UNITED STATES OF AMERICA FOOD AND DRUG ADMINISTRATION CENTER FOR DEVICES AND RADIOLOGICAL HEALTH MEDICAL DEVICES ADVISORY COMMITTEE GENERAL AND PLASTIC SURGERY DEVICES PANEL + + + + + 64th MEETING + + + + + FRIDAY, NOVEMBER 21, 2003 The panel met at 8:00 a.m. in the Walker/Whetstone Rooms of the Gaithersburg Holiday Inn, Two Montgomery Village Avenue, Gaithersburg, Maryland, DR. PHYLLIS CHANG, Acting Chairperson, presiding. PRESENT: PHYLLIS CHANG, M.D. Acting Chairperson GRACE T. BARTOO, Ph.D., R.A.C. Industry Representative BRENT A. BLUMENSTEIN, Ph.D. Voting Member JOSEPH V. BOYKIN, JR., M.D. Temporary Voting Member ROBERT F. DIEGELMANN, Ph.D. Temporary Voting Member JOHN DOULL, Ph.D., M.D. Temporary Voting Member PRESENT (Continued): LeeLEE DOYLE, Ph.D. Consumer Representative JOHN F. HALSEY, Ph.D. Temporary Voting Member JOSEPH LoCICERO III, M.D. Voting Member MICHAEL J. MILLER, M.D. Voting Member AMY E. NEWBURGER, M.D. Voting Member MICHAEL J. OLDING, M.D. Temporary Voting Member ON BEHALF OF Q-MED: N. FRANKLIN ADKINSON, JR., M.D. BENGT AGERUP, Ph.D. GARY JANSSON, Ph.D. JAMES LEMAN, M.D. Z. PAUL LORENC, M.D., F.A.C.S. KJELL RENSFELDT, M.D. JONAH SCHAKNAI JUR STROBOS, M.D. SUSAN C. TAYLOR FDA REPRESENTATIVES: ROXOLANA HORBOWYJ, M.D. TELBA IRONY, Ph.D. DAVID KRAUSE, Ph.D. STEPHEN RHODES ANTHONY D.WATSON CELIA WITTEN, Ph.D., M.D. I-N-D-E-X AGENDA ITEM PAGE Call to Order 5 Conflict of Interest, Temporary Voting Member 6 Deputization and Opening Remarks David Krause, Ph.D., Executive Secretary Update Since Last Meeting 13 CDR Stephen Rhodes, Branch Chief, Plastic and Reconstructive Surgery Devices Branch Open Public Comments 16 Elizabeth Santoro 16 Dr. N. J. Lowe 20 Applicant Presentation, Q-Med AB, Restylane 27 Jur Strobos, M.D., Council to Medicis 27 Bengt Agerup, CEO, Q-Med AB 27 James Leyden, M.D., Professor of Dermatology, 30 University of Pennsylvania School of Medicine Paul Lorenc, M.D., Assistant Professor of 52 Plastic Surgery, New York University Medical Center Susan C. Taylor, M.D., Director, The Skin of 66 Color Center, St. Luke's-Roosevelt Hospital Center FDA Presentation 127 Introduction and Preclinical 127 Anthony D. Watson Clinical Review 133 Roxolana Horbowyj, M.D. Statistical Review 151 Telba Irony, Ph.D. 151 Panel Deliberations and Address FDA Questions 159 I-N-D-E-X (Continued) AGENDA ITEM (Continued) PAGE Open Public Comments 188 Arnold W. Klein, M.D. 188 Jill Follows 196 Dr. Trevor Born 201 Concluding Panel Deliberations and Vote 214 P-R-O-C-E-E-D-I-N-G-S (7:59 a.m.) CALL TO ORDER EXECUTIVE SECRETARY KRAUSE: All right. Good morning. We are going to be running on a fairly tight schedule today. So I would like to try to get the meeting started as soon as possible. If everybody could please have a seat? Thank you. Good morning, everyone. We're ready to begin this, the 64th meeting of the General and Plastic Surgery Devices Panel. My name is David Krause. I am the Executive Secretary of this panel. I'm also a biologist and a reviewer in the Plastic and Reconstructive Surgery Devices Branch. I would like to remind everyone that you're requested to please sign in on the attendance sheets, which are just outside the door. At that table out there, you can also pick up an agenda, a roster of the panel members, and information regarding today's meeting. The information includes how to find out about future meeting dates through the advisory panel phone line and how to obtain meeting minutes or transcripts. I don't know if everybody knows, but the FDA normally posts the transcript of these meetings within about two or three weeks after the meeting on our Web site. So you can get them there. CONFLICT OF INTEREST, TEMPORARY VOTING MEMBER DEPUTIZATION AND OPENING REMARKS EXECUTIVE SECRETARY KRAUSE: Before turning this meeting over to Dr. Chang, I am required to read two statements into the record. The first statement that I read is the deputization of temporary voting members. And the second is the conflict of interest statement. I am going to read the deputization statement first, "Pursuant to the authority granted under the Medical Devices Advisory Committee charter dated October 27, 1990 and as amended on August the 18th, 1999, I appoint Joseph Boykin, Robert Diegelmann, John Doull, John Halsey, and Michael Olding as voting members of the General and Plastic Surgery Devices Panel for this meeting on November 21, 2003. In addition, I appoint Phyllis Chang, a voting member, to act as temporary chair for the duration of this meeting. "For the record, these individuals are special government employees and consultants to this panel or other panels under the Medical Device Advisory Committee. They have undergone the customary conflict of interest review and have reviewed the material to be considered at this meeting." This memo is signed by Dr. David Feigal, who is the Director, Center for Devices and Radiological Health. The second statement that I read into the record is the conflict of interest statement, "The following announcement addresses conflict of interest issues associated with this meeting and is made a part of the record to preclude even the appearance of an impropriety. To determine if any conflict existed, the agency reviewed the submitted agenda for this meeting and all financial interests reported by the committee participants. "The conflict of interest statutes prohibit special government employees from participating in matters that could affect their or their employers' financial interests. However, the agency has determined that participation of certain members and consultants, the need for whose services outweighs the potential conflict of interest involved, is in the best interest of the government. "We would like to note for the record that the agency took into consideration certain matters regarding Drs. Diegelmann, Halsey, and Miller. Each of these panelists reported current and/or past interest in firms at issue but in matters not related to today's agenda. The agency has determined, therefore, that they may participate fully in today's deliberations. "In the event that the discussion involves any other products or firms not already on the agenda for which an FDA participant has a financial interest, the participants should excuse him or herself from such involvement, and the exclusion will be noted for the record. "With respect to all other participants, we ask in the interest of fairness that all persons making statements or presentations disclose any current or previous financial involvement with any firm whose products they may wish to comment upon." I would also like to remind anyone who has a cell phone to please put that cell phone on some kind of a silent mode so we don't hear phones ringing all day. At this point I would like to turn the meeting over to Dr. Chang. ACTING CHAIRPERSON CHANG: Good morning. My name is Dr. Phyllis Chang, and I am the acting panel chair for this session. I am an associate professor in the Department of Surgery and staff surgeon, plastic surgeon, and hand surgeon in the Department of Surgery and Orthopedic Surgery at the University of Iowa Carver College of Medicine. Today the panel will be making recommendations to the Food and Drug Administration on two pre-market approval applications. The next item of business is to introduce the panel members who are giving of their time to help the FDA in these matters and the staff here at this table. I am going to ask each person to introduce him or herself, stating his or her area of expertise, position, title, institution, and his or her status on the panel, whether voting member, industry or consumer representative, or deputized voting member. I would like to begin with Dr. Witten on my far right. And then let's please go around the table. DR. WITTEN: I'm Dr. Celia Witten with FDA. I'm the division director of the reviewing division for these products. MEMBER LoCICERO: I'm Joseph LoCicero. I'm professor and chair of the Department of Surgery at the University of South Alabama. I'm a thoracic surgeon by training. And I'm a voting member of the panel. MEMBER MILLER: I'm Michael Miller. I'm a professor of plastic surgery at the University of Texas, M. D. Anderson Cancer Center. I do clinically primarily cancer reconstructive surgery. And I am a voting member of the panel. MEMBER NEWBURGER: I'm Amy Newburger. I'm director of Dermatology Consultants of Westchester, which is a private practice in dermatology in Scarsdale, New York. I teach at St. Luke's Roosevelt Hospital Medical Consortium. I am a voting member of the panel. MEMBER DIEGELMANN: I'm Robert Diegelmann. I'm a professor of biochemistry at the Medical College of Virginia, Virginia Commonwealth University in Richmond, Virginia. My specialty is in the area of tissue repair. And I'm a deputized member of the panel. MEMBER BOYKIN: Dr. Joseph Boykin, clinical assistant professor of plastic surgery at the Medical College of Virginia in Richmond and also the medical director of the Wound Healing Center Retreat Hospital. I'm a deputized voting member. And areas of interest are wound healing, reconstructive and cosmetic plastic surgery. MEMBER HALSEY: John Halsey. I'm the owner and director of IBT Reference Lab, a clinical immunology laboratory and a contract research facility in the areas of allergy and immunology. I'm also chair of the Clinical Laboratory Immunology Committee for the American Academy of Allergy, Asthma and Immunology and a member of the Immunology Devices Panel. MEMBER BLUMENSTEIN: I'm Brent Blumenstein. I'm a biostatistician. I had my own company, TriArc Consulting, out of Seattle. And I am a voting member. MEMBER DOULL: I'm John Doull. I'm a clinical toxicologist from the University of Kansas. I'm a deputized member. MEMBER OLDING: Michael Olding. I'm chief of the Division of Plastic Surgery, George Washington University, associate professor at that institution. And I am a deputized voting member. MEMBER DOYLE: I'm LeeLee Doyle. I'm professor emeritus of obstetrics and gynecology. I'm the associate dean for continuing medical education and faculty affairs at the University of Arkansas for Medical Sciences College of Medicine. I am the consumer representative, which is a nonvoting position, on this board. MEMBER BARTOO: Finally, I'm Grace Bartoo. I'm the vice president of clinical and regulatory affairs at a company called Instruments for Science and Medicine, which is a small consulting firm to the biomedical device industry. My expertise is in biomedical engineering and software development. And I'm the industrial representative, which is a nonvoting member. ACTING CHAIRPERSON CHANG: Thank you. I would like to note for the record that the voting members present constitute a quorum, as required by 21 CFR Part 14. Now I would like to introduce Commander Stephen Rhodes, the branch chief of the Plastic and Reconstructive Surgery Devices Branch, who will update the panel since the last meeting. CDR RHODES: Thank you, Dr. Chang. UPDATE SINCE LAST MEETING CDR RHODES: I am the branch chief here at the Plastic and Reconstructive Surgery Devices Branch. My update today will be brief since this panel last met about five weeks ago to discuss a PMA for a silicone gel-filled breast implant, which the FDA is still reviewing the recommendations from the panel for that. Today we are going to be talking about two wrinkle products. In the morning, we will be discussing a product called Restylane from Q-Med and in the afternoon a product called Hylaform from Genzyme Corporation. I want to extend my appreciation to you for your participation. I also want to thank the public speakers, who have chosen to elect to speak in the public sessions and also the two companies who are going to be presenting their safety and effectiveness data in their PMAs. That concludes my update. Thank you very much. ACTING CHAIRPERSON CHANG: Thank you, Commander Rhodes. We will now proceed with the open public hearing session of this meeting. All persons addressing the panel are asked to speak clearly into the microphone as the transcriptionist is dependent on this means of providing an accurate record of this meeting. Both the Food and Drug Administration and the public believe in a transparent process for information gathering and decision-making to ensure such transparency at the open public hearing session of the advisory committee meeting. FDA believes that it is important to understand the context of an individual's presentation. For this reason, the FDA encourages you, the open public hearing speaker, at the beginning of your written or oral statement to advise the committee of any financial relationship that you may have with the sponsor; its product; and, if known, its direct competitors. For example, this financial information may include the sponsor's payment of your travel, lodging, or other expenses in connection with your attendance at the meeting. Likewise, FDA encourages you at the beginning of your statement to advise the committee if you do not have any such financial relationships. If you choose not to address this issue of financial relationships at the beginning of your statement, it will not preclude you from speaking. We will start with those individuals who have notified the FDA of their intent to testify during the open public session. Is Elizabeth Santoro present? Please come to the microphone and make any disclosures that you wish. OPEN PUBLIC COMMENTS MS. SANTORO: Good morning. My name is Elizabeth Santoro. I'm a registered nurse and also have a Master of Public Health with a concentration in health policy. In addition, I'm a health policy fellow at the National Center for Policy Research for Women and Families. This morning I will be reading the testimony of our president, Dr. Diana Zuckerman, who, regretfully, could not be here today. Please note that I am waiving my testimony for her. She has no conflicts of interest. Neither do I. Our center is a think tank that translates research findings into meaningful information for the public. We use that research information to advocate for policies to benefit the health and safety of women, children, and families. It is clear that both women and men alike search for the Fountain of Youth. We know that these products are used widely. And that's why they should be carefully studied. They should be approved if they are safe and effective. Of course, it's difficult to make this statement before the data are presented, but based on what was made available by the FDA yesterday on their Web site, these are our concerns. Our main concern about Restylane is the lack of data for African Americans and Asian Americans. Only two of the patients are African American, and only two are Asian American. Research clearly shows that African Americans are more likely to produce keloids and can respond differently to procedures involving the skin. In addition, African Americans are more likely to develop autoimmune diseases than white women. The company has not studied a reasonable number of African Americans or Asian Americans to approve the product for those populations. Our center has joined with the National Medical Association to express our very strong concerns on this issue to the FDA commissioner. It is a great concern for all of the products of this type, not just the products under review today. The FDA has suggested one solution: post-market studies. We strongly believe it is not appropriate to require studies for minority populations on a post-market basis since the FDA has no authority to enforce these requirements. The company should be required to do the studies before the product is approved. It is also inappropriate to label the product "For whites only." I am sure that I am not the only person in the room who believes that it would be inconsistent with the values of our country to approve products only for white people unless there was a compelling reason; for example, if a product was found to be safe for whites but unsafe for other racial or ethnic groups. Such a label is not an appropriate way around a sponsor's failure to conduct research on people of color. Moreover, if there are no data on people of color, it is likely that the product will be used off label by them anyway. And that could be potentially very dangerous. Research is needed. And it won't take long to do it. And it should be done. Another shortcoming on the research on Restylane is the relatively small sample size. The sample starts with only 138 people. And only 125 are still in the study after 12 months. Since this is a cosmetic procedure that is likely to be used by hundreds of thousands, perhaps millions of people, the product should be tested on a larger sample to determine if there are rare adverse reactions that are serious enough to be considered before approval. Our final concern is a lack of long-term follow-up and a lack of research on women who undergo the procedure multiple times. It is clear from published reports that women who have a good outcome the first or second time they use this product may have serious adverse reactions after the third or later procedure. This needs to be studied before approval since it is clear that their product will be used more than once or twice. We would like to make a final comment about the risks and benefits of this product. According to the company's own data, the product is not necessarily better than the comparison product Zyplast. For that reason, we believe rushing this product to market without gathering the additional data listed above is unwarranted. Thank you. ACTING CHAIRPERSON CHANG: Thank you, Ms. Santoro. And now is Dr. Lowe present? DR. LOWE: Yes. Good morning. Thank you to the FDA for allowing me to present some information. I am clinical professor of dermatology at UCLA, but I also have private practices in London and Santa Monica and also research, clinical research, facilities. I am presenting experience with the Hylaform and Restylane products, particularly since 1996, in my London practice. It's that data that I wish to present this morning. Essentially in Europe, certainly in the U.K., Restylane has become the most widely used hyaluronic acid filler in the United Kingdom. And, as we will shortly see, I think that I will show reasons for that. I wrote a publication published in the Journal of the American Academy of Dermatology that was published in the year 2001 in which we looked at over 700 patients that had received both Hylaform and Restylane. We found that there was an approximate .4 percent incidence of delayed nodular inflammatory reactions in the skin. And we followed up by testing some of those individuals with forearm skin test challenge and finished up by getting positive results in some of those patients. Since the year 2000, here are my slides. Actually, we can go through them a little bit quickly. As I say, I'm a consultant dermatologist and faculty member in London as well as at the University of California in Los Angeles and have practices and clinical research units in both places. ACTING CHAIRPERSON CHANG: Dr. Lowe, would you be willing to share with the panel whether or not the sponsor has supported your travel? DR. LOWE: Yes. This is my slide. And I want to disclose conflicts of interest in two areas. One is my research site in Santa Monica was one of the research sites for the Hylaform product. And that was funded by Genzyme. And I have received educational grants from both Medicis and Q-Med. And Medicis has enabled us to do some recent research studies on our U.K. patients and has allowed me the funding to be here this morning. So I make those disclosures. This was a summary of our Journal of the American Academy of Dermatology report, where we found, as I said, with the old Restylane, which was modified in the year 2000, and with Hylaform, we found an incidence of about .4 percent delayed nodular reactions. In a total of six patients, three of others that were referred to me, we found that four patients actually I was able to elicit positive forearm testing. This is published in that article. Since the year 2000, I have changed almost entirely over to using Restylane products in the United Kingdom for skin-filling scar revision and other deformity-filling for the reason that it is a non-animal hyaluronic acid. And there was considerable improvement in the formulation in the year 2000 with a considerable reduction in protein load. So the actual numbers of patient treatments that we have been able to review in a chart and case review from 2000 to 2003 is 1,537 patients. I acknowledge my coworkers, my dermatology colleague, Dr. Anne Maxwell; my plastic surgical colleague, Mr. David Ross. So we have 1,537 patients that we have been able to review charts and cases of, 1,537 treatments in a total of 558 patients. So, as you can see, many of those patients received, actually, at least three or more injections, some up to five or six injections, some one or two injections. The demographic grouping was preferences. We got far more females than males. And I didn't have the breakdown of racial or ethnic subsets, but significant numbers of these patients were Asian and some black patients as well. Age range was 22 to 28. And with a review of these 1,537 patient treatments, we found with the new formulation of Restylane zero incidence of hypersensitivity reactions. This somewhat is reinforced. This is the old data with the old Restylane and present Hylaform. You can see the old data presented here again. This is the new formulation Restylane, Perlane. And there was a previous manuscript by Friedman, et al., published last year in one of the derm surgery journals that showed an incidence of about one in a thousand hypersensitivity reactions. So the adverse reactions that we saw in the 1,537 patients that we reviewed, 1,537 patient treatments in 558 patients that we reviewed. MEMBER OLDING: Excuse me. I hate to interrupt you, but your slide said one in 5,000, I believe, and you said one in 1,000. DR. LOWE: I apologize. The correction is one in 5,000. Thank you. The adverse events in the group of patients that we have recently looked at is that we find common immediate erythema, which is clinically not of great significance and usually results in a matter of one to two days. ACTING CHAIRPERSON CHANG: Dr. Lowe, could you please summarize? DR. LOWE: I will. This is my last slide. Edema common with Perlane, which is the thicker one, transient lumping, and one technique-dependent vascular occlusion in the forehand. This is the sort of delayed reactions that we see, nodular painful reactions in this instance with Hylaform. My final slide is that the delayed allergy risk with Restylane products is extremely rare. We found no allergy in 1,537 patient patients in 558 patients. Previous reactions observed with the old form of Restylane was less severe than that observed with Hylaform. All the hyaluronic acid reactions observed were less severe than with the Zyderm/Zyplast. And, in conclusion, Restylane, Perlane products are the most frequently used hyaluronic acid fillers in the United Kingdom. Thank you for your attention. And I apologize for the problems with the computer. ACTING CHAIRPERSON CHANG: I would like to thank all of you for taking time of your schedules to testify to this panel. I would like to remind public observers at this meeting that while this portion of the meeting is open to public observation, public attendees may not participate except at the specific request of the panel. We are now ready to begin with the applicant's presentation. APPLICANT PRESENTATION, Q-MED AB, RESTYLANE DR. STROBOS: Hi. My name is Jur Strobos. I'm a physician. I change as a general surgeon. And I am working as a consultant to the pharmaceutical industry and today for Medicis and Q-Med. We are going to try and stick to pretty much the schedule that you have laid out there. For some reason, not all of our speakers got on the agenda. We are going to have Dr. Agerup as the CEO of the company and inventor of the product as well as four physicians to the clinical investigators discussing the product. And I will introduce them as we go through. We did time the talk yesterday, and I think we are going to try and keep it to 45 minutes. I understand that would be about 30 minutes for questions. That said, let me introduce Bengt Agerup, who is the president, CEO, and inventor of the Restylane product. DR. AGERUP: Good morning. It's a pleasure and honor to be here. What we have designed when we designed the Restylane is a product that would reduce immunogenicity. That means it would not be based on foreign proteins or have too much protein contaminants. And they are also, of course, nontoxic. And we would refrain from using animal-origin substances. So, for instance, rooster combs, bovine collagen, et cetera, were not an origin. We also wanted to decrease the esterase and protease-mediated degradation. That always happens in the skin. So we used biotechnology to derive hyaluronic acid, a non-animal source. And we used the purification process that we even increased in efficacy in 1999 that you heard this morning to reduce the protein contaminants. We are now down to less than six parts per million, and we are still working on this subject. We don't have any animal nucleic acids. And we think this is the first or it is the first dermal filler that is not classified as a xenotransplantation product. Hyaluronic acid is completely useless as an implant unless you modify it. We have chosen modification products that are commonly used in household articles and also in glues and other things, other products. We also use this BDDE in ether form of binding that makes it very stable and less sensitive to esterase. We also patented a way to use these BDDE cross-links at very, very low concentrations. So, for instance, it's about one percent of the material used. So that leaves very small amounts of BDDE in the final product. So this is non-animal. Then we call this non-animal stabilized hyaluronic acid. And we call it stabilized because it's not really cross-linked in a way that you would normally find in modified products. I thank you very much for your attention. DR. STROBOS: Now I would like to introduce Dr. James Leyden, who is a professor of dermatology from the University of Pennsylvania. He was one of the investigators in the pivotal study. He is going to present the data from the pivotal study. DR. LEYDEN: Thank you. Good morning. My name is Jim Leyden. I am now professor emeritus, actually, at the University of Pennsylvania. I've been a member of the department since 1967, I guess, had a wide range of interests. About 20 percent of my research interest has been in appearance-related issues. I have been asked by Medicis to present the data from the multi-centered clinical trial, of which I was one of the investigators. As far as my connections with Medicis, I am not a consultant. I don't own any stock. I have participated in some studies several years ago, microbiologic studies. I have also served on advisory panels. Perhaps my major connection is that I am a co-chair of the clinical conference called the Valley of the Sun, which preexists Medicis in how long that meeting has been going on. But because Medicis is in the Valley of the Sun, they have been a major supporter of our annual conference. So, with that introduction, I would like to present to you the results of this randomized, double-blind, multi-centered comparison of the safety and efficacy of Restylane and Zyplast. It was a six-center study. There were plastic surgeons and dermatologists involved. Each center had a treating physician and then a blinded evaluating physician. This is the design of the protocol. As I said, it's multi-centered. It was a patient-controlled kind of study in which each patient received both Restylane and Zyplast. It was randomized by side and blinded to the patient as well as to the evaluating dermatologist. And in the evaluation, a validated wrinkle severity score that we will discuss a little bit in a few minutes was used. Patients were basically recruited and tested with collagen and then randomized as far as which eye got Zyplast and which eye got Restylane. And then there was a period of time when both the patient and the treating physician would decide when optimal correction was achieved and there was the opportunity for so-called touch-up injections to whatever side seemed not to be optimally corrected. Once that was stabilized for two weeks, they were launched into the evaluation phase and seen at two, four, and six months. At this point, patients had the opportunity to enroll in an open label extension, where they would receive Restylane. Most of the patients, in fact, did enroll in that open label portion of the study. These are the demographics. As you can see, as was pointed out in the open session, these were predominantly white women, as you see here. You will hear later about a study that Medicis is going to do, will do in African Americans in America. Contrary to what was said in the open session, there actually is an extensive experience in other populations. There is extensive experience in Asia and in South America. But definitely a study in African Americans is indicated and, as I say, will be done. Now we get into the wrinkle severity rating scale, as you can see here, is a one to five, with one being basically the ideal situation with no visible nasolabial fold or wrinkling, ranging up to a very severe form, which even after stretching the skin, you still had roughly a two to four-millimeter visible groove. This scale was developed in cooperation with the FDA; validated; -- and we will discuss that in a second -- and, in fact, has been submitted for publication. Just to give you some ideas of what these scales look like, here on the one side, you can see sort of a mild grade two. Here is another individual and another. These are grade scores two, a little more intense here with three, another three there, another three, and then more severe forms here. You can see that even when you stretch the skin back, there is still a prominent groove in the nasolabial area and another four and another. Now, before the study began, there was a validation study. There were five investigators who looked in 2 sessions separated by I believe a week, looked at 30 photographs of individuals ranging with different severity of nasolabial grooving. We have displayed it here this way, and we take a second to go through this because the same kind of chart will appear when we look at the six-month primary efficacy data. If you look here, you see the session two with grades one through five and session one with grades one through five. And if you go down this diagonal, sort of light green, those are the times when the scores were identical. And you can see that for the left and the right, there was a high degree of concordance, in the range of 70 percent. And here is the kappa ratio, kappa coefficient. The yellow represents where there was discordance. And you can see that basically all of the scores were either equal or within one grade of each other. There was no instance of a wider discrepancy. MEMBER LoCICERO: Excuse me. Could you define who the observers are? DR. LEYDEN: They were five of the investigators in the study. MEMBER LoCICERO: Were they blinded to who these patients were? DR. LEYDEN: These weren't patients. These were photographs. This was before the studies. They were looking at photographs similar to the kinds of photographs I showed you initially. So they didn't know who they were if that's what you're getting at. Now, here is the primary efficacy analysis using the same kind of chart. This is the comparative change in wrinkle severity score at the six-month period in the so-called intent-to-treat population. That means everybody who got launched. Those who were lost to follow-up were counted basically as no change from baseline, which weighs against any effect for either treatment. So we have the change in severity rating scale. A plus three would mean that a patient went, for example, from a four to a one. Two would be, say, from a three to a one or a four to a two. And this is for Restylane. And this would be for Zyplast. Now, again, if you look down the diagonal in this sort of grayish zone, that's when there was equivalent grade given on both sides. Anything above this line, Restylane, had a better score that Zyplast. And anything on the lower end of this diagonal, Zyplast, had a better score, rating score, than Restylane. I think you can see a lot more numbers up here than there are here. And down here we have summarized that, the Restylane side, with one grade or more improvement compared to the Zyplast side. There were approximately whatever that is, 57 percent. And equivalent grades were given in approximately a third and then nine and a half percent on the Zyplast side. There was a better score, a higher score, than was seen on the Restylane side. These differences were statistically significant by a variety of analysis, as listed here. Now, in the information that was submitted to the panel that I saw and in some of the slides from the FDA that I saw, there are a few issues that I would like to bring up and discuss. One of them is that the wrinkle severity score may lack strength at less than one plus change and that the scoring system was not revalidated, that the McNemar analysis may disregard patients with equivalent results and tends to focus on those results that are discrepant from equivalency that there wasn't a longitudinal analysis performed, that there is no evidence of effect beyond six months, and that incomplete masking raises a possibility of unmasking and bias. So let's address those issues. Actually, if you look at the data between the treating physician and the evaluating physician as far as grading, there is a very high degree of concordance and correlation and grades given that exceeds what was seen in the initial validation event. I think that reflects the fact that this is with live patients and you can actually stretch the skin and you can get a better judgment of what is left after stretching the skin; whereas, in the initial validation, they were looking at photographs. Now, as I understand it, the McNemar analysis does actually account for non-discrepant cells in the denominator. The way that type of analysis is done in the case of Restylane, there are 78 out of 137 that were superior and in the case of Zyplast, 13 out of 137. So it does take into consideration the individuals in which there was, in fact, no difference. In terms of the superiority, which obviously is an important issue that you as a panel have been asked to address as to whether or not the data shows superiority of Restylane over Zyplast, there are several things listed here. And then we will go through an individual slide for each of them. If you look at the responder rate of patients with one-plus or even a more conservative analysis of a two-plus improvement at six months after that initial injection, Restylane is superior statistically. The question has been asked of you if at the end of 6 months you take all patients into consideration and look at the difference between the mean of those 2 groups, the difference is .56. And the question is, is that mean difference significant, particularly in consideration of the question that we just discussed about the strength of the scale in terms of less than one grade? Using two types of analysis, both parametric and non-parametric, Restylane was superior statistically to Zyplast. There was a longitudinal assessment done. And it also showed Restylane superior to Zyplast. Then I think importantly, very importantly, is that patient evaluation also gave almost the same numbers as the evaluating dermatologist. Then let's just look at those in a little detail. Here we're looking at the responder rate of those with a one-plus or a two-plus improvement still present at six months. And you can see that for the one-plus, we have a 70 percent for Restylane versus 32 percent for Zyplast and the much more conservative, more significant clinical response of two-plus improvement still present. Again, there is more than a three time improvement for Restylane compared to Zyplast. And both of these are clearly statistically different. If you look at the means, as I said, that mean difference at the end of 6 months was .56. Here you can see for anybody who is interested the confidence intervals. But the important point is that with both parametric paired t-tests and non-parametric signed rank tests, these means are significantly different statistically. Here is the longitudinal analysis over two, four, and six months. You can see as early as two months. It's not easily seen here, but there are three crosses there, indicating a .001 significant difference at this point, out here and here. I would absolutely agree with the reviewer that after six months, there is just not enough information to say anything. So I think up to six months, there's a lot of information that says that Restylane is superior to Zyplast, but after six months, I would agree there is not enough data. Most of these people basically at the end of six months said, "Yes, I would like the injection on both sides." They got the injection, and they said, "Aloha." And that was it. They really didn't return. There was a very poor follow-up. Here is the patient assessment data using two things, the relative improvement and wrinkle, as well as the global improvement. And you can see that here Restylane is superior to Zyplast, both of them in the range of 50 to 55 percent and equivalency here and much lower rate for Zyplast. So the patients agreed that they got greater improvement with Restylane than with Zyplast. I think that's important. Let's get into this issue of masking. Unmasking, of course, could serve as a signal of possible unblinding. The evaluators who were involved in this study tested in writing apparently that they basically were guessing. They had no idea. They were just guessing. I don't think there's any reason to impute bias. These people have no financial reasons or other reasons to be biased one way or the other towards Restylane or Zyplast. I think an important point in this that is different than what I have seen at least in one or two of the slides from the FDA for your afternoon session, is that, contrary to the study that you're going to be discussing this afternoon, evaluators were required to make a forced choice. They did not have the opportunity to say, "I don't know. I really don't know." They had to make a choice. Incidentally, if you remove the incompletely masked sites at different points, they vary. It's not the same sites that are always "potentially unmasked." If you do that and do an analysis again, you get the same results. So take that into consideration. Now let's get into the adverse reactions. First we'll talk about serious adverse reactions and then briefly all the emergent events. We will obviously concentrate mostly on the local events, particularly the persistent erythema and whether or not allergic or immunologically driven hypersensitivity reactions took place. There really were only two serious adverse events. There was a patient who had a laminectomy, another patient who got a pacemaker installed six months after treatment. It's fairly clear that these are unrelated. Here is the last of all the things that come out in the usual studies. The way they're coded, there are basically 142 that were for collagen and Restylane that were judged to be related to the treatment. So we'll be discussing them. They were captured in two ways. There is a patient diary during the first 14 days following that initial injection and launched into the evaluation period in which patients were encouraged to write down anything and everything and to try as best they could to make a judgment as to whether they thought it was mild, moderate, or severe. Then, of course, there's the case report form, where the injecting physician captures information and reports that historical information from the patient to capture the entire event and follow it to its completion. That, as we will be discussing, is primarily this persistent erythema issue. So in terms of severe reactions, basically in the case report form, there were four. And they were one patient who reported severe events of redness and swelling on two different days, who then got followed by the treating investigator until that event was over. This is a photograph from that patient. This photograph was taken on 4-30. You can see that there are about ten days after 4-20 when it was judged to be severe. This is the Zyplast side. We didn't show you the Restylane side because you can't see anything in it at 4-30. So this shows you how this patient looked ten days after she personally judged what she saw in terms of redness and swelling to be severe. I just show that to show you that that was resolved fairly quickly and appears to be one of those typical kinds of things that all of us who have injected patients over the years with collagen know that some people who get erythema, just persistent. It's very interesting. And this brings up that subject of this persistent erythema. Now, here we have listed the sites, all six sites. These are the number of patients who had persistent erythema on the Restylane site alone, the Zyplast site alone, or both. You can see that there were more with Zyplast in terms of persistent erythema beyond that 14-day or 2-week period following the initial injection than there was with Restylane, where there were 6. And there was persistent erythema in both, which I think speaks to this persistent erythema as probably more patient-driven than what was injected. There are people who get this persistent erythema. I have some ideas of who they are and why they are, but perhaps that's for another day. Who knows? I may be even right. This is a busy slide, but I think it is an interesting slide. It portrays all of the persistent erythemas. The reds are Zyplast. The sort of green/yellow is Restylane. I think, first of all, you can see there are more reds. The longest ones are not the lasting ones, turn out to be Zyplast. You can see for the most part when it happens, it is somewhere in the two to three-month period for most. But then there are these other ones that just last. I am going to show you some photographs so you get a feeling of the quality of these reactions. First we'll look at this patient at that time point. Then we'll look at this patient at three time points and this patient at three time points with the lights up. This one I guess is a little hard to see, but you can see this is a two-month period of this sort of relatively mild and typical of these persistent erythema reactions. Here is a patient who looks like she could use the help of some members on this panel. In addition to being injected here, she could certainly use some help down here. Here you can see this reaction, persistent for a relatively long period of time, several months you can see here is being judged as moderate. And then at this point, it's mild. By this point, it's pretty much gone. Here's another one that lasted two months. You can see at this time point it's being judged as moderate and then mild and gradually goes. So I think they are fairly representative of the quality of this persistent erythema that was seen in these patients, with both, more with Zyplast than with Restylane but clearly with both. Now, one of the questions that has been raised for your consideration is that there is a significantly greater incidence of events in the patient diary, moderate to severe, mostly moderate, particularly for bruising, erythema, and swelling in the first 14 days. I think that's probably true. I think that is the experience with the European studies and others in the literature that there is a little more acute reaction in the skin following injection of Restylane than with collagen. But if you look at that data, you can see that within five to seven days, it's over. These are events that are short-lived, not serious. And what persists is this persistent erythema. So personally I think -- and I have discussed it with Nick Lowe, who has a lot more experience because he is bi-continental and has a great experience in London. You treat someone who has had collagen. You tell them, "You may experience a little more bruising, in particular." Collagen I think helps to minimize micro hemorrhaging into the skin. "You may experience a little more bruising. This is a gel. It may seem to you like it's a little swollen for the first few days, but do not be alarmed. This is not a sign of something going wrong." So I think it is probably true that there was more of these minor acute reactions in the first few days but not of any clinical significance. Now let's talk about allergic or hypersensitivity reactions. There were no immune-driven allergic hypersensitivity reactions, no antibody urticarial-type reactions or t-cell delayed hypersensitivity reactions. In this protocol, investigators had the discretion as to decide as to whether or not they thought an allergic hypersensitivity reaction was occurring. Dr. Lowe showed you a picture of the way allergic reactions look. I will show you one, too. They are very, very different than this flat persistent erythema. They are qualitatively very easily distinguishable as well as allergic reactions invariably have significant itching or pruritus associated with them. So most of what was seen was, as I said, this persistent erythema. And it was often bilateral. I think very, very important in trying to sort out whether or not there could have been a subtle allergic reaction that wasn't so obvious in that persistent erythema is that all but one of these patients chose at the end of the treatment, of the evaluation period to be reinjected. They were reinjected bilaterally. Now, when you have an allergic immune-driven reaction with subsequent reexposure, the reaction is reproducible and often more intense. And nothing happened with these individuals to suggest, even remotely, that there was an allergic reaction on reinjection. For that reason, I concluded that there are no immune-driven allergic reactions in this study. You will hear more on this subject subsequently. This is a typical allergic reaction. As in the FDA, one of the FDA slides, it's qualitatively indurated, edematous, itchy, lumpy. It's very, very different. And this is similar to the reaction that Nick lowe showed, where he had that patient with the lumpy, indurated, erythematous, edematous reaction around the mouth for injection of these vertical lines that women tend to get. So this qualitatively is very, very fundamentally different than these persistent flat erythema, non-immunologic events. So, in summary, as far as the adverse events go, these were usually seen with Restylane and with Zyplast. For the most part, they were mild and short-lived with the exception of that persistent erythema that we discussed in detail. No immunologic hypersensitivity allergic events were seen. Actually, the persistent erythema was seen with both agents and was seen to a greater degree than with Zyplast. And the type of thing that those of us who have experienced with injecting collagen have come to realize is something happens. When it happens, you reassure the patient. You say, "You look terrific. Keep using the makeup. It will go away." And it does go away. So, in summary, I think it's fairly clear to me that from these data, Restylane is superior to Zyplast at the six-month period. It's also superior at the two-month and four-month period. This is shown both statistically. It's shown in terms of responder rates, in terms of longitudinal assessment, and by patient evaluation and was seen across centers. No immunologic hypersensitivity, allergic reactions were seen. And skin testing seems to be an irrelevant issue in terms of this particular agent. The local adverse events were overwhelmingly self-limited with the exception of those patients with persistent erythema. And there were no serious adverse events. And I think that concludes my presentation. I will now introduce another one, the investigator site 5 plastic surgeon of New York University, Dr. Paul Lorenc. DR. LORENC: Thank you. Good morning. First I would like to thank the panel for allowing me to make this presentation to you this morning. I am Paul Lorenc. I am an assistant professor of plastic and reconstructive surgery at New York University Medical School. I am also in private practice in New York, in solo practice for the last 15 years. I was one of the clinical investigators in the pivotal study, but I also have an extensive clinical experience in Restylane injection in my other practice in beautiful Montego Bay. I do have an extensive experience in injections with patients from Montego Bay, of course. I would like to present to you the study, a clinical study. We referred to it as the Olenius study made in Sweden in 1995 to 1996, where it was a single arm, open label study of 112 patients. The eligibility of this study was patients that had wrinkles or folds that were not deeper than four millimeters and suitable for injection. A hundred and one patients were followed for 12 and 26 weeks in follow-up. No skin test was performed on these patients. The whole cohort was naive to Restylane injection. The protein levels in the Restylane preparation at that time was 16 times higher than the reformulated Restylane, which was involved in the study that was discussed just before. So please keep that in mind. This is just the efficacy report, both efficacy by the treating physician in four centers and the patients. And you can see that it starts off very close to 100 percent, the initial treatment, and then it goes into the 60 percent range, a little bit higher for the perception by the physician versus the patient. As far as the adverse events, the unrelated ones were perceived to be unrelated. I'll summarize. As you can see, they include tics, telangiectasia, strings, and acne formation. The numbers are on your right. They range from 2.7 percent to 0.9 percent. The adverse events as assessed as possibly being related to the injection procedure included red spots, dark spots, and bumps. Total number of injections were 285 and the percentage as far as listed 5.4, 1.8, and 1.8 percent. The results of the study showed that in eight percent of the injected sites experience adverse events with less than one week's duration. This was mainly, as discussed before, redness and swelling. there was no hypersensitivity reactions that were observed, and no adverse events were assessed as device-related. This is just a summary slide that looked at the adverse events at 12 and 26 weeks. And it was for a total of 16 percent or 16 out of 102. The ones that were deemed related were 11 out of 101. And, again, they include the minor redness and swelling. As far as the acute events that were noted in less than 14 days after the injection included 51 patients from 112. And they included redness, swelling, hematoma, pain, and darker pigmentation, for a total number of patients of 51. In conclusion, based on the Olenius study, reactions were minimal, even with higher protein level. That was later on reformulated. And no skin testing was involved. The product was very well-tolerated. And the efficacy supports the pivotal study, in which I was involved. Thank you very much. DR. STROBOS: The next presentation I'm going to do is fairly short. We just wanted to remind the panel that the product was originally introduced in Europe in 1996 and it's now marketed worldwide, including Canada and Mexico. There's no requirement for skin testing in any of these countries. We did report to the FDA the spontaneous adverse events that have been reported. I think many of you are familiar with spontaneous adverse events reporting. Basically the company receives calls from health practitioners, reporting events, and those events are typically a little bit more unusual, so adverse events reporting that is frequently sort of a signal as to the occurrence of some unexpected event that may occur in a low percentage of patients. This slide is a little bit difficult to see from here, at least for me. What we have done here is basically provide a duplicate of a listing that you have probably already seen in the materials provided. These are the reports for 1999, 2000, 2001, and 2002. Now, these are coded according to an international disease classification. And you can see on this slide here these are injection site reactions. And this would be hypersensitivity reactions. We have also provided a little column here just to provide a little bit of context. What this represents is the number of syringes that have been sold. To a certain extent discounted by the fact that, as you noted from Dr. Lowe's presentation and others, there are multiple injections per patient. So we have discounted the number of syringes sold, estimating that there may be somewhere between 1.7 and 2 syringes used per patient. So these provide those numbers. And you can see that there is sort of a gradually increasing usage. Nineteen ninety-nine was the year in which there was a formulation change. I think you can see in terms of the hypersensitivity reactions, even though there is an increasing usage, there is actually a decreasing incidence of reported hypersensitivity reactions. So you can't read too much into that because, of course, these are spontaneous reports. However, we did do an analysis again using the denominator of adjusting for increasing volume of use. And I think you can see that there is a fairly striking fall in the reported hypersensitivity reactions, which you just saw on the table and represented here graphically, no particular reason for this fall. And, of course, it has continued at the same level for those years. So I think it's reasonable to suggest that the formulation change did, in fact, reduce the incidence of hypersensitivity reactions. What I have done here is a bit of a busy slide, but I thought it would be important for you to see. What we have done is taken the entire 27 reports of hypersensitivity reports. And this, again, is in your panel package. In one of the later sections, we gave a volume listing of all of the reports that were received. And these were all ones that were coded as hypersensitivity. Typically these occur at some delay after the initial injection. They are coded largely because they are reporting erythema and swelling. There are obviously some reactions here. The investigator may also have thought that the reaction was an infection because of the expression of pus, so forth. If you go back to that slide, the previous two slides, infections are reported as well in this database. That said, I think the incidence of the reports, especially the hypersensitivity and inflammatory reaction, appear to decrease following decrease in the protein level, 1999. There are delayed, rare delayed, erythema and swelling reactions. They tend to be self-limited, tend to be treated with topical steroids, sometimes oral steroids. However, it's not been proven that these reactions are immunologically mediated. We just thought that would be a thorough way of making sure that you're aware of the fact that there is international experience and there is a database to look at these reactions. That said, we had asked Dr. Franklin Adkinson, who is a professor of allergy and immunology at Johns Hopkins, to basically review the entire world of literature as well as our database on allergy and immunology and briefly render his opinion on the likelihood of an immunologic mediation of any of these. DR. ADKINSON: Good morning. My name is Franklin Adkinson. I am a professor of allergy and immunology at Johns Hopkins, just up the road. I have enjoyed a 30-year academic career at that institution, where I have taken a longstanding interest in immunologic and idiosyncratic reactions to drugs, both marketed and in development. I was pleased to have been asked by the sponsor a number of months ago to take a comprehensive and independent look at their own safety database and what may have been published in the literature with regard to the possibility that high molecular weight hyaluronates can or do induce hypersensitivity reactions. I have done so. What I have looked at is the entire safety data set that has been reviewed for you this morning from the two clinical trials and the spontaneously reported adverse reactions. I have also reviewed the literature, both with regard to facially injectable hyaluronics but also with regard to other high molecular weight forms that are used for intra-articular injections, for example, looking for evidence of immunogenicity and demonstrably allergic reactions and at any published reports in the literature that might suggest evidence for immune responses to these materials. I would like to just review with you some observations I made during that review and the conclusions that I have come to. The first observation I think is important is that all of the reactions have been labeled by various investigators and reports is hypersensitivity were local at the injection site only. This would be very unexpected were true immunological hypersensitivity being manifest. Almost all of them required days or weeks to be manifested and included, as you have heard, erythema, red spots, local swelling, pain, and tenderness, some of which has an inflammatory component but none of which are accompanied by the hallmarks of true allergic disease. The pattern, the temporal pattern, under which these reactions emerged, is also not suggestive of any particular form of immunopathology. And high variability among the patterns suggests that something else is going on that must be a function of either the host or the technical properties of the administration of the agent. All the reactions that were observed in the clinical trials resolved without treatment. The most unexpected result if you were dealing with true hypersensitivity was immunologically mediated. And almost all of the local reactions occurred at some time but not at all injection sites. That is, I was impressed that over half of the reactions occurred at one but not at other sites injected with the same material, again, a most unexpected if one were dealing with immune-mediated or driven reaction. Finally, when patients were re-treated after a seminal event that was labeled as hypersensitivity and were observed thereafter, if anything, there are fewer reports, spontaneous reports, of adverse events following re-treatment after an initial reaction that is labeled as hypersensitivity, rather than more, as we would expect. Some of this may be due to reduced surveillance in an open follow-up, but the fact that there are not more or more severe reactions I think supports my own conclusion in reviewing all of these features of the reactions that an immunological basis for them is most unlikely. I also looked at case reports in the literature that examine some of these nodular, late appearing reactions. One involved an excisional biopsy, which showed a granulomatous reaction with a mild inflammatory infiltrate. This had all of the features of a foreign body granulomatous reaction, rather than one that had an immune pathogenesis, and suggests the possibility that failure of the material to resorb entirely in certain susceptible individuals may lead to this type of granulomatous inflammation, which is again entirely local and not likely to be a systemic problem. Almost all of the patients, as I mentioned, who were repeatedly challenged after an incident labeled as hypersensitivity, had no further problems with the second injection. Those who did reported a second episode. It was usually not like the first. It was temporally at a time point very difficult to explain by any known immune mechanism. There is one case series in the literature accompanied by reported lymphocyte stimulation studies and ELISA measurements done in a reputable laboratory in Paris. However, looking at the technical description of these assays in the paper as it's reported, I was unable to come to any firm conclusion about the validity of these studies. There was no dose-response curve demonstrated with the lymphocyte transformation studies. No controls were included in the studies. And the highest titer of IgG antibody, if I interpreted the paper correctly, was observed in a patient who was a non-treated control, raising serious questions about the specificity of the assays. Now, when this report occurred, the sponsor, I think quite commendably, attempted to pursue this and asked Dr. Michel, who published this series, to make available these patients for additional studies. Two of his most sensitive patients were again restudied at the same Paris laboratory that did the original studies in lymphocyte transformation. And ELISA studies were repeated. This time they were entirely negative. So not only were these poorly documented to begin with, but they appear not to be reproducible. To my knowledge, this is the only reported immune-specific activity to these products that's available in the literature. So, in conclusion, I find no convincing evidence that the high molecular weight, hyaluronic products are immunogenic. There is the occasional granulomatous reaction, which appears to resemble a foreign body reaction, which appears to be random and idiosyncratic and not reproducible. The common reactions that we have heard about today, including the redness and erythema, all seem transient. And they're exclusively local and in my judgment do not suggest the participation of hypersensitivity mechanisms. Thank you. DR. STROBOS: Finally, the company has proposed a phase IV study in the African Americans. I would like to introduce Dr. Taylor from Columbia University to describe that. DR. TAYLOR: Good morning. My name is Dr. Susan Taylor. I am the director of the Skin of Color Center at St. Luke's-Roosevelt Hospital Center in New York and assistant clinical professor of dermatology at Columbia. I will discuss with you a planned phase IV study of Restylane therapy in African Americans. Dermal fillers have been used successfully in patients with skin of color, including African Americans. Restylane has been used extensively in South America as well as Asia and has not been associated with a different safety profile. Clearly safety profiles for African Americans may be different. Abnormal healing responses and pigmentary responses are theoretical adverse clinical outcomes in this subpopulation of patients. In specific post-inflammatory pigmentary changes, either post-inflammatory hyperpigmentation or hypopigmentation is a theoretical adverse clinical outcome. Keloidal scar formation is another theoretical adverse clinical outcome. And we do know that in African Americans, in particular, there is a higher incidence of keloidal scar formation. We plan a phase IV multi-center observational safety study of Restylane treatment in African Americans. Eligibility requirements include self-identified African Americans. The age range is between 35 and 75. Patients will have Fitzpatrick skin types V or VI. We propose ten sites, which will be selected based upon prior demographics. Sample size will include 100 patients as our target. The enrollment, however, will close six months after the first patient is enrolled to ensure FDA reporting within one year. Our endpoints include keloidal scar formation, which will be examined at weeks 12 and 24 as well as pigmentation changes, which will be examined at weeks 2 and 6. We feel that a phase IV study is indeed an appropriate study to observe possible safety issues in this subpopulation. Thank you very much. DR. STROBOS: That pretty much concludes our presentation. We do have a few just summary slides. If I could have Dr. Leyden and Dr. Gary Jansson perhaps sit up here because I know you probably will have some questions to ask? And then I can just briefly review my summary slides. We believe in terms of the clinical efficacy that the study satisfied the mutually agreed predefined criteria for establishing superiority. It's my personal view -- you may differ, but it's my personal view as a physician that a superiority or a statement about superiority is appropriate and that not all patients have to do better. The principles underlying superiority I think are that more than half should do better and most of the rest should do the same. That's my view. You may differ, but we do have a superiority statement in the proposed labeling, which I am going to show on the last slide. I believe a question has been directed to you about that. In terms of clinical safety, overall clinical safety, we think there is a low rate of clinically significant adverse events from the three data sources that have been put into the PMA, the pivotal study, the Olenius study, the spontaneous reports in the medical literature. We think most of the adverse events are self-limited, last less than two weeks after injection. There are, as has been noted, rare serious dermal sequelae, but those are almost uniformly reported on in the medical literature, which obviously has a selection bias in terms of reporting. We have proposed as the indication for the product that Restylane is indicated for the correction of moderate to severe facial wrinkles and folds, such as nasolabial folds. We believe that this is principally supported by the pivotal study. We do nee