelson Virgil. I have no financial interest or ties to
Dermik or any other facial reconstruction product company. I'm here representing the AIDS Treatment
Activist Coalition, ATAC, and also as a founding member of
facialwasting.org. I've been HIV
positive for 21 years, and I've had facial reconstruction done on my face in
the past, so I've also suffered from facial wasting in the past five years.
I'm
honored to be here, and I'd like to read a letter that the AIDS Treatment
Activist Coalition wrote in support of this application.
"Dear
Dr. Krause: With this letter, the Drug Development Committee of the AIDS
Treatment Activist Coalition, ATAC, wishes to express its support of Dermik
Laboratories premarket approval application, PMA, for Sculptra brand
poly-l-lactic acid, an injectable device intended for the use in the correction
of lipoatrophy of the face in HIV infected patients.
The
ATAC has closely followed the clinical development and reporting of
poly-L-lactic acid for facial lipoatrophy most notably under the European brand
name New-Fill, and is extremely pleased that an application seeking commercial
availability in the United States is now before the U.S. Food and Drug
Administration.
Based
on our knowledge of the available data and our communications with clinicians
and HIV infected people who have used this product, we would like to see
Sculptra approved.
As
will clearly be highlighted in this meeting, facial lipoatrophy, believed to be
a side effect of antiretroviral therapy is a condition that results in loss of
fat in cheeks, temples and eye sockets.
While facial atrophy is not believed to be associated with an increased
risk of mortality and morbidity, it can have devastating effects on self-image
and confidence, lead to anxiety around HIV disclosure forced by hallmark body
habitus changes and significantly contribute to demoralization and depression.
In
turn, this can lead to reduced adherence to antiretroviral medications. In fact, the effects of facial wasting can
be so severe that HIV infected individuals may jeopardize their health by
refusing antiretroviral agents believed to be associated with this condition,
or worse, discontinuing antiretroviral therapy all together.
We
take comfort in the extensive experiences in poly-L-lactic acid injections in
Europe, where it was approved by the French Notified Body G-Med in 1999 as a
wrinkles filling product, and has been marketed as New-Fill. It has been used by an estimated 100,000
people in more than 30 countries through Europe and South America, and in
Australia for the treatment of a range of facial body imperfections, including
signs of aging, such as wrinkles, folds and sunken cheeks.
We're
also encouraged by the growing body of preliminary data reported at various
Medical Congresses, and published in the November 21st, 2003 edition
of AIDS. The study enrolled 50 patients
with a medium facial fat thickness of zero, and patients were injected with
poly-L-lactic acid every two weeks for six weeks. The medientor or cutaneous thickness increased by 5.1 millimeters
at six weeks from baseline, 6.4 millimeters at 24 weeks, 7.2 millimeters at 48
weeks, 7.2 millimeters at 72 weeks, and 6.8 millimeters in 96 weeks.
The
proportion of patients with cutaneous thickness greater than 10 millimeters
peaked at 61 percent at week 48, and ended the 96-week study at 43
percent. The only significant side
effect noted in 44 percent of the patients was the appearance of palpable but
non-visible subcutaneous micro nodules with spontaneous resolution in six
patients at week 96. No side effects
were serious enough to discontinue injections.
Based
on the safety and efficacy data demonstrated at 72 and 96 weeks, we consider
Sculptra to be a device worthy of approval and commercial availability in the
United States. With this support,
however, we wish to raise four key issues, not only with the General and
Plastic Surgery Devices Panel, the
Medical Devices Advisory Committee, but with Dermik Laboratories.
First,
we sincerely hope that the FDA will approve Sculptra as a reconstructive
corrective therapy, not simply as a cosmetic morality. Facial lipoatrophy is very similar to the
body habitus altering effects of other therapies, including but not limited to
mastectomies and amputations. The
nomenclature of a device or surgical procedures indication, particularly from
the FDA, carries significant weight when we negotiating with third-party health
care providers in seeking coverage for a particular procedure, which will be
vital for HIV infected individuals with facial lipoatrophy.
Second,
for Sculptra and other facial fillers, to yield safe and effective outcomes, it
must be administered by clinicians who are experienced in using injectable
devices of this nature. We as a group
of HIV/AIDS Treatment Activists are not in any position to recommend minimum
criteria that must be met by clinicians.
However,
we do recommend that Sculptra only be available to and administered by
clinicians who have met specific training or experience criteria specified by
the FDA and Dermik Laboratories.
Three,
long term safety and efficacy data are limited, and most of the data relate to
applications of much lesser volumes of a product than are anticipated for
correction of facial wasting. There are
lingering questions regarding the durability of Sculptra injections and the potential
for long-term complications.
In
turn, we would like to see Dermik Laboratories commit to a long-term follow-up
study to evaluate the durability of Sculptra injections. The factors associated with premature
reversal of treatment benefit, i.e., ongoing use of nucleoside reverse
transcriptase inhibitors like Zerit, and long-term events.
Four,
pricing and reimbursement concerns are of significant importance to ATAC. We're aware of the challenges that we, as
consumer advocates, will face in terms of achieving payment and reimbursement
from private and public health insurance.
In
turn, what is needed from the FDA is the strongest possible labeling language,
indicating the reconstructive corrective nature of Sculptra. What is needed from Dermik Laboratories is a
strong patient assistance program commitment which must include steadfast
support and advocacy to secure treatment reimbursement from public and private
health insurance. And when necessary,
free or low-cost therapy administered by clinicians with consultation,
administration, and follow-up fees contracted through the IP.
Respectfully,
we submit this letter to the FDA and hopefully we'll get some approval of this
first of its kind facial wasting reconstructive product. Thank you.
CHAIRMAN
CHOTI: Thank you very much. The
next scheduled speaker.
DR.
KRAUSE: I have a few testimonies that were sent in to be read. I can read these now while we're waiting for
the other speakers.
"Dear
Esteemed Members of the FDA Advisory Committee: I truly wish that I could
testify in person to the panel.
Unfortunately, given the presence of the media and the taping of the
hearing, I am unable to do so as it would more than likely jeopardize my
position at my firm.
I
want you to know how very difficult of a decision this has been for me. Given
the overwhelming benefits of Sculptra, I wanted to testify in-person to let you
know it has changed my life.
Unfortunately, in balancing this desire with my need for anonymity, I
concluded that it would be impossible for me to testify in-person.
However,
given the importance of Sculptra, I felt that it was imperative to, at a
minimum, provide you my testimony in writing.
Of note, I have not received compensation in any form with respect to
Sculptra as a whole, or my testimony in the specific.
Who
am I? I am a 42-year old Caucasian
male. I am a senior partner in an
international professional services firm which has in excess of 700 offices
worldwide. I have been HIV positive for
approximately 22 years, and I'm currently healthy with T-cells in excess of
1,200, and a very low viral load. My
current regimen of antivirals consists of four Class I drugs, which include
Zerit.
I
have been on antiviral therapy for nine years.
Due to adverse reactions, I have been unable to successfully change my
regimen to other antivirals that are perceived to be less detrimental with
respect to fat depletion and facial wasting.
Why
did I receive treatment? Unfortunately,
the life-saving antivirals have caused significant fat depletion and facial
wasting specifically. I have loss of
fat in my arms and legs, and have begun to have significant facial
wasting. I sought treatment in the
hopes of restoring my face.
Treatment
results. The results of the treatment
have been nothing less than miraculous.
I have the following to report.
I have full facial restoration.
Friends and family who know my condition are amazed at the success of
the product and the complete facial restoration that has been
accomplished. Business associates and
friends that do not know my condition have provided numerous unsolicited
comments ranging from what you have done, you look fantastic, to you look so
rested and healthy, what is your trick?
The
process is fast. The treatments are
done in less than 30 minutes. Although
they are not pain-free, the discomfort is tolerable. With the use of ice to keep the swelling down, I return to work
either the next day or the day after.
Other than facial fullness which I commented was as a result of allergies,
there were not telltale signs that treatment had been performed. The process has been side effect free. I am not aware of any negative side effects
from the treatment.
My
conclusions. The product has been
miraculous. Previously, I was concerned
that I would be in my position for no more than another year before the facial
wasting was so obvious that I would have to retire early or choose another
profession. With the restoration that
has taken place, I no longer have concerns about my visual appearance. As long as I am wearing long-sleeved shirts,
which is always, there are no telltale signs that I have fat depletion issues
as a result of the medicine I am taking.
Personally,
my views about my physical appearance have improved substantially. It is very depressing to use medicine that
allows me to remain healthy internally with the knowledge that it is creating
such physical distortions and it will make me look unhealthy externally.
I
am personally aware of individuals who are HIV positive that have chosen to go
off their medication because they cannot handle the resulting physical
distortions. This product will
alleviate the need to make that decision.
Panel
members, I cannot imagine a valid reason not to approve this product. Please know that my experience has been
nothing less than life-changing.
Respectfully, a Sculptra patient."
I
have a second one that I'm also going to read anonymously.
"I
am a recipient of New-Fill treatments performed through the organized FDA
testing study in the United States.
There hasn't been a day go by that I haven't appreciated how very
fortunate I have been to participate in the review process for this
product. At times, it seems as though
the reality of my illness was more than I could deal with. Without many choices, I was faced with many
life-altering experiences. I made many
trips to the doctor, consumed thousands of pills, but the most devastating
effect of all was watching myself take on disfiguring changes in my facial
appearance.
It
was my opinion that image cast back from my reflection was death. I lost all self-esteem and confidence. I had no desire to leave the house. My will to fight the disease was
exhausted. I was prepared to
discontinue all medication regime and accept the course and consequences of the
disease.
All
of my concerns were discussed with my physician. It was suggested that I research information and alternative
treatments regarding facial wasting on the Internet before making any decisions
of this magnitude.
That
is when I made the discovery of the product New-Fill. I consulted with a local cosmetic surgeon about the product and
he said it wasn't approved by the FDA for distribution in the United States. However, he was interested in performing
another procedure, an invasive type of correction using cheek implant
devices. Unfortunately, there was a
huge downside to this procedure. There
was a possibility the syndrome of facial wasting may cause outlines of the
cheek implant device to show through my skin.
I quickly declined the option.
I
went to great lengths to find out where I could receive treatments of
New-Fill. That's when I stumbled upon
information concerning a trial study and product review of the New-Fill for FDA
consideration. I was quick to call and
ask if I met the protocol to participate.
Once
accepted, I invested a great deal of time, effort and expense in this study,
affected by a job lay-off and very limited income. I was persistent to stay in this study not only for my benefit but
the future benefit of this product in regards to others. The effectiveness of these treatments on my
facial wasting has given me personal satisfaction, self-confidence and a
greater state of overall well-being. I
have a desire to lead a productive life, and to do that I know the importance
of staying on track with my healthcare and medication regime.
I
have great respect for my physicians and the results that this product has
given me. These treatments are directly
responsible for my renewed feeling of confidence and emotional strength. I hope my contributions to this study
enables others to benefit from this product as I have, without enduring the
excessive hardships and expense.
I
offer my thanks to the Committee for the opportunity I have been given to
submit this written testimony.
Sincerely, a Sculptra patient."
CHAIRMAN
CHOTI: Yes.
MR.
LAND: Good morning. My name is
Bradley G. Land, and I am HIV positive, Fifth District Commissioner for the Los
Angeles County Commission on HIV Health Services, serving the Honorable
Supervisor, Michael Antonovich and the Los Angeles County Board of Supervisors.
Dermik
Laboratories has paid for my travel, accommodations and expenses for my trip to
this hearing. I have no additional
financial relationship with the company.
The
statement I am providing today is my own opinion, and Dermik has not advised me
what to say to the panel. I am also
here today to offer my personal testimony as a private citizen in support of
New-Fill, not as commissioner. I am
here today thanks to a new lease on life called New-Fill Sculptra.
I
have also passed out pictures prior to diagnosis - actually, not prior to
diagnosis, prior to treatment. I am going to take you with me to the brink of
suicide.
At
age 17, which was the early 80s, I was diagnosed with Epstein Barr
Syndrome. Unbeknownst to me and my
physician at that time, Epstein Barr Syndrome was secondary to what we later
found out, although I denied for some time was GRID, gay-related immune
disease, now known as HIV/AIDS. The
year was now 1987.
Eventually
my denial reluctantly retreated, and my involvement and awareness quickly grew
as I devoured whatever information I could find. By 1990, I became a co-facilitator for a group called Positive
Teens & 20s. By `93, this being a
live Los Angeles support group had grown to over 100 members that met on Sunday
afternoons at the Los Angeles Gay and Lesbian Community Center. I am approximately ?? I think I'm one out of ten of us living. In fact, a documentary was made about the
group which centered on how we coped independently, as well as in the group
when confronting fears, social stigmas associated with HIV and AIDS.
Because
people and friends dying of HIV and AIDS couldn't wait for openings in the
already over-crowded hospices, I turned my home into a hospice for my friends
and peers who needed help. It was
during this time my ever-changing symptoms and emotions came face-to-face with
wasting, or what is now known as lipoatrophy.
I've been calling it that for years.
This
was absolutely devastating. I couldn't
hide that drastic debilitating change in my appearance. By 1998, I actually looked as if I was on my
deathbed. Isolation became my way of
life. By 2000, I was not only
contemplating, I was looking forward to suicide.
Through
this period of time, kindness shown to me by compassionate strangers was
emotionally overwhelming.
Psychologically, I felt I was too young to have doors opened for me, or
to have restaurants give "a little discount" because they could
physically see I was very, very ill. My
face was so concaved that at my ten year high school reunion my friends were
pretty sure that they would be doing a memorial for me at the 20-year, if I was
to ever get there, or my death.
By
2003 with depression again taking hold, my psychologist warned me that lifetime
drugs would be needed to combat the depression. It was then that my HIV/AIDS physician offered a glimmer of hope. The hope was a new drug trial called
New-Fill.
I
received six treatments for approximately $2,300, $2,400 from June, 2003
through October, 2003 from Dr. Humble at the Blue Pacific Aesthetic Medical
Group located in Los Angeles, California.
From the moment I started those treatments, my friends and neighbors
immediately noticed a physical notice.
I began to notice that although people would look at me, they were doing
so without pity. I was being looked at
as a normal person. My appearance no
longer silently screamed AIDS when I entered a room. Now when acts of kindness are shown to me, I think and feel that
it is probably because I'm a kind person.
Today
as I offer testimony before you with the face I shied away from myself, I can
now tell you I can look at my reflection more often than not, and am very proud
and thankful to have returned to the human race.
At
my 20-year high school reunion we celebrated at Dodger Stadium. That was just last year, where I proudly
stood and tearfully sang the "National Anthem". I am a living, not dying, living result of
new treatments. Thanks to New-Fill, I
have a new lease on life, a new beginning and self-esteem to match. I can hold my head up high and look people
in the eye and know that they aren't pitying me.
I
am a proud American citizen living in the best country in the world, and I am
thankful and grateful America has a Federal Drug Administration in place that
dutifully, mindfully, and aggressively investigates and approves life-saving
drug trials and treatments, such as New-Fill Sculptra.
Today
I can proudly look at all of you, and let you know that yesterday was the a day
I thought I would never see. It was my
39th birthday, and what a great place to be, in the nation's
capital. I now not only have hope for
the future, I live with hope for the future.
Thank you.
I
noted today that there were not a lot of consumer speakers, and if you have
questions, or if the panel have questions throughout this morning, that I'd be
more than willing to answer them. Thank
you.
CHAIRMAN
CHOTI: Thank you.
MS.
DOE: Good morning, panel. Dermik
Laboratories has paid for my travel, my hotel and expenses for this trip to
this hearing. I have no additional
financial relationship with the company.
The statement I am providing today is my own opinion, and Dermik has not
advised me what to say.
I
also want you to know that I took 30 hours of my personal vacation time,
including time away from my family, to be here today. Also, I will not be using my real name in my statement.
I
was diagnosed with HIV in 1996. From
the beginning, I didn't want to be treated any different than I was before
diagnosis. I had decided to tell my
immediate family and close friends, since I am concerned about any stigmatism
that might affect my career, or that my child might receive if my diagnosis was
public.
I
have been on combination therapy since the end of my pregnancy in 1997. I have never had an opportunistic infection
and consider myself in good health.
In
2000, I first recognized the subtle changes, the lipoatrophy, as I was putting
on a formal gown. I noticed that my
arms were not as fat as I remember them from the previous year.
Prior
to that, I would hesitate to wear a sleeveless gown due to my
self-consciousness about my fat arms.
But little did I know that over the next two years, the fat would
continue to disappear, leaving my arms, my face, and my legs.
By
early 2002, my appearance had changed dramatically in comparison to how I
looked in 1999, so I decided to look into cosmetic procedures. I asked my HIV physician what he
recommended, and he sent me to a doctor that did Fascian injections in my
cheeks and temples. Twenty-four hundred
dollars worth of painful injections gave me lumps, and after they subsided
there was no improvement.
By
late 2002, my atrophy had progressed to the point that I'd already resolved to
the fact that I would never wear shorts or sleeveless shirts again in
public. I had decided to save money and
continue to research for something else to try. I had heard of New-Fill and had interviewed two patients in my
city who had it done by a nurse at a spa, but I wanted a licensed, insured,
trained, and experienced doctor working on my face. This is my face, it is my calling card, and it is who I am. I didn't want a nurse without any legal
ramification giving me injections, but at this point I was getting worse by the
month and getting desperate.
At
Thanksgiving dinner that year, relatives that I had not seen in years were
there. During the day, I saw family
members pulling my mother over for private conversations, and my parents and I
had a family discussion about it later about how my facial appearance had
caused concern about my health. My
family was asking things such as is she okay?
What is wrong with her? She
doesn't look well. Do you think that
she's anorexic? The interesting thing
about all this was that I was still wearing the same size, but because of my
thin arms and my face, they felt that I was ill.
Another
memorable incident that year, I had attended a baby shower that my mother
hosted, and some of my mother's dearest friends were there, people who were
unaware of my diagnosis, and afterward called her to inquire about me with
loving concern, saying things such as what is going on with your daughter? There is something terrible wrong with
her? You have to do something. And my mother uncomfortably tried to dismiss
their comments, but they were not persuaded, saying can't you see your
daughter's health is deteriorating?
What kind of mother are you? So
my mother naturally asked me well, what do I tell people? And at the same time, my husband was also
getting approached from people that we knew with questions about me.
At
work, my profession entails that I'm on the phone thankfully with customers,
and I was considered for a position that required face-to-face customer
interaction, but my atrophy was so bad that I would never feel comfortable in
that type of a job. I felt an immediate
need to do something about my face or disclose the diagnosis, real or made-up,
it might offer some explanations.
I
saw numerous plastic surgeons in the major metropolitan area in which I live,
and none had anything to offer me. For
example, fat transfers might not be the same from one cheek to the other, or
might get reabsorbed totally or unevenly.
Cheek implants might be seen through thin skin or might have to be
anchored with pins to prevent flipping due to lack of tissue.
Some
European approved injection materials have a lumpy appearance that I would
never consider, and collagen doesn't last.
Sculptra is the only product that met my needs and addressed my concerns
about safety, natural appearance, longevity, and my face would be in the hands
of a licensed trained physician.
Sculptra
has changed my life. I now have the
confidence to pursue my professional goals.
I have also noticed that my family and colleagues are not concerned
about my health. If it wasn't for
Sculptra, I'd be retreating from professional endeavors, as well as avoiding
family and other social situations.
Thank you.
CHAIRMAN
CHOTI: Thank you. Are there any
other public statements? If not, I
think we can move ahead to the Applicant Presentation.
Let
me remind the public observers that while this portion of the meeting is open
to public observation, public attendees may not participate, except if panel
members ask specific questions. And
there will also be another opportunity this afternoon for additional public
comment. So we are now ready to begin
the applicant's presentation, representatives from Dermik Laboratories.
DR.
FORBES-McKEAN: Good morning, Dr. Choti, Members of the Panel, and Members
of FDA. My name is Kim Forbes-McKean,
and I'm the Senior Director of Product Development and Commercialization at
Dermik Laboratories.
Thank
you for giving us the opportunity today to present our data on Sculptra. We hope that you found the panel package
informative, and that with our presentation today, we may address any questions
that you may have.
I'd
like to start with a brief overview of our presentation. First, I will give a brief introduction to
the product, and following that, Dr. Marcus Conant will discuss the condition
of lipoatrophy in general. Following
Dr. Conant, Dr. Jeffrey Handler, who is the Director of Safety Assessment and
Evaluation at Dermik Laboratories, will present a description of Sculptra, and
also present the pre-clinical studies in support of the safety of this device. Following Dr. Handler, we will have Dr.
Sharon Levy, who is our Senior Director of Medical and Scientific Affairs at
Dermik Laboratories summarize the rationale and the clinical data, and post
marketing data available that supports the efficacy of this device in people
with Human Immuno Deficiency Virus.
After that, Dr. Peter Engelhard will present his experience obtained
through the use of this device in both sponsor investigator studies and through
a compassionate use study. At the
request of FDA, the results of these studies are also included as supportive
data in our PMA. Lastly, I will return
to present the final conclusions of the presentation today.
We
have with us a number of colleagues and invited experts that are available to
assist us in answering any questions that you may have. They are listed here on this slide, and I
would specifically like to point out that we have Dr. Mest from the Blue
Pacific Aesthetic Medical Group in California, who has gained clinical
experience in the U.S. with this product through a sponsor investigator
IDE.
We
also have Dr. Danny Vleggaar who has acquired clinical experience with this
product outside of the U.S. in a large number of patients. We have Dr. Dror Rom, our consulting
statistician, available, as well as Dr. Russell Parsons, a materials expert,
available as well.
Dermik
Laboratories is a division of Aventis Pharmaceuticals, and has been in the
business of developing and marketing prescription and OTC drug products for
dermatological applications for over 50 years.
The subject of today's advisory panel is Sculptra, and the proposed
indication that Dermik is seeking for this injectable poly-L-lactic acid device
is to correct shape and contour deficiencies resulting from facial fat loss,
lipoatrophy, in people with Human Immuno Deficiency Virus.
As
we have just seen and heard in these patient testimonies, the condition of
facial lipoatrophy is a debilitating condition, and one for which there is
currently no approved medical treatment.
Because of these reasons, and for the best interest of the patients
involved, this PMA was granted expedited review by the FDA.
The
product was originally developed by a French dermatologist of Biotech
Industries. The device was originally
approved in Europe in 1999 under the name New-Fill. The original indication is shown here on this slide, and that is
New-Fill is suitable for increasing the volume of depressed areas, particularly
to correct skin depression, such as in skin creases, wrinkles, folds, scars and
eyerings.
Recently,
as recently as February in 2004, the indication in Europe for New-Fill was
expanded to include the use for large volume corrections of the signs of
lipoatrophy. The product is intended to
be marketed by Dermik in the United States under the trade name Sculptra. In this presentation, we will refer to the
product as Sculptra.
To
illustrate a brief history of the product, on this slide, as I pointed out, the
product was originally approved in Europe under the trade name New-Fill, and is
currently marketed in 33 countries outside of the United States.
The
pivotal lipoatrophy studies which are included in this PMA were initiated in
2000 in France and the United Kingdom.
Limited patient access in the U.S. began in 2001 through the Direct
Access Alternative Information Resource buyers network, and also under sponsor
investigated U.S. IDE studies.
Dermik
acquired the product in May, 2002, and then gained access to the data after the
pivotal lipoatrophy studies were completed.
For patients whom reconsent was obtained, Dermik source verified all
primary efficacy data, and Dr. Sharon Levy will present a summary of this data
later this morning.
Dermik
then prepared the necessary documentation to submit the PMA in December,
2003. And as I mentioned previously,
because we are seeking approval for a device for a condition for which there is
an unmet medical need, the FDA granted expedited review status for this
PMA.
I
would like to now introduce Dr. Marcus Conant, who will speak about the
condition of lipoatrophy in general.
DR.
CONANT: Thank you, Kim. Mr.
Chairman, ladies and gentlemen of the panel, thank you for the opportunity of
addressing you this morning. I'm Mark
Conant from San Francisco. I'm Clinical
Professor at the University of California in San Francisco, where I have been
since 1964. I am currently Chairman of
the Conant Foundation, which is a patient advocacy education group, and I've
been caring for HIV/AIDS patients since 1981.
I actually described the first patients of Kaposi's sarcoma in San
Francisco.
My
colleagues and I built the largest private HIV practice in the world, which
existed until sometime about 1998. I
have no financial investment in Dermik.
I'm not a Dermik employee. I
recently became a Dermik consultant. I
don't own stock in Aventis.
I've
been doing what's called protocol for the last four months. This is not supported by Dermik. It's a physician initiated protocol
supported by the Conant Foundation.
Dermik did supply the New-Fill for me to use in these patients. Dermik did pay for my travel and lodging
here. So I speak to you this morning
from an unusual position. I not only am
an AIDS doctor, and have cared for some five to six thousand HIV positive
patients. I've been caring for those
patients since 1981, but I'm also a board-certified dermatologist who has used
this product.
In
the time period from 1981 until 1996 when we had highly activated
antiretroviral therapy available to us, the major problems that we faced
managing our patients were first, Kaposi's sarcoma and the cosmetic and medical
ravages of that disease, obviously Pneumocystis pneumonia, which until 1987-88
was the major cause of death resulting in some 60 to 70 percent of the deaths
in our HIV positive patients.
After
we began prophylaxing against PCP, Mycobacterium avium became the most common
cause of death in my practice in the time period 1989, `90, and `91. And so the opportunistic infections leading
to death were really the issue that confronted us until we had ways of reducing
the viral load below the level of detection.
Next slide, please.
From
1996 until today, from the introduction of highly activated antiretroviral
therapy, our priorities have changed considerably. As all of you know, our patients are now living much longer. As a matter of fact, when I'm asked how long
will they live, I can't answer the question because our patients are, in fact,
doing extremely well. We have some
concerns, concerns perhaps about HAART disease later on. But right now, managing HIV patients has
changed dramatically.
The
biggest problem we have is compliance.
How to ensure that patients are taking their medication, because as we
know, if their viral load rises, they will become resistant to the drugs they
are taking, and we will have to change their medication. So compliance, resistance, drug side effects
are a major problem. Each drug has its
own particular set of side effects. And
fortunately, now we have enough different drugs that we can usually change the
patient's drug treatment regime to address these issues.
Most
patients on these drugs, particularly the protease inhibitors, suffer from
diarrhea. That's a constant complaint
that I hear in my practice on a daily basis.
But the thing that was bothering our patients the most is the facial
lipoatrophy. And you may ask well, what
number of patients are we talking about?
There
have been various estimates. Carr has
the best data from Australia. It looks
like somewhere in the range of 50 percent of patients will have perceptible
facial lipoatrophy three years after they've started highly activated antiretroviral
therapy. And so the lipodystrophy
syndrome of which facial lipoatrophy is a component, is the biggest problem
that we're facing in our day-to-day practice of seeing people who are stable on
their antiretroviral therapy, who have viral loads below the level of
detection, who are compliant with their treatment program, and whose CD4 counts
are slowly rising. You heard in one of
the letters that the patient who was anonymous, CD4 count was over 1,000. We would not have seen that prior to 1996.
The
lipodystrophy syndrome consists of the components that I've put on the
board. It is hypercholesterolemia,
sometimes to considerable heights, hypertriglyceridemia, sometimes over 1,000,
insulin-resistant diabetes, particularly in patients who are on protease
inhibitors. The facial lipoatrophy, the
loss of fat in the face, but it's a strange syndrome because not only do you
lose fat in certain areas, you gain fat in other areas.
Patients
develop abdominal obesity and buffalo hump.
And again, as you heard in the testimony from the public, they then
begin to lose fat peripherally, so there's peripheral fat loss, abdominal fat
gain, buffalo hump. For the clinicians
in the audience, I'm describing Cushing's disease. Right? That's what we all
thought it was initially, but it's not Cushing's disease.
We
don't know if this syndrome is because of HIV infection. Many patients showed facial atrophy before
highly activated antiretroviral therapy.
Rock Hudson did. Was it due to
the disease itself? Was it due to
certain of the antivirals we were using, Crixivan and d4T were implicated, or
was it because the new drugs just kept people alive long enough to see it, or
is it a multi-factorial syndrome that we don't fully understand?
The
pharmaceutical industry is currently investing considerable amounts of money
looking for drugs that don't cause this problem, because obviously if you could
develop an antiretroviral that didn't do this, that is a tremendous market for
you. But unfortunately, we do not
understand the true ideology of this syndrome.
Now
let me show you a couple of pictures.
This is severe facial atrophy in one of my patients. And as I say, this or a lesser degree of
this is now being seen in about half of the patients that we are managing in
San Francisco.
This
is a buffalo hump. The patient has
accentuated fat pad across the shoulders.
I don't need to suggest that this is abdominal obesity. This
man has gained weight. He has
increased omental fat again as part of this syndrome. And the peripheral wasting, patients call this
"roping", becomes clearly demonstrable. As the patient loses peripheral fat, the vasculature is
accentuated.
Facial
lipoatrophy, the subject that we're discussing this morning, has become the
Scarlet Letter of AIDS. Early on we
could identify AIDS patients when we would go out in public in San Francisco. Remember we lost 36,000 men before we had
high active antiretroviral therapy in a city of 700,000 people. You could identify AIDS patients because
people had Kaposi's sarcoma that you could see.
I
could go to the opera and pick out people who were HIV positive because they
had seborrheic dermatitis at the corner of their nose. Today when you go to the opera, it's not
seborrheic dermatitis you see, it's facial lipoatrophy. You can identify the patient when he walks
into the room, particularly in an area with lots of HIV positive patients,
where everyone recognizes this syndrome as being HIV positive.
I
think that was clearly demonstrated with the testimony you heard this morning,
where the individual speaking did not want to be identified. And yet, they are identified simply by their
appearance. Because of this, patients refused
medication. They wait to start, even
doctors wait to start medication until the CT4 count falls down to something
like 300.
Why
do we wait? Wouldn't it be better to
treat patients? Mighten we reduce
transmission if we treated patients?
Yes, but we wait because of the side effects of the medication and the
fear of developing resistance. So
doctors delay treatment, patients refuse treatment, patients fly to Mexico, or
Europe, or Brazil for treatment. And
unfortunately, some patients even discontinue their treatment because of the
facial lipoatrophy.
And
so this morning, speaking as someone who has managed thousands of these
patients, and as someone who has used this product, I feel that the product is
safe and effective, and that my patients would be tremendously benefitted by
the approval of Sculptra. Thank you
very much.
DR.
HANDLER: Good morning. My name is
Jeff Handler. I'm the Director of Drug
Safety Assessment and Evaluation for Dermik Laboratories. And what I'll be doing over the next few
minutes is taking you through a description of Sculptra, including the physical
description of the product, a bit about poly-L-lactic acid or PLLA, and a
summary of the biocompatibility studies that were conducted to support the
product.
Sculptra
is provided in vial as a sterile lyophilisate reconstituted in 3 mLs of sterile
water for injection, USP using a 26-gauge needle for administration. Some of the critical design elements and
product characteristics, particle size, molecular weight which is controlled
after gamma-irradiation, sterility, stability.
Sculptra is stable for up to 72 hours after reconstitution, and up to
two years as a lyophilisate. Also, ease
of use - the wetting and syringeability of the product.
Poly-L-lactic
acid is a synthetic polymer. It's
non-animal/non-human sources. The
L-form was selected for slower degradation than either the racemic mixture or
the D-form. Sculptra consists of
microparticles of irregular shape with a particle size distribution, the d50 is
28 to 60 microns. A variety of devices
contain PLLA. PLLA has been used for
over 20 years with excellent safety profiles.
Devices that use PLLA include absorbable sealants, flow restrictors,
fixation systems, suture anchors and absorbable sutures, fixation screws, and
tissue regeneration products.
A
bit about how poly-L-lactic acid degrades, starts as a polymer and through a
non-enzymatic hydrolysis goes to lactic acid monomers, which are then either
metabolized by the Kreb's cycle to carbon
dioxide, or incorporated into glucose via the chore E cycle.
Other
components of Sculptra include carboxymethylcellulose as a suspending agent,
and mannitol as a lyophilization enhancer.
Both of these chemicals are safe and very widely used in a variety of
injectable products.
Just
a bit about potential lactic acid burden.
It's important to note that PLLA is hydrolyzed slowly, not
immediately. There is no evidence of
lactic acidosis in the preclinical or clinical studies, as you'll hear a bit
later. Sculptra has a minimal impact on
lactic acid burden.
Biocompatability
testing was based on the ISO 10993 standards and the FDA G95-1 guidance for
tissue and bone devices with duration of greater than 30 days. A variety of tests were conducted, including
cytotoxicity, acute toxicity, the subchronic toxicity, sensitization and
irritation, genotoxicity, implantation, and also hemocompatibility and
pyrogenicity. And I'd like to note that
Sculptra passed all of these tests.
The
only findings of note in any of these studies was in the rate subchronic 90-day
study, the finding of focal granulomatous inflammation with giant cells
surrounding foreign polarizing substances in deep dermis in five out of 20
animals, and in a rabbit implantation study where observations of macraphages
and giant cells organized around the PLLA crystals was noted. These were very expected foreign body
reactions that had been noted previously in the literature for PLLA-containing
devices.
Sculptra
was well-tolerated in mice, rats and rabbits.
It was non-irritating after intraperitoneal subcutaneous or intradermal
administration. Sculptra was
non-sensitizing, devoid of genotoxic potential. There were no indications of systemic toxicity in any study. And as I noted on the previous slide, there
are minimal and expected local tissue responses which are characterized by foreign
body reactions.
On
the basis of these data, Sculptra is safe from the non-clinical
biocompatibility test. I'd like to turn
the presentation over to Dr. Levy, who will discuss the clinical data.
DR.
LEVY: Thank you, Jeff. My name is
Sharon Levy. I'm the Senior Medical
Director of Scientific and Medical Affairs at Dermik Laboratories, and I'll be
reviewing with you today post marketing experience with Sculptra.
As
stated earlier, Sculptra has been available commercially since 1999. It is currently marketed in 33 countries
worldwide, and over that time frame it is estimated that more than 150,000
patients have been treated with Sculptra through December of last year.
Over
that same time frame and with that patient usage, there have been 251 adverse
event terms reported to the Pharmacovigilance Safety Database. These reports are from 188 individuals.
The
most common event reported to the Safety Database was injection site
nodules. That's the top line here,
reported in 124 instances, followed by injection site induration, granuloma,
inflammation. Other adverse event terms
were reported at a frequency of six or fewer over this time frame.
In
that same time frame, over the same commercial use of the product for four
years, which is primarily cosmetic in the rest of the world, six adverse events
were termed serious by the reporters.
One of these involved an infection, two allergic phenomena, and three
nodules.
The
first case, infection, involves a 54-year old woman from Germany who experienced
a facial abscess following Sculptra treatment.
She was hospitalized, treated with intravenous antibiotics and surgical
drainage.
The
next two cases involved allergic phenomena following Sculptra treatment. In both instances, the patients developed
facial edema. They had no other
systemic symptoms. Patients were
hospitalized, treated with steroids and symptoms resolved.
The
fourth case is listed here as an injection site granuloma. And it's included as serious because it was
in the setting of a previous hospitalization for colitis. That patient was treated with parenteral
anti-inflammatory therapies, and in the course of that treatment developed
swollen nodular areas at sites of previous Sculptra treatment.
Biopsy
of the nodules showed a foreign body giant cell reaction with elements
consistent with Sculptra. The patient's
symptoms at those sites resolved over a period of time, with continued
anti-inflammatory treatments.
The
last two cases, injection nodule and ectropion involved nodules in the
peri-ocular area. In those instances,
the patient had been treated with Sculptra and developed nodules around the
eyes. In the first case, the patient
was treated with steroids and there was incomplete resolution of the
nodule. The nodule was excised.
The
final case, the nodule interfered with proper closure of the eye. It was termed an ectropion. It was also treated with steroids and
excised. The histology of that nodular
example showed foreign body giant cell reaction again with particles consistent
with Sculptra.
Now
let's look at the clinical data supporting the lipoatrophy indication. These data which we'll review over the
balance of the presentation come from two pivotal studies in France and the
U.K. I will present those in a moment,
and they are also supported by experience in the U.S. Dr. Peter Engelhard will review this data. He was an investigator on two of the three
studies that will be discussed.
Now
for the pivotal clinical studies - the two studies were termed VEGA Study in
France, and Chelsea and Westminister studies.
These were independently designed and conducted studies by investigators
at their own academic medical centers.
In both instances, the studies were ethics committee approved. And Dermik, as mentioned previously,
acquired access to the data after the studies were clinically complete.
At
that time, Dermik sought authorization from the individual patients for review
and verification of source documents for those cases. That was granted in 82 percent and 93 percent of the cases for
the two studies. At that juncture,
Dermik's source verified 100 percent the efficacy and safety data for the
authorized cases.
Now
the VEGA Study. This was conducted by
Professor Christine Katlama and colleagues at Hopital Pitie-Salpetriere in
Paris, France. This was a study of the
impact of Sculptra cheek implants on HIV positive patients with severe facial
lipoatrophy. This was a prospective but
open label study with a planned two-year follow-up.
Patients
were treated with Sculptra to effect, to clinical effect and, therefore, they
received three to six injection sessions depending on that effect. The product was injected one vial per cheek
per session.
In
terms of the efficacy and safety parameters, the primary efficacy parameter was
total cutaneous thickness or TCT. This
was measured by ultrasound by a single ultrastenographer for the study. Serial photographs were captured over the
two year study course, and there was an assessment of quality of life by a
visual analog scale. Safety events were
captured as adverse events and laboratory measures over the two year study
course.
Now
let's look at a schematic of the study protocol. We can see on the bottom the injections which were performed
every two weeks, three to six as needed.
The upper portion we have a recall of the efficacy and safety parameters
I just mentioned. These were performed
at baseline and over the two year study period or out to week 96.
This
is a picture of the ultrasound equipment that was used in the study. It was a Logic 7 machine using a
multi-frequency 7.5 to 13 megahertz transducer.
This
is an individual from the study, and I think as we've heard and seen today, you
can see all the hallmarks of this condition of lipoatrophy on this individual's
face. He has dramatically hollow
cheeks, and there you can see an outline of the skeletal and facial musculature
from this condition. And if we were
able to see the upper portion of this photo, we would also see hollow eyes and sunken
temples. This individual had an ultrasound measurement of zero for his adipose
at baseline.
Because
the facial landmarks are so outlined, it is actually quite easy to localize and
control the placement of the ultrasound transducer.
The
main inclusion/exclusion criteria for the study. All patients were, of course, HIV positive and greater than 18
years of age. They were on stable high
reactive antiretroviral therapies, and clinically stable, as well, with viral
loads of less than 5,000 copies.
However, they had severe facial lipoatrophy as noted by cheek adipose
tissue levels of less than 2 millimeters at baseline.
Confounding
treatments were excluded in the study, and there was a significant commitment
on the part of the patients for the study course because they were committing
to a two-year process including multiple procedures.
The
patient accountability for the VEGA Study, 50 patients enrolled and were
treated, 47 completed the two years of follow-up. Three individuals discontinued, one because of an unrelated
serious adverse event, lymphoma. And
two patients due to choice after the week 72 visit.
Here
are the demographics in the study, 49 males and one female were included with
an average age of 45 years. The
patients were primarily Caucasian, although 16 percent non-Caucasians were
enrolled. The patients had been on
longstanding HAART therapy, CD4 counts of about 400 cells, and viral load on
average 200 copies. At baseline, their
adipose tissue measured .5 millimeters on average, although most of the people
in the study had no detectible fat. The
total cutaneous thickness or TCT was 3 millimeters at baseline.
Now
we'll look at some data from an individual in the study, and he is actually
quite typical of the patients in the study.
On the lower portion of the graph, you will see his TCT measurements
over time. Time is on the X axis
starting at baseline zero weeks, extending out to end of study of two
years. On the X axis, we have the total
cutaneous thickness as measured in millimeters, and we can see his response to
treatment over the study course.
Here
is the gentleman with his correlating photo at baseline. Again, you can see all the hallmarks of
testimony. His baseline TCT measure was
about 3.5 millimeters. This patient was
treated with five injection sessions and here is his TCT response at midyear or
22 weeks, and the correlating photo. He
has a significant change in his facial appearance, and his TCT measure
increased, as well.
Over
the course of the study, his TCT measurement remained relatively stable in the
neighborhood of 10 millimeters, and you can see his accompanying photograph at
end of treatment. And I will mention to
the panel members that additional to these photographs in their panel pack in
the second volume behind the green tab in the second attachment area are
photographs for all 28 of the study patients who authorized viewing of their
photographs. And they're presented with
their photographs and their graphical display of TCT measures for your review.
Now
we'll see another gentleman in the study.
This is a gentleman in his mid-30s.
He had a TCT measure of 3.3 millimeters at baseline. His adipose layer was a little bit less than
a millimeter, and you see on the left again the signs of facial lipoatrophy in
profile. And here is the same gentleman
at about the one year mark, TCT measure of 10.2 millimeters. And again, you can see the change in facial
appearance. The same gentleman at end
of study, the stability of his facial appearance and a TCT measure of 12
millimeters.
Now
the next gentleman we'll see had a TCT of 3 millimeters at baseline, no
detectible fat, and again, very severe facial lipoatrophy just as explained
earlier in the presentations. This same
gentleman is shown at the one year mark, 48 weeks. His TCT has improved, but only to 7 millimeters. Again, you can look at the change in facial
appearance significantly improved, if not exact restoration of his facial
appearance.
Now
let's look at the data for the entire cohort.
This is a graphical display. On
the X axis we see weeks out to two years, again TCT measure on the vertical
axis. There are a grouping of dots at
the zero timeline because those are the baseline measures for the cohort which
range from two to four millimeters prior to treatment.
One
can see from the data displayed that all patients increased their TCT measures
at all time points and, in fact, this is the gentleman who we just saw a moment
ago with the increase to 7.4 millimeters, so he was one of the less dramatic
responders by TCT, and you saw his visual appearance.
Now
let's look at these same data from a statistical standpoint. The data are grouped by visit from baseline
to week 96, numbers of observations, the treatment mean which we just saw,
three millimeters at baseline increasing to eight, nine, and ten over the study
course, and the accompanying increase in mean change from 5 to 7 millimeters
over the study course.
All
of these increases in skin thickness were highly statistically significant. At the P less than 0.001 level. There were other assessments made in the
VEGA Study. This includes an assessment
of quality of life by visual analog scale.
Improvements from baseline were seen at all time points, but were
significant only at months six and twelve.
During
the study course, there were no clinically or statistically significant changes
observed in laboratory parameters including blood lactate. No clinically relevant changes were detected
in CD4 counts or viral loads.
Over
the two-year study period, six events which were unrelated to treatment were
reported as serious, and these events were deemed so because they involved
hospitalizations. They're shown here.
Additionally,
35 patients had one or more treatment-related adverse events during the VEGA
Study. The most common of these were
related to the injection procedure itself, including bleeding, bruising, and
edema. Additionally, investigators
noted nodules in 26 patients.
These
nodules were described by the investigator as "palpable but non-visible
subcutaneous micro nodules." These
were observed in 26 of the 50 treated patients. The majority of them occurred within the first year, actually the
first six to twelve months. In five
instances, they resolved without treatment.
The others remained stable. In
no instances were there any medications or treatments involved. In fact, the nodules were primarily
identified by the investigator rather than the patients.
This
is a gentleman, patient number 30, who you again can see in your panel pack at
baseline. The same gentleman at week 27
when he was noted by the investigator to have bilateral nodules. And I'll just give you a moment to examine
the photo.
To
my viewing of the photograph, I cannot see any nodules here. And in the next photograph, we see the same
gentleman at end of study, week 104, when again he was noted by the
investigator to have bilateral nodules ongoing.
For
ease of review for the panel in the panel pack again in your second volume
behind the yellow tab, you will see photographs of all the patients who were
identified as having nodules and allowed review of their pictures. Those are 12 individuals, and you may review
the photos. There are full-page photos
from each of the photographic visits.
Overall
from the VEGA Study we see that Sculptra was effective out to two years as
demonstrated by significant increases in total cutaneous thickness, along with
confirmation of improvements in facial photographs.
Additionally,
there was improvement in quality of life measured by visual analog scale. And as studied in this protocol, the
treatment was shown to be safe and well-tolerated by the patients.
Now
we move to the second pivotal study.
This was the Chelsea and Westminister Study conducted by Dr. Simon
Barton and colleagues in London, England.
It was a randomized open-label study of Sculptra injections for cheek
fat pad wasting in persons with HIV-related lipoatrophy.
The
study employed an open label design with a planned 24 weeks of follow-up. It also included randomization to immediate
or delayed treatment. This allowed for
an internal control, but additionally, all patients still received treatment. I'll review this in a moment.
Patients
were treated with three injection sessions, so this differed from the VEGA
study in that treatment was fixed.
Outcome measures, however, were similar. The primary efficacy was evaluated by skin thickness, again
measured by ultrasound.
Additionally,
there were assessments of anxiety and depression using a validated hospital
scale, and laboratory measures which followed over the study course including
blood lactic acid levels. Body shape
changes were evaluated by questionnaire, and patients were photographed at
their study visits.
Additional
to this, for the purpose of acquisition to data, a post study visit was
conducted at approximately one and a half to two years after the study start,
at which time the patients were queried for any additional safety events.
This
is a schematic of the study design. We
have on the X axis time and study from baseline to 24 weeks. In the upper portion, we see the regime for
the immediate treatment group. These
individuals received treatment at weeks zero, two, and four. Then they were reassessed at weeks 12 and
24. The delayed treatment group were
merely observed for the first 12 weeks.
Then they received Sculptra treatment at the 12th week, 14
and 16 week visits, and were re-evaluated at week 24. Again, all patients came back for the post study visit for data
access and capturing of any additional adverse events.
The
patients included in the study were all HIV positive with signs of moderate to
severe facial lipoatrophy. Confounding
treatments were excluded. Thirty
patients were treated, thirty patients completed. One patient at the time of the post study visit declined access
to his data and, therefore, today for this presentation results from 29
individuals are presented.
Demographics
of the cohort, 27 males, 2 females, with an average age of 41 years. Twenty-eight percent of the patients were
non-Caucasian, and patients overall had been on HAART treatments for an
extended period. Their CD4 counts were
in excess of 400 cells, and at baseline their skin thickness measure was from
2.1 to 2.7 millimeters on average.
These
are the results of skin thickness in the treatment areas for the immediate and
the delayed treatment group. The areas
that were treated in the study were, of course, the right and left side of the
face. The patients were treated in the
nasolabial fold in the cheek. They were
also assessed at non-treated sites at the corner of the mouth and at the upper
cheek bone or the zygoma.
We
see the results here for the immediate and delayed treatment group for the left
side of the face in the treatment area.
The bars indicate time in study, with baseline in gray, 12 week mark in
yellow, and 24 weeks in white. One can
see in the immediate treatment group that at both the 12 and 24 week time point
at both treatment areas, there are significant increases in skin
thickness. For the delayed treatment
group who received their treatment only starting at 12 weeks, there is an
increase in skin thickness only observable at the 24 week mark.
These
are the results for the non-treated areas for both of the groups. These are at the corner of the mouth and the
upper cheek bone. And one can see from
this display that those measurements were relatively stable over the course of
the evaluation period.
These
are the results shown in a statistical format.
We'll look now at the immediate treatment group at 12 and 24 weeks. The changes for treatment areas of
nasolabial fold and cheek left and right side are displayed as changes from
baseline.
One
can see the increases in skin thickness or these changes at the 12 and the 24
week mark. All of these changes are
statistically highly significant in all instances.
Now
the results for the delayed treatment group.
At 12 weeks there are very minor changes in skin thickness at the 12
week mark. However, 24 weeks following
treatment, we see a significant increase in skin thickness. Again, highly statistically significant at
all the assessed areas.
Other
efficacy assessments in the Chelsea/Westminister Study included measures of
anxiety, depression, and face shape change.
For the immediate treatment group, these were improved at both 12 and 24
weeks. In the delayed treatment group,
improvements were only seen at the 24 week mark.
Laboratory
parameters. There were no statistically
significant or clinically meaningful differences seen in laboratory measures,
including CD$ counts, viral load, and lactate levels.
Treatment-related
adverse events. There were no serious
adverse events reported in the study.
There were 45 treatment-related events reported in 17 patients. The most common of these were similar to
what we saw from the VEGA Study, and related to the injection itself, including
bruising, discomfort, redness, inflammation.
Additionally,
one patient was reported to have a "infected lesion". The investigator described this as a
reddened area similar to a pimple, but without any pustular component. It was observed and resolved without any
specific treatment.
Additionally,
at the post study visit, nine patients were noted by the investigators to have
nodules. These were similar in
character to those described in the VEGA Study. So what we see from the Chelsea and Westminister study is
reviewed here.
In
this study, with Sculptra treatments, there were significant improvements from
baseline as noted in skin thickness measures, via ultrasound, patient rated
assessments of facial change, anxiety and depression. Additionally, the product was shown in this study protocol to be
safe and well-tolerated by these patients.
When
we look across the two pivotal studies, we see that Sculptra was effective out
to two years as measured by increases in skin thickness, and associated
improvements in facial appearance.
Adverse events with the product were generally limited to reactions at the
site of injection.
Sculptra
was shown to be effective and safe in these studies for treating the shape and
contour deficiencies resulting from facial fat loss or lipoatrophy in people
with Human Immuno Deficiency Virus.
Thank you. And now Dr. Peter
Engelhard will review the clinical data from the U.S. experience. Dr. Engelhard.
DR.
ENGELHARD: Thank you, Sharon. As
Sharon stated, I'm Dr. Peter Engelhard.
I'm in private practice in Miami, Florida. I've been treating HIV positive patients for 11 years, and have
had particular interest in the lipoatrophy syndrome for the last 5 years. Next slide, please.
I
am not a Dermik employee. I have been
recently made a Dermik consultant. I do
not own Aventis stock. I have two
protocols involving New-Fill or Sculptra for which I was the sponsor and
investigator, and no product or financial support was provided by Dermik. Dermik did pay for my travel and lodging
here today. Next slide.
The
U.S. data that we have on Sculptra and lipoatrophy falls into three
categories. The first category involves
patient acquisition of product mainly through buyers clubs. The second was a compassionate use study
that I initiated in 2001. And the third
are two sponsor investigator IDE protocols begun in 2002, one by myself and one
by Drs. Mest and Humble in Los Angeles.
Next slide.
Patient
acquisition of product has been going on since 2001. Most of this product has been made available through DAAIR as was
previously described. We do have
statements from six physicians administering this product through this
acquisition method, which encompassed 1,200 treated patients. In these statements it has been said that
all the patients are quite satisfied and that no serious adverse events have
been reported, and that the injection procedures have been well tolerated. Next slide.
I
was actually made aware of the Sculptra product by a patient in 2000 who was
treated in Paris. I was very
interested, so I went to Paris and met with Dr. Laglenne, the developer of the
product, and went through a couple of her training sessions which she did on
weekends for European dermatologists. I
was so impressed with her results and her interest in this product for
lipoatrophy that I actually decided there needed to be some sort of controlled
method of following this product to the United States, so I initiated an IDE ?? an IRB approved protocol in 2001 which I will
call APEX 001. I enrolled 100 HIV
positive males with lipoatrophy, 82 percent were Caucasian and 18 percent were
non-Caucasian. The average age was 44
years and they had been greater than 10 years with HIV. Next slide.
In
this study, the patients received an average of three treatment sessions. However, the range was one to six, depending
on the severity of their disease. And
the follow-up period was two years after the initial treatment series.
On
a scale of one to ten with ten representing the greatest satisfaction rating,
patients gave a satisfaction rating 12 months after the initial treatment
series as 8.0, and 24 months after the initial injection series as 7.5, so
patients were very satisfied which is really our best outcome measure from the
study.
Adverse
events that I reported during this time period were three that were completely
unrelated to product, two were deaths due to progression of HIV disease itself,
and one was a stroke that was judged to be unrelated to New-Fill by the
attending neurologist. The
injection-related events fell very much in line with what has already been
presented, some pain with injection, transient bruising, tingling and swelling.
I
reported nodules in this case in the 52 percent range. I grouped together both my reports and the
patients' reports of palpable but non-visible nodules all into one number. Next slide.
The
IDE study which I began in 2002 was very similar in its structure, involved a
series of treatments. There were both
my ratings and patient ratings, as well as photographs done over the course of
time. In this case, serial laboratory
testing was also performed.
The
demographics of the patient population was almost exactly the same, 85 percent
Caucasian and 15 percent non-Caucasian, all HIV positive males, all in their
mid-40s, and mostly with long-time HIV exposure. Next slide.
The
results of the study at this point, 95 patients have completed treatments. An average of 3.5 initial treatments were
performed, touch-up treatments are ongoing as necessary, and there is again a
very high patient satisfaction in this group.
This time I used a scale of one to five, with five being the most
satisfied. And the average rating at
month six was 4.7, and now we have 61 percent of patients at month 12, again
reporting numbers in the same range.
Next slide.
The
adverse events reported in this case were two unrelated serious adverse events,
one for melanoma of the abdominal wall in a non-treated area, and one for an MI
which underwent coronary artery bypass grafting afterwards. The same effects of
mild swelling and soreness at the injection sites initially, and in this case I
only reported the nodules which the patients reported on their questionnaires,
which at this point was 6 percent.
There were no effects on laboratory values over the course of the
treatments. Next slide.
This
is an example of a patient that I consider to be a better than average
responder. This patient had six
treatments and ten months after his final treatment you can see that he has
excellent results in correcting his lipoatrophy. Of note, this patient's body weight is the same at both of these
photo visits. Next slide.
Here
is a patient that I consider to have below average but still good results. This patient had four treatments, and you
can see his physical appearance six months after the four treatments. Also of note, this patient has lost 10
pounds of body weight between these two visits.
Also
of note, I included treatment of temples in most of my patients, and none of
these photographs actually reflect how good the appearance of people is after
the treatment of temples, as well. Next
slide.
And
to show you a demographic that's a little bit different, this is a 66 year old
black lady that self-acquired product, and she had excellent results. Two months after her third treatment, she
has almost full correction of her facial features. Next slide.
Also
in 2002, Dr. Mest and Humble started an IDE study with very similar structure
to my IDE study. In addition, they
added evaluation of skin thickness throughout the injection series, as well as
digital photography. And again, a patient
questionnaire and well-being scale.
They also took laboratory values throughout their studies. Their demographics included two females, but
otherwise mostly males. And again,
mostly Caucasian with 15 or 14 percent non-Caucasian. Next slide.
At
this point, 86 of their patients have been treated. At month six, using that same scale of one to five they get
almost the exact same ratings that I get, so opposite coasts, different
investigators, still same results.
They
have had most of their patients now reach the 12 month point and still have the
same satisfaction rating, and they have shown with their skin caliper ratings
that there is a definite increase in the skin thickness. Next slide.
There
have been no serious adverse events reports from Dr. Mest and Dr. Humble. They have had the same incidents of mild
transient bruising and pain on injection, and about the same incidence of
nodules as reported by patients, again small, non-visible and palpable. They have shown no clinically significant changes
in laboratory measurements. Next slide.
In
conclusion, looking at these 286 patients, we can say that Sculptra treatments
are safe and well tolerated, and seem to have a durability at least out to two
years. They are effective and have very
high patient satisfaction. Next slide.
Also,
there are many HIV positive patients still out there that would benefit from
treatment, as you've heard today. And
because lipoatrophy appears to be strongly related to the number of years with
HIV, number of years on antivirals, there's going to be increasing numbers of
HIV positive patients with significant lipoatrophy, so this is an increasing
problem. I'm going to turn things back
over to Kim.
DR.
FORBES-McKEAN: Thank you, Dr. Engelhard. I would just like to conclude our presentation today by going
over some of the key points that you heard this morning.
Under
the trade name New-Fill, this device has been available outside the United
States since 1999, and has been used in an estimated over 150,000 patients. Poly-L-lactic acid is a synthetic
biodegradable polymer that has been used in surgical products safely for
decades. Additionally, the pre-clinical
testing, as well as the clinical results, demonstrate that Sculptra is
biocompatible and safe for use as a device.
You've
heard and seen today that facial lipoatrophy is an emotionally devastating
problem for people with Human Immuno Deficiency Virus. People who suffer from this condition may
feel well but look the opposite, and are stigmatized by their appearance. The psychological impact may be severe
enough that it may affect one's desire to continue their much needed
antiretroviral therapy.
For
these reasons, a safe and effective treatment to correct the shape and contour
deficiencies resulting from facial lipoatrophy in people with Human Immuno
Deficiency Virus is needed.
Dermik
believes that the data presented in this PMA meet FDA regulatory requirements
for valid scientific evidence and for demonstration of safety and
effectiveness. Based on this data,
Dermik believes that Sculptra has demonstrated a favorable risk to benefit
ratio in people with Human Immuno Deficiency Virus who are suffering from the
stigmatizing effects of facial lipoatrophy, a condition for which there is
currently no approved medical treatment available to them in the United
States. Therefore, Sculptra would
provide a much needed treatment option to meet this unmet medical need.
This
concludes our presentation today, and on behalf of Dermik, I would like to
thank all of the panel members for their time in preparing for this advisory
meeting, and for your attention today.
Thank you.
CHAIRMAN
CHOTI: Thank you, Dr. Forbes.
That concludes the presentation from the sponsor. Are there questions from the panel that can
be directed to the sponsor? Dr. Olding,
go ahead.
DR.
OLDING: I just have a couple of questions. During your presentation, you spoke about total cutaneous
thickness. You talked about the
thickness of the adipose tissue, and you talked about the skin thickness. I'm not sure after hearing your presentation
that I'm sure what's thickened. Is it
really the dermis? I don't think the
skin has thickened to a millimeter or in some cases 1 point something
millimeters. I think that would create
a very mask-like effect, and particularly since it's meant to be injected in
the deep dermis. Where is the
thickness?
DR.
FORBES-McKEAN: I'd like to address this question to Dr. Sharon Levy.
DR.
LEVY: If I may clarify, the increase in total cutaneous thickness is
indeed in the dermis. The initial
measurements from the VEGA Study included the epidermis, dermis, and the
adipose layer. Subsequent to that, the
area that was measured for follow-up was the epidermis and dermis, so those
changes reflect actual changes to the dermal thickness.
DR.
OLDING: And there's no subsequent change in how the skin looks with skin
that's suddenly become a millimeter or more, a centimeter or more in thickness
because that's thicker than any skin that I've seen.
DR.
LEVY: Right. Well, let me address
that in two ways. One, we were able to
see, I think, as a group here the photographs that accompanied those
transcutaneous thickness changes. But I
would also ask the clinical investigators who have seen the performance of the
product in their clinic to comment on the feel of the product for their
patients, if that would be useful to you.
Dr. Engelhard.
DR.
ENGELHARD: Again, I'm Dr. Engelhard.
What patients report and what we can feel in patient's faces is simply a
firmness in their face. The skin itself
does not feel hard or rock-hard.
Basically, you can tell the difference between treated areas and
non-treated areas by simply a firmer palpation. There doesn't seem to be any gross abnormality when the patient
is in their usual daily activities of washing their face. Nor does anybody associated with the patient
notice anything different about the appearance of their skin.
DR.
OLDING: Perhaps while you're up there you could answer another
question. The nodules that were
discussed, is there a preponderance of location for those nodules? Injecting other facial fillers, if I have a
problem it's usually around the periorbital area where the skin is very thick. Are the nodules then located in those areas
which perhaps are ?? you know,
have a more cautionary note any time you inject fat or other fillers.
DR.
ENGELHARD: Absolutely. A lot of
the nodules that have occurred have been in patients treated outside the usual
clinical settings, and the most common place for people to have complaints
would be in the thin periorbital area, or in areas where there is underlying
bone and the skin is stretched over bone.
For example, stretched across the forehead or stretched over the zygomatic
arch, and that way you may be able to actually see one of these nodules, as you
said, particularly around the eye.
How
I describe these to patients when I'm having initial consultation is that you
may feel very soft small little B-Bs in your skin. Some patients are actually disappointed when they don't. Why don't I feel these little B-Bs, but in
general, patients do not complain of them, nor do they say that they have any
problems with them. And again, as you had
said, when they do become obvious often in patients treated outside the usual
clinical setting, it's usually right around the eye in patients that are a
problem with any injectable product.
DR.
OLDING: But in the clinical study from the presentation from your
experience, there has never been a nodule that's been visualized? It's only been palpable. You've never seen a nodule.
DR.
ENGELHARD: These have only been palpable in the studies that we've done.
DR.
OLDING: But none visible.
DR.
ENGELHARD: Non-visible. The
visible ones that we had seen have been done outside the setting.
DR.
OLDING: Okay. And do you have any
patients or experience of patients, the study went to two years. That doesn't really answer how long you
think it lasts. Can you comment on
that?
DR.
ENGELHARD: I think our use in HIV patients is somewhat different than the
general cosmetic use which has been in Europe for several years. Besides the actual presence of product
itself, the presence of the collagen accumulation because of product itself,
but also in HIV patients you're going to have continued fat loss, so response
and time to touch up treatments is dependent on, I think, three factors - how
long the product actually stays within the skin, how long the collagen
stimulation or response to the product is apparent, and whether or not there's
continued fat loss.
In
our touch-ups that we've seen in our patients, the average patient that
requires touch-up usually gets a single partial treatment about once a
year. Now whether that is because of,
again, continued product breakdown or because of continued fat loss we are not
sure. However, in general cosmetic
patients in Europe, the average touch-up treatment seems to be two to three
years, so there must be confounding factors involved in our HIV patients.
DR.
OLDING: Thank you.
CHAIRMAN
CHOTI: Dr. Newburger.
DR.
NEWBURGER: Thank you. I have
quite a few questions. Number one, I'm
a little bit confounded by the use of the term nodule in these studies. In dermatology, a nodule is generally
considered by definition to be a lesion that is one centimeter or greater. Okay.
And this doesn't follow what the French study has, where they're talking
about one to two millimeter nodules, or indeed what Dr. Engelhard is talking
about in terms of the little B-Bs, so what exactly do you mean by nodules?
DR.
FORBES-McKEAN: Again, I'll ask Dr. Sharon Levy to come up to address this
question.
DR.
NEWBURGER: And then I have many other questions.
DR.
LEVY: Regarding nodules, concentrating first on the presented
studies. From the VEGA studies, as you
mentioned France, the events were termed nodules, or more specifically micro
nodules, so this did not fit the one centimeter definition. In fact, from the investigator they're
actually quite indistinct, and were felt as more like an irregularity in the
deep dermis on direct palpation, so they would not have met the one centimeter
criterion in that respect.
DR.
NEWBURGER: So we really don't have a consistent sense of what these are.
DR.
LEVY: Yes. You are correct that
there is some variability there, because of course, the two pivotal studies
were conducted and designed independently, so investigators used their own
concept for describing these events.
DR.
NEWBURGER: Thank you. My next
question is for Dr. Conant. Do you have
a sense, sir, of the total number of patients in the United States who are
currently on HAART treatments?
DR.
CONANT: Yes. We think that there
are probably somewhere between 900,000 and a million cases of HIV positive
people in the United States. Probably a
third of them do not know that they are HIV positive, and probably somewhere in
the range of 20 to 30 percent are on HAART therapy.
As
I said in my remarks, if it were my choice, I would start everyone who is HIV
positive on HAART the minute they were diagnosed. To date, there has been no direct demonstration that progressive
therapy reduces transmission. It's hard
to believe that if you're reducing the amount of virus the patient is shedding,
you're not reducing transmission, but that study has not been shown.
However,
as I mentioned earlier, remember that people apparently progress to facial
lipodystrophy, lipoatrophy even in the absence of HAART therapy. I have pictures of Rock Hudson before and
after his diagnosis. That was in
1985. AZT was not introduced until
1987, and he clearly had what we today call lipoatrophy. It was being called wasting. Everyone was worried about keeping him
alive, and no one was concerned about the cosmetic appearance of his face.
May
I also return to the question of nodule?
You're absolutely correct, they are papules, they are not nodules. They're deep papules. I've seen one that was located up near the
periorbital area in a physician who had gone to Europe to be injected. I have not seen those.
And
following up on the question about the thickness of the dermis, in my informed
consent I tell a patient do you understand that we're replacing fat with scar
tissue, and all of the patients say yes, I understand that. And yet, in the patients that I've seen who
have been injected elsewhere and in the patients that I have done over the last
four months, the consistency feels pretty normal. So while we are injecting a preparation that is primarily water,
which then stimulates collagen formation at the dermal fat junction, the feel,
the consistency of the skin feels essentially normal, and their facial
expressions are essentially normal. Of
course, you have some people here who have been injected. They could probably comment on that, as
well.
DR.
NEWBURGER: Thank you. So then if
I can extrapolate from your statement that perhaps 50 percent of individuals
have ?? will develop
lipodystrophy, then you're looking potentially at this time somewhere between
150,000 and 300,000 individuals in the U.S. who would benefit from a filler
such as this.
DR.
CONANT: That would be my guess.
The Dermik people probably have even a better guess, because they've
probably looked at the market.
DR.
NEWBURGER: Thank you. My next
question is, I'm not clear from the submission what you feel the mechanism of
action of this product is, since the product itself seems to be resolving in a
relatively short period of time, and yet the cosmetic benefit persists. And I'm wondering ?? I'm sure you have studies which will show
this. Could you share some of them with
us?
Additionally,
the mechanism of action of these papules or nodules since they can develop as
late as two years after initial therapy, what is the mechanism of action
there? I'd like to get a little greater
sense of what's going on here.
DR.
LEVY: I'll provide as much insight into this as I can, and maybe
supported by some of the colleagues in other disciplines.
Regarding
mode of action, in the data that we presented that was not specifically
addressed, as you saw. Really what we
saw, just as you pointed out, were increases in skin thickness over time, and
the time course suggested activity actually some number of weeks and months
following last treatment that suggests that there's an active process in the
skin.
We
know from animal data with this product and in the data with other lactide
products that when implanted into the skin, there's typically a tissue
response. There may be foreign body
reactions. There is dissolution of
product over time, and then there's gradual stimulation of fibroblastin
collagen, and that has been seen in animals. It's possible that that's the
mechanism that we're observing overtly by the increases in skin thickness
measurements.
Now
if I could ask you to repeat the second question regarding nodules and time
course?
DR.
NEWBURGER: In the packet from the European studies, there's data that
shows that some individuals developed or noted the onset of these
nodule/papules at a great interval after their initial treatment up to two
years later. And I'm asking, do you
have any insight as to what this mechanism of action is? Something clearly is going on.
DR.
LEVY: Yes. Again, it's
speculation, and I'm thinking back to the case you're referring to here from
the VEGA Study. Again, the nodules that
were identified in that study were really micro nodules, didn't meet your
definition of nodule, and were identified by the investigator, so the patient
did not identify them.
In
the case I believe in VEGA that was noted at the last visit out at two years,
patient 35, again when one looks at the photograph, we looked at this to
understand, we couldn't see any of the micro nodules that were defined. In speaking with the investigator to
understand in more detail what this was, understanding that they were
identifying these irregularities deep in the skin as nodules. It's possible that there may not even have
been a change in physical exam. They
may have been picked up one visit or another, but we cannot know for certain.
CHAIRMAN
CHOTI: Final question, Dr. Newburger.
DR.
NEWBURGER: Thank you. I'm wondering about the stability of the product
once it's solubilized in the vehicle; that is to say, how much settling occurs
of the product? How fast does it have
to be used, or does it just remain in an equal homogeneous suspension?
DR.
FORBES-McKEAN: Actually, we have a draft in the PMA to recommend that the
product be reconstituted and allowed to sit for two hours before it is
injected. And we've actually done
laboratory studies to demonstrate that the product is stable for a period of
three days once it is reconstituted.
CHAIRMAN
CHOTI: Dr. Chang, question?
DR.
CHANG: I have two questions I'd like to address to Dr. Engelhard. And in the APEX studies 2002, the report
reported palpable nodules went down drastically from 50 or 30 percent if you
reported those that were perceived or picked up by the patient, so they've
dropped to 6 percent, and then the Mest and Humble study down to 9
percent.
Do
you have data of what percentage of papules or nodules were still picked up by
clinician by your exam, and do you know of the Mest-Humble study reported
papules or nodules picked up by physician examination?
And
then my second question is, were any of these patients post two year study
requiring a touch-up or additional treatment?
My final question can be answered by anyone, because this was a patient
on the VEGA Study, patient number 30 that was shown. When I did look at the pictures at the completion of the study
where the nodule was present but not visualized, to my eye, on a right lateral,
right oblique picture at the very last session, there seemed to be some
pinkness or redness over the cheek. So
my last question for anyone is were these nodules that were not visible
associated with any pink or red color, just a faint pink color over this area?
DR.
ENGELHARD: I'll actually answer your last question first. There does not seem to be any erythema, or
pinkness or redness associated with any of these micro nodules in my
experience. As to your first question,
I'm responding to number of patients reporting nodules, let's call them micro
papules to make it more clear, patients reporting micro papules as compared to
myself, in the first APEX 001, again I had presented this data with my findings
and the patient's findings lumped together.
In
that case, the patient's findings were about the same as what was seen in other
studies. And 6 to 9 percent reported
feeling these soft micro nodules within their face. However, I can feel, if I feel carefully in most of my patients,
some irregularities deep in their skin.
And I simply reported this.
There
were no patients in either one of these studies that recorded these as
bothersome, probably because they were pre-warned and pre-told that this might
be something that they feel. None of
the patients reported them as painful or otherwise bothersome to them. And as I previously mentioned, some were
upset that they didn't feel them because they thought that maybe the product
wasn't working as it should.
As
far as touch-up treatments, now I have my first patient was injected almost
exactly three years ago, and I would say that about half of the patients so far
are requiring at least a partial treatment every year or so, probably my guess
is because of continued fat loss.
In
the patients that are not requiring touch-up treatments, they tend to be
patients either that have switched antiviral therapy, or have otherwise
maintained visibly their fat elsewhere in their body, as well. So I think that is a dependent process
somewhat based on additional fat loss.
In
the patients now that are at least a couple of years out, I've had several that
have actually looked even better than they looked initially, and maybe this is
because of some slight regain of fat because of switching their regimes. I have not reported any additional nodules
that have occurred after the first noted ones.
It seems that when these micro papules form, they're going to form in
the first couple of months as the tissue responds to injection of product. I don't see them forming anew later, so I
don't find any new significant micro nodules forming later.
I
do not know if Dr. Mest and Humble have reported any additional or have any
different findings that I've reported, and I'll let Dr. Mest answer that.
DR.
CHANG: Thank you.
DR.
MEST: Thank you, Peter. Dr. Doug
Mest, Clinical Director of Blue Pacific Aesthetic Medical Group in Hermosa
Beach, California. I am the principal
investigator of one of the IDEs and as such, was asked to be here by Dermik and
they, therefore, paid for my travel and lodging. Due to my experience with the product they've also asked me to be
a consultant. Otherwise, I have no
financial interest in Sculptra or have any ownership stock in Dermik or its
parent company, Aventis.
A
couple of questions. I'm going to try to get them all because so many things
went through, so if I forget to answer something, please remind me.
CHAIRMAN
CHOTI: Just try to be brief.
DR.
MEST: We have not seen any redness, irritation, erythema around any of
the nodules that have occurred in our IDE, these are all patient reported
events. That was one of the questions
asked and the answer we did not search
for them. But again, to reinforce it,
they are not bothersome. Our nodules
tended to occur within the first six months.
We did not see any late occurrence of nodules, and we now have patients
out from ?? DAAIR patients all the
way out two years.
I
believe Dr. Vleggaar may have information on histology of what they actually
look like in answering. The assumption
is that they're excess product and a reaction to them.
CHAIRMAN
CHOTI: Well, one question, Dr. Mest.
There seems to be quite a variability in these micro nodules from 9
percent, even in the two pivotal trials, 30 percent to 50 percent. Do you think there is a technical aspect to
the development of these nodules? And
if so, what's your opinion regarding special training in the technique?
DR.
MEST: I think it's both. I think
it's one - if you look for them, you'll find them, and that was probably
evidenced in the VEGA study. If they
press the skin and are specifically looking for micro nodules, you'll probably
find them. The other is, I think it's
technique-dependent in terms of if there's excess product put in. This product is a little different than say
collagen or something like that where if you have this huge depression you're going
to put more product in that area. In
this product, you wanted to wait and act, and so therefore, less may be more in
terms of allowing it to work. And so
the amount of product placed needs to be non-excessive. And so in terms of specialized training, I
think that's relatively easy to get across.
It's just different than what people who are used to using other facial fillers may know to do, and so
some simple training to that effect, that this is different. You need to treat, wait and assess is
probably all that's necessary.
CHAIRMAN
CHOTI: Thank you. Let's go to Dr.
Munk, and then Dr. Leitch.
DR.
MUNK: Yes. I have a couple of
questions about your definition of success, and then some on durability. One of the studies used a 10 millimeter
thickness as a criterion for success, and I'm curious what that's based on.
DR.
LEVY: You're correct. That was
included in the plan for the VEGA study, and it was really just an estimate at
the beginning for the purpose of sample size computation at the beginning. And we can show a slide here that was used
really arbitrarily for the calculation of how many patients they would need to
have entered in the study. And those
patients were termed responders.
We
can see here that the proportion of the patients at each visit who were
"responders" peaking at the one year mark, 61 percent of the
patients, went tailing off a bit over the balance of the study after two years.
DR.
MUNK: Okay. Maybe we can keep
this slide for a minute.
DR.
LEVY: Certainly.
DR.
MUNK: In the VEGA study, the inclusion criterion was total cutaneous
thickness, less than 2, and yet the baseline slide indicated that the average
baseline was 3.
DR.
LEVY: May I make a clarification here?
DR.
MUNK: Please.
DR.
LEVY: I'm sorry. The inclusion
criterion was that their adipose layer be less than 2 millimeters, which it
was. Actually, one patient was 2.1 at
study start, but on average most of the patients had no detectible fat. The remainder of the skin layers that we
were discussing earlier, that is what averaged 3 millimeters at baseline.
DR.
MUNK: Okay. In the Chelsea and
Westminister study, in the delayed group there was a marginally significant
increase in cheek thickness in the delayed group. I think my question may have been partially answered in that
treatment changes were allowed. And it
appears that no data were collected on total weight changes in the patients
over the course of the study, so these may have contributed to facial fat thickness or skin thickness.
DR.
LEVY: You are correct that in the delayed treatment group prior to
treatment, there was one skin thickness measure in the left cheek that reached
statistical significance. And that
measure - and if we can go back to the main presentation when we see the
histogram of the untreated areas - the slide before that. The visual helps.
Although
there was statistical significance at that point, the increase in skin
thickness was very small. It was .4
millimeters in keeping with the rest of the changes. Additionally, as our statistician explained to us, when one takes
what were done, 24 measures of untreated areas, it's actually expected that one
will be statistically significant.
This
is the statistically significant. And
with delayed treatment group, the second panel there, the ?? yes, that's it, the left cheek. You can see in the delayed treatment area
that that yellow bar is, indeed, a bit higher than baseline measure. But in terms of absolute increases, we did
not feel that that was statistically, clinically relevant.
DR.
MUNK: Okay. So going back ?? if you can go back to that earlier slide, one of
the things that is difficult for me to understand is the durability of the
product, and the various studies. There
was either a fixed number of treatments, or treatment to effect. In some cases there have been touch-ups, and
yet this clearly shows that there is some reduction in total cutaneous
thickness. And I guess I would take
some exception to the statements that have been made about continuing fat loss
because the studies I'm familiar with typically show lipoatrophy stabilizing
after two to three years. So I'm
wondering about long-term durability of the product.
DR.
LEVY: If we could go back to the main presentation slide, the data cloud
that shows the data points from all 50 patients. And let me just address that from the reference that's correct,
from the VEGA study. We want to look at
the data here again. So these are the
data.
In
this case, as you mention, patients did not receive a fixed regime. They received treatment to effect. In fact, most patients, I think it was about
85 percent, had either four or five treatment sessions on average, completing
it about week 14 of the follow-up period.
So these are the data from all the patients. This is a bit different design than the other studies, but this
does give us a good time frame for two years.
The Chelsea and Westminister study was not initially planned to go out
two years, so efficacy results can really not be looked at the two year
mark. We use that for safety.
The
other comments from Drs. Engelhard and Mest are coming from a more clinical
situation in the course of their trials.
Is that helpful to you?
DR.
MUNK: Yes. And finally, I guess a
comment which is as much for FDA staff as anybody regarding the photos. There seems to be fairly low interrater
reliability on grading the photos, and I would confess to some great difficulty
in comparing them. And I wonder if FDA
doesn't have a guidance for investigators on the lighting, the distance from
the camera, the positioning of the subject, and so on, so that there would be
greater comparability of pre and post treatment photos, because I think that
would have been very helpful in this case.
CHAIRMAN
CHOTI: Dr. Leitch.
DR.
LEITCH: I have a couple of questions,and one again is sort of related to
durability issues. The Chelsea and
Westminister study photos that are in the booklet towards the back, and they
didn't have so many photos, and there were comments that were written on the
bottom regarding the progress of those patients. And seeing that there were several in which the comments were the
patient didn't feel like the product lasted in one case I think passed three to
four months, and another at six months noted sinking-in at that interval, so
that is one question that I have.
And
the other sort of a bit referable to that is again this idea of mechanism of
action. If this is a filler, what I was
sort of hearing is that when you do the injection, you don't
"fill-out" the whole defect because there is something else that is
happening, so if it's not really the idea of filling, I think for us in terms
of making recommendations for labeling, or as you instruct physicians, there
needs to be some understanding of the mechanism for how it acts to attain the
thickness because people might be inclined to fill the defect.
And
I was wondering since there is a lot of usage of this product in other
countries, is there not any investigational data on skin biopsies in the
patients who have received these not just the nodules, but I mean actually of
the skin that's being treated to give a sense of what is the mechanism of
action of the filler.
DR.
LEVY: It's a several part question, and I think I'll be able to address
some parts of the first portion, and then we call a colleague with experience
in Europe, Dr. Danny Vleggaar, to answer some of your questions at the end.
Regarding
the Chelsea and Westminister study, you're right. In that study, patients had a fixed regime of treatment so if
they needed more at that point, as judged by the patient or the investigator,
by protocol they didn't get it as part of the treatment beyond their three
injections.
In
the photographs that we've presented to you, those are all the photographic
data that we've gained consent for, was about 15 patients out of the cohort in
Chelsea and Westminister. And the
comments that you see at the bottom were collected at the one and a half to two
year mark after the study had been completed.
And that was included in the interest of fullness of understanding the
clinical situation.
In
many instances as you remarked, patients were not satisfied with three
treatments, and either asked for additional treatment with the Sculptra
product, which sometimes in cases they got, or sought other treatments over
that intervening period of time. And
looking at the photographs as well, I think it harkens back to the earlier
question - yes, there are differences in photographic technique between the two
studies. And as we reviewed the
photographs in Chelsea-Westminister, they were taken in a standardized fashion,
but our sense is that they may not have been taken with the optimal technique
to highlight the defects. They were
taken at a 45 degree angle, but without the type of overhead lighting that may
have best shown the changes in facial appearance. And we say that in looking in particular at the baseline
photographs in individuals who had very little fat, but yet did not always have
such a demonstrated defect. You may
actually be looking into the defect from that angle.
Regarding
information of mechanism of action, I would ask if Dr. Danny Vleggaar could
address this from his experience.
DR.
VLEGGAAR: Good morning. My name
is Danny Vleggaar. I'm working in
Europe with various injectable devices since four and a half year. I gained quite extensive experience with the
product Sculptra. I am since one and a
half year a clinical consultant for Dermik.
They paid for my travel and lodging to come here, and I have no other
financial interest in the product.
To
answer your question, indeed we see a correction in patient after injection
which goes beyond the physical volume of product that has been injected. There, to my knowledge, are no such studies
in Europe performed to demonstrate this mechanism of action, this delayed
mechanism of action in patients.
There
are animal studies, of course, one described at Goglewski. What I can tell you from personal experience
and watching histological samples from
patient is that there is a foreign body reaction and we see a fibroblastic
response with formation of in the beginning very young and early layers of
fibrous tissue which are developing in the later states to more extensive
layers of mature collagen. And I think
that this is another reason for the clinical result, an increase in tissue
which is suggestive for formation of new collagen.
I'm
only aware of some slides from the very early days where the tissue has been
marked with a collage type one marker, and there was an increase in collagen
type one in the sample.
CHAIRMAN
CHOTI: While we're on dermatic pathology, Dr. Penneys, any questions for
the sponsor?
DR.
PENNEYS: Many of my questions have been answered. As a dermatipathologist, there wasn't much
really for me to evaluate. I mean,
there's a lot of conjecture in these patients.
I have a number of questions.
If
the reaction to this material is a foreign body-type reaction, then why are
papules local? Is it at the end of the
syringe that there's an accumulation of material? Is it site-specific, or is not even related to the
injection? For example, when you put a
needle through the skin, you could perforate a hair follicle. I mean, there are many different reasons why
people get ?? actually people get - I
hate to use the word - papules, because as an aside, as a dermatologist,
language is important. And the words
I've heard this morning don't exist in our dictionary. I mean a micro nodule is like jumbo
shrimp. Is that something you see under
a microscope? Is it a micro nodule? Same with a micro papule - I mean, these
terms have actual specific sizes.
For the company's benefit going forward,
please ask your investigators to estimate the size in millimeters or something
like that. Then there will be no
confusion about terminology.
And
regarding the photographs, these photographs - I realize you purchased
them. They came ?? you had no control. However, they're an example of what you could teach what not to
do. The backgrounds are so distracting
that it's hard to look at the dramatic changes which are there. I mean, the shadows. It's incredible. I've never seen anything like it in a submission anywhere. If you look in a journal, you won't see
photographs like this. However, that's
irrelevant.
To
get back to histology, it would be nice to know what is there at the end of the
period of time. I mean, I recognize
that this is a reconstruction, and that there's an obvious clinical benefit,
but at some point, somebody's going to have accumulate data because of what's
going to happen to this material once it's available outside of this
population. So I have no other comments
because again, a dermapathologist, there wasn't anything for me to evaluate in
terms of micrographs. It's people's
opinions about what might be there, what was there in a rat, or what was there
on one patient - none of which represented accumulation of scientific data, to
me.
CHAIRMAN
CHOTI: Okay. Thank you. Dr. Miller and then Dr. Fish.
DR.
MILLER: Yes. I have a question
about the use worldwide. What
percentage of patients worldwide do you think are the HIV lipodystrophy
patients compared to the ones getting it for cosmetic purposes?
DR.
LEVY: We don't know specifically, but in discussion with the commercial
partners, our estimate is that it's very low use for lipoatrophy worldwide.
DR.
MILLER: One percent, ten percent?
DR.
LEVY: We have estimates somewhere in the 5 percent, maybe 10 percent
range. But the experience that we've
gathered worldwide is predominantly in cosmetic usage.
DR.
MILLER: So why is the PMA focusing on use in lipoatrophy patients rather
than just as a general filler, tissue filler?
Why the focus on the lipoatrophy patients?
DR.
LEVY: Well, I think as Dr. Forbes-McKean mentioned, first of all most
importantly, there's a real medical need.
That's the first issue. And then
the data that we have available, the data for presentation meeting scientific
rigor for your review are in this population.
DR.
MILLER: Well, how does it compare - I mean, it appears to me to be a
filler, tissue filler like ?? I mean, I
haven't seen anything presented which suggests to me, especially knowing now
that it's injected into the dermis. I
was trying to envision where this exactly is injected, and it sounds like it's
injected into the dermis like other fillers.
And it has some unknown mechanism of action which you have to ?? I heard someone say you have to wait and let is
act which is something you don't have to do with other fillers. So there's something going on here perhaps
that's different than another filler, but they compare the effectiveness against
other fillers. And since that what it really is competing with, and I'm
concerned that this appears to be a product really designed for aesthetic
tissue filling like all other tissue fillers basically are, but it's being
pitched as a unique product addressing a very difficult, and no question, big
problem of lipoatrophy. But I'm not
sure why this is uniquely suited to address that problem.
DR.
LEVY: Just as a point of clarification, I hope this helps. I don't know if it does for your question -
this is just a schematic to understand where the product would be implanted, as
many of the clinicians have mentioned, really at the deep dermis, the dermal,
hypodermal junction. And it's typically
implanted using a number of injections with a condition like lipoatrophy that
will involve a large area. This could
be delivered by a grid pattern, so it's well distributed in the area right at
that junction.
Regarding
the initial uses of the product, you're correct - it was developed in Europe as
a product for the category, cosmetic category filling and augmenting tissue for
those type of defects, wrinkles, folds, eyerings. But it was shown very early on in its product history that it was
particularly useful in treating the larger volume defects associated with
lipoatrophy.
DR.
MILLER: Just there's a number of questions I have too. I can stop, I guess, but I'm just curious
about how long does the product stay? I
mean, the PLLA has a certain degradation and life, but how do we ?? do you know how long it remains present in the
injection site after injection?
DR.
FORBES-McKEAN: Just before we move onto that next question, we would like
to also ask Dr. Peter Engelhard to come up and comment to your previous
question about why this particular product has been used more successfully in
the condition of lipoatrophy versus other fillers that you brought up. Would you like to have that addressed
further?
DR.
MILLER: Well, if he has data I would like to see data on that
comparison. What I'd be curious about would
be a direct comparison of this product to other tissue fillers, which appears
to me to be a tissue filler. But yet,
there's no comparison of how this product performs compared to other tissue
fillers.
DR.
FORBES-McKEAN: Initially, as Dr. Levy said, the subject of this PMA is
the data that we feel is valid scientific evidence for the intended use of the
product as we've proposed with this application. That other data is not currently available, so I was ?? we were mentioning that Dr. Peter Engelhard has
some experience clinically with the other fillers for lipoatrophy, if that's what you would like to have addressed.
DR.
MILLER: Sure, I'd like to hear that.
DR.
ENGELHARD: First of all, I think we're all aware that the general
cosmetic use of this product is the big deal in Europe, and will probably
eventually become the big deal here.
But the present application is for lipoatrophy, again because of this
expedited review for a need which is really poorly met with most of the
available filling agents or procedures.
And what I do with each of my patients as they come in is review what
options are open to them, and what the pluses and minuses are of each of the
options. And that basically falls into
really a few broad categories.
You
have surgical implants, which you've heard from patients and from other
physicians have their drawbacks. The
surgical implants, whether they be solid teflon or silicone, are usually only
designed to fit one discreet area. And
often, the lipoatrophy loss is spread throughout the cheeks and the temples,
and cannot be fully addressed or adequately addressed by a solid implant. Often we have to use the solid and
injectibles around it.
As
far as injectibles go, the collagens, whether they be bovine or human origin,
seem to be lacking in their durability.
It's an extremely expensive procedure to fill multiple dents as compared
to just wrinkles, and it really does go away within a couple of months.
Also,
perhaps lasting a little bit longer are some of the particular fascia
products. But again, constant refills
being necessary, and cost being prohibitive in the long run of continuing these
injections.
There
are permanent silicone products on the market being used off-label, and I think
there are multiple concerns on the parts of the patients and the physicians
with silicone injections. Most notably,
migration, and also as you know, residual effects, even years later the
formation of new granulomas, even years down the line based on silicone. So of the current available options, there
aren't any that really meet the need of long-lasting enough, and cost-effective
enough.
After
a series of New-Fill injections or Sculptra injections, you really have a
respite of a year or two before you need touch-up treatments. However, there does seem to be some
degradation, some loss of product effect, so you're not talking about an
absolute permanent effect as you would with the silicones. So it does sort of nicely fit this niche,
whereas other products don't fit this niche as well presently.
CHAIRMAN
CHOTI: Dr. Fish, quick question.
Dr. Lee, and then we'll take a break.
DR.
FISH: My question is related to the baseline CD4 and viral load
strata. The first question is, in the
viral load criteria for the VEGA Study, we have viral loads less than 5,000. I'm not actually sure why that criteria was,
but when we look at the range of viral loads, it was up to 96,000 copies were
allowed to enter the study. And it
looked like maybe 14 percent or so of patients actually didn't meet that entry
criteria. So that question.
And
then the other question pertains to the
CD4 strata, in terms of did you look at those in the
Chelsea-Westminister trial. We do have
the range provided to CD4, so percent with CD4 is under 200 in terms of
severity of lipoatrophy presentation, the response to treatment, and/or the
adverse events of the skin nodular formation.
DR.
LEVY: You are correct. There were
some instances where the ?? in terms
of CD4 count or viral load that there were patients who enrolled, sometimes
outside the initial criteria. We did
look at treatment effect by CD4 count and viral load, I believe, and I'm going
to confirm this over the break with our statistician.
My
recollection on that is that we stratified by the medium values, and then
looked for treatment effect and did not see any. But we'll be able to get back with you on that probably after the
break specifically.
DR.
FISH: And one last question. In
terms of the reconstitution in the Chelsea-Westminister trial, they had some
lidocaine, one CC of lidocaine. Can you
comment, your recommendation it looks like from your draft would be sterile
water. Was that an adverse thing? Did that help, did it hinder with lidocaine?
DR.
LEVY: You are correct that again these were investigator designed, and
the investigators chose in the Chelsea and Westminister study for the
reconstitution volume of 3 mLs to use.
One of those mLs was lidocaine for patient preference just as an
anesthetic. And I think again, that was
used uniformly. We can look at the
results of that study and look at the results of VEGA.
In
terms of skin thickness at the referable time points, three months, six months,
results were very comparable.
CHAIRMAN
CHOTI: Dr. Li.
DR.
LI: I have kind of a follow-up question to Dr. Newburger's and Dr.
Leitch's about mechanism. What is the
role of the PLLA in this formulation?
You know, it's 40 percent PLLA and 60 percent other things,
carboxymethyl cellulose and the mannitol, so exactly what is the role of the
PLLA in this?
DR.
LEVY: Well, we can tell you that the other components, the excipients are
reasonably handled by the body, the carboxymethyl cellulose and the mannitol.
DR.
LI: I understand that.
DR.
LEVY: And reconstitution volume is very transient. The issue of mechanism of action has been
coming up this morning, and the durable component of it is the PLLA, so our
feeling is, of course, that the tissue effects that we're seeing are in
response to that PLLA, which is implanted.
When we've had scant information typically from adverse events from the
worldwide database, one could see a foreign body giant cell reaction, and
that's consistent with what was seen in the pre-clinical studies. Dr. Handler could address that further if
that's helpful to you.
DR.
LI: Well, this is kind of a lead-up question too. If the PLLA is important to the mechanism of
filling in the tissue, how did you optimize the PLLA? In other words, why did you pick the PLLA you picked? You know, why not some other particle size,
why not some molecular weight? Why not
some other resorbable polymer, or why even a resorbable polymer?
DR.
FORBES-McKEAN: Okay. Well, we
chose a resorbable polymer for the biocompatability advantages that it
offers. And as far as the particle size
range, this particle size range was selected because it was believed that the
particles were big enough to cause the effect that's clinically desired. However, not so large that it would be
impossible to inject the product. And
also, not small enough so that you would get an immediate engulfing by the
macrophage, and get an inflammatory response that you didn't want.
DR.
LI: Was the empirically determined or was this based on some studies, or
just really good luck for the first three guys that did it?
DR.
FORBES-McKEAN: I think there's a lot of available information out in the
literature about PLLA, and I'd ask Dr. Russell Parsons to come up to
specifically address the properties of the PLLA.
DR.
LI: Well, at this point I'm just kind of more interested in kind of the
general how you picked it. My concern
is, you know, let's just say it works well the way it is, how sensitive is it
to changes? In other words, if you put
in a little more, a little less of the particle size, you drift the time, just
how sensitive is the PLLA characteristics to the performance of the
product? Do you know?
DR.
FORBES-McKEAN: Well, we actually have looked historically at the lots
that have been used out in the ?? with the
current use of the product in Europe, and that's how we devised the
specifications that we have proposed for the PLLA, which will be controlled
after the PLLA is milled and then gamma irradiated. And we'll have a desired range that we've shown in the clinical
use of the product that is giving us the desired safety or the desired
efficacy, as well as the safety with the product in that range.
DR.
LI: So, it's empirical basically, based on your experience essentially
then.
DR.
FORBES-McKEAN: Yes.
DR.
LI: Okay. Then my final question
for the moment is for these - whatever - is papules the correct - for these
little lumps there. Is the material
involved in those nodules, in other words, in the histology of those nodules,
the center of those nodules, is there material?
DR.
LEVY: Those nodules that were described in the pivotal studies, none of
them were biopsied. I mentioned in
comments about the post marketing experience, there have been individual
reports with commercial use of the product of cases that have been
biopsied. In general, those show
foreign body reactions. Sometimes there
are particles detectable through polarized light.
DR.
LI: The reason I ask is in other studies and other orthopedic devices
specifically, where you've injected a whole host of things into the
subcutaneous layers of many animals, that you often get what we would call
nodules or growths around clumps or concentrations of material. So my question is, is there ?? have you looked for any kind of correlations
between the presence and the size of these nodules to perhaps the number of
injections the person's got. I
understand that sometimes more than one dose is applied, and there's also some
difference apparently in the amount of material in each vial. You know, you focus around 400 milligrams,
but it goes from like 270 to 500 or something like that. Is there any correlation between the amount
of material and the presence of these nodules?
DR.
LEVY: The VEGA study was not designed ?? I mean, the adverse events such that we could analyze that versus the
amount of treatment, but the treatment sessions which should reflect amount of
the product because that was fixed on a per cheek per session. The patients in the VEGA Study, virtually
all of them had four or five treatment sessions. There were few people who fell to either side at three or six, so
that doesn't give us a great span to try to examine that, the nodules in that
population.
DR.
LI: Thank you.
CHAIRMAN
CHOTI: I think the best term I thin are "Bbs", probably the
most accurate. Why don't we take a 15
minute break now, and then we may follow-up with some additional questions with
the sponsor, and then proceed to the FDA presentation. Thank you.
Let's start promptly at 11:00.
(Whereupon,
the proceedings in the above-entitled matter went off the record at 10:41 a.m.
and went back on the record at 11:01 a.m.)
DR.
KRAUSE: We are going to start again in
a minute. There were a few comments, a
few points, that I wanted to point out before we start again. Some individuals who may have wished to
speak, and who got here a little bit late, or were not here at the scheduled
time, we would still like for you to be able to speak.
So
if you contact Ayana, you can either give me your written statement, or give
her your written statement, and it will be read in the afternoon open session
by one of us if you would prefer not to read it yourself.
And
also I would just like to remind all the speakers when you do get up to the
podium, please adjust the microphone so that it is in a position where the
things that you say will come out clearly.
It
is important for the transcriptionist and for us in the audience. Since you are facing this way the audience
has difficulty hearing you if you are not speaking directly into the
microphone. I appreciate that. Dr. Choti.
CHAIRMAN
CHOTI: Thank you, Dr. Krause. I think most of the panel has asked their
questions of the sponsor, and so now we will move ahead to the FDA
presentation. Dr. Lerner.
DR.
LERNER: Good morning, Dr. Choti, and
Dr. Krause, and Members of the Panel, and guests. I am Dr. Herb Lerner, a reviewer for the Plastic and
Reconstructive Surgery Devices Branch at the ODE. Today, I will be presenting the FDA's review of the PMA for
Sculptra.
Sculptra
is intended to correct the shape and contour deficiencies resulting from
patient fat loss from lipoatrophy in people with human immunodeficiency virus.
Sculptra
is a sterile solution consisting of PLLA, sodium carboxy-methyl cellulose,
mannitol, and sterile water. Listed on
the screen are the members of the review team for this PMA.
Dr.
David Berkowitz will be making a few remarks regarding the toxicology of the
device, and then I will be presenting the PMA.
Dr. Berkowitz.
DR.
BERKOWITZ: Good morning. The components of Sculptra have long
histories of medical use. The
components are carboxmethyl cellulose, aerolaytic acid, and mannitol. The components of Sculptra have long
histories of use in medicine, and the carboxmethyl cellulose is used, for
example, in wound dressings and
adhesion barriers.
Larger
amounts are used orally as bulking agents and laxatives. Polylactic acid is used in orthopedic
implants and sutures, and all of the polylactides, or if all of the
polylactides from three vials of Sculptra were hydrolyzed at once, the lactic
acid produced would be less than the amount present in 500 mils of lactated
Ringers Solution.
The
use of microparticles for PLLA is new.
Mannitol has been used systemically at does of 2 grams per kilogram to
reduce intracranial pressure. The dose
of Mannitol in three vials of Sculptra is about 6.4 milligrams per kilogram for
a 60 kilogram patient.
So
all of these have histories of safe use.
The purpose of the toxicology testing is to assess the safety of this
particular combination of products. The
slide summarizes the testing performed.
Cellular toxicity was done by placing Sculptra directly on a lawn of
L929 cells. There were no significant
cytotoxicities.
Sensitization
was tested in a Magnusson-Klingman test, and Sculptra was diluted one-to-one
for sensitization, but was used undiluted in the challenge. There was no significant sensitization.
The
acute systemic toxicity Sculptra was tested by IP injections in mice at doses
of 5 grams per kilogram, and again there was no systemic toxicity. Subchronic toxicity was tested by following
in cutaneous injection for 90 days in rats.
Extensive
general health parameters were monitored, and no significant toxicity was
observed. At the implant site, there
was a normal foreign body reaction that we heard about.
Implant
material was present at 90 days, though only five implant sites were examined
physiologically. Genatoxicity was
tested in a bacterial reverse mutation assay, a chromosomal aberration assay,
and an in vivo micronucleus test.
Sculptra
did not increase mutations, chromosomal aberrations, or mouse micronuclei. Complement activation was not affected by
Sculptra. Both the CH-50 test and the
measurement of the amount of SC5b-9, and that is the membrane attack unit, were
measured and both were normal in human serum.
So
none of the testing raised significant toxicological concerns. All of the essential toxicological testing
was completed. Sculptra physical
characteristics are described here.
The
molecular weight is 40 to 50 thousand, and the PLLA particles are of irregular
shape, and the sizes of the particles are 40 to 63 microns, with 10 percent of
the particles allowed to be less than 40, and 2 percent that exceed the 63.
Two
hours are required for optimal suspension of the material, and the two hours
are primarily for wetting. Sculptra is
physically, chemically, and microbiologically stable for 72 hours after
suspended as we discussed, or as was discussed previously.
Sculptra
resorption kinetics were looked at, and there was no weight loss for 24 weeks
in phosphate buffer 7.4, at 37 degrees.
There was a 19 percent weight loss at 50 degrees.
Foreign
material was seen histologically for 90 days after implant, subcutaneous
implants in rats. So it means that at
least some of the material was present after 90 days.
The
resorption rate is a function of molecular size, weight, crystalinity, and
particle size. Gogolewski did some
studies on various types of PLLA implanted, and in this particular study, he
used 4-by-7 millimeter rods subcutaneously in rats.
And
the material was 95,000 molecular weight, and 19 percent was degraded by one
month, and by 3 months, 40 percent was degraded, and at 6 months, 56 percent
was degraded.
But
the published material indicates that PLLAs in several cases in fibrous tissue
actually outlived the material itself.
That is, it took longer for all of the fibrous tissue to disappear than
it did for the PLLA to disappear.
That's
all I have, and I think that Dr. Lerner will now present a summary of the
clinical testing.
DR.
LERNER: New-Fill is the name of the
device that is commercially available outside of the United States. Sculptra is the intended name of the device
as it will be marketed within the United States.
For
this review, the use of these names is interchangeable. The safety and effectiveness of the device
is supported by five investigator sponsors' clinical studies. As noted on the slide, two studies were done
in Europe, one in France, and the other in England.
The
U.S. studies were done in Florida and in California. None of the trials were controlled, randomized, or blinded. All were open labels and were single center
studies. Note that the C&W study
had a delayed treatment group to serve as a, quote, control.
Additionally,
photographs were taken during all studies.
Panel members were presented a copy of these photos for their
review. Patient confidentiality does
not allow us to project these photos for public viewing.
All
the studies used some measurement of skin thickness to assess the effect of
device implementation. In the VEGA
study performed in France, total cutaneous thickness was measured by summoning
the ultrasound measurements of the buccal ft pad and skin thickness.
In
the C&W study from England, there was a Doppler ultrasound measurement of
the full thickness of the area to assess the thickness. Common to all of the studies that I will be
presenting is the inclusion criteria that the patients be HIV positive, and
have been on antiretroviral therapy prior to enrolling in the study.
It
is recognized that some patients stopped these medications to prevent the
sequelae of lipoatrophy. This was taken
into consideration when the FDA terminated that this PMA should receive expedited
status.
For
the VEGA study in France the inclusion criteria included HIV positive, a plasma
viral count of less than 5,000 copies, current antiretroviral therapy of
greater than or equal to 3 months, with at least a previous 3 years of a
history of antiretroviral therapy, and an buccal adipose tissue of less than 2
sonometers.
As
noted the sponsor used the measurement of buccal adipose tissue as a criteria
for inclusion and for success. As I
will discuss shortly the total cutaneous thickness measurements were determined
for each of these patients and used for the effectiveness evaluation.
Exclusion
criteria included cutaneous Kaposi's sarcoma of the face, infections, or
concurrent herpes labialis, previous facial fillers within 6 months, and
patients unwilling to meet the study follow-up timetables.
The
study was an open label, non-randomized, and uncontrolled study. Patients were given biweekly injections to
maximum correction, and in this study the device was mixed with 3 cc's of
sterile water.
All
patients had at least three treatments; three patients had six. They were followed for up to 96 weeks to
gather data on adverse events, and total cutaneous thickness measurements.
Measurements
were again made by Doppler ultrasound at several predetermined locations on the
face, including the zygomatic arch and the center of the buccinator
muscle.
Fifty
patients were enrolled and 47 patients completed the trial. Two withdrew at 72 weeks, and one withdrew
due to an unrelated event. The average
mean years of age was 44.9, and 98 percent were mail, and 84 percent were
caucasian, and 6 percent hispanic.
Fifty
percent of the patients had had an AIDS defining event as was previously
mentioned, and I won't repeat them, but the CD4 HIV viral loads, TCT
measurements, and adipose tissue measurements are on the screen.
Safety
endpoints. The design to look for
changes in standard biological parameters.
Several events, such as injection site bruising, 3 percent of the
patients; hematoma, 30 percent; and nodule formation in 52 were noted during
this study.
Nodules
appeared from 9 days to 2 years post-treatment. Most nodules were of mild intensity, as judged by the
investigator. There was one patient
with injection-site hemorrhage, and another with edema.
There
were no clinically significant changes in CD-4 salt count, and there were no
clinically significant changes for baseline in viral load or lactic acid
levels, during this study.
The
mean increase above baseline ranged from 5.2 to 7.2 millimeters throughout the
study period for the total cutaneous thickness measurements. These were statistically significant at each
time point.
The
number of responders, those defined as a gross TCT greater than 10 millimeters,
peaked at Week 48. This was an
arbitrary point. In addition to the
TCT, the sponsor performed a Visual Analogue Scale for evaluating global
well-being, and assessing quality of life.
At
baseline the median score was between 6.1 and 6.7, indicating a satisfactory physical
or emotional state. After treatment the
scores increased by .3 to .8, which was statistically significant at 6 and 12
months.
Remember
that there are no controls for evaluating these results and the data must be
looked at accordingly. This slide you
have already seen. The efficacy
endpoint was established as a proofing on the TCT over time, and as you can see
on this slide again, the increase is constant and reproducible.
The
Chelsea and Westminister study in England, inclusion criteria again were HIV
positive, with mild to severe lipoatrophy, and not pregnant or lactating.
Exclusion
criteria included active opportunistic disease or wasting, current growth
hormone therapy, current chemotherapy for malignancy, or non-hypersensitivity
to PLLA. Thirty patients were enrolled,
and again an open label, non-randomized, and uncontrolled study.
Patients
in this study received three treatments, spaced approximately 2 weeks
apart. The patients in the delayed
group had treatments at Week 12, 14 and 16.
In
this study the device was mixed with 2 cc's of sterile water, and one CC of
lidocaine. Ultrasound was used to
determine facial thickness at the nasolabialfold, the corner of the mouth,
zygomatic arch, and centrally in the buccal fat pad.
Visual
analogue scores were between zero and ten, with zero being as thin as it had
ever been, to 10, not thin at all.
Antidepression/anxiety scores were scored between zero and 21, and with
zero as normal, 8 to 10 suggestive of a mood disorder, and 11 to 21 with the
possible presence of a mood disorder.
The
demographics are similar to that in the previous VEGA study. The safety end-points included a change in
viral load, a change in CD4 count, a change in blood chemistries, or adverse
events, and there were no significant changes in the CD4 count or viral load
counts over time for either treatment group.
As
in the VEGA the most common adverse events were treatment related, with 80
percent of the patients experiencing at least one event. The most common event was bruising, and 31
percent of the patients developed an injection site nodule. Few of the events were severe. One patient did develop a skin infection.
For
all measures there was significant improvement from baseline. There was significant changes in dermal
thickness in each group. Generally
there was a 4 to 5.5 millimeter improvement in buccal thickness at week 12 and
24 of the first group, and at week 24 in the second.
The
VAS scores showed improvements in body perception, and HAD scores changed from
suggestive of a mood disorder to normal.
For the face the VAS scores improved from 2.3 mean at baseline, to 7.2
at week 12.
And
from 2.3 to 6.1 at week 24. HAD scores
changed from 7.9 to 7.2, and anxieties from 5.1 to 4.8, indicating improvement
in patient self-assessment.
In
this study the device was injected into several areas of the face. The slide shows the improvement of buccal
thickness for the initial group of patients, and the results are comparable to
the delay group. I know that it is hard
to see, but if you look at the cheek area, you will see that the range of
improvement over the period of time for the study.
Common
findings in both studies. There was
modules at the injection site, 52 percent in the VEGA study, and 31 percent in
the C&W study. The average on-set
was up to 218 days, with a range from 9 to 748.
Most
of the nodules were reported as mild and not visible, and there is no
histologic data available. A review of
Dr. Englehard's study, and is a investigative sponsored compassionate use
study.
This
is the APEC-001, the inclusional criteria include HIV positive and demonstrable
photographic lipoatropy, and exclusion criteria included active infection,
Kaposi's sarcoma, or Herpes.
They
must not have had facial injections within the last 3 months or be on
interferon or steroid treatment. This
study and the two which follow are primarily valuable for their safety
analysis.
In
this study, treatment could be to the cheeks and temple, but not to the temples
alone. Subjects could receive up to six
treatments, and the majority had up to three.
Patients
were treated with 1 to 8 CC's of New-Fill.
Treatment was at 3 to 4 week intervals, and two patients in the group
have died, one due to , crytosporidiosis, and the other to mycobacterium
infections.
Four
patients did not return for their first visit, and 38 of 96 have not completed
the 24 month follow-up. Fifty-eight
have reached the 1 year point, but not the 2 year point.
Nodules
were reported as the main device-related adverse event. Subject satisfaction with the correction at
6 to 12 months after treatment was high; a rating from 8.1 to 10 on a 10 point
scale.
At
24 months, it was 7.5. These are not
validated scores, but due reflect patient responses. Investigative ratings showed continued improvement, with almost
complete facial satisfaction at 12 months.
Again,
although not validated, investigative ratings went from 3.2 at baseline on a
scale of five, with five being worse, to 1.36 at 12 months.
The
APEC 002 study. A hundred subjects were
enrolled, and 37 of the 99 patients had completed their 6 month follow-up, and
34 subjects have completed their 12 months.
The
remainder are still within the study guidelines. The majority of the patients received 3 to 4 treatments at 4 to 6
week intervals. Subjects received an
average of 7.8 cc's of New-Fill at each treatment session.
Please
note the similar HIV and HAART data compared to all the previous studies. As in the other studies, treatment related
events predominated, but were generally mild.
There have been six nodules reported to close the data.
Subjects
related their lipoatrophy on a scale of 1 to 5, 5 being low scale, and most
severe. At baseline, the average score
was 3.71, and at 6 and 12 months, it was under one.
The
California study. This study is
ongoing, and 15 of 95 patients have completed their 6 month follow-up, and
patients received 1 to 6 cc's at each treatment, for up to 6 treatments.
Adverse
events, again, mostly treatment related, with 8 nodules in 87 patients. Again, note the similar HIV and
antiretroviral therapy. Inclusion
criteria was similar to the APEC study.
HIV positive for lipoatrophy, infections, treatment with interferon or
steroids, uncontrolled diabetes, or lactic acidosis.
The
endpoints were to evaluate the quantifiable improvement in facial wasting after
serial intradermal injections. The
safety endpoint were determined for repeated treatments, and the efficacy for
durability of New-Fill, and the psychological impact on patients.
For
this study, caliper skin measurements were taken at treatment sessions, and up
to 12 months. The results were that
there were eight nodules in 87 patients, and the remaining treatment-related
events were reported as mild.
There
was high patient satisfaction, and the average change in the total cutaneous
thickness was 6 millimeters at 6 months, and the ranges are projected on the
slide.
The
overall conclusion for safety in general, the majority of treatment-related
events were mild, and one being mild pain, bruising and swelling at the
injection site. Device events were
generally palpable subcutaneous nodules up to 15 percent, and no major events
were reported.
Total
cutaneous thickness analysis in the VEGA study showed an increased
thickness. Normal thickness changes in
the C&W study showed significant enhancement of the overall fitness.
Photographic
evidence indicates sustained effectiveness, and quality of life assessments
show improvement from baseline. While
the study did not use a validated statistical method, my review of the photos
shows effectiveness. We await your
opinion.
I
will finish with a short statistical summary.
Our statistician is here if you have any questions. A mass assessment using a validated severity
scale was not performed.
Changes
in ultrasonic measurement of subcutaneous skin thickness were taken to be a
surrogate endpoint for improvement in facial appearance.
There
was a statistically significant increase from baseline in total cutaneous
thickness at every follow-up for two years for the VEGA study, an through week
24 for the Chelsea and Westminister study.
There
was no evidence that the effect of the treatment was related to the length of
time on antiretroviral therapy, baseline CD-4 count, or baseline skin
thickness. However, there was more
change in skin thickness compared among those patients who skin was thinner to
start.
Overall,
the sponsor demonstrated that increased skin thickness was pictorially
correlated with improved appearance.
Thank you
CHAIRMAN
CHOTI: If that is the end of the FDA
presentation, it's open for the panel to ask any quick questions to the FDA if
there are any. Yes, Dr. Fisher.
DR.
FISH: This may be a question for the
statistician. In the breakdown, there
was a breakdown in the information that we received regarding stavudine use and
non-stavudine use in the Chelsea-Westminister study.
In
the immediate treatment group, where we would be expecting a treatment response
at Week 12 in the non-stavudine use, it looked like that there was not a
treatment response at Week 12, and yet it came at Week 24. The end is certainly smaller.
Is
that a statistical anomaly or is there an explanation for that?
DR.
SILVERMAN: Well, the statistical
significance is very highly correlated with sample size, and if the study is
not powered to detect a certain difference, then things can come out either
statistically significant and clinically meaningful, or not come out
statistically significant when they are clinically meaningful. So it is really just a function of the
sample size.
CHAIRMAN
CHOTI: Dr. Miller.
DR.
MILLER: Yes, in your review of the VEGA
study there was one event of a difficult granulomas problem in a patient, and I
think I recall it being mentioned that this patient had a granulomatous
disease, like Crohn's, or something, or Cushing's. Well, not Cushing's.
But
could amplify that a little bit? Do you
recall that or is that an issue that we have to be concerned about with this
device, and in somebody who has a granulomatous disorder, they will be prone to
forming unfavorable granulomas with ingestion of this device.
DR.
LERNER: There was no data of that
patient population in the PMA. I don't
particularly remember the one patient that you are referring to, but we did not
have any data to correlate a patient population with some sort of granulomatous
disease with outcomes in the PMA.
DR.
MILLER: Okay. I guess it was just mentioned in the sponsor's material.
DR.
LERNER: Right.
DR.
PENNEYS: I have a related question
actually because there are also variables that exist. For example, what happens with this material if it is injected
into someone who forms keloids?
There
is no information. I mean, their
response to trauma is markedly different than other folks, and it is very
common. So if you inject this into a
lipoatrophy and somebody who gets keloids, what are you going to get? Are you going to get too much response, or a
lumpy response, or a keloid? Does
anybody know?
DR.
LERNER: I could think that they might
want to, but I might want to address that given the fact that there has been a
lot of experience, not with this product, but with similar products.
We
use Vicryl, for example, all the time, and as far as I know, there is no
significant difference in patients who have keloids. That is something that is -- you really don't -- I would not stop
using Vicryl because of keloids.
In
fact, I probably would use it so that I would not have to have stitches that go
through the dermis.
CHAIRMAN
CHOTI: Any other specific questions for
the FDA?
PARTICIPANT: In the IDE study it was an uncontrolled
study, and I was wondering from the FDA's perspective if you discussed that
with the sponsor, the fact that it was uncontrolled?
DR.
WITTEN: Well, can I just comment, which
is that all of these studies are sponsor investigator studies. So they were not initially designed to
support a marketing application.
CHAIRMAN
CHOTI: Yes, Dr. Leitch.
DR.
LEITCH: I am still trying to get back
to our mechanism of action. For the
evaluation of long term reaction in tissues, the injections in the rates were
subcutaneous, right; here you had the five sites with -- and looking at
degradation of the product over time.
And
so there was some histologic findings there, but because the injections were
subcutaneous does that -- would there be a difference in degradation or
reaction, or product performance; subcutaneous versus intradermal?
DR.
BERKOWITZ: It is hard to know that, but
all the reactions that we saw were normal foreign body reactions, and they are
similar generally wherever they are placed.
And
it may change the kinetics of the reaction; that is, there may be depending on
where it is, there could be a longer initial inflammatory response and take
longer for cells to go through those kinds of changes. So I would assume that
would make a difference.
DR.
PENNEYS: A follow-up question to that
point. Do you think that the responses
are directly proportional to the intensity of the foreign body response?
DR.
BERKOWITZ: I don't have any data to
have --
DR.
PENNEYS: What I am really asking is if
this were used in people with normal immune resistance or more vigorous
inflammatory responses, would there be a different clinical response?
DR.
BERKOWITZ: It is really difficult to
judge that.
CHAIRMAN
CHOTI: Dr. Leitch, a question?
DR.
LI: Yes. You compared or you spoke about the use of PLA in orthopedic
devices, and the fact that the amount of PLA was equivalent to what one might
find in a bottle of Ringers.
However,
a comment on that is that you are not putting all the lactic acid in a Ringer
solution into one very small area, and so I am not sure that the analogy to
Ringers is actually relevant in this particular case.
And
also you mentioned that it is used in orthopedic devices, but I am not aware of
any orthopedic device actually that uses a PLA with such low molecular weight
and with such a high surface area, and placed into a relatively small area.
Are
there any analogues that you can think of other than the genetic fact that
there are PLA-containing materials in orthopedic devices?
DR.
BERKOWITZ: Well, because these
particles are so small the surface area is relatively huge. So I think that is a new feature of the
material.
CHAIRMAN
CHOTI: Could you please use the
microphone for your comments.
DR.
BERKOWITZ: I'm sorry, yes. The surface area of the small particles is
huge, and so I think that is one different feature of this material, as opposed
to just say a plate of material that is put over a bone, for example, so that
the surface area is much greater. So
there really are not direct analogues to this particular thing.
DR.
LI: How about molecular weight? The molecular weight that you are using is
40-to-50,000 by the time that they are done gamma sterilizing and injecting
into the patient. Are there any
orthopedic devices that use lactic acid in that low molecular weight range?
DR.
BERKOWITZ: That I don't know. Sorry, I don't know.
DR.
LI: And then a kind of follow-up
question about that. I think it was you
that presented the degradation rate of literature study using rods of PLA. But those rods of PLA were double the
molecular weight of the material being used in the Sculptra.
And
there was a 19 percent degradation in one month in those rods, which have a
smaller surface area and higher molecular weight. And yet -- I will ask the same question to the applicant later
on, but in their studies of degradation at 24 weeks, they saw no
degradation.
So
how do you rationalize the fact that you have a literature study that has a
smaller surface area, high molecular weight material, that degrades 19 percent
in one month, compared with a very high surface area, low molecular material,
that does not dissolve at all in 24 weeks.
DR.
BERKOWITZ: Well, it is very difficult,
and I can only guess at that, and I would assume that the particles -- it would
depend upon whether the particles are coated, and if they are coated with
collagen, or how exactly the reaction forms.
I mean, it is purely speculative.
DR.
LI: Well, this was even in the in vitro
test if I understand right. At 24
weeks, they saw no degradation.
DR.
BERKOWITZ: Pardon me?
DR.
LI: That was also in the applicant's --
is that correct, in their in vitro testing where there was little or no
collagen available, but they were still showing no degradation at 24 weeks.
DR.
BERKOWITZ: Right, but I think that is
just for -- that was at 7-4, and so that was normal aqueous hydrolysis, whereas
I think that tissue fluids may have esterases that could speed up that
degradation process.
DR.
LI: Okay. Thank you.
CHAIRMAN
CHOTI: Final questions for the
FDA? Yes, Dr. Fish.
DR.
FISH: In the conclusions line, if I
understood it correctly, you stated that the effectiveness occurred across CD4s
counts. Do you have the data in terms
of the percent of patients in the various trials who had CD4s under 200?
DR.
LERNER: I don't have the documents with
me. I mean, it is in there, but I don't
have it with me.
CHAIRMAN
CHOTI: Dr. Leitch.
DR.
LEITCH: I know that you were charged
with looking at these trials -- the clinical trials is what I am talking about
now -- that were related to the HIV positive patients, but did the FDA look at
other clinical trials done for cosmetic uses in Europe to get a sense of issues
like longevity of response of the product?
DR.
LERNER: No, we just looked for
this. We went back and looked at the
data that the sponsor submitted.
CHAIRMAN
CHOTI: Yes, Dr. Li.
DR.
LI: Just a quick question. I think that this would be kind of a yes or
no question. I was a little confused as
you read through the material descriptions, the difference between
specifications of the product and what they actually measured.
So
I saw a lot of measurements that they made on the products that they did a nice
job on, but I don't recall seeing like a little table that says the
characteristics of these products shall be, for instance, must be between such
and such a particle size, or the molecular weight must be between a certain
area.
Are
those specifications in this filing, or are they not?
DR.
BERKOWITZ: Yes. I did not review all of that, but you might
ask the sponsor for that table. I
presume --
DR.
LI: I think especially in the absence
of any kind of mechanism. You know, if
you are just, you know, by gosh or by golly, you kind of have the magic
formulation. If you don't understand
the mechanism, I think the requirements of making that product ought to be very
tight.
DR.
DURFOR: Charles Durfor, the FDA chemist
who reviewed this application. I
certainly don't want to have the company come after me, but in answer to your
question with regards to specifications.
This
is a discussion that we have ongoing with the sponsor. There are refining the specifications at
this time, and they have done a lot of work to characterize the product, and we
are working with him to make sure that the specifications reflect the product that
was used in the clinic.
DR.
LI: My only comment that in the absence
of a mechanism, that the specifications should be relatively tight, because you
don't know what the response is to small changes in the material.
For
instance, if you have a batch that for some reason has a 30,000 molecular
weight in the absence of a mechanism, that might cause a very large
histological change. I mean, I am just
kind of making that up as an example.
In
the absence of a mechanism, I think the specifications should be very
tight.
DR.
DURFOR: I fully agree. I think that Dr. Berkowitz in this
presentation talked about some of the factors that are involved in the kinetics
of resorption and obviously related to the foreign body response.
And
we are requesting that the sponsor work with us to make sure that those
specifications with regard to particle size, molecular weight, and the like,
all those things that can impact the resorption kinetics of the product are
defined as final product specifications.
CHAIRMAN
CHOTI: May we hear from the sponsor
just to address this specific question, if you would.
DR.
FORBES-MCKEAN: I am Kim Forbes-McKean
from the Drmik, in the product development area and commercialization, and as
Dr. Durfor mentioned, we are currently working with the FDA on what will be our
final product specs for the product, and also what we plan to do as in-process
control to ensure that we have consistent quality in specifications of the PLA
after it is milled and sterilized, and then put into the product.
We
have done extensive work to understand what happens to particle size and
molecular weight, and crystalinity, et cetera, after the product or during the
process of making the product to ensure that either through our in-process
control specifications, or our finished product specs, that we will deliver a
consistent high quality product.
DR.
LI: Just as a follow-up question. How will you determine what is an acceptable
specification? In other words, pick a
factor. It does not matter what it
is. You know, how do you know if for
instance the molecular weight is too low or too high?
How
do you set those limits for the particle size of the crystalinity? How would you actually establish a link
between those limits and the clinical performance?
DR.
FORBES-MCKEAN: We have done a
significant amount of work to characterize historical batches that we have
obtained through our -- who have worked with the prior manufacturer to
characterize what were the characteristics of particle size and molecular
weight, and inherent viscosity, and all the parameters that we have been
discussing here on the lots that were used in the clinical studies that are the
subject of this PMA, as well as commercial batches that have been out in use
that have collected the safety data through our adverse event reporting system
to characterize the product that we consider was used to be validated in a
clinical program, as well as in the use that has been available in the
commercial distribution of the product, to devise the specifications that we
have proposed, which we feel are suitable to represent the lots that were used
to do the clinical work, as well as what has been out there commercially
available.
DR.
LI: So in a nutshell, we did it
empirically, and basically go back and look at all of the specifications in all
the lots that were successful, and stay within those specifications?
DR.
FORBES-MCKEAN: Yes.
DR.
LI: Okay.
CHAIRMAN
CHOTI: Thank you, Dr.
Forbes-McKean. Dr. Newburger, questions
for the FDA?
DR.
NEWBURGER: In your studies with the
rats, Dr. Berkowitz, did you by any chance characterize what the pH in the
tissue was once the PLA started to degrade?
Was there any alteration? Did
you ever do --
DR.
BERKOWITZ: No, I don't think -- that
has not been studied as far as I know.
There are -- when PLA degrades rapidly, it can increase the osmotic
pressure and there can be some swelling in tissue, and that would have been one
of the published reports from other authors.
And
in fact I think it was for an orthopedic implant, and two years after it was
implanted and it sort of got to a critical stage of degradation, where esterase
could reach it, and very quickly release monomer, which increased the osmotic
strands.
And
there was a time when there was edema surrounding the tissue and it eventually
went away on its own.
CHAIRMAN
CHOTI: Thank you. So we have heard information from the
company, and from the FDA, and now it is time to summarize the comments from
the panel.
What
I would like to do is get opinions from all members of the panel if we could,
and just kind of general comments and overview. Why don't we go ahead. We
are not going to be showing anymore presentations, and why don't we clear the
table in front.
Let
me start if I could ask Dr. Olding to start with some comments, please, and
then we will kind of work our way around.
DR.
OLDING: I have a relatively limited
background in terms of serving on these panels before, but I must admit that
the characterization which we have asked about here today anyhow.
The
characterization and how the material works, and how long it lasts, and why it
lasts so long, are for me -- and I would suspect many panel members -- very
murky. The details for that are.
We
don't know what the ideal-sized particle is really. We don't know what the ideal concentration of PLLA is even, and
what is the ideal reconstitution.
We
also are unclear about the nodule formation, although to be honest with you,
having done some research with related products, and looked at that
histologically, it causes a relatively intense histologic foreign body
reaction, which we have not seen any slides of, but we presume exist, and I
don't think it is rocket science from my point of view.
I
think that it is an inflammatory reaction, and probably the reason if you look
back at the studies, the nodules were often noticed first I think at 24 weeks,
I believe.
But
the injections were at 2, 4, 6, 8 and then the first visit was at 12
weeks. Any experience that I have had
with injections of materials that cause foreign bodies, you have a generalized
sort of swelling and edema for a while, and so they probably weren't seen at
that 12 week period simply because it was generalized swelling in the area.
Then
the next time they came back was 24 weeks, and that does not necessarily mean
that they first noticed the nodules as they first developed, but in fact you
might be able to palpate it at that point.
So
that does not really bother me, and the comments about the surface area, I
mean, none of those things have really been characterized very well. So for me it is a little bit of an
uncomfortable feeling. However, I have
had a lot of experience with injectables, and I have seen a number of patients
who are HIV positive patients, with wasting.
And
I actually ended up sending them to someone in town who did use New-Fill, and I
did that because I didn't feel that I had an acceptable alternative. I had seen the other ways of treating these
patients, and they have not been good, and the results have not been good.
And
I calculated just in between how much it would cost me to inject, or how much
it would cost the patient to inject similar volume with either collagen or with
a relatively new product, Restylane.
For
me, a patient coming in averaging 7.8 cc's per treatment would be $6,000 per
session. So we are talking about
$12,000 a year if you presume that it lasts 12 months.
Collagen
is purported to last 3 months and in my experience it lasts less than
that. But again we are talking around
$8,000 a year for those treatments.
So
this product, although it has not been well-characterized from my point of
view, certainly does what it is intended to do, and it does it at a relatively
inexpensive price, and it seems to really fill a gap that is much needed.
CHAIRMAN
CHOTI: Dr. Li, comments?
DR.
LI: Similar comments. Let me first of all say that it appears to
work first and foremost, although I am a little puzzled as to why. Which basically I think that it focuses my
discomfort that the mechanism is unknown, and although the applicant has done a
lot of material testing, it is not particularly type testing, where every lot
of material was tested in the exact same way to give you one very clear
picture.
There
is a lot of mixed lots, and different tests, and there is actually anomalous
data about how much -- about the crystalinity and some x-ray data that were --
there was some hypothesis of why that was done, but there were some anomalies
in the data that is very common for PLA material.
And
which is a very difficult material to synthesize and it is kind of made a batch
at a time, and my own experience is that there is lot to lot variations, and it
just does not seem in the absence of specifications, which I hear they are
developing, they are either very lucky about what they are using, or in fact
that they are very insensitive to all these factors.
And
at this point, I really don't know which it is. So that is kind of my discomfort. I have a lot of specific questions about the materials testing
that I will maybe ask later, but in a nutshell, it seems to work and I don't
know why.
And
I don't think that the characterization is as stringent as it should be given
that a lot more patients is going to get this, and probably in the HIV
population, and that the material specs are not well worked out.
CHAIRMAN
CHOTI: Thank you. Dr. Penneys.
DR.
PENNEYS: Thank you. Well, I would like to say that the presenter
has made a very effective presentation of the need for this, and even though
the photographs were lousy, there was dramatic improvement, and it was obvious
that it benefitted these patients.
And
as a dermatopathologist, I have nothing to say because I have had nothing to
review, and as a dermatologist, I have a major concern. I basically do a lot of CME and everyone in
the -- and a large percentage of the discussion is off-label use.
Twenty-four
hours after this is available, it is going to be used off-label, and I don't
know if it is appropriate for this panel to discuss, but my major concern was
in that area, and that is that it is the other uses and the other possible shoe
reactions, and all the other unknowns that I am concerned about.
CHAIRMAN
CHOTI: Dr. Fish.
DR.
FISH: As an infectious disease
physician, the infection rate is certainly low and negligible, and I am very
pleased with that. Clearly it seems
safe. There was one abscess that I
think was reported and that was about it in the infection category.
I
think also that I agree with Dr. Li that it appears to work. I am certainly convinced, and I think there
is urgency, and Dr. Miller brought this up earlier. Patients really do need something. I really appreciate the consumers that came today and gave up
their time to tell their stories.
These
stories are very real, and I have had patients travel to New York City and
travel to Montreal to get these treatments, and they are effective.
Their
appearance has improved and it appears to last. How long it lasts I think we don't know, and probably is very variable from person to person.
So
I appreciate that and I think I do also worry about how they are used for a
non-HIV infected population, and a non-lipoatrophy patient.
CHAIRMAN
CHOTI: Thank you. Dr. Miller, any comments?
DR.
MILLER: Well, I appreciate the comments
that have been made and I agree that there is a real need for something to
address this problem like with atrophy.
I feel that there is a pressure being placed to approve this particular
device because it appears to address the problem.
But
I have a tremendous discomfort over all the uncertainties about this device
that have been mentioned already, in terms of mechanism and in terms of many
aspects of it that are really not well characterized and they are not really
even addressed in this study, which basically tells us that the skin appears
better after its use in this very select group of patients.
It
is very difficult to say that this shouldn't go ahead because of the dire need
of this specific patient population, but all the uncertainties about it make me
very concerned about the issues, and the off-label use, and the possibility of
this being used by many thousands of people who don't fall into the specific
category that we looked at in these very limited and incomplete studies. And it puts us in a very difficult
situation.
CHAIRMAN
CHOTI: Dr. Leitch.
DR.
LEITCH: Well, I certainly have concern
about the lack of understanding of the mechanism, and I think there are some
questions about duration of response from the Chelsea and Westminister study as
was mentioned, and in some of the other studies injections were allowed to
continue based on response, and over time as people were dissatisfied, which
was not allowed in the other studies.
So
perhaps that duration of response is somehow related to getting more and more
treatment. And the failure to have an
understanding of the mechanisms and the impacts on how this influences the
injection technique, and discriminating it from different fillers, where people
might be accustomed to using other fillers in some way.
But
if this mechanism is different as is being suggested based on the duration of
the response, then that has to be addressed in the education of physicians.
And
then I was also surprised that we really did not get any data about its use and
the usual cosmetic use in Europe, and outcomes there in duration of response.
Or
if there is data from both studies about the mechanisms of actions with having
skin biopsies that would reflect that.
And, of course, none of these studies were controlled, and comparing
them to other known agents, although I think we heard from people on this panel
that perhaps those other agents have not been as effective for these patients.
Clearly
I think, you know, that we have a great sympathy for the patients experiencing
problems that greatly impact their quality of life, and their ability to go
about in public.
So
I think that when we are faced with that type of a problem, then you may
compromise on what you think you would like to have in the circumstances of
approving this for cosmetic uses and general use.
And
I think what others have expressed is that once it is approved that it could be
used in other contexts which have not been appropriately tested based on the
data that we have had presented here.
And
the other thing to emphasize is that the HIV population does have other -- you
know, a baseline medical condition and other medical issues that impact their
overall well-being.
And
I think the idea of could there be unusual reactions that occur in the long
term, either due to repeated injections, or a change in their disease status
that could be problems in the long term.
CHAIRMAN
CHOTI: Thank you. Let me make a few comments. I really do agree, and my comments reflect
what has been said as well. I think the
problem in this specific indication I agree was well defined, and I think it is
important regarding the efficacy in spite of the concerns.
And
my concern as well about the mechanism and the design of the trial. I think really based on the photographs, and
on the satisfaction, and as best as can be perhaps designed in the trial
design, and it appears to work, and it appears to be effective in my opinion.
So
that is part of the concern. As far as
the safety, I think the other issue is that the numbers are relatively small,
and it is a relatively defined group of young caucasian males. So we really don't have good evidence in the
female gender, or in other races, especially if it is going to be applied in
other patient populations.
But
also in the HIV population, and so can it be extrapolated to a larger
population and these are still unknown questions. But I do think that as well that it appears to be based on the
product and based on at least the numbers that we have seen at least relatively
safe and effective. Dr. Chang.
DR.
CHANG: I believe that from the data
presented here that two major questions that will be asked of the panel is
whether this product is effective for the use that is proposed, yes, and is it
safe, and the data reflects that it is relatively safe.
In
the back of our minds, yes, there is concern about off-label use, but a
particularly off-label use by persons of color. There is that issue of how does one or how is one to predict who
will be a keloid-former, and that would be potentially disastrous with
injection and such reaction in the face.
My
question is about potential long term consequences and the data presented speak
to a two year follow-up. But if indeed
a product is absorbed and if indeed the thickness changes and touch-ups for the
treatment are required, then the question that I would raise would these small
palpable nodules potentially coalesce.
Would
they then become visible in the future, and we don't have data for long term
studies.
CHAIRMAN
CHOTI: Dr. Blumenstein.
DR.
BLUMENSTEIN: Well, despite being a
statistician, I am also a human, and I even have kids and everything. I don't just work with numbers, but anyway,
I think certainly there is an unmet medical need here, and I am quite
sympathetic to that.
However,
I feel like I have to comment as a statistician here. First of all, I think that there is a really cunning regulatory
strategy going on here, and at least that is one way to characterize it.
That
there will be off-label use, and I can't bring myself to ignore the
inadequacies of this study relative to the potential for the off-label
use. For example, I just don't think
that the safety database is large enough given the data that we have been
presented.
And
furthermore even the ethicacy may not be applicable to a wider use. We have very limited data on gender, and
racial issues are quite limited. And
keloids, which I am not even sure what they are, but I hear that is a problem.
And
then another thing that I would add to that is the possibilities of technique
in a wider use leading to other kinds of problems. So from a pure statistical point of view, that the end-points are
invalidated, and they are highly subjective.
The
photographs that we were given, one thing is when you have an unvalidated
end-point, one of the things that is going to be used to talk about the need of
that end-point is whether it has face validity.
Well,
it is a mixture of what we were shown here, and it is so obvious that you
really don't have to do the validation testing. But in this case, I am still disappointed with the photographs
because first of all there was no quantification of it.
The
quality of them is poor and there seems to be systematic writing changes across
time and some sets of these photographs, I found them to be completely
difficult with respect to helping me understand that.
And
then the study designs were just completely inadequate, and the lack of a
control group, and the lack of randomization, and the one study where
randomization could have really helped out there was none.
You
don't know what kinds of patients were in those two groups. And in short, yes, there are significant
P-values, but that does not validate the study designs or the end-points.
As
I already mentioned about the safety database, there has been some word here
about nodules and what is the other term, papules, and so forth, I mean, these
are anomalies.
And
I don't know whether there is enough experience here, especially given in a
wider use that there would be skill issues and other things like that, and
whether there is enough data to know what these anomalies would -- how frequent
these anomalies would be in wider use.
And
therefore I am coming back to the statistician at the end of this, and I have
to state that I find this data leaving me in a state of inclusiveness.
CHAIRMAN
CHOTI: Dr. Newburger.
DR.
NEWBURGER: I can't recall ever being in
such a peculiar position. I think we do
have a tremendous amount of pressure on us to give approval for this very well
established need on an expedient basis because we are compassionate
individuals.
But
the information that we are given right now is really empiric. There is no other material that we have ever
seen presented that has had such a paucity of data, true data, and this makes
me very uncomfortable.
CHAIRMAN
CHOTI: Thank you. Dr. Munk.
DR.
MUNK: I don't want to repeat what
others have said, but I would stress that there is risk to patients and
clinicians in any off-label use of any FDA approved product, and I think that
the particular application, whether it is a cunning market strategy or not,
this is a very serious leap for HIV patients with facial fat loss and I think
that we do need to respond to that need, which has been stated in the
application.
I
mean, it leads to discontinuation of antiviral treatment, and in some cases it
leads to avoidance of anti-viral treatment in the first place. It is a very critical need.
CHAIRMAN
CHOTI: Dr. Bartoo.
DR.
BARTOO: Since we are getting to the end
of the table, there is not a whole lot of new comments that I can make, but
clearly we keep saying that it appears to be work, as opposed to having valid
scientific evidence potentially that it does work, and that it is effective,
and safe, and so that is something to consider.
However,
especially in terms of long term effects.
However, there is this pressing need, and I would like the panel to
consider the possibility of potentially post-approval studies to address some
of these concerns, as opposed to recommending not approvable.
CHAIRMAN
CHOTI: Dr. Doyle.
DR.
DOYLE: Yes, I think I have decided that
everyone who has spoken on this is a scientist so far, and so I put on my consumer
hat, and I was very moved by the people who spoke this morning, and I think
that there is definitely a need -- and poor pun -- needs to be filled.
But
I am somewhat disturbed by the lack of women in the data, because we do know
that this is for wasting, and women's fast deposition and metabolism does
differ from males. Any woman who has
gone on a diet at the same time as her husband can tell you that.
And
while I think that this is important, and I think that in many of the things
that are brought up here, I would like to know the answers to some of the
questions.
On
the other hand, speaking strictly from the consumer point of view, I appreciate
the panel's need and want to protect me down the line, but if this were me, and
I had wasting disease, I would be less concerned that you were worried about
what would happen 5 years out when there are no indications from the data so
far that I could tell even of any hint of serious long term reactions from the
data that we have been presented, that I would be concerned rather than what
was going to happen to me 5 years out, if whether I would go off my medication
and whether I would commit suicide because I was so unhappy with my current
existence.
And
to me it is not a question from a consumer point of view, but at this point
certainly what we know from my point of view, the benefits would certainly
outweigh the risks for me.
CHAIRMAN
CHOTI: Are there any other general
comments from the panel? So that
concludes sort of our general discussion.
Now, I would like to move to the specific FDA questions.
What
we will do is go to about 12:30, and then we will resume with the
questions. So the plan is not to
complete the entire discussion before lunch.
DR.
LERNER: Question 1: 11 CFR 860.7(d)(1) states that there is a
reasonable assurance that the device is safe when it can be determined that the
probable benefits thereof from use of the device for its intended uses when
accompanied by adequate instructions for use and warnings against unsafe use, outweigh
any probable risks. Considering the
data in the PMA, please comment on whether there is a reasonable assurance that
the device is safe.
CHAIRMAN
CHOTI: So for each question, I would
like to go through the panel and get the comments and opinions. Let's start on the other end of the table
with Dr. Doyle. Response or comments to
question number one?
DR.
DOYLE: I don't think we can ultimately
know if it is safe without long term data.
However, the data or lack of data of unsafe and serious adverse
consequences from Europe, where it has apparently been widely used in
uncontrolled conditions, and in the data here, I don't see any indications from
the data here of any dangers at this point.
CHAIRMAN
CHOTI: Dr. Bartoo.
DR.
BARTOO: I would have to agree with
LeeLee, in terms that we don't know the long term safety at this point, but
there is good evidence I feel for short term at least to your safety data, both
for the intended use, as well as potentially cosmetic use from the European
data.
CHAIRMAN
CHOTI: Dr. Munk.
DR.
MUNK: I think we have all kind of
underscored the lack of data that would give us comfort about this question
globally. However, for the proposed
indication, I think the answer has to be yes.
CHAIRMAN
CHOTI: Dr. Newburger.
DR.
NEWBURGER: I agree with Dr. Munk's
response and also I just want to reiterate that it is only approved this last
February for HIV lipoatrophy in Europe.
So there isn't a long term experience with it for that use.
CHAIRMAN
CHOTI: All right. Dr. Blumenstein.
DR.
BLUMENSTEIN: I agree within the context
of the proposed use. There is enough
data to support short term safety.
CHAIRMAN
CHOTI: Dr. Chang.
DR.
CHANG: I believe that it has been show
in the population of white male patients who are HIV positive that it is safe.
CHAIRMAN
CHOTI: Thank you. Dr. Leitch.
DR.
LEITCH: I would agree that it is safe
in the proposed population for this PMA.
CHAIRMAN
CHOTI: Dr. Miller.
DR.
MILLER: Considering safety, the balance
of benefit and risk, the benefit appears tremendous for this, and because of
that, we are put in the position of accepting a tremendous amount of unknown
about the risk, and I am a little bit irritated by the day that it is presented
that it puts us in a position to have to accept that because the benefit is
truly enormous.
And
I would certainly would like to have had more of an understanding of this
material and how it works. But I think
it is difficult to argue that the benefits are so enormous that we just have to
accept the situation.
My
concern is that 10 years from now we are going to have another hearing with a
different group of patients, who purport to be damaged by this material, and
questioning why did we let this go through without understanding more about it. I mean, I look forward to or I will be off
the panel by then probably.
CHAIRMAN
CHOTI: Dr. Fish.
DR.
FISH I am concerned about the lack of
data for women, and it is predominantly males as we saw here, and then also
certainly the other racial and ethnic groups.
However,
I like the way that Dr. Doyle put it, there is nothing that has been seen thus
far that I think would preclude the approval, with the caveats that Dr. Miller
just stated.
CHAIRMAN
CHOTI: Dr. Penneys.
DR.
PENNEYS: I agree that for this specific
indication in this PMA that this is safe.
CHAIRMAN
CHOTI: Dr. Olding.
DR.
OLDING: I have a question of Dr.
Witten. Dr. Witten, shall we totally
disregard in making our decision about this product for its intended use the
possible off-label use of this product in making our decision?
DR.
WITTEN: Well, when you make your
recommendation about the approvability of the product, yes, you should focus on
the intended use proposed by the sponsor, but certainly in the discussion we
are interested in hearing what you have to say.
But
when it gets to -- when we are asking about safety and effectiveness, we are
asking specifically for the intended use proposed by the sponsor, and the same
would be true of the vote when we get to the vote.
DR.
OLDING: Thank you for the
clarification. I believe that the
product is certainly safe for its intended use.
CHAIRMAN
CHOTI: Dr. Li.
DR.
LI: The product appears to be safe from
what they presented, although I don't really understand why. My own experience with these materials is
that this molecular weight, this particle-sized distribution, there should be
some inflammatory response that we don't seem to be getting.
So
I don't really quite understand why that is, but I have no evidence that it
isn't safe, and so I will go along with it being safe, but I would like to keep
pointing out that I don't really know why.
And
when I say it is safe, I mean under the conditions that the material can be
characterized and say that future batches of this material are exactly the same
as possible to what has been tested.
And if they can't do that, then I think you have
to remove the safety feature.
CHAIRMAN
CHOTI: So I think I can summarize by
saying in response to Question Number 1, if this is all right with you, Dr.
Witten, that I think the consensus is that for the proposed indicated use, I
think the consensus of the panel feels that there is reasonable assurance that
this device is safe.
DR.
WITTEN: Thank you.
CHAIRMAN
CHOTI: The next question.
DR.
LERNER: 21 CFR 860.7(e)(1) states that
there is a reasonable assurance that a device is effective when it can be
determined, based on valid scientific evidence, that in a significant portion
of the target population, the use of the device for its intended uses and
conditions of use, when accompanied by adequate directions for use and warnings
against unsafe use, will produce clinically significant results. Considering the data in the PMA, is there
reasonable assurance that the device is effective?
CHAIRMAN
CHOTI: Regarding question number 2, can
I ask Dr. Miller to start the specific comments.
DR.
MILLER: I think that based upon the
material that we have that it appears effective.
CHAIRMAN
CHOTI: Dr. Leitch.
DR.
LEITCH: I think the material appears
effective. The duration of that effect
though does remain a question in my mind.
CHAIRMAN
CHOTI: Dr. Chang.
DR.
CHANG: The product appears to be
effective.
CHAIRMAN
CHOTI: Dr. Blumenstein.
DR.
BLUMENSTEIN: For the patients study and
for the face validity issues, I think it appears to be effective.
CHAIRMAN
CHOTI: Dr. Newburger.
DR.
NEWBURGER: I agree that it appears to
be effective in this use.
CHAIRMAN
CHOTI: Dr. Munk.
DR.
MUNK: I agree. I have some questions about what are
adequate directions for use.
CHAIRMAN
CHOTI: Dr. Bartoo.
DR.
BARTOO: I agree that it is effective
for its intended use.
CHAIRMAN
CHOTI: Dr. Doyle.
DR.
DOYLE: I also agree.
CHAIRMAN
CHOTI: Dr. Li.
DR.
LI: It appears effective.
CHAIRMAN
CHOTI: Dr. Olding.
DR.
OLDING: I agree.
CHAIRMAN
CHOTI: And Dr. Penneys.
DR.
PENNEYS: I agree.
CHAIRMAN
CHOTI: And Dr. Fish.
DR.
FISH: I agree based on its face
validity.
CHAIRMAN
CHOTI: Dr. Witten, based on the
comments that you have heard from the panel do we think that we adequately
addressed question number 2 specifically considering the data that there is a
reasonable assurance that the device is effective, and I think there is a
consensus that most felt that it is.
DR.
WITTEN: Thank you.
DR.
LERNER: Question Number 3. Patients in the European studies were
followed-up for periods ranging from 24 weeks to 2 years, and those in the
United States were followed for up to 2 years.
If you agree that there is enough evidence in the PMA to support the
safety and effectiveness of the device, do you feel that a post-approval study
to assess the long term use of the device should be initiated, and if so,
please advise FDA as to the type of data that you feel should be collected, and
the appropriate duration of the follow-up.
CHAIRMAN
CHOTI: Dr. Newburger, I would ask you
to start the discussion in Question Number 3.
DR.
NEWBURGER: Since I consider this
application to really be a work in progress, sure, I think that there should be
a post-marketing study. Some of the
things that I would like to see are standardized photographs.
And
attempt more to characterize the reaction of the material in tissue by getting
study subjects to agree to give small biopsy samples. I work for a cosmetically important or known as cosmetically
significant area.
I
would also be interested in having the rate of formation of these
papules/nodules correlated with the total number of CD4 cells since apparently
there is some type of non-inflammatory foreign body reaction, and that seems
like a paradoxical, and so I am wondering if the relative reduction in CD4
cells have something to do with this powerability in this particular
population.
And
so those are some of the things that I would like to see looked for.
CHAIRMAN
CHOTI: Dr. Munk.
DR.
MUNK: I feel strongly that there needs
to be a longer term follow study, and in terms of how long it should run, and I
would say by at least 5 years.
I
think that the study should collect information on adverse events, and it
should collect patient weight and satisfaction over time, and the number of
touch-up treatments and whether those are at patient request or on some other
basis.
Any
changes in antiviral treatments, and the prior duration of treatment before the
application of the device.
CHAIRMAN
CHOTI: Dr. Bartoo, comments?
DR.
BARTOO: I agree that there should be a
long term study, a post-approval study, and I would like to see in this long
term study multiple treatments applied and followed up afterwards so we can see
the effect of having multiple treatments.
I
would like to suggest that these would become well designed controlled studies,
as opposed to what we have been able to see so far.
CHAIRMAN
CHOTI: Let me just ask you. Give me a clue on how you would design your
control trial?
DR.
BARTOO: Well, I mean, potentially you
can compare it to other fillers, for example, with randomization of the peer
group, and to have characterization of the two randomized groups, for
example. Or to stratify between
different factors, such as viral load and other things like that.
CHAIRMAN
CHOTI: Dr. Doyle.
DR.
DOYLE: I think that there should be a
long term follow-up and it should be particularly directed to looking at the
increasing number of women and minorities in this. Also, some follow-up of some of what the -- on whatever you
decided to call them, the histologic follow-up on some of those in actual
analysis of what is constituting, and at least is there AIDS left there.
CHAIRMAN
CHOTI: Dr. Li.
DR.
LI: I would like to -- I think there
should be additional studies, and I would like to see some correlations if you
will, or associations, of the amount of material, and perhaps in key material
characteristics of the presence of nodules, and this actually might also fit
into different gender issues then as well.
And
actually I have not seen any information about any kind of scaling of
nodules. You know, like there is one
reported as a nodule, or is it hundreds, and if it is location related, and is
it more applicable, and did it happen more often in the temple, or some other
location.
So
some of this information I think is needed.
They actually might already have it if they went back and kind of mined
their own data, but if they don't have it, I think these would be critical in
the absence of any longer term data.
CHAIRMAN
CHOTI: Dr. Olding, comments?
DR.
OLDING: I, too, would like to see a
histological and chemical characterization of the mechanism of action of this
product, as well as the characterization of the adverse effects.
I
think that there is really a surprisingly small amount of concern about
characterizing those adverse effects.
CHAIRMAN
CHOTI: Thank you. Dr. Penneys.
DR.
PENNEYS: Well, I think it would be
great fun to look at the reactions in a microscope, and using markers,
determine if it varies, depending on the set-up of the individual, but I would
urge the company to anticipate the wide range of off-label use, including use
in children.
And
the obvious immune status, and stating the obvious, cosmetic uses, and every
time that a person gets an intralesional shot of corticosteroid there is going
to be atrophy and depression, and in children who get it for alopecia areata.
People
will be using this for these entities, whether you like it or not, and so the
company should anticipate all these, and meet with the panel and dermatology
consultants, and think about looking at all these various applications.
CHAIRMAN
CHOTI: Thank you. Dr. Fish.
DR.
FISH: I also have a question of
clarification if I may for Dr. Witten.
How common is it that a sponsor would come without a sponsored -- a
company-sponsored trial, as opposed to independent investigators?
DR.
WITTEN: Well, certainly the most common
thing is for a sponsor to actually design and conduct a trial, but we have had
other products, applications in which there is other ways in which the
information has been gathered.
The
ones that I can think of off-hand involve information that was gathered by
investigators and published in literature, and so we look at product
applications based on literature articles, for example.
DR.
FISH: Is this related to the
accelerated?
DR.
WITTEN: No, there is a hierarchy of,
quote, valid scientific evidence for FDA, and it just fits within the spectrum
for devices, and this fits in within the spectrum of what we would like at
potentially to support product approval.
DR.
FISH: Thank you. I, too, would agree though that I would
certainly like to see a follow-up study, and in particular looking at issues of
CD4 stratification, and might there be different responses.
And/or
different nodule formations in people who are more immune-replete, versus those
who are more CD4 depleted, and then also this group that we have already
mentioned, or in the minority population.n
CHAIRMAN
CHOTI: Dr. Miller.
DR.
MILLER: I agree with all these views
expressed. I think the company needs to
work with the FDA to ensure that the post-approval trials would be very well
designed, and answer a lot of the questions.
I
think if this were for any other target population that these things would be
probably required before we would even move ahead on the PMA, but it is the
strength of the value to the target population that is really guiding us. So we need to have post-approval studies.
CHAIRMAN
CHOTI: Thank you. Dr. Leitch.
DR.
LEITCH: I would agree that we do need
to have longer term follow-up studies, and I think that this is in
consideration of the patient population that we are considering this for, and
as Dr. Miller said, we are sort of making some exceptions here.
But
we also want to ensure the safety for that population given all the medical
problems that they deal with, and that we won't give them another one to deal
with. So I do think that is also
important, and as you can probably tell from my other comments, I am highly
interested in studies that address the mechanistic action for the response.
CHAIRMAN
CHOTI: Thank you. Dr. Chang.
DR.
CHANG: If the sponsor has originally
been able to plan a prospective study, I would have loved to have seen a
planned randomized study comparing the sponsor's product with native fat
injection, and it could have been randomized according to one side or the other
for the nasolabial fold or the cheek.
But
be that as it may, my recommendation for a post-marketing approval study would
be to address the questions of again what happens over time, and if a patient
in this population acquires multiple treatments, and then what happens to
persons of color, and to women who receive this product.
Just
as a comment, minority may be -- actually the persons of color may soon be the
majority demographically in the country, and so these questions have not been
answered thus far with the data presented.
CHAIRMAN
CHOTI: Dr. Blumenstein, are you going
to recommend a post-approval randomized trial?
DR.
BLUMENSTEIN: I am not going to add
anything to what has been said.
CHAIRMAN
CHOTI: Dr. Witten, at least no one said
that they want MRI scans of the nodules every three months. Do you think based on the -- and I am not
recommending that, but based on the panel's discussions do you think we have
adequately addressed Question Number 3?
DR.
WITTEN: Yes, thank you.
CHAIRMAN
CHOTI: At this point, why don't we go
ahead and take a break for lunch, and I will resume the FDA questions. Why don't we meet promptly at 1:30 to
resume.
(Whereupon,
at 12:28 p.m., a luncheon recess was taken 1:31 p.m.)
DR.
KRAUSE: Good afternoon, everybody. It's time for us to start again.
I
hope everybody had a good lunch. If
everybody could please grab their seats, I think we'll go on with the FDA
questions as soon as everybody's situated.
Before
I start, I just wanted to reiterate what I said earlier. Anyone who felt like they were passed over
or didn't get a chance to speak at the earlier open session, we're going to
have another open session. If anyone's feeling a little self-conscious and does
not wish to make their statement because there are cameras in the room, they
can give their statement to Ayana Hill.
Ayana,
can you stand up so people can see who you are? You can give your statement to Ayana and she will give it to me,
and I will be glad to read it into the record.
So
if everybody's situated, I think we'll get started for the afternoon.
Dr.
Choti, please
CHAIRMAN
CHOTI: Thank you, Dr. Krause.
So
we've responded to questions 1 through 3, that's correct. So we're on question 4.
DR.
LERNER: Question 4: A large volume of this device, up to 11 ccs
per treatment is required to achieve an optimal cosmetic effect and precise
placement of the material in the correct dermal plane, deep dermis or
subcuticular layer is important. Please
advise FDA whether a physician training program is indicated for those wishing
to use this device, and if so what type of training would be appropriate.
DR.
MUNK: Excuse me. I have a question for
FDA. Do these questions become part of
the public record? The questions
themselves?
DR.
KRAUSE: Yes, they already are.
CHAIRMAN
CHOTI: And your comments?
DR.
MUNK: Well, what I was hoping is that
we could edit one word and change "cosmetic" to
"corrective." Is that
possible?
DR.
WITTEN: Well, it's certainly I think
appropriate for you to make the comment that you think that, you know,
cosmetics should be corrective. I mean,
these questions are up on the web and they're part of the transcript of the
meeting.
DR.
MUNK: Okay.
DR.
WITTEN: But any comments to the
questions themselves certainly I think would be of value.
CHAIRMAN
CHOTI: Why don't we start with Dr.
Chang.
DR.
CHANG: To answer question four, I
believe the answer is yes that there should be a physician training program on
the proper application of this product, proper use and application as well as
to achieve the optimal desired effect.
And the type, I believe, should be modeled after the type of training
that Dr. Engelhard received when he went overseas to know how this product was
being used overseas. So before he
started using this in the United States there was a training process, however
long it took. It may not require a long
time period as there has been some experience by clinicians for tissue
fillers. But I've heard from the
presentation that there is a difference. And so certainly there should be a
training process so that clinicians would be able to do this correctly.
CHAIRMAN
CHOTI: Dr. Blumenstein?
DR.
BLUMENSTEIN: I don't have any comment
on this.
CHAIRMAN
CHOTI: Dr. Newburger?
DR.
NEWBURGER: I agree. Training has to be
done in a formal hands on setting.
CHAIRMAN
CHOTI: Dr. Munk?
DR.
MUNK: I agree. And, you know, my understanding not being a
dermatologist is that there is substantial variation in different filler
products, whether there's injection at a single point or at multiple points and
deep to go and what pattern to use. So,
definitely, yes.
DR.
BARTOO: I agree that training should be
done.
DR.
DOYLE: I think it's important,
particularly since many of the physicians who may be later using it will not be
dermatologists and will not have the necessary skills in this type of
injection. So I think they should have it and it should be hands on.
DR.
DOYLE: Dr. Li.
DR.
LI: Well, I'm in a quandary because if
I remember right, almost all the data was between 1 and 8 cc, so I'm not quite
sure that I know what 11 cc does. I'm
not at all sure that we have an optimal effect and we've talked nothing about
placement. So I'm left with a feeling
that the physicians do need training, although I'm very unclear as to what that
training would be given the absence of that information.
CHAIRMAN
CHOTI: Dr. Olding, can you give us more
details how you thin should be doing this or should it be restricted and how
should those individuals be trained?
DR.
OLDING: May I answer a different
question? I think that's what you're
supposed to do when you're uncomfortable with the question you've been asked.
First
of all, I think I'm going to be in the minority here in saying that I don't
think you need special ability to inject this product. I don't think you have
to have special training to inject this project. It's not injected any different than in any other product. But what makes it different is the response
to its being injected is different. It just doesn't theoretically sit
there. We have this inflammatory
response.
So,
although I will inject in the same or nearly the same location as I do other
products, I don't know what the response to all of this, what really the
mechanism of action is. So I think I'm going to go ahead and agree with the
rest of the panel or what I suspect will be the rest of the panel that you do
need some hands on training with the product.
Not to learn how to inject the product, that it's any different than any
others, but rather to experience firsthand the result of that injection.
CHAIRMAN
CHOTI: Dr. Li?
DR.
LI: Can I ask Dr. Olding a question?
Are
there any other fillers that require you to premix the slurry or the suspension
prior to injection?
DR.
OLDING: There are certainly products
that you have to refill or that you have to reconstitute. The most commonly used one is Botox. But of the fillers that are currently on the
market, this is really the only one that I'm aware of that requires a
reconstitution. Perhaps Dr. Newburger
might refute that, but I think it's the only one.
DR.
NEWBURGER: Isn't Symmetra --
DR.
OLDING: I don't use Symmetra, so I'm
not sure.
CHAIRMAN
CHOTI: Dr. Penneys?
DR.
PENNEYS: Yes, I would agree that
education is necessary, but I'm not sure about training. I mean, this morning on the record we heard
from a physician that less is more, that you inject and wait. Well, so that's education to me. In other words, there has to be suitable
education on how people respond to it.
And I'll defer to the people who actually inject it in terms of what the
people need for learning how to inject it.
CHAIRMAN
CHOTI: Dr. Fish?
DR.
FISH: I'm just wondering about the
practicality of a hands-on training program and, you know, how many people
actually have that experience to actually do it. So that thought has come to mind.
I
would think that probably plastic surgeons and dermatologists who are doing
this would already know how to do it.
So I'd have to defer to the experts in that regard, whether those folks
would need additional special training.
I think certainly if someone were not doing this and were wanting to do
it outside of those subspecialty fields, would certainly need some kind of hands-on
training.
Someone
else can comment in terms of the training if it were needed for dermatologists
or plastic surgeons.
CHAIRMAN
CHOTI: Yes, Dr. Newburger?
DR.
NEWBURGER: My comment is that the
current approved fillers all you fill either to complete correction or
overcorrection depending on the substance.
This is different and it seems to keep on developing a response, so I
think there has to be simply from that point of view a difference in terms of
injection technique. Because if you just take people who are used to injecting
for corrective or cosmetic uses and have them inject this, you're going to end
up with more prominent lumps where there, perhaps, defects -- yes, depressions.
DR.
FISH: Yes. I understand. Thank you.
So
there's two kinds of trainings then.
Kind of an education, kind of letting people know versus a hands-on kind
of training; is that feasible?
DR.
NEWBURGER: Right now there is from the
last approved filler Restylane, they do have a training program that is both by
CD-ROM as well as hands-on training. And that seems to be going fairly well in
the community. And it's not
insurmountable. That was also done for
collagen way back when it was approved several decades ago.
DR.
OLDING: Just a question, though. That, as I recall, is not a requirement to
have a hands-on training for Restylane.
There is no requirement that you have a hands-on. We did not do that at that panel, I do not
believe.
CHAIRMAN
CHOTI: And although we've heard
anecdotally that there's a certain technique not to fill, overfill and so
forth, I don't think we've seen any data regarding whether technique makes a
difference that overfilling will result in a more prominent -- and so
forth. It's pretty hard to say.
Dr.
Miller?
DR.
MILLER: I think if this is identical in
use to other fillers, then probably training is not necessary. If there are nuances in using this that are
different, then I think the clinician who uses it needs to be instructed about
that.
CHAIRMAN
CHOTI: Hands-on? Videotape?
What are some specifics?
DR.
MILLER: Well, I think that you know,
ideally hands-on. I mean it maybe
require nothing more than the rep whose serving that clinician just being there
to talk to him as he does his first one or something. I mean, i'm not sure.
But,
you know, supposedly this is a very specific indication for people with a very
specific program. And I don't know what
the numbers will be, but if the clinician wants to begin to care for these
people, I think that some training and how specifically to care for this
particular problem is indicated to have instruction.
CHAIRMAN
CHOTI: Dr. Leitch?
DR.
LEITCH: I think as Dr. Miller was
saying, you know there's the issue of doing a procedure in a population that
other medical issues. And so you don't want it done by somebody who is
oblivious to those other issues that these patients may have or at a spa or
whatever. You want it done by someone
who is attentive to the issues of that patient as a whole. And so since it's being approved for that
particular population, then I think there should be training materials that
reflect that population as well as the issues we've already discussed about,
you know, that you don't quite fill the defect because it was have this later
effect and how that might be different from what people have typically done
with injections.
Again,
the idea of whether everybody would have hands-on training, you know sometimes
that can be technically difficult to accomplish. But there should be some
training that is available and enthusiastically supported by the company in
order to be certain that it is applied properly.
CHAIRMAN
CHOTI: Mr. Witten, I think a little bit
of mixed feelings here, mixed views, but I think the consensus is that some
kind of specialized training would be felt to be indicated. How the specifics
of that are somewhat unclear with some mixed opinions.
Does
that adequately address some of your concerns regarding question four?
DR.
WITTEN: Yes. Thank you.
CHAIRMAN
CHOTI: Is that all for the
questions? Yes.
We
can have a little bit of general discussion.
Dr. Blumenstein?
DR.
BLUMENSTEIN: I'd like to ask Dr. Witten some questions.
If
this is not approved, can patients still get access to it?
DR.
WITTEN: Well, in general if a product
isn't commercially available, there are mechanisms for it to be available to
them through studies and different study designs. So that would --
DR.
BLUMENSTEIN: You mean if they agree to
participate in a future study, then they would --
DR.
WITTEN: No. They could get it as part of a study of some nature. I mean,
there's different kinds of studies, as we've heard. There's sponsor investigator studies, you know. Studies supported by the sponsor. There's you know different study designs
depending on what stage of product development a sponsor is in. So there's continued access. But there's specific requirements for each
of those access mechanisms.
DR.
BLUMENSTEIN: And can you explain to me
what compassionate use really means and how broadly can that be applied, that
sort of thing?
DR.
WITTEN: Yes. Well, compassionate use is -- we encourage there to be a study,
for patients to be enrolled if a product is not available as part of a study. So in general for compassionate use, it's if
there's a study ongoing and then there is a patient who shows up who is in part
of that specific study protocol, then we may make an exception for them under
compassionate use. So it's not really
meant to be a widespread distribution mechanism. It's meant to be a couple of patients here and there type of
thing.
DR.
BLUMENSTEIN: Okay.
DR.
WITTEN: Does that answer?
DR.
BLUMENSTEIN: Yes, that answers my
question.
Now
my next question is if this is approved, then could you describe to us
mechanisms that we as a committee could discuss or modify the indication or
whatever things are there to minimize offlabel use or at a minimum, make it a
problem for those who wish to make it, to use it offlabel?
DR.
WITTEN: I think beyond expressing the
concern, which we've heard very clearly today, I can't think of any specific
regulatory actions that you can suggest or that you have as part of your
discussion to suggest. I mean, you
could comment on labeling, specific labeling that you think ought to be -- you
know, information that should be in the label about the product. But in terms of suggesting a mechanism for
it, you know, not to be available -- once a product is on the market, it's
really pretty much practice of medicine how it's used. But there is --
DR. BLUMENSTEIN: But if we put things in the label that indicate specific concerns
and so forth like that, does that the effect of limiting offlabel use?
DR.
WITTEN: I can't say what effect it has
on practice. It doesn't have a
regulatory effect.
I
mean there is one mechanism which, I don't know whether -- there is one
mechanism which we have never used since I've been here. So I can't really tell you exactly --
DR.
BLUMENSTEIN: Oh, good. I want to hear
about this.
DR.
WITTEN: Where you can make something a
restricted device. And I must admit
since we haven't done that ever, I can't tell you exactly what that would
entail. But, you know, you can express the concern.
CHAIRMAN
CHOTI: Dr. Newburger?
DR.
NEWBURGER: Thalidomide is available to
patients who have very clearly defined and documented diagnoses. And if a patient fills out and their
physician fills out that documentation, then the patient can purchase that
drug.
Is
there perhaps a similar mechanism, or if that's not the one that you were
obliquely referring to, is it possible that something like that can be
established?
DR.
WITTEN: As far as I know, there is
nothing like that that could be established for devices. I'm not aware of anything and it's not
something that since I've been here that we've done.
You
know, if you make that recommendation, we could certainly look into it. Cut isn't something where I could tell you
this is the regulatory path we would follow.
CHAIRMAN
CHOTI: Yes.
DR.
BLUMENSTEIN: There's Accutane. It seems like that that has some kinds of
restrictions and might be a model, is that --
DR.
WITTEN: Well, that's a drug.
DR.
BLUMENSTEIN: A drug, yes.
DR.
WITTEN: Both of what you're citing are
drugs. And so they may have additional
regulatory authority that we don't have.
So I can just say that you can make the recommendation about what you
think we ought to try to achieve and then if, you know, we can go back and
evaluate that assessment and decide whether we want to do that and what the mechanism
would be.
In
the time that I've been at FDA, I'm not aware of anything like that being done
for any devices.
Do
you have anything? no.
CHAIRMAN
CHOTI: Dr. Witten, just along those
lines, short of in the final recommendations of the panel, if there are some
panel members concerns regarding offlabel use, how is that, in what context,
short of just seeing the transcripts of the panel's discussion is that
transmitted in the recommendations from the panel? Is there some way to do that in the conditions or in some other
--
DR.
WITTEN: Well, you know, again we
certainly take every part of the discussion into account when we complete our
review. So we've certainly heard the message about the panel's concerns about
offlabel use already in the discussion.
You
know, it is something that if the panel wanted to suggest as a condition that
we look into this possibility, you could add it as one of your recommended
conditions. And as I've already said,
I'm not sure exactly what that would translate to in terms of regulatory action. But you could make that recommendation.
In
addition, I think we've heard it very clearly already in the discussion to
date. You certainly are free to make
that recommendation additionally when you go to the vote with the conditions. And I think that's the panel choice.
CHAIRMAN
CHOTI: Yes, Dr. Monk?
DR.
MUNK: May we ask the clinicians present
to comment on the training, especially the idea that physicians who are HIV
specialists but not necessarily dermatologically trained maybe using this
product?
CHAIRMAN
CHOTI: Which clinicians?
DR.
MUNK: The ones who conducted the
studies.
CHAIRMAN
CHOTI: Yes. Which specific one would you like to hear from?
DR.
MUNK: All three of them in the front
row.
CHAIRMAN
CHOTI: Please, go ahead and address
your specific question.
DR.
MUNK: Okay. Dr. Engelhard, Dr. Conant
and Dr. Humble, what's your perspective? My impression is that all three of you
have experience with using various filler products. When you think about this product if it were to be approved, if
it were to be used by a more general population of HIV treating physicians,
what's your perspective on whether or not training would be required and what
type of training?
CHAIRMAN
CHOTI: Could you please use the
microphone?
DR.
ENGELHARD: I agree that this product is
no more difficult to inject, per se, than say collagens or Restylane, but again
the difference being that you do treat to an under treatment point and then
wait is the message that has to be conveyed.
I
think a non-dermatologic physician or someone that's not used to injecting
intradermal or subcutaneous injections anyway needs to be trained whether
they're going to be giving Restylane, collagen or New-Fill or Sculptra. I don't think that is particularly product
dependent.
What
is product dependent is the fact that you under treat in areas with this
product and wait.
So
I don't know if that answers your question, but I think a physician that is not
using dermatologic procedures should be trained in any of these soft tissue
correction techniques. Is Sculptra
going to be significantly different training wise? Only in the under treatment
area.
DR.
MUNK: Thank you.
CHAIRMAN
CHOTI: Dr. Conant?
DR.
CONANT: You said guys that aren't
dermatologists, but unfortunately I'm a dermatologist, too.
But
I think quite honestly, you can train people with a CD-ROM. I'm not even sure you need hands-on.
I
went to the Netherlands and studied with Danny Vieggaar, not so much because I
thought I needed the training. I mean I
had read about under treating and where to put. I wanted some proof that if I
got sued, that I had gone to the proper extent. And I think a lot of physicians
are not going to need regulations from the FDA. If it's simply labeled, if you don't know what you're doing be
careful with this stuff, that's enough.
Because there are other mechanisms that control physician behavior,
including liability.
CHAIRMAN
CHOTI: Dr. Mest?
DR.
MEST: I agree that hands-on physician
training probably isn't necessary as long as the message of -- there's no much
water that you put in this and then that's reabsorbed; you actually have this
fill and then it goes down. You have to manage the patient's expectations that
they've lost their correction because it is over a period of time. And that's when you reassess and
retreat. But that can easily be, I
think, disseminated by probably the reps.
CHAIRMAN
CHOTI: Yes, Dr. Witten?
DR.
WITTEN: Yes. I wonder if I can add to
my answer to two prior questions.
And
the first is for Dr. Monk. Perhaps my
answer wasn't complete. And, you know,
we have heard the concern about what this is to be used for and how it is to be
characterized. And I think you certainly could feel free to make a comment on
the indication statement when it gets to the discussion of this product and
approvability. When you're talking
about public record, that probably is what's the most important to I think many
people, would be my guess, is the indication and how that's worded. So that would be a place to make your
comments if you wanted.
And
then the second regarding offlabel use. I'll just say the panel could ask the
sponsor what they intend to do about the issue of offlabel use. So that might be a question you want to ask
the sponsor.
CHAIRMAN
CHOTI: Why don't we go ahead and ask
the sponsor now that very question. As
good a time as any.
Who
wants to field that question? Dr. Levy?
DR.
LEVY: Well, I think that relates to the
whole arena of training that was brought up today. And the focus of our support program if the product is eventually
approved will hinge around training and assuring that the appropriate
injectors; it was mentioned today most likely dermatologists, plastic surgeons
who have experience with injectable materials so they're technically
proficient. And we would expect as
well that there'll be a number of HIV specialists who will be interested in
providing this kind of care to their patients.
And we want to be able to support them in appropriate use of this
product.
Right
now we're in the midst of working through the appropriate training program
which would include many of the things that were brought up today with emphasis
on very specific materials that highlight technique. And we're planning to
provide a video CD format because I think that the technical aspects have been
brought up from a lot of the clinicians as well as the panels. And that needs to be conveyed in a format
that physicians have available to them over time so they can continue to refer
to it.
We
also will have available to the physicians who will needs it, and perhaps those
are physicians who are less acquainted with the technical aspects of the
product, workshop formats, regional meetings so that they can see the product
and experience it closer and know more firsthand how to use the product, as
well as having support in terms of the availability of peer-to-peer
consultations.
So
we'll do that to try to focus the appropriate support directed to the use
that's been approved.
CHAIRMAN
CHOTI: Although that addresses, perhaps
the training question. How will you address the panel's concern regarding
offlabel use?
DR.
LEVY: Yes. Again, the information that we've brought forward to the panel
today deals with the indication at hand, which is in correction of the defects
of facial lipoatrophy in HIV effected patients. And part of the training effort will be directed toward education
of the physician population in the appropriate use of the product in the
appropriate patients.
CHAIRMAN
CHOTI: Dr. Blumenstein?
DR.
BLUMENSTEIN: Do you have any plans to
study the use for cosmetic purposes in other than HIV patients?
DR.
FORBES-McKEAN: Currently we do have an
open IDE that we are working on with the FDA and are currently finalizing the
plans for a protocol that will look at the cosmetic use in a well controlled
comparative trial for that indication.
CHAIRMAN
CHOTI: Yes?
DR.
FISH: Do you have the data now from a
lot of the European usage, as we understand that it seems to be quite extensive
for non-HIV infected individuals or for cosmetic purposes?
DR.
FORBES-McKEAN: As Dr. Levy pointed out
this morning, we do have post-marketing experience base don the European use of
this trial which, you're correct, has been in more than the HIV population has
been in the cosmetic use of the product. However, to get the required valid
scientific evidence for safety and efficacy in that population and for that
use, we're going to complete a comparative study as is required by FDA for
approval in the U.S.
CHAIRMAN
CHOTI: Just a reminder panel, that we
really are focusing on the intended use based on this PMA, but I think it just
does transmit to the FDA the concern about what may be a large population of
patients treated offlabel.
Yes,
Dr. Newburger?
DR.
NEWBURGER: I'm sorry. Back to the attempt to control the
conditions for which this device is used. I'm still not clear how you're going
to control that.
You
know, with the other fillers we see all manner healthcare providers injecting
them. We certainly have nurse
practitioners, we have podiatrists in our community injecting Restylane and
collagen. What kind of mechanism would
you think would be effective in helping the healthcare provider to use it for
this indication?
DR.
FORBES-McKEAN: As Dr. Witten noted, and
with those other products that you noted as well, all companies receive an
approved label for their product. And
the intent is that label will reflect the intended use for that product both in
the indication as well as in the clinical section of that label we have
proposed the intended use for this product, as do other product. And that
approved labeling is what the product then is intended for its use and it's
what the company is bound to promote the product according to that approved
label. And that is what we will intend
to do.
CHAIRMAN
CHOTI: Yes. Last few question. Dr. Monk?
DR.
MUNK: Do you have any experience with
reduction of overcorrection?
DR.
FORBES-McKEAN: Sorry. Could you repeat the question again?
DR.
MUNK: Do you have any experience with
reductions of overcorrection?
DR.
FORBES-McKEAN: For that question, I
would have to address that to the clinicians that have been injecting the
product and ask if one of the clinicians we have here has any experience, they
can comment on that, please. Dr. Danny
Vieggaar
DR.
VIEGGAAR: Again, my name is Danny
Vieggaar.
When
I started to use the product 4? years ago
with some other dermatologists plus experience from other countries, we were at
that moment not completely aware about the right technique. We had advice, of
course, but it was the beginning.
We
had some overcorrections in the early days and it seemed to vary amongst
colleagues who had several hundreds of patients between 2 and 6 percent.
Now
for us at that time to avoid future overcorrections. By discussing our experience and extending our experience and
fine tuning the technique, we were able to diminish those overcorrections to
under 1 percent varying from 0.3 to 0.6 percent.
Now
to follow up on those overcorrections I've been doing in some of the patients
gave me the impression that the overcorrections, like already the discussed
nodules, appear within the first year and then stay stable for let's say a time
of 2 years. And in this time there is
not really any signs of activity or clinical complication. And what I observe now, which is beyond 3
years in some overcorrections is that without interfering there is a
spontaneous regression going on of these overcorrections.
Other
management of overcorrections, of course, have been tried in the way that
overcorrections with other products also have been addressed, like
intralesional injections. But after a period of 3 years there does seem to be
spontaneous regression.
CHAIRMAN
CHOTI: Dr. Bartoo?
DR.
BARTOO: I'd like to find out if the
sponsor has any plans or protocols for further studies related to this intended
use?
DR.
LEVY: Well, as we hard today from Dr.
Engelhard and Dr. Mest, they have ongoing protocols which are still following
patients for an extended period for which additional data will be gained. And as I understand from Dr. Mest as a
follow on to the IDE protocol that was addressed this morning, there will be a
retreatment protocol.
At
this time we do not have an additional study that we have submitted to the FDA
for review.
CHAIRMAN
CHOTI: Thank you. If there are no further questions, why don't
we go on to the second open public comment session.
As
we stated earlier, all persons addressing the panel speak clearly into the
microphone, again as the transcriptionist are dependent on this for
documentation.
Both
Food and Drug Administration and the public believe in a transparent process of
information gathering and decision making.
To ensure transparency at the open public hearing session of this
Advisory Committee meeting, the FDA believes it is important to understand the
context of an individual's presentation. For this reason, FDA encourages you,
the open public hearing speaker at the beginning of your written or oral
statement to advise the Committee of ny financial relationship that you may
have with the sponsor, its product and if known, its direct competitors. For example, if this financial information
may include the sponsor's payment to your travel, lodging or other expenses in
connection with your attendance to this meeting.
Likewise,
the FDA encourage you at the beginning of your statement to advise the
Committee if you do not have any financial relationships.
If
you choose not to address this issue of financial relationships at the
beginning of your statement, it will not preclude you from speaking.
Why
don't we begin again with those individuals that are scheduled. The first listed is Dr. Saylan.
DR.
SAYLAN: My name is Saylan. I'm from
Germany. I'm a general surgeon. I inject the facial fillers a lot.
I'm
sorry. I have no financial
interests. Nobody paid my trip to
Washington. I came yesterday from
Germany, Dusseldorf, for a meeting which is starting tomorrow. I am the invited
chair of the meeting.
And
I have been injecting in the past years the New-Fill or Sculptra several
times. And I had some concerns about
the material.
I
was here six weeks ago at the dermatologic meeting. I presented this
presentation, I said why don't you present it to the FDA. I send my
papers. Thank you very much that you
give the possibility to talk here.
The
material as the Sculptra is called here, it is a poly lactic acid,
natrium-carmeliose and mannitol. They
are all sugar products. I hope that this morning here the discussion here about
the product itself, there was no concerns, but I do have some. I want to share them with you. And these are all sugar products. And as we know from the basic science and
microbiology, where you use them to breed microbes in agar plates, which is
also possible for the HIV patients with not an intact immune system to help
infections. This is also true for the
non-HIV patients. But I advise the panel to limit the use of this material only
for the HIV patients with intact immunologic system.
I
had talked to Dr. Michael Cole at the Georgetown University. He also said to me it will be not advisable
to use PLA and the mannitol sugar as a skin filler for HIV patients since they
could be regularly utilized as carbon
sources by bacteria. For example,
mannitol is regularly by Staphylococcus or those bacteria that is commonly
found in the skin.
And
I got it written here. I can give it to the panel, the original piece.
And
as I started injecting it in 1999, I comment in this paper, I also original
piece here in German, I have it here.
It can cause like all -- fillers.
It can cause bleeding, hematomas, infections, abscesses, damage to
nerves. And it causes an infection of the veins of the occur. You will see some vasculitis, okay. But I haven't seen this complications in the
description to other fillers, like the abscess or like the necrosis, or the
nerval damage.
And it come from the manufacturer, which I heard
several times here today, should be injected subdermally, not deeper. And then my colleagues just a few minutes
ago, it should be injected subcutaneously, which is logic if you want to
augment the cheek bones of a patient, you have to inject a lot of material
there, at least 11 cubic centimeter, which is more sugar, more additional
infection and it may cause some trouble.
And in my prescriptions I have from the German company it says don't
inject more -- all 7 centimeters, it's same side. Okay. This is another
thing.
And
it says if there is any kind of dermal infection don't apply any new fill. This is what I got written here, the
original pieces. And this is my
infections up to 14 days. This is not
an HIV patient, I must tell you, but it happens by healthy patients. It will
also happen by the HIV patients.
This
is the scars left after the incision. And this is another thing which I have a
discussion with the company. The
company blames me -- I've got it also written here -- that I had injected Botox
to the glabella of the patient and for that reason the New-Fill is infected
here. I don't agree with this, but the company wants to tell me like. And I
just want to present it here.
These
are some directions. I have given
antibiotic and they answer to antibiotics, which means it is a bacteriologic
effect. And this is in my opinion, I
don't know, I'm not a microbiologist, it comes from the sugar in the material.
And
another things is the granulomas. This
is a powder here to m ix it with the water, saline or you can mix it with local
anesthesia. At the beginning to
compensate 3 milliliters, now they say 6, where some of you say 8 or 10. I
don't know. But I cannot mix it well. Powders stay. And they cause foreign body reactions and they end up result with
such granulomas. You take them
surgically out. It is not a problem by
HIV patients? I don't believe
that. It will be also problem there.
And
this -- I bought a machine, a shaking machine that shakes the solution for
hours, for a day. It's supposed to melt
the powder. It doesn't function every
time. Some powder particulates stay and
they cause the infections.
CHAIRMAN
CHOTI: Why don't you summarize please,
for us?
DR.
SAYLAN: Okay. I'll finish.
I've
got some HIV patients. I had not
problem. These are infections I had with the things and this is the -- it's my
statistics here. I got five severe
infections, 12 case of hardening, 3 cases of allergic reactions.
I
believe it is -- it should be allowed to inject, but only to the patients with
intact immunologic system.
Okay. Thank you very much.
CHAIRMAN
CHOTI: Thank you, Dr. Saylan.
Are
there any questions from the panel to Dr. Saylan? Yes, Dr. Li?
DR.
LI: Maybe not to Dr. Saylan, but
perhaps a sponsor comment. Is the
New-Fill used in Europe exactly the same as the ones that were used in the
clinical trials here? I mean like
exactly the same, not just generically?
DR.
LEVY: Yes.
DR.
LI: They were?
DR.
SAYLAN: It was the same I've seen, the
same product. Same sugar in it, same
mannitol and poly lactic acid.
DR.
LI: Now it's going to a little finer
cut. So same molecular weight, same
crystallinity, same everything?
DR.
LEVY: Yes.
DR.
LI: Okay.
CHAIRMAN
CHOTI: Sorry. Dr. Olding, a question?
DR.
OLDING: Dr. Saylan, I have a question
over here. Dr. Olding.
It
is surprising for us sitting on this panel to see the number, I don't know how
many this represents; there's no denominator to the numerator of X number of
infections that you've shown us. But
I'm surprised to see them because we haven't seen it in the other studies that
we've discussed.
DR.
SAYLAN: Yes.
DR.
OLDING: And also I believe there's a
reporting system in Europe, much the same as there is here, for adverse
effects. And I don't have that data in
front of me, but I believe in those adverse effects lists from 1993 to 2003
there were only two reported infections.
Now,
that tells me either they're not being reported -- and in fact because you've
presented more than two, you're not reporting them.
DR.
SAYLAN: That's the point. I just told Dr. Krause today, I got a
meeting, doctors says I two cases of the New-Fill injections. I go where, which patients? They don't say anything. They don't give me any information.
I
was going to come here and show you more statistics, but I couldn't go -- the
doctors cooperate. They all keep quiet. They don't want to talk about -- some
of the patients you have seen. You have
seen that infection is already healed.
It came from other doctors to me. I call the doctor, how much you
injected, what you have done --
DR.
OLDING: Sir, I'm sorry. I got the
impression when you gave this talk that it was your patients. Now you're telling us that it's not? It's somebody else's patients?
DR.
SAYLAN: Two of them were other doctors.
DR.
OLDING: Okay. And we don't know if they're physicians or nonphysicians.
DR.
SAYLAN: I think that they were
physicians.
DR.
OLDING: Okay.
DR.
SAYLAN: I treated them, yes.
DR.
OLDING: Okay. So, again, it's surprising when they're in the national
statistics from Europe, there were only two infections reported and you've seen
more than two. And, you know, one would
think that since you are very interested in this sort of thing that you might
report those so that we would have data, because we're obviously using
them. That's just a comment.
And
secondly, at least in the United States most injectables are at least at the
beginning in the realm of the plastic surgeon, the dermatologists who is
experienced. I just wonder. We were talking bout experience here. I
wonder how you gained your own personal experience for injection?
DR.
SAYLAN: Before I tell you about it, I
want to tell you something else. In
Germany where I come from, we've got a wonderful system which includes
everything. Since we've got the
European community, they all come from other countries. From Portugal, from Spain, from Holland from
other countries to us, which we have no control about this material
anymore. You see, before the German
authorities approved all the filler themselves. Now we cannot do it. We
cannot do it because they come from Belize or from other countries.
My
trouble is that I know that many doctors, they got infection with the facial
fillers, not only with New-Fill, others.
And there's a big -- I don't know --
about the companies in Germany that they bring this -- such material
without any tests, without any clinical tests or microbiologist tests like in
-- you talk to a microbiologist about it.
And we need an organization like you have here in Germany. It's not that good in good in Germany like
you have it here.
CHAIRMAN
CHOTI: Okay. Thank you, Dr. Saylan.
Our
next public speaker listed is Dr. Frechette.
DR.
FRECHETTE: My name is Gervais
Frechette. I was -- I didn't have my
travel sponsored by Dermik and my lodges, but I have no personal interest would
with the company. Sorry about this.
So
I'm an HIV specialist working in New York City. I have been working with people with HIV for 17 years and for the
last 6 years, I would say that lipoatrophy --
CHAIRMAN
CHOTI: would you please speak up a
little bit?
DR.
FRECHETTE: I'm sorry. Lipoatrophy,
which is the larger syndrome where facial lipodystrophy is one of the problems,
has been one of our major concern.
I
went, Dr. Engelhard, to get trained in France with Dr. Lagienne with several
workshop in the year 2000/2001. And I was going to present five patients of
mine who have had different treatment or possibility of treatment with mostly
plastic surgeon. I don't know if we're
going to be able to get them. I
definitely have not seen any rate of infection like the gentleman before me has
presented that. And I've injected
several hundred patients in the year 2001/2002.
So
hopefully you will be able to see the pictures. I apologize for this.
The
first picture is a patient who saw a
plastic surgeon in New York City who was telling him that, you know, if you
have like -- I mean, if you could provide $24,000 I will give back your face to
you. This patient was extremely fit and
had like no fat where it could be like liposucked and reinjected in his
face. With six sessions you see the
difference, and I apologize for not having the proper pictures. I am a
physician, I am not a professional photographer. But you can easily see that with six sessions this patients has
regained a lot of his -- what I would call -- would I would say normal
appearance even in the temples on the left side as well. And that was like six sessions.
This
patient came back. He was -- we did the
six sessions, the last session was in the mid 2002. And he came back from a
retouch in 2003.
He
did not report any adverse events.
Second
patient is a Haitian patient. I
apologize again for the poor quality of the pictures. But you'll see better on the second pictures that he has facial
lipoatrophy on both sides. And a lot of
the scar from his acne when he was a teenager.
With
again six sessions with this patient we were able to: (1) correct the facial lipoatrophy. You see that very well on the top pictures on the left side
compared to the right side and on the left side. And you even correction of the scar from the acne.
The
consistency, the texture of the skin is very, very nice with this patient.
I
spoke to all these patients in the last days and everybody's very happy.
This
patient, a plastic surgeon said let's cut some of your muscles, it will help
you to masticate. And we see the result
on the left side. And almost more than
a year letter I saw him, and did about 7 treatment of New-Fill -- I'm sorry,
Sculptra and you see the result.
The
plastic surgeon kept saying to the patient you will have -- I mean, these scar
that you see on the top left and the lower left will disappear, but they were
never disappearing. And, again, I spoke
with this patient. He is from the midwest.
Is very happy with his result with no retouch. And we're talking about two years now.
This
patient has seen another plastic surgeon in the south where he has two implant
go like asymmetrical, not only just like -- one is like lower than the other
one, but the right one on the right side actually you don't really see right
now, was like sticking out a little more on his right side. So my concern was that I didn't want to give
him a more like fat face since the
patient was really fit.
You
see the correction after six treatments of this patient. He did come back for a touch-up. You see
that I was unable to cover the right side implant on this patient, but the left
side was like totally covering. The
patient is still very happy. Again, mid
2002.
The
fifth patient, a patient who was receiving collagen treatment about $1,000
every like two months and a half and was unhappy with the result. After six sessions you have the result on
the right side. Patient was very happy.
Did come back for a touch-up because he wanted to have like more perky
cheeks.
So
not only you see the correction of the fat pad or the cheek, but you see also
the correction of the temples on both side.
And, again, no infection or like adverse that the patient reported.
Thank
you.
CHAIRMAN
CHOTI: May I ask you, were you
participating in a trial or how did you get access to the New-Fill?
DR.
FRECHETTE: With the buyer's club in
2001/2002.
CHAIRMAN
CHOTI: Thank you.
DR.
FRECHETTE: Thank you.
CHAIRMAN
CHOTI: Our next speaker is Diane
Zuckerman. Is she here?
MS.
FOLLOWS: Good afternoon.
Most
of you probably recognize that I am not Dr. Diane Zuckerman. My name is Jill
Follows, and I speak on behalf of the National Center for Policy Research for
Women and Families, of which Dr. Zuckerman is our President.
Dr.
Choti, Dr. Krause, members of the panel, I have no conflict with either the
sponsor or its competitors even outside of my capacity as the senior health
policy fellow with this national center, I also serve as a judge pro tem in the
Philadelphia County Court of Common Pleas and I am an acting practicing
attorney in Philadelphia. And I have a
master's in nursing.
The
center has great respect for the work of this panel and for the Food and Drug
Administration. And we concur in large part with the expressed and reasoned
opinions of this esteemed panel up until this point today.
We
additionally, are very sympathetic to the desire of people with AIDS to look as
healthy as possible; facial fat loss can mark a person as having AIDS and
therefore, certainly has implications for that individual's mental health and
could help target that person for discriminatory behaviors. Having given this preliminary statement, the
center now raises two particular concerns.
First,
our center is committed to the fundamental scientific principle that clinical
trials evaluating the safety of medical products should reflect the diversity
of the population that will use the medical product.
We
are supported in this position by the expressed policy of the U.S. Department
of Health and Human Services, which is to promote the availability of standard
racial and ethnic data. That goal
should apply to all medical products, including Sculptra. When there is reason to believe that
variation among racial or ethnic groups may influence the safety or
effectiveness of a medical device, then the manufacturer should include all
relevant racial or ethnic groups in its studies.
The
record will clearly show this panel's concern over the lack of pertinent data
on women and minority groups, and even children query whether it is timely and
reasonable to pierce the veil of this sponsor's regulatory strategy and look
below the surface for scientific evidence that addresses the concerns of the
obvious offlabel uses for this device among varying populations that are not
studied.
The
lack of data on women and minorities has consistently been raised before this
panel. The National Center for Policy Research respectfully asks when will this
panel make it clear that data on people of color and of all gender is expected
for FDA approval?
By
taking such a position, this panel would be in good company with former FDA
Commissioner Jane Henney who said it is only through participation of many
populations that will ultimately receive a new product that we can ensure that
the medical products we approve are appropriate, safe and effective for all
Americans and not just a narrow cut of our country's population.
In
the Center's view, FDA approval should require adequate research on human
subjects that are representative of the target population intended to be
treated by the medical product. The
only exception should be when the manufacturer presents compelling scientific
evidence for the exclusion of a racial or ethnic population based on legitimate
study concerns and agrees to label the product as contraindicated for that
population.
Our
second concern at the National Center mirrors that of this panel. The potential
for, indeed, imminent likelihood of offlabel use of this product. We encourage you to make recommendations
about dealing with conditions of offlabel use.
The Center's view is not constrained by the FDA's comment that
forecloses you from considering offlabel use in deciding on this particular
PMA.
The
Center is greatly concerned about offlabel use of this product and at a minimum
requests your consideration of a black box warning specifying the lack of long
term safety data on health risks to patients who are not HIV positive, as well
as the lack of scientific data on the risks of this product on women,
minorities and children.
Thank
you for your attention.
CHAIRMAN
CHOTI: Thank you.
That
concludes the scheduled speakers for the open public comment session. Is there
anyone else in the audience that requests that would like to address the
panel? If so, please approach the
podium.
If
not, then again I would like to thank all of you for taking time out of your
schedules in order to testify to this panel.
All
right. Why don't we take a 15 minute break and then we will proceed after. Thank you.
(Whereupon,
at 2:34 p.m. a recess until 2:51 p.m.)
DR.
KRAUSE: Find your chair. We don't have far to go, so if everybody
could find their chair, we could start to get to the end.
Okay.
I think we're just about to go here.
And I'd like to turn the meeting back over to Dr. Choti
CHAIRMAN
CHOTI: Thank you, Dr. Krause.
Before
we proceed with a vote, are there any further comments from anyone from the
FDA? Dr. Witten?
DR.
WITTEN: No. No further comments from FDA.
Thank you.
CHAIRMAN
CHOTI: Is there any further comment or
summary from the Dermik Laboratories?
DR.
FORBES-McKEAN: On behalf of Dermik, I'd
like to thank the members of the Advisory Panel and the members of the FDA for
their constructive discussion and comments today.
We
are looking forward to further collaboration with the Agency to make this
important treatment available to people with human immunodeficiency virus.
Lastly,
Dermik would also like to extend a special thanks to the patients themselves
that had the courage today to provide their personal experiences with this
debilitating condition.
Thank
you.
CHAIRMAN
CHOTI: Thank you.
Now
we can proceed to the voting part.
Dr. Krause, will you read the voting
instructions to the panel at this time?
DR.
KRAUSE: Okay. I'm going to read the voting instructions. Please listen carefully.
The
Medical Device Amendments to the Federal Food Drug and Cosmetic Act as amended
by the Safe Medical Devices Act of 1990 allows the Food and Drug
Administration to obtain a
recommendation from an expert advisory panel on designed medical device
pre-market approval applications or PMA that are filed with the Agency. The PMA must stand on its own merits and
your recommendation must be supported by safety and effectiveness data in the
application or by applicable publicly available information.
Safety
is defined in the Act as reasonable assurance based on valid scientific
evidence that the probable benefits to health under the conditions on the
intended use outweigh any probable risks.
Effectiveness
is defined as reasonable assurance that in a significant portion of the
population the use of the device for its intended use and conditions of use
when labeled will provide clinically significant results.
Your
recommendations options for the vote are as follows:
Approval,
if there are no conditions attached.
Second
choice: Approvable with
conditions. The panel may recommend
that the PMA be found approvable subject to specified conditions such as a
physician or a patient education, labeling changes or a further analysis of the
existing data. Prior to voting, all of
the conditions should be discussed by the panel.
The
third choice is not approvable. The
panel may recommend that the PMA is not approvable if the data do not provide a
reasonable assurance that the device is safe or if a reasonable assurance has
not been given that the device is effective under the conditions of use
prescribed, recommended or suggested in the proposed labeling.
Following
the voting the Chair will ask each panel member to present a brief statement
outlining the reasons for their vote.
CHAIRMAN
CHOTI: Thank you.
Is
there a motion from the panel? Dr.
Newburger?
DR.
NEWBURGER: I move that the device be
voted as approvable with conditions.
CHAIRMAN
CHOTI: Is there a second? Dr. Olding?
DR.
OLDING: Second.
CHAIRMAN
CHOTI: Motion has been made for
approvable with conditions. So,
therefore, no vote at this time but we will then proceed with defining
conditions.
Do
I have a motion for a first -- or a condition?
Dr. Chang?
DR.
CHANG: One of the conditions is that a
study be undertaken so that the use of this product in persons of color and in
women be pursued, a minimum of 2 years as this PMA is brought forth today,
ideally for at least 5 years.
CHAIRMAN
CHOTI: So the motion is for a
post-approval study with some of the points you mentioned. Is there a second to that motion?
DR.
NEWBURGER: I second it.
CHAIRMAN
CHOTI: Dr. Newburger second.
Why
don't we open this condition for discussion.
Dr. Blumenstein?
DR.
BLUMENSTEIN: I think we had a
discussion earlier today about all of the features of the study that we would
like to see. So maybe we could ask the
FDA to just cut and paste those things into this proposal?
CHAIRMAN
CHOTI: Well, why don't you start by
giving some specifics regarding the general design and then perhaps, what data
elements we can then summarize which we think are important?
DR.
BLUMENSTEIN: We hall went around and
there were so many of them. Yes.
CHAIRMAN
CHOTI: Well, there was anything from a
randomized trial to a long term follow up in the broader patient population to
both histologic and clinical end points.
So how do you see -- what would you recommend as a post-approval trial
as part of the condition?
DR.
BLUMENSTEIN: Let me think about the
exact structure of the trial. I mean, I
think others can make their favorite comments about addressing different
populations and so forth. I'll come
back to this.
CHAIRMAN
CHOTI: Well, I wrote a few things we
can talk about that were mentioned.
Women and minorities, looking at adverse events, some questions
regarding mechanistic action although that data elements, that was a little bit
hard to define. Some mentioned variable duration of follow up. Again, weight, number of touch-ups,
antiviral treatment, multiple injections, CD4 stratification. These were some of the things mentioned at
our earlier discussions.
Can
we crystalize that a little bit more?
Dr. Fish?
DR.
FISH: I think ideally it would be nice
to have a randomized trial. And I liked
the design of the Chelsea-Westminster trial in terms of the delayed treatment
group and an immediate treatment group as an internal strategy as opposed to,
you know, comparing it to some other product which might be much more
challenging. And I think the issues
were that -- that my concerns were looking at the durability and the duration
of the effect, the adverse events that you elucidated, long term potential side
effects and analyses by CD4 strata was their different responses based on low
CD4s versus those with higher CD4s under 200, maybe 200 to 500, above 500;
something like that.
And
those, I think, were the important points.
And then an attempt to stratification of demographics to include the
groups that were left out here in terms of women and minorities and potentially
even children, although I know that it's tricker.
CHAIRMAN
CHOTI: Dr. Witten, may I ask you if a
post-approval study such as this is recommended, how does one follow up the
results of such a trial? Who is that
reported to? Is that something that the
panel needs to see back again or --
DR.
WITTEN: If a post-approval study is
recommended and then agreed to between FDA and the sponsor, the sponsor will
work with FDA to design the study to achieve the objective that we decide
on. And the study ultimately would get
reported in a label.
So
ultimately it doesn't come back to the panel. It could if we had some specific
questions about how to interpret the results. But in general, those get added
to the label as extra information for the clinicians who may use the product.
CHAIRMAN
CHOTI: Thank you.
Yes,
Dr. Penneys?
DR.
PENNEYS: I think a small study needs to
be included that addresses the histologic changes that occur following
injection over time. And it doesn't
have to be a big thing. It could be an
area, a non-cosmetic area that's 2 centimeters by 2 centimeters and injected at
times zero and 3 mm punch biopsies taken, for example, quarterly over a period
of 2 years maybe, or every 6 months. And then I would be interested in seeing
that in the target populations that's the subject of this PMA versus a similar
identical study done in immunocompetent individuals who are going to be used in
the other study that is being planned for cosmetic purposes.
And
then all sorts of things can be done with the histologic material once it's
available.
DR.
NEWBURGER: Excuse me. And I agree with Penneys' suggestion. And
that could also be done in another area effected by lipoatrophy such as an
extremity which is not going to be cosmetically evident, but you would think
that many of the similar local environmental issues are operant there.
CHAIRMAN
CHOTI: Any other discussion? Dr. Li?
DR.
LI: I think if you're going to do a
histology, I think I would put in some assessment of the actual amount of PLA
that's left in at those different time periods, seeing as how there's some
discrepancy over the rate of degradation between the in vitro and the in vivo
data. I haven't seen anything that
actually tells me how long that material is actually still around.
CHAIRMAN
CHOTI: Is anybody thinking about,
perhaps, recommending a post-approval randomized trial perhaps compared to
another agent? Dr. Blumenstein?
DR.
BLUMENSTEIN: Yes. I'm -- of course. I think that would be the ideal.
In thinking about it, though, I wonder whether we wouldn't get the same
kind of information from the trial they're planning for strictly cosmetic
use. So I'm a little reluctant to be
very firm on that. I think that I would
rather leave it more open to address the issues and leave the structure of the
trial, the specific structure of the trial more open.
CHAIRMAN
CHOTI: Any further discussion on this
motion for this first condition?
The
first condition motion is to recommend a post-approval study, the specific of
which, obviously, we're not going to outline but there are defined general
areas regarding longer term side effects, adverse effects, a broader
population, some stratification regarding the groups of patient, histologic
changes, addressing women and minorities and perhaps other sites and multiple
or repeat injections.
Show
of hands for approval of this first condition. Those in favor? Let's record. Nine in favor. And those
opposed? Zero.
So
the first condition was approved.
Is
there a motion for a second condition?
Yes, Dr. Blumenstein?
DR.
BLUMENSTEIN: Based on concern about offlabel use, I would put a condition that
the training program include a module explaining to the student the
consequences of offlabel use with respect to liabilities and a potential for
lawsuits, etcetera.
CHAIRMAN
CHOTI: Let me just rephrase that as a
motion to recommend a training program.
Any seconds for that motion?
Yes,
Dr. Newburger seconds.
This
condition is open for discussion.
DR.
PENNEYS: Can I ask a question. I'm not sure how training connects to
liability, but if it's in the package insert, if there's all sorts of negatives
about we're not to use it in the package insert, that will certainly control
part of offlabel usage. Because that
for sure can be used as a denial for a malpractice coverage in a difficult
situation. Is that what you're talking about?
DR.
BLUMENSTEIN: Well, i was going to get
there, too.
DR.
PENNEYS: Okay.
DR.
BLUMENSTEIN: I just think it would be a
good idea for there to be something in the training program.
CHAIRMAN
CHOTI: So the issue about concerns with
offlabel perhaps could be addressed in the labeling, but you're bringing up the
possibility of bringing it up somehow in the training program?
The
suggestion was if somehow that if the training program could include
indications or risks of offlabel use. I
think is that a fair way to specify?
DR.
KRAUSE: Just thinking about it, I would
go even further and make sure that the training program includes a very careful
review of the data collected so far and its limitations, in particular its
limitations with respect to uses and other -- or the lack of data for the
possible approval here.
DR.
BLUMENSTEIN: Can I just get a
clarification? I'm writing this
down.
And
I know that we were -- you know, everybody here at the table were discussing earlier
a training program. So do you want to make a motion for a training program that
includes not only training for the device, but to include these other factors.
DR.
KRAUSE: Yes.
DR.
BLUMENSTEIN: We're talking one training
program as --
DR.
KRAUSE: Yes, we're talking about one
training program, one component of which would be a module having to do with
the potential for legal ramifications for offlabel use. I think there are other issues that we
discussed with respect to the training program, such as hands-on versus CD
versus all that other stuff. I'm not
addressing those things at this time.
CHAIRMAN
CHOTI: But your motion is this idea
about offlabel, some education to be incorporated within one training program?
DR.
KRAUSE: Yes. Just this one part of the
training program, yes.
CHAIRMAN
CHOTI: One part of it. Any other discussion on a training program
in general? Dr. Miller, you think
hands-on should be the way we should try to craft it?
DR.
MILLER: I think ideally hands-on, at least
with a rep present in first injection, especially for people who don't have
previous training in other injectables.
So
some way to assure that the person using this is qualified to use injectable
tissue fillers.
CHAIRMAN
CHOTI: Any other discussion. Dr. Olding?
DR.
OLDING: It's difficult for me because
what I want is to make sure that people who have the problem and that it go for
its intended use only. I don't know how
strongly I want to feel about doing these things based on how restrictive we
can be in the final analyses.
Somewhere
along the line I want to be as restrictive as possible in the use of this
devise. I don't think that restricting it to a hands-on session is particularly
necessarily, as I've stated before, but I think it has to be limited to people
who are comfortable doing it and who have had experience with injectables
before; and I don't know how to do that.
I wouldn't want to be too restrictive.
So
I would vote against us having a hands-on session for the same reason that we
voted against it another panel, the Restylane panel.
DR.
KRAUSE: Can I just clarify what Dr.
Miller said? He said hands-on training
for individuals with no previous experience with tissue filler.
DR.
OLDING: Who is going to monitor
that? I think that any logical
respectable physician would certainly not inject a product that they had not
injected before without the rep being there at the very least, no matter what
the product was.
CHAIRMAN
CHOTI: The hands-on may focus more on
technique, I would think, than indications.
Although I may be wrong. Maybe that would some enforce indications.
Comments,
Dr. Newburger?
DR.
NEWBURGER: My comment really would
relate to the another condition that I'd like to --
CHAIRMAN
CHOTI: Yes?
DR.
MILLER: Isn't it possible to have the
person ordering this material have to check off a box or something saying that
I have experience with injectables or whatever? Some way to get an indication to the company before they ship it
to this person that that person needs to have the rep come by and show them how
to do it? Because I'm impressed. Because the long last nature of this and
some of the nuisances of injecting it and things like that, I mean I'm
impressed enough with it. And I don't
do a lot of injections, so I may have a greater discomfort level than my
colleague here who does a lot of injections.
It's a little more of a mystic to me about doing the injections than
maybe the average plastic surgeon.
So
I would feel better if there was someway to be sure that there was some control
over who does this so that it just -- you know, the nurse in the HIV clinic
can't just pick up the phone and order a bunch of this and start injecting it
and learn how to do it in the first 50 patients, and then start getting good
results. I mean, that's what I would
like to avoid.
CHAIRMAN
CHOTI: Any other discussion regarding
training?
If
not, then the motion is that of incorporating as the second condition a
training program for the use of this device and the nature of which needs to be
defined a little bit more clearly, but the theme is that it's incorporated a
combination of improved or quality and technique as well as clarifying
indications.
Can
we have a vote? A show of hands for
those in favor of this second condition as described. Those in favor? And those
opposed?
Let
the record show an unanimous decision in favor of the second condition.
Do
we have a motion for a third condition?
Dr. Newburger?
DR.
NEWBURGER: Thank you, Dr. Choti.
We're
being asked to approve this device on a compassionate basis. Not on a scientific basis really, but on its
empirical performance. And as such, I
would like to take whatever steps are necessary to limit its use to those who
require it on a compassionate basis. I
don't know if the best way to do that would be to have a physician registration
program such as is being anticipated now for Accutane, which is above and
beyond the SMART program which was initiated by the manufacturer, the original
manufacturer or whether it would be to provide documentation in the records
that those for whom it is being used have presence of virus, CD4 counts that
have been compromised in some way. I
don't know what that mechanism is. But
I would like to take stringent measures at this time until we have more
information about its activity; all the other things that we normally require
to approve such an injectable device where this would be used offlabel.
CHAIRMAN
CHOTI: Can you summarize that in a
sentence?
DR.
NEWBURGER: I'd like to limit in the
employment of this device for those who have HIV associated lipoatrophy. I
would like to do that either by documentation that the subject has HIV induced
lipoatrophy or by registration of the physician who gets the device shipped.
CHAIRMAN
CHOTI: Okay. So the motion is as stated
to limit this device to HIV by some form of documentation or registration. Do I have a second for this motion? Dr. Olding seconds it.
This
condition is open for discussion. Dr.
Penneys?
DR.
PENNEYS: Dr. Newburger, I'm just
curious, what does registration of the physician do? In other words, suppose they order it and they use it anywhere
they want? Is there any penalty for
that in this type -- in other words, I can understand limiting it to HIV
positivity. That absolutely limits it
pretty much to this group. But what
does physician registration really do?
DR.
NEWBURGER: Physician registration could
-- physicians who would be registered would be those, really who you could be
sure have read the package insert. Because most physicians don't read package
inserts of devices they use or medications even that they prescribe. And
sometimes you have to get someone's attention by with a 2x4 when they won't
listen to your words.
So
it would just be a way to triple underline the use of this device and put the
physician really on notice.
DR.
PENNEYS: But they still, because they
have a license to practice medicine, can take this material and use it
cosmetically, for example, or for something else?
DR.
NEWBURGER: Indeed. My preference would
be the documentation of HIV associated lipoatrophy.
DR.
OLDING: Is it possible for us to make
that recommendation as two separate or just as a documentation of HIV? It would be my preference that we do the
former rather than the latter.
DR.
FISH: Yes, I would agree. I think I would potentially keep them a
separate issue and just have the indication or the recommendation for the
indication to be restricted to those who are HIV positive, period. And the documentation of that being in the
hands of the physician.
DR.
NEWBURGER: I would agree with that.
CHAIRMAN
CHOTI: So we're going to reformulate
this motion, this description as to limit this device to HIV by documentation.
DR.
FISH: Of HIV positive sero status.
CHAIRMAN
CHOTI: And we have a second for the
motion. So now this condition is open
for discussion now as rephrased.
Yes,
Dr. Li?
DR.
LI: Perhaps this is a question for Dr.
Witten. I'm completely in agree with
Dr. Newburger's wishes.
How
is this different from perhaps putting an exclusion in the labeling, like we
can exclude patients that are not HIV positive? Which would be the most effective way to do that?
DR.
WITTEN: Well, I think what I'm hearing
the recommendation is that -- at least what it sounds like is that it not
actually provided unless there is documentation that the patient is HIV
positive. I mean, I'm responding to
what I'm hearing the panel recommend.
DR.
LI: Okay. But that's kind of a
practical suggestion or that -- that is the question?
DR.
WITTEN: That's a very good question.
And as I said earlier, it's not something that we've ever done that I'm aware
of or at least since I've been there in my division I'm not aware of that. And so we will do with this panel's
recommendation for this product, as we do anytime we have a panel
recommendation, is take the recommendation back and evaluate it as we complete
or review and see whether there is something that we need to explore that would
accomplish the goal incorporated into this recommendation from the panel. If this is actually a condition that you all
vote and agree on.
CHAIRMAN
CHOTI: But, Dr. Witten, this may limit
the ability to vote for this approval with condition if we don't know whether
this condition can actually be met. Is
there a way we can find out a little bit more detail about a restricted
condition that would actually restrict its use?
DR.
WITTEN: Well, when you vote if you
vote, you're voting with recommendations.
You know, with recommendations for conditions. So that's your vote. I
mean, that's the same with any recommendation for conditions that a panel
makes.
You
know, the panel makes recommendations and we don't follow all of them.
CHAIRMAN
CHOTI: Right.
DR.
WITTEN: But the panel's made its
recommendation based on their best advice to us about what they thin would lead
to safe and effective use of the product.
So we're just asking you to make your recommendation about what you
think would lead to safe and effective use of the product. And if that incorporates this
recommendation, you make this recommendation and you make your vote
accordingly.
CHAIRMAN
CHOTI: But it sounds like the panel
needs to know that this condition may not be possible to be met, it sounds
like. We don't know enough about it.
Yes,
Dr. Monk?
DR.
MUNK: Yes. I'm wondering if perhaps an
effective way to do this would be in the labeling as a contraindication that
the product should not be used in any patient without evidence of HIV
infection?
CHAIRMAN
CHOTI: Dr. Newburger?
DR.
NEWBURGER: That still has an issue as
is the physician going to comply with the insert. As I mentioned before, Thalidomide is a medication which is
available for certain specified conditions that the treating physician has to
document to the manufacturer before the manufacturer will allow the pharmacy to
sell it. Now, once a patient fulfills
those conditions, they can certainly gain access to it very easily. Myeloid dysplasia is one condition. And these people get a month's supply at a
time, and they go through this documentation every single month they get the
medication.
And
I don't see that this would be onerous.
After at least the first few treatments, it wouldn't be on a monthly
basis, you know, for a couple of years.
So I'm wondering if that would give us closer control.
DR.
MUNK: My thinking, too, is that if is a
contraindication, that it's clearly a liability exposure for a physician who
uses in a patient without HIV infection.
And perhaps FDA can work on the best way to implement this. I don't
know.
CHAIRMAN
CHOTI: Although that may be more in a
labeling condition.
And
then the other issue is the definition of contraindication without hard data
supporting its contraindication as opposed to -- yes. So anyway we can discuss that if that's proposed as a separate
condition.
Yes,
Dr. Leitch?
DR.
LEITCH: Well, the idea of reporting to
someone that the patient is HIV positive in order to get the product, that may
be unacceptable to the patients and maybe somebody should speak to that who is
a patient. But I would think there would be some reluctance on the part of
physicians to reveal that information, you know, all these HIPAA issues that
have come up these days. So I think
particularly that type of information to be released to a company might be
distasteful both to physicians and to patients.
CHAIRMAN
CHOTI: Well, it sounds like we've
modified this condition not to a registry, per se, a registration but not --
DR.
LEITCH: No, not registering the
physician, but you said one way would be like with the Thalidomide, confirming
to the company that the patient is HIV positive.
CHAIRMAN
CHOTI: But this is really restricted to
HIV patients. It's just like antiviral.
It's a therapy that we're recommending restricted to HIV patients with
lipodystrophy.
Dr.
Fish?
DR.
FISH: Yes. I think a parallel could be
using zidovudine, using AZT in someone who doesn't have HIV. I mean, it would be malpractice, it wouldn't
be done or if it was done, you know, it just wouldn't happen. So I think that the labeling if we just
restrict it, I agree with you that we don't need a patient registration sent
into the company. I'm not advocating
for that. But just documentation the physician needs to know that they are
treating HIV associated lipoatrophy.
CHAIRMAN
CHOTI: Two separate things,
though. It is not a labeling issue,
this is a recommendation that it has -- if possible, a restricted use.
Yes.
Dr. Blumenstein?
DR.
BLUMENSTEIN: Well, I think there's lots
of levels of restriction on this. One is that you identify the specific patient
to the company before their product is released. The other is that the physician who wants to use the product or
the health care provider, I suppose I should say it that way, would just, in
the order that there would be a pledge that it is being ordered for a patient
to take that's HIV positive, in which case you're not revealing the--I think
the FDA has to be the one to work this out.
And I believe that they have some analogies. The Accutane. What was it
you said? Thalidomide and so
forth. So I think that this is a problem
we have to let the FDA figure out the details.
But I don't believe -- I think if the spirit of your recommendation is
to have something more than just words in the label, and I think that's -- I
definitely go along with that.
CHAIRMAN
CHOTI: Any other comments?
So
the condition as specified is condition 3, which is to limit the use of this
device in a restricted fashion to patients with HIV and lipodystrophy.
This
is now up for a vote. Those in favor of such a condition raise your hand? It looks like it's unanimous. So let the
record show that it's a unanimous vote in favor of this condition.
A
motion for an additional condition? Dr.
Li?
DR.
LI: This must be the first application
for something for a device where the material specifications are still being
worked out before they get to the panel.
So I think the product specifications have to be specific and in place.
Specially going over the information they provided, I believe that the primary
specification should be based on the final objected project, although the
starting material and process are important, I think the most important thing
is the characteristics of the final injected product. This includes molecular weight, crystallinity.
We're
injecting small particles. It's a
little peculiar to me, i spend the rest of my life trying to keep small
particles out of the human body and now I'm here sitting on a panel, presumably
to approve injecting particles into the body.
But we don't really have a good idea of the particle size distribution
of these. And we do know that that is a
very important factor in cell response.
We've
conflicting data on resorption rate.
And near as I could tell, no in vivo resorption rate for this rate.
And
the thing I'm perhaps most bothered about, we don't seen to have any positive
or negative controls on this. You know, we don't really know how much is too
much. We don't know how fast is too
fast. And the other variables
superimposed upon that.
So
I think the product specifications have to be worked out and they have to be
worked out in the absence of, I think I've said this before, in the absence of
a mechanism I think the product specifications have to be in a very narrow band
limited to their actual experience. Because we have very little scientific
data. This whole application, it's all
based on experience. So I think the product specifications must be -- and they
may be doing this already, be limited very specifically to things they have
already direct experience with.
CHAIRMAN
CHOTI: So you're not a post-approval
trial to look at some of these questions, but--
DR.
LI: Well, I think when we talked about
-- I meant, anyway, when we talked about the post-approval studies are things
like the actual concentration of the lactic acid remaining at different time
periods be assesses and the histology I think which was raised. So I think those would be my material
characteristic that I would like in the post-market study.
But
I guess what I'm raising here is I'd like to put in this -- the approvable has
to be, in my mind, a specification sheet of what this material actually is at
the time it's injected, which we don't have in front of us right now.
CHAIRMAN
CHOTI: Okay. So the motion is for product specification. Is there a second to that motion? Dr. Pennys second.
This
condition is open for discussion. Any
other comments?
So
this information would be identified if not currently available, then through
additional animal studies or other studies, is that your suggestion?
DR.
LI: Well, the only thing I could see
where you'd want to do an animal study would be if you wanted to do some in
vivo resorption rate. But if you're
going to histology on patients, I would propose that would be a better source
rather then get into an animal study.
So I could get it however you could get it. If it's already done, that's great. But if they don't have the information to do these specifications,
they should get it.
CHAIRMAN
CHOTI: Any further discussion on that
condition? Dr. Chang?
DR.
CHANG: I'm presuming that there is a
standard of good manufacturing practices so that any product that has been on
the market has to have some range and consistency. That's what I'm presuming that it is even for this PMA, that
there has been some consistency in the product that's being used for the
clinical studies.
And
so the question to Dr. Li is do you want that tightened up so that they know
specifically what is in this vial that's being injected? Is that what you're --
DR.
LI: Well, what I saw -- and again you
could me if I missed it in the volumes of data that was supplied, was what I
saw was a lot of characteristics of what was used, but no list of what the
product should be. In other words, if
they said for instance the molecular weight was 40 to 60,000 after milling and
in gamma irradiation. Well, if they get
a 30,000 is that acceptable, or if they get a 70,000 is that acceptable? That information is nowhere in there.
In
other words, they told us reasonably well what they're using, they just didn't
provide us any limits of what that window is.
DR.
CHANG: So you want a tighter limit?
DR.
LI: Well, I want limits, period. I didn't see any. Okay.
CHAIRMAN
CHOTI: Any further discussion?
So
this motion number 4 is up for a vote, that is of providing more specifics
regarding product specification.
Those
in favor raise your hand. I think it's
unanimous, is that right? Yes. So for the record it's unanimous to approve
that specification or that condition.
Is
there a motion for an additional condition?
Yes, Dr. Mock?
DR.
MUNK: I'd like to propose that the
Committee consider some wording changes in the labeling.
CHAIRMAN
CHOTI: So a condition regarding
specifications within labeling. Is
there a second? Dr. Fish seconds.
This
is open for discussion. Yes, Dr.
Olding?
DR.
OLDING: Are we going to go through them individually as part of this now?
DR.
FISH: I have some specific ones to
propose.
DR.
OLDING: Okay.
CHAIRMAN
CHOTI: Yes. So the motion is really to define some aspects, specific aspects
regarding labeling.
DR.
FISH: And these are all in the first
two pages of the labeling. The first
under intended use and indications, it currently reads "Intended to
correct shape and contour deficiencies resulting from facial fat loss,
lipoatrophy in people with human immunodeficiency virus." I would propose changing that to facial fat
loss, lipoatrophy caused by human immunodeficiency virus infection or its
treatment, the reason being the possibility that some reimbursement programs
may bulk at the fact that we've got HIV and we've got lipoatrophy but we have
no statement connecting them causally.
CHAIRMAN
CHOTI: Yes, Dr. Olding?
DR.
OLDING: If I could just make a friendly
maybe amendment to that. Because I feel
so strongly about the use in this population, I would say Sculptra is only
intended.
CHAIRMAN
CHOTI: And particularly if that third
condition, that is the restricted use, becomes difficult then I think it makes
sense if we're concerned about it to emphasize it again as strongly as possible
in the labeling, if that's what the feeling is.
DR.
MUNK: I don't know if you want to go to
the other comments?
CHAIRMAN
CHOTI: Yes, why don't you.
DR.
MUNK: Under the warnings, I would like
to see a stronger statement about overcorrection. It currently simply says that it should be avoided, but the
information we heard is that overcorrections may persist for two or more years.
CHAIRMAN
CHOTI: Okay.
DR.
MUNK: On the second page there is a
statement that the safety of Sculptra for use during pregnancy or in infants
and children has not been studied. And
I think there ought to be a parallel statement about populations other than
caucasian adult males. I mean, I don't
know how you would word it exactly.
There has been some study, but insufficient study to reach conclusions
about safety.
CHAIRMAN
CHOTI: We can also specify that that be
highlighted in a black box or emphasized within the label as well.
DR.
MUNK: I'm not making that suggestion.
CHAIRMAN
CHOTI: Okay.
DR.
MUNK: And then the last one I have is
under adverse events, the "nodules" appears several times. And I
would defer to my esteemed colleagues who know more about dermatology than I do
and suggest a change in wording to something that is consistent with
dermatologic practice.
CHAIRMAN
CHOTI: Any other discussion on labeling
recommendations?
DR.
OLDING: I have some other recommendations
also in the warnings?
CHAIRMAN
CHOTI: Dr. Olding?
DR.
OLDING: Should I do that now or--
CHAIRMAN
CHOTI: Yes.
DR.
OLDING: I would say in the warnings,
you know 52 percent of these patient have nodule formation whether it's
palpable or visible, they have nodule formation. So I would like to include that in the warnings. It brings it more to the forefront rather
than just putting in with a whole bunch of other things. And I would suggest that in the warnings we
write "Nodular formation occurs in 52 percent of the patients and extreme
caution must be exercised in the per-orbital and peri-oral areas." Perhaps taking out from the overcorrection
should be avoided change, just removing that peri-orbital and peri-oral area
and moving it up to the separate out.
And
I would also suggest that in the precautions to be consistent with what we're
recommended for the training program that we add to the -- it should be only
used by health care providers with expertise in the correction of valan defects
and after completing the required training program, or something to that
effect, and familiarizing themselves with the product and its complete package
insert.
CHAIRMAN
CHOTI: Since we're going to vote on
these as a group, the recommendations that were brought up, are there any
discussion regarding any specific points that were mentioned, agree or
disagree?
DR.
MILLER: Can I make one more
recommendation? Can I make more?
CHAIRMAN
CHOTI: Yes, please, Dr. Miller.
DR.
MILLER: In the warnings, just again to
emphasize the fact that this is not to be use din non-HIV patients, maybe we
could say something like the performance of this device in immunocompetent
individuals is uncertain and unproven and may be hazardous to your health, or
something like that. Something to
emphasize that this is not to be used in that population because it really has
not been demonstrated satisfactorily that the -- the risk profile has not been
demonstrated satisfactorily.
CHAIRMAN
CHOTI: Not to be used in non-HIV
patients.
DR.
MILLER: And we keep saying it over and
over, I know. I mean, if a person reads
this and sees in over and over again, then I mean every little reenforcement of
that may be one fewer episode where a person gets this who doesn't fit this
criteria.
DR.
OLDING: Yes, Dr. Bartoo?
DR.
BARTOO: I have another recommendation
under the precautions. There's a
section on no studies of interactions with other drugs. Perhaps a statement
that there have been no studies of long term safety or efficacy.
CHAIRMAN
CHOTI: Any other discussion regarding
labeling changes or specifications, recommendations?
So
the fifth condition is that of the recommendations of changes in the labeling
as specified in the transcripts. I'm
not going to go over all of them. This
is as a group of labeling changes, this is now up for a vote.
Those
in favor of these labeling changes, raise your hand. Let the record read that it is unanimous in favor of that
condition.
Any
other motions for additional conditions? It looks like we have a total of five conditions.
Just
to summarize them briefly, the first condition is that of a post-approval study
with various issues that we're concerned about. The second is that of a training program. The third condition is to define restricted
use to HIV patients only with lipodystrophy.
The fourth condition is product specification regarding providing more
information about the specifics of the product. And the fifth condition about labeling recommendations.
So
now this PMA is -- we are to vote on whether approvable. So this has been moved and seconded for the
pre-market approval application for Sculptra from Dermik Laboratories to
recommend approvable with conditions.
Those in favor, raise your hand.
Let
the record show that it's unanimous for approval with conditions.
At
this point, I'd like to just briefly go through and -- why don't we briefly go
through the group and just a summary statement regarding why you voted as you
did. Why don't we start with Dr. Li?
DR. LI:
Well, I have to say I voted for approval, interestingly enough, more
with my heart than my head. I'm moved
by the general need by this specific patient population. I was moved by the
personal presentations of those who have benefitted from the device. And I was also convinced of the efficacy by
the physicians that made the presentations.
But
what we seem to have here from my view on a scientific side is a really large
anecdote. And as I tell my students,
data is not the plural of anecdote.
The
science really just isn't there. It seems to work, but we don't really know
why. And the scary part there is we
just really don't know what the boundaries of this are; you know if you put in
a little too much, if you change your particle size, if this really works
there'll be competitors that will use PGA, PGA-PLA blends and there's basically
no basic understanding for this device although it seems to work in this
patient population that they've studied.
I'm
really bothered by we can't even answer the question is this material dependent
or not. You know, we don't even know
that much about it. So the fundamentals
are really virtually absent in why this works the way it does.
So
this is a vote from my heart and not from my head.
CHAIRMAN
CHOTI: Dr. Olding?
DR.
OLDING: I won't spent a lot
talking. I'll just tell you that I am
not comfortable with the science involved.
I believe that a great deal more work needs to be done by the company on
that science, and I think that, hopefully, the conditions we've placed on the
approval of this product and the limitation to the people who it is intended
for have at least done those things.
And
I would echo the fact that one must vote from one's heart to approve this
today. And I will be happy to see it on the market for the patients for its
intended use.
CHAIRMAN
CHOTI: Dr. Penneys?
DR.
PENNEYS: Well, I certainly with
that. I keep having images of a Trojan
Horse in my mind, but I hope I'm wrong.
In the end, there's real pain and there's real improvement in the real
time, and I think in this case I'll take the real gain and the real time and
hope that we can work out these unknowables going forward.
CHAIRMAN
CHOTI: Dr. Fish?
DR.
FISH: My approval vote is based largely
on the urgency of the need. Clearly
that has been demonstrated by those of you who have taken the time to come
today, and that is much appreciated.
I
think that I, too, am bothered by the really hard scientific data that we
really like when we're going for approval and it puts you in somewhat of an
uncomfortable situation when we're making a recommendation based on somewhat
empiric information. Our basic tenant
is do no harm, and we don't want to be back in five or ten years seeing pictures
and people very, very unhappy with treatment outcomes. And so I think that's
the intent of the conditions.
CHAIRMAN
CHOTI: Dr. Miller?
DR.
MILLER: Yes, I agree with the
sentiments that have been expressed.
And it's really the desire to see something done for these people
suffering with this problem that motivates me to vote for it. But I would so much prefer to have a lot of
these questions resolved before we ever had to vote to release this. And I will be extremely disappointed if in
the future we see that this has been sort of a back door way of getting a
product available whose real intention is for basically to handle the hundreds
of thousands of people who want tissue fillers rather than the thousands of
people who have HIV and lipoatrophy. So
I hope the sponsor will take the conditions very seriously and do all they can
to handle this in a responsible manner.
DR.
OLDING: Dr. Leitch?
DR.
LEITCH: Well, my approval also is
highly based on the desire to help the patients and listen to what they have
told us today, and also the data that was presented by the physicians where the
satisfaction seems to be very high from the patients. And notably, we did not hear from the patients a strong objection
to approval of this product.
I,
like the others on the panel, feel strongly that the manufacturer should take
to heart what we've talked about in terms of what the requirements would have
been in order to approve this for other uses.
We have not been presented any data that would approve it for uses
outside of this population. And I think
we've given some hints and clues about what would be required in order to do
that. So, I hope those recommendations
will be heeded.
CHAIRMAN
CHOTI: Thank you.
Dr.
Chang?
DR.
CHANG: For myself, this is primarily a
compassionate vote. And also with the
expectation of future today and a true earnestness on the part of the sponsor
to provide the information that has been lacking for this presentation.
CHAIRMAN
CHOTI: Dr. Blumenstein?
DR.
BLUMENSTEIN: I think what we've been
given here is a whiff of efficacy data and a whiff of safety data. And my vote is mainly based on the
perception of compassion needed for the patients to which this is directed.
The
rest of my considerations are all based on scaring the sponsor. Without the registration condition, I don't
think I could have voted for this; that is the necessity to somehow or another
indicate that the product is to be used in
HIV patients.
I
also feel that our discussions here have relayed to the sponsor the necessity
for rigor about any future study for cosmetic use and the need to have those
studies really well and to have the data that's missing from here, both product
data, safety data, etcetera.
And
finally, I feel like that what our discussions here have done has given some
lawyers who are paying attention to some bullets. And I hope that everybody's paying attention to that and so that
any offlabel use would be conditional on knowing that those lawyers have some
bullets.
CHAIRMAN
CHOTI: Dr. Newburger?
DR.
NEWBURGER: I'm in accord with my
colleagues. I voted for approval because of the very pressing need for a long
lasting filler for this terribly disfiguring condition, which is not trivial,
it's not simple rejuvenation or filling in wrinkles. But it really relates to the fact that an individual puts to the
public and impacts tremendously sense of self and ability to function in the
world.
It
certainly wasn't a yes vote on the basis of scientific data, which is virtually
absent. We've been asked to suspend our
criteria that we normally use for other cosmetic type fillers. We have made other companies really jump
through hoops.
I'm
kind of surprised that Dermik had this substance for just about two years, and
we don't have any further data in terms of what it does, there hasn't been
anything implanted. This isn't the
company that I know of that has an extraordinary reputation in terms of their
scientific studies. So I hope, along
with my panel members, that this is just a temporary stopgap measure to make
this product available and that the due diligence and rigor with which previous
studies from this company have been conducted, we will be able to read about in
short order.
CHAIRMAN
CHOTI: And comments from our non-voting
but very instrumental members of the panel, Dr. Monk, comments?
DR.
MUNK: I'm just very pleased with the
Committee's decision and I think that the critical needs of patients with HIV
facial lipoatrophy will be served by this decision and this product.
CHAIRMAN
CHOTI: Thank you.
Dr.
Bartoo?
DR.
BARTOO: From an industry representative
point of view, I have to echo the rest of the panel's sentiment that the data
that has been provided here is well below par of what's industry standard in
terms of what kind of data people would present in their PMA. I can only hope that the motivation for
submitting this type of data is to get it approved quickly for this group of
patients who have the urgent need. And
I think that's a good reason to come forward.
But I think it would behoove the sponsor to really do due diligence in
their post-approval studies.
CHAIRMAN
CHOTI: Dr. Doyle?
DR.
DOYLE: I think the Committee has used
the old fashioned benefit and ratio of risk to benefit well today. I think until such time as the patient with
AIDS does not base subtle but certainly real discrimination and that this is a
condition that is just, to me, it looks as clearly as though you had painted on
somebody's forehead the word "AIDS," that is a definite need that we
did do for a compassionate vote, whether the science is there or not. The non-science was compelling to me in this
issue.
CHAIRMAN
CHOTI: Dr. Witten and members of the
FDA, I think the panel has spoken, fortunately unanimously this time. And so I think our message is pretty clear.
Did
that fulfil the requirements you asked of us?
DR.
WITTEN: Yes.
I'd
like to thank the panel for their participation in our process today. Thank you.
CHAIRMAN
CHOTI: Thank you very much.
And
now this meeting is adjourned.
(Whereupon,
at 3:50 p.m. the meeting was adjourned.)