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                   65TH MEETING


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                  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.




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


   Ph.D., M.B.A., Temporary Voting Member

DAVID KRAUSE, Ph.D., Executive Secretary



CELIA WITTEN, Ph.D., Division Director
















                    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



      Introduction ........................... 133

      Herbert P. Lerner, M.D.



      David B. Berkowitz, Ph.D., VMD.......... 134



      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




                                       (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.)