DEPARTMENT OF HEALTH AND HUMAN SERVICES FOOD AND DRUG ADMINISTRATION CENTER FOR DEVICES AND RADIOLOGICAL HEALTH

In 2002, the FDA classified silicone sheeting for scar management as class I, the least restrictive category for non-prescription medical devices, confiming safety and effectiveness for normal usage. Devices in this category include tongue depressors, bedpans and elastic bandages.

Sec. 878.4025 Silicone sheeting.
(a) Identification. Silicone sheeting is intended for use in the management of closed hyperproliferative (hypertrophic and keloid) scars.
(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in Sec. 878.9. Dated: July 28, 2004. Linda S. Kahan, Deputy Director, Center for Devices and Radiological Health. [FR Doc. 04-18074 Filed 8-6-04; 8:45 am]
BILLING CODE 4160-01-S Class I: General Controls Class I devices present minimal potential for harm to the user and are often simpler in design than Class II or Class III devices. These devices are subject only to general controls. General controls cover such issues as manufacturer registration with the FDA, good manufacturing techniques, proper branding and labelling, notification of the FDA before marketing the device, and general reporting procedures.[2]
(Most Class I devices are exempt from the good manufacturing practices and/or the FDA notification regulations.)[2] These controls are deemed sufficient to provide reasonable assurance of the safety and effectiveness of the device; or the device is not life-supporting or life-sustaining and does not present a reasonable source of injury through normal usage. Devices in this category include tongue depressors, bedpans, elastic bandages, most hand-held dental instruments, examination gloves, and hand-held surgical instruments and other similar types of common equipment.
Depending on the "stated/purported use" of a device, it may be necessary to obtain a Premarket Approval or 510K for the device, which is otherwise classifiable as a Class 1 device. Such devices are referred to as "reserved devices". The electrically powered arthroscope (which is really an endoscope powered electrically) is a case in point. While endoscopes are Class 1 devices, the electrically powered arthroscopes need a pre-market notification (510K) although the manual arthroscopes do not. Pre-market notified devices are marketed as "at least as safe and effective, that is, substantially equivalent, to a legally marketed device."

GENERAL AND PLASTIC SURGERY DEVICES PANEL OF THE MEDICAL DEVICES ADVISORY COMMITTEE OPEN SESSION 60th Meeting

This transcript has not been edited and FDA makes no representation regarding its accuracy

Monday, July 8, 2002 1:20 p.m. Gaithersburg Holiday Inn
Two Montgomery Village Avenue
Gaithersburg, Maryland

PARTICIPANTS Thomas V. Whalen, M.D., Chairman David Krause, Ph.D., Executive Secretary VOTING MEMBERS: Phyllis Chang, M.D. Michael A. Choti, M.D. David L. DeMets , Ph.D. Robert L. McCauley, M.D. Michael J. Miller, M.D. TEMPORARY VOTING MEMBERS: Nancy A. Dubler, LLB Amy E. Newburger, M.D. CONSUMER REPRESENTATIVE: LeeLee Doyle, Ph.D. INDUSTRY REPRESENTATIVE: Debera M. Brown

C O N T E N T S
Conflict of Interest Statement, David Krause, Ph.D.
Introductions
Panel Update, Mr. Anthony Watson
Classification of Silicon Sheeting for Scar Management: Industry Presentation: Mr. Mark E. Dillon, Bio Med Sciences
Mr. Tom Fallon, ReJuveness Pharmaceuticals  

FDA Presentation, Sam Arepalli, Ph.D.
Panel Discussion
Classification Questionnaire and Vote
Reclassification of Absorbable Hemostatic Agents and Dressings:

Industry Presentation: John D. Paulson, Ph.D., Johnson & Johnson 
Ms. Ronnemoes Bobak, Ferrosan A/S
Ms. Judith E. O'Grady, Integra LifeSciences
FDA Presentation, David Krause, Ph.D.

P R O C E E D I N G S Call to Order and Conflict of Interest

DR. KRAUSE: I think we have reached critical mass so we can start the open session of the panel meeting. Good afternoon, everyone. We are ready to begin the 60th meeting of the General and Plastic Surgery Devices Panel. I am David Krause and I am the executive secretary of this panel and also a reviewer in the Plastic and Reconstructive Surgery Devices Branch, in the Division of General and Restorative and Neurological Devices. I would like to remind everyone that you are requested to please sign in on the attendance sheets, which are available at the tables just outside the door. You may also pick up an agenda, panel meeting roster and information about today's meeting at those tables. 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. This and other panel meeting information, including panel meeting summaries and transcripts, are now also available on the worldwide web. Advisory panel meeting activities are available by clicking on the CDRH home page from the FDA website, which is www.FDA.gov. By clicking on premarket issues and then advisory committees, the summaries, transcripts and other advisory committee material section may be accessed. You can then access the CDRH advisory committee database. Before turning this meeting over to our Chairman, Dr. Whalen, I am required to read two statements into the record. First I will read the conflict of interest statement into the record: The following announcement addresses conflict of interest issues associated with this meeting, and is made part of the record to preclude even the appearance of an impropriety. To determine if any conflict of interest existed, the agency reviewed the submitted agenda 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.

Therefore, waivers have been granted for Drs. Michael Choti and Michael Miller for their financial interests in and firms at issue that could potentially be affected by the panel's recommendations. The waivers allow these individuals to participate fully in today's deliberations. Copies of these waivers may be obtained from the agency's Freedom of Information Office, Room 12A-15 of the Parklawn Building. We would like to note for the record that the agency took into consideration certain matters regarding Drs. Choti and McCauley. These panelists reported current interests in firms at issue but in matters that are not related to today's agenda. The agency has determined, therefore, that they may participate fully in all discussions. 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. Thank you. The second statement I am going to read into the record is the temporary voting memo.

This is a memo that is signed by Dr. Feigal who is the Director of the Center for Devices and Radiological Health: Pursuant to the authority granted under the Medical Devices Advisory Committee Charter, dated October 27, 1990 and as amended August 18, 1999, I appoint Nancy Dubler and Amy Newburger as voting members of the General and Plastic Surgery Devices Panel for this meeting, on July 8 and July 9, 2002. For the record, these individuals are special government employees and consultants to this panel or other panels under the Medical Devices Advisory Committee. They have undergone the customary conflict of interest review, and have reviewed the material to be considered at this meeting. At this time, I would like to turn the meeting over to our Chairman, Dr. Tom Whalen.

DR. WHALEN: Thank you, Dr. Krause. Good afternoon. My name is Dr. Thomas V. Whalen. I am the chairperson of the General and Plastic Surgery Devices Panel. Today the panel will be making recommendations to the Food and Drug Administration on the classification of silicone elastomer for scar management devices and on the proposed reclassification of absorbable hemostatic agents and dressings from Class III to Class II. I would like to note for the record that voting members present constitute a quorum, as required by 21 CFR Part 14. Before we begin this meeting, I would like to ask our distinguished panel members, who are generously giving their time to help the FDA in the matters being discussed today, and the other FDA staff seated at the head table to introduce themselves. I would ask that each state their names, affiliations and positions and area of expertise, starting to my right with Dr. Witten, please. Introductions

DR. WITTEN: I am Dr. Celia Witten, division director of the Division of General and Restorative and Neurological Devices at FDA, which is the reviewing Division for these products.

DR. DEMETS: I am David DeMets. I am professor and chair of the Department of Biostatistics and Medical Informatics at the University of Wisconsin, in Madison. I am a statistician by degree and have been involved in clinical trials for a long time.

DR. CHANG: I am Phyllis Chang, associate professor in the Division of Plastic Surgery and also in the Division of Hand and Microsurgery for the Departments of Surgery and Orthopaedic Surgery at the University of Iowa. I am an FDA panel member.

DR. MILLER: I am Michael J. Miller. I am an associate professor of Plastic Surgery at the University of Texas, MD Anderson Cancer Center. DR. NEWBURGER: I am Amy Newburger. I am a dermatologist in New York, in private practice, and I am an attending physician at White Plains Hospital Medical Center, and I teach at St. Luke's Roosevelt Medical Consortium. DR. KRAUSE: I am Dave Krause.

DR. CHOTI: I am Michael Choti, associate professor of surgery at Johns Hopkins University in Baltimore, Maryland, and I am a general surgeon and surgical oncologist. DR. DUBLER: I am Nancy Dubler. I am trained as an attorney. I direct the Division of Bioethics at Montefiore Medical Center, and I am a professor of epidemiology and social medicine at the Albert Einstein College of Medicine.

DR. MCCAULEY: Robert McCauley, professor of surgery and pediatrics at the University of Texas Medical Branch, and chief of plastic surgery services for the Shriner's Burn Hospital.

DR. DOYLE: I am LeeLee Doyle. I am a professor of obstetrics and gynecology, and associate dean for continuing medical education and faculty development at the University of Arkansas for Medical Sciences, College of Medicine, and I am the consumer representative on the panel.

MS. BROWN: I am Debera Brown. I am the vice president of regulatory affairs for Broncus Technologies, which is a medical device company. I am also the industry rep on this panel.

DR. WHALEN: As stated, my name is Dr. Thomas Whalen. I am chief of the Division of Pediatric Surgery and professor of surgery and pediatrics at Robert Wood Johnson Medical School in New Brunswick, New Jersey. Before we continue with the classification and reclassification portion of the hearing, we will have Mr. Anthony Watson, acting branch chief of the Plastic and Reconstructive Surgery Devices Branch, provide an update on general and plastic surgery device activities since the last meeting. Mr. Watson? Panel Update

MR. WATSON: Thank you, Dr. Whalen, and good afternoon. I am Anthony Watson, the acting branch chief of the Plastic and Reconstructive Surgery Devices Branch at FDA. Welcome, members of the panel, members of the public and manufacturers to this two-day meeting of the General and Plastic Surgery Panel. This panel last met on July 17, 2001 and recommended approval of Ortec's PMA application for OrCel Bilayered Cellular Matrix for use on donor sites on burn patients. The agency approved this product on August 31, 2001. On November 19, 2001, the agency approved a PMA application for Lifecore's Intergel Adhesion Prevention Solution. This application was reviewed by this panel at the January, 2000 panel meeting and was recommended to be not approvable. The agency agreed and, after receiving a not approvable decision, the sponsor requested review at the newly formed Medical Device Dispute Resolution Panel. This panel met on September 6, 2001 and recommended that the application be approved. On June 18, 2002, the agency released an updated guidance document, entitled, "Guidance for Resorbable Adhesion Barrier Devices for Use in Abdominal and/or Pelvic Surgery." Today, you will make classification recommendations to the agency on two types of medical devices: the silicone elastomer for scar management and the absorbable hemostatic agent and dressing intended for hemostasis during surgical procedures. Tomorrow the panel will be presented with an update of the conditions for approval for the two saline-filled breast implants approved in May of 2000. As a reminder, tomorrow we will not be discussing silicone gel-filled breast implants, and I request that panel members and members of the public limit their comments to saline-filled breast implants. Panel members, we appreciate your commitment. Members of the public who have requested time to address the panel, we appreciate your comments. Manufacturers, we appreciate your participation in presenting the information you have to the panel and answering questions that the panel may have. Thank you for your attention.

DR. WHALEN: Thank you, Mr. Watson. We will now proceed with the first open public hearing session of this day. I would ask at this time that any and all persons addressing the panel, please come forward, speak clearly into the podium microphone as the transcriptionist is dependent upon this to provide an accurate record of this meeting. We are requesting that all persons who make statements to the panel during the open public hearing portion of the meeting disclose whether or not they have financial interests in any medical device company whatsoever. Before making your presentation to the panel, in addition to stating your name and affiliation, please state the nature of your financial interests and if you have none, please so state. Is there anyone who wishes to address the panel? Please indicate by show of hands. Since there are no requests to speak in the open public hearing, we will now proceed to the open committee discussion. At this time, we will begin the discussion with the classification of silicone elastomer for scar management. We will start with the presentation by Mr. Mark Dillon, president of Bio Med Sciences. This will be followed by a presentation by Mr. Carey Rehder, plastic reconstruction division engineering manager of PMT Corporation, who will be followed by Mr. Tom Fallon and Mr. Mike O'Brien, of ReJuveness Pharmaceuticals. The FDA presentation and a reading of the FDA questions will follow the industry presentations. We will then have a general panel discussion of this topic, followed by a more focused panel discussion aimed at answering FDA's questions. Following the panel discussion, we will complete the reclassification worksheet and supplemental worksheet. The vote on these worksheets will constitute the panel's recommendation to the FDA. I would like to remind public observers at this meeting that while this portion of the meeting is open for public observation, public attendees may not participate except at the specific request of a panel member. If any of the industry representatives addressing the panel have copies of the remarks that they are making to us today, it would be greatly appreciated if they could pass them to the transcriptionist so that accuracy can be assured in what you are bringing to us today. We will begin with Mr. Dillon's presentation. Classification of Silicon Sheeting for Scar Management Industry Presentation

MR. DILLON: Thank you very much, Dr. Whalen. I am Mark Dillon, the president and founder of Bio Med Sciences. We have been marketing silicone-based products for scar management since the early 1990's. As we are all aware, these are products that are used for the prevention and reduction of hypertrophic scars and keloids. It is my opinion that these devices have substantial importance in preventing impairment of human health and present a potential risk of illness or injury if misused. I think it is common knowledge that some devices are intended for lay use instead of use by healthcare professionals. I, therefore, believe that these products should be classified as Class I, reserved or non-exempt, therefore, requiring a 510(k) notification. I have several reasons for this position. First, there is a wide variety of devices that are on the market. There are rigid, non-adhesive silicone elastomer materials and these generally require some type of tape to hold them in place. There are also adhesive gel type products. Some of these contain other materials as an embedded mesh or some type of reinforcing mechanism. There are past products that are essentially massaged onto the surface of the scar. There is even one product that I am aware of that is a silicone gel-filled cushion that is indicated for this purpose. There are also mineral oil-based materials that are silicone-containing, as well as products that are called tri-block copolymer compounds. In addition, there are a number of composite type structures such as splinting materials that are lined with silicone, padding type products and even textiles that are laminated to silicone. I think that there are likely to be new designs and new products that are introduced to the market, and I think it would be difficult to show substantial equivalence without having some type of review process involved with that. Another consideration is the indications for use. Some of these products are marketed strictly for cosmetic purposes, but others are marketed more for a professional audience, for use with burn patients. Functionality and the patient's health is a critical issue. Furthermore, I think that there has been a wide variety of claims that have appeared in the marketplace with these types of products. I have seen over the years products that claim to heal scars or are even positioned as an alternative to surgery. Likewise, I think these claims should be confirmed through the 510(k) process. Additionally, I believe there are some risks involved with the use of these products. I think patients need to be adequately warned not to use these products on open wounds. Also, there is a possibility of skin irritation or rash, particularly with some of the products that require use of adhesive tape or contain other materials, other than silicone. Lastly, I think that some of these products can be positioned to discourage adequate professional supervision or compliance. Therefore, my concern is that without the premarket notification system some devices may emerge in the marketplace that are not substantially equivalent, are positioned with inappropriate indications and claims, and may pose undue risk, including the discouragement of professional supervision when appropriate. Thank you.

DR. WHALEN: Does any panel member have a question for Mr. Dillon? [No response] Thank you, sir.

MR. DILLON: Thank you very much.

DR. WHALEN: We will now continue with Mr. Rehder's presentation, if Mr. Rehder is available. [Mr. Rehder is not present] Very well, the final identified industry speakers today jointly are Mr. Fallon and Mr. O'Brien.

MR. FALLON: Hello, panel. Thank you for letting me speak today. My name is Tom Fallon. I am president of ReJuveness Pharmaceuticals. We market a silicone sheeting product for hypertrophic and keloid scarring. I would like to address the proposed regulation identification in two parts. A scar management device is a silicone sheeting product intended for use on uncompromised skin for scar management. The first part--a scar management device is a silicone sheeting--we fully concur with this identification. Silicone should not be treated as some homogeneous category. Only silicone sheeting has been demonstrated to be effective on problem scarring. The oil and liquid forms of silicone have never been shown, in any peer-reviewed study that I know of, to be effective and are potentially toxic. The difference between the two, as we see it, is that the silicone sheetings give off silicon when hydrolyzed. The silicone oils do not. They give off just silicone. We fully agree with the first part; we fully disagree with the second part of the identification--intended for use on the uncompromised skin. The skin covering keloids and hypertrophic scars seems to be compromised in every way but appearance. The FDA's position is that the skin is not compromised because it is visually intact. We admit that it seems ironic but the functional measures of the stratum corneum covering these scars have been demonstrated to be compromised in three ways. In a study of the functional analysis of the stratum corneum in scars, which I have included in the package that I recommend you read, it was shown that these problem scars yield the same measures as open blister wounds in the categories of transepidermal water loss, electric conductivity and stratum corneum turnover rates. They are four times higher in keloid and hypertrophic scars as they are in atrophic scars and normal skin. Since scar management refers to hypertrophic and keloidal scars and not to atrophic scars, we would have to conclude that scar management refers to compromised skin. I also include a couple of papers by Dr. Peter Elias and his group, out at the University of San Francisco Veterans Administration Hospital. It demonstrates the theories emerging centering around the driving function of the stratum corneum and many maladies of the skin once thought to be originating in the dermis. In "The Mystery Widens" he applies the skin-drive principle to hypertrophic scars and keloids. Another paper included is the "Investigation of the Keloid-Derived Keratinocytes on Fibroblast Growth." It demonstrates that the production of collagen in keloidal and hypertrophic scars is caused by the compromised skin covering them. Our proposed mechanism of action is taken from a paper, "Hypertrophic Scars and Keloids: Immunophenotypic Features and Silicone Sheets to Prevent Recurrences." In this study they took 20 keloidal scars, excised them and in ten of them they put silicone sheeting over them; in the other ten they put nothing. In nine of the ten of the scars without the silicone sheeting keloid scars came back. Almost all of them, except four, under the silicone sheeting the scars came back. They did immunophenotypic analysis and they found the scavenger receptor CD36 in large amounts under the silicone sheeting. These scavenger receptors are essential in rebuilding the stratum corneum. The most important component of the stratum corneum is cholesterol. It is not effective when applied topically, and it is transported by these scavenger proteins from high density lipid proteins to the stratum corneum. So, with the proposed identification it will be quite difficult to make the correct structure, function and mechanism of action claims. The last paper that I have included is release and distribution of silicone-related compounds in the skin exhibits the release of silicon from silicone sheeting into a buffer solution and into normal and keloidal skin. If silicon is the active ingredient, then there are dosage and shelf-life issues. We did our own study, which is also included in the packet, where we put ReJuveness Spenco gel sheeting in ten-year old Cica-Care under the same testing, and what we found was that the rates of silicon release were different for different sheetings, and in the ten-year old Cica-Care there was no silicon released at all. In conclusion, we feel as though the silicone sheeting is completely safe and that it should be a Class I but that the scars that it is addressing, hypertrophic and keloid scars, are composed of compromised skin and it is the driving mechanism in these maladies. That is it.

DR. WHALEN: Are there questions for Mr. Fallon?

MS. BROWN: I have a question. You proposed Class I. Would that be with or without a 510(k)?

MR. FALLON: I would say with a 510(k).

MS. BROWN: Thank you.

DR. WHALEN: With your objection to the second part to what has been proposed, is your statement in the center of your third page what you are proposing as an alternative wording, "scar management device...?"

MR. FALLON: I really didn't know if we were going to participate on that level to suggest what the wording should be until yesterday. So, yes, I think that it should be changed. I mean, if you would like a suggestion from me, I just need probably a day or two where I could come up with a suggestion.

DR. WHALEN: But your viewpoint or your company's viewpoint is that focally hypertrophic scars and keloids are not uncompromised skin. You are not saying to the panel that you think we should consider applying this on open wounds, fresh wounds in the operating room when we have just made an incision, etc.?

MR. FALLON: Well, I really don't see why not; I don't see why they shouldn't be applied to open wounds. In the Italian study, where they put it over excised keloids, they do put it on excisions that were open. They did it prophylactically. So, I they are safe enough, yes, to put on open wounds and perhaps that would be a different classification for that use. DR. WHALEN: Any other questions? Dr. Miller?

DR. MILLER: Thank you for your presentation. I just want to make sure I am clear about what you are calling an open wound. I mean, when I think of an open wound I think of a wound where the epithelium is not in contact across the wound; you have exposed tissue below the epithelial level that is exposed.

MR. FALLON: Right.

DR. MILLER: So, your thought is that it is okay. You would suggest that we can place these devices on those types of wounds?

MR. FALLON: If they are properly sterilized, yes. I mean, I don't know what effect they would have on open wounds. I know they work on ulcerated wounds, and keloid and hypertrophic scars are very similar to an ulcerated wound in that they are microvascularly cut off. Keloid and hypertrophic scars are composed of essential fats, basically fats. So, the difference between the two is slight.

DR. WHALEN: Dr. Newburger? DR. NEWBURGER: Excuse me, have you see any evidence of any type of foreign body reaction from the silicon which is released from the gel across this compromised epidermis?

MR. FALLON: Yes, we have had a couple of reports of women using the sheeting applied to the scars after breast implantation. I don't know if there is something going on between them, but we have had several complaints on that. But, for the most part, we have sold over 100,000 of these devices and we have had basically no complaints, just the tape occasionally.

DR. NEWBURGER: I am asking specifically about a foreign body reaction as opposed to an irritation or a folliculitis and occlusion. In other words, here is a molecule that is going through the compromised epidermi, are you getting a soft tissue reaction in the dermis with foreign body cells?

MR. FALLON: I don't know that exactly. Our scientific advisor is Dr. Arthur Brawer, who is a noted expert on silicone. But it basically is like coal miner's disease, that is, the action of the silicone sheeting on the hypertrophic scar. It goes down as an antigen, stimulates the scavenger CD36 and marshals them to the site, it seems, and then from there they are able to produce and serve their many different functions, versatile functions that they are able to do--transporting cholesterol, essential fatty acids, as well as taking away excess materials in the extracellular matrix. So, that is what we think is going on.

DR. WHALEN: Mr. Fallon, are your remarks everything or is Mr. O'Brien still going to be speaking?

MR. FALLON: Oh, Mr. O'Brien couldn't show, I am sorry.

DR. WHALEN: Thank you. We will continue now with the FDA's presentation with Dr. Sam Arepalli. FDA Presentation

DR. AREPALLI: Good afternoon. We are here this afternoon to seek a panel recommendation to classify scar management devices indicated for management or scars. My name is Sam Arepalli, reviewer in Plastic and Reconstructive Surgery Branch, Division of General, Restorative and Neurological Devices. I will be presenting device identification and health risks aspects of the device. Reviewers from the Office of Surveillance and Biometrics, CDRH are in the audience to clarify any questions regarding Medical Device Reports. After my presentation, Ms. Marjorie Shulman will walk you through the classification worksheets. This slide is on regulatory history. As you know, medical devices are classified into three classes, namely, Class I, Class II and Class III. Examples of Class I exempt products include hydrogels or hydrogel wound dressings and manual surgical instruments. Class II devices include implantable surgical meshes and sutures. Examples of Class III devices are interactive wound dressings and barriers. At the time of the Medical Device Amendments of 1976, a few medical devices were unclassified. They include devices like scar management devices, the one that we are going to discuss today. They were unclassified. These devices are currently regulated as unclassified devices. The FDA has been making efforts to classify and reclassify medical devices since 1976 into the lowest regulatory class that can reasonably assure safety and effectiveness of their intended use. I would like to bring to your attention that the same panel several years ago provided a recommendation to classify non-interactive wound dressings. This slide gives a brief description of the proposed identification of the device: A scar management device is a silicone sheeting product intended for use on uncompromised skin for scar management. This slide gives a brief description of FDA-cleared scar management devices. FDA has regulated silicone sheeting intended for scar management as an unclassified pre-amendment device. It has been cleared for marketing under several names. They are silicone sheeting, silicone elastomer and silicone gel for hypertrophic and keloid scar management. Also, the agency cleared a hydrogel for the same intended use. There are about 75 scar management devices on the market. We searched the Medical Device Reports database for device adverse events. Two adverse events were found. The first adverse event, reported in January of 1998, was a significant blistering caused shortly after using gel sheeting followed by full-thickness skin necrosis due to secondary infection. The blistering was not at the site of the gel sheeting application but in the areas nearby. It was determined by the reporting physician that the event was unrelated to the device but we could not rule out the possibility that the device was involved. The second adverse event, reported in June, 2001, was an allergic reaction following the use of silicone sheeting. Following 39 hours of continuous use, the patient developed a severe red rash and flaky rough skin. This was determined as an isolated event and not likely that it was due to the use of the device. Some possible causes for the reported incident may be a reaction to the tape used to hold the sheeting in place or moisture created under the silicone sheeting after wearing the product for such an extended period of time. This slide is the questions to the panel. Can I read them out?

DR. WHALEN: I will just interject that we will not be answering the questions at this time; we will at a later point in time, but please do proceed, if you would.

DR. AREPALLI: Thank you. We have these two topics for panel discussion. Following this, Ms. Marjorie Shulman will walk you through the classification work sheet. Here are the two issues: Please discuss the proposed classification for the scar management device for the management of hypertrophic and keloid scars. Also, discuss what descriptive information and intended use should be included in the proposed classification identification. Number two, please discuss the risk of possible adverse skin reaction due to lack of biocompatibility for the scar management device and identify any other risks to health for these devices. Thank you. Marjorie? Panel Discussion

DR. WHALEN: Just a moment, does any of the panel members have questions of Dr. Arepalli on his presentation? [No response] Thank you. We will get to Ms. Shulman in a moment but we are going to have a general discussion first. Are there comments or questions of any of the panel members about what we have just heard on these devices? If I could kindle the fire by asking Dr. Chang if she has any comments on the subject that was raised about intact skin.

DR. CHANG: I have a comment and a recommendation for the panel to consider which is, rather than saying that this management is for uninjured skin, to describe it as that it should be intended for closed or intact skin, "closed, intact skin" as a replacement for the wording "uninjured" because, by definition, we are--

DR. WHALEN: Uncompromised.

DR. CHANG: Yes, uncompromised. We are proposing this device for scar which is not the same as uninjured skin. The other question I had would be to ask Dr. Newburger's opinion regarding whether or not a skin rash could occur at a site distant from where this product might be applied. In other words, what is the potential for development of a rash to be related to use of a gel padding in one location and seeing a rash appear at a different site in the body?

DR. NEWBURGER: To my knowledge, the issue of silicones and true allergic reactions is pretty well limited to foreign body reactions. We use various types of silicone gel sheeting in our practice and we have never seen a true allergic reaction to it, and you might say, well, in a private practice how substantial is this? Well, we have over 30,000 patients and we are using it multiple times every week and we have never seen a true allergic reaction. We have seen folliculitis. We have seen irritant reactions. We have seen problems with tape. But when we are putting it over skin which has healed over, and that is the only time we use it, we have not seen allergic contact dermatitis, nor have we seen distant reactions. We have had a number of patients who have had solid silicone implants and we have seen distant reactions which have been identified as silicone granulomas. So, I am a little concerned about this information that silicone is actually released into the scar tissue. This is new to me and I thought I had read rather extensively on the area. I am concerned about that possibility. Certainly, the identity is not the same as you are going to see in the solid silicone rubber implant, which is what we have seen occur, but this raises more questions to me rather than fewer.

DR. WHALEN: Dr. McCauley?

DR. MCCAULEY: One of the things that we actually think about when we are using these types of products is that we actually talk about using them in hyperproliferative scar disorders, which keloids and hypertrophic scars fall under. I guess that would distinguish it from some of the other hyperproliferative skin disorders that occur without trauma and that occur in dermatology. But I would propose that actually rather than say "uncompromised skin" we actually focus in on hyperproliferative scar disorders which hypertrophy scars and keloids represent.

DR. WHALEN: Dr. Witten, if I could ask a question, it strikes me that if FDA were going to be considering the use of this product on an open, fresh wound that it would go well beyond the scope of a reclassification or classification type of process. Am I correct in that? Would that require some other initiative on the part of a manufacturer or sponsor wishing to have that indication?

DR. WITTEN: Well, we are really asking you to classify what we have actually seen or cleared, which have been these devices for scar management. DR. WHALEN: But within the scope of what we are classifying, we are going to be defining the safety and efficacy of the product with its intended use in mind. So, are we at liberty in a classification hearing to be considering a broad scope of indications?

DR. WITTEN: We are only asking you to consider the scope of indications for which we have cleared the product. DR. WHALEN: Thanks. Other issues or points? Dr. Miller?

DR. MILLER: Yes, I would like to emphasize that I think this product should probably not be used on an open wound. It is a very different situation than a closed wound with hypertrophic scarring and I think that should be emphasized. The use should be limited. I like the words of an intact wound, an epithelialized wound or a closed wound. I agree, uncompromised skin is not very precise but, certainly, it needs to be a closed wound.

DR. WHALEN: Any other comments specifically on the semantics of the indication or any of the issues that have been brought up?

DR. CHANG: I would like to second and ditto Dr. Miller's comments that this should be limited to closed, intact skin and not be placed on an open wound.

DR. WHALEN: Dr. Witten?

DR. WITTEN: Yes, I just wanted to say what Mr. Hurts clarified for me. Actually, I should have remembered to say this, but we already have a classification for open wounds. I mean, there are Class I exempt wound dressings for open wounds. So, there already are classifications for products intended for open wounds; they would already fit into a different classification. DR. WHALEN: Is there a consensus on the wording, that we are going to go forward with? Are we are going to say closed wounds or, Dr. McCauley, if you could say it again?

DR. MCCAULEY: Closed hyperproliferative scar disorders.

DR. WHALEN: That implies that you are talking about closed wounds.

DR. MCCAULEY: Right.

DR. WHALEN: Are there any other comments? [No response] Then, at this time we would like to begin to focus our discussion on the FDA questions that Dr. Arepalli has brought forward to us and that remain projected on the screen. At this time we will not refer to the reclassification questionnaire. We will do that after this discussion that is focused upon those questions. Please consider, panel members, the silicone elastomer for scar management device wile responding to the questions before us taken one at a time. The first question again, discuss the proposed classification for the scar management device for the management of hypertrophic and keloid scars. Also, discuss what descriptive information and intended use should be included in the proposed classification identification. Dr. McCauley, would you care to start off on that one?

DR. MCCAULEY: First, I would like to have some comments. Basically, this is related to the information which has been presented to us relative to this whole classification of silicone polymers. Number one, they have been around for quite a while and, number two, they have not, in my opinion, posed a significant danger, if you will, to patients. However, what bothers me is the fact that there are a number of studies which have been published that are, number one, anecdotal or, number two, if they have been controlled, randomized studies they are very small. Number three, the mechanism of action for these materials really has not been clarified. I think that is very important in our deliberations in terms of exactly how you want to classify these devices. If you say that silicone leaches out of these polymers into the wound and affects CD36 cells, then you are really talking about something that is more interactive and something that may be classified as a Class III. If you feel that the silicone in and of itself is non-interactive but that it achieves this effect just by coverage, although we know it is probably not pressure that gives this effect, there is some controversy in terms of whether temperature really matters. Some studies by Lee suggest that two degrees centigrade elevation in the temperature underneath these materials causes a tremendous increase in the action of collagenase, which is how these effects are achieved. Other studies have not shown that. Other studies have said that hydration may be the mechanism by which we see improvement in the wounds. But I think it is very important to try to decide what is the mechanism of action before we can actually properly classify these compounds.

DR. WHALEN: Just to play the devil's advocate, if these have been in use for so many years and, in your opinion, you say you feel pretty much that they are safe, from a pragmatic point of view do you think it is that critically important after all these years to delineate that mechanism of action?

DR. MCCAULEY: I think it is important to delineate that. Whether or not that is important enough for classification, I think if we consider the fact of this new data which was presented relative to the leaching of silicone out of the compound into the wound, I think that is a little disturbing to me.

DR. WHALEN: Dr. Dubler, any comments?

DR. DUBLER: Dr. McCauley, in the study that showed there might be some leaching of the silicone into wounds---

DR. MCCAULEY: I am sorry, this is information that was just provided to us by Mr. Fallon.

DR. DUBLER: That is right, because there are no published studies that we have reviewed that have indicated that.

DR. MCCAULEY: Exactly.

DR. DUBLER: I also don't know what to do with that piece of information. If that were, in fact, the case then I think it would require the sort of monitoring and data collection that would probably only happen in Class III and, yet, the published studies thus far--I can't comment, obviously, on their statistical validity. They are somewhat small but they didn't indicate that sort of a problem so I wasn't prepared for that.

DR. MCCAULEY: Exactly.

DR. DUBLER: Therefore, based on the studies that were here, it seemed to me that the descriptive information would be relatively easy to compile and prepare; now I am a little uncertain.

DR. WHALEN: Dr. Choti??

DR. CHOTI: I agree. I was kind of expecting this to be fairly straightforward but if it is really a topical application of an agent that really has a direct impact on the local tissue, then it muddies the water a little bit. But simply based on the track record that these have been safe and the reactions have been very minimal, I think that the clinical safety data presented is quite good. I think there is little clinical evidence to suggest that there is any untoward effect of this material and, therefore, I am not sure that the Class III classification is warranted.

DR. WHALEN: Dr. Newburger?

DR. NEWBURGER: I concur with Dr. McCauley's assessment about the need to clarify the mechanism of action. Historically what we know about this type of dressing, I would agree with Dr. Choti.

DR. WHALEN: Dr. Miller?

DR. MILLER: Yes, I agree with all the comments that have been made. I wonder, can we invite our discussant back to the podium?

DR. WHALEN: The panel is free to ask anyone a question that they wish.

DR. MILLER: Could Dr. Fallon come back up because I too have been unaware of data which shows there is a leaching of silicone into the wound that is speculated to be the cause of the effect that we see.

MR. FALLON: It is study number nine in the packet.

DR. MILLER: Who is the author of that one?

MR. FALLON: That was Shigeki, Nobuoka. It is a study done in Japan, published in Skin Pharmacology Applied Skin Physiology.

MS. BROWN: I would like to ask a question. Is this study relevant to silicone sheeting or silicone gels?

MR. FALLON: Silicone sheeting, and we believe the distinction between the sheeting and the gel sheetings and the ointments is the release of silicon, not silicone, from the sheetings. It is hydrolyzed and these layers of silicone are released. I also have a study that shows all the other proposed mechanism of actions have pretty much been disproved. I really can't give it out but it was done at Northwestern University by Dr. Mustow.

DR. WHALEN: I am just perusing this for the very first time, but it seems to me that these are mostly in vitro skin specimens--

MR. FALLON: Yes.

DR. WHALEN: --where they are looking at the distribution simply locally in a piece of skin.

MR. FALLON: Yes.

DR. WHALEN: It is not like they put this somewhere in the groin and they--

MR. FALLON: Yes, correct, in vitro study, yes.

DR. WHALEN: So, I am having a hard time, again from first blush rapidly absorbing this, saying that there is documentation of absorption and systemic redistribution of silicone by this. There is nothing in here that states that to me.

MR. FALLON: Yes, I was very surprised when I saw that too. In reconsidering it with the mechanism of action, as it is known, these scars mostly happen to people that are from the tropics and the CD36 has been connected to the prevention of malaria and an antigen could have come--well, I wasn't prepared for this, but I can prepare--

DR. WHALEN: Well, let me ask you a more focused question. It is perhaps a slightly touchy area. I would think from your particular vantage point that you would not want to demonstrate that this is systemically absorbed. Am I correct there? [Laughter]

MR. FALLON: Yes, I am just presenting what appears to be happening. I don't know, I mean, I know I have a duty to my company, I own my company but I am just presenting and I know it is not helping and, you know, that is what it is. I am presenting to the board what our findings are and what we think. D

R. WHALEN: Are there any other questions? Dr. Doyle?

DR. DOYLE: If we have something that has been on the market this long with no untoward effects, is it necessary that we know the mode of action before we can approve it for classification?

DR. WHALEN: This is akin to the question I asked Dr. McCauley a short time ago, and there are certainly two answers to that question. There is long-term demonstrated efficacy and, yet--it may not be a related example--if we look at the explosion of latex allergy, I am sure twenty years ago people would have said there is millions and millions of use of latex without too much of a problem. So, without putting words in Dr. McCauley's mouth, I think he is suggesting that if, indeed, this is being now proposed as an effect we certainly can't ignore it, and I would agree with him. But I personally, from the perusal of this letter, don't think that what we earlier had suggested to us has been demonstrated by this particular investigation.

MR. FALLON: And also, the study we did, the ten-year old Cica-Care did not throw off any of the silicon particles and that needs to be investigated. It is thought that silicone becomes toxic. DR. WHALEN: Are there other questions for Mr. Fallon?

DR. MILLER: I just have one more. Based upon what you are telling us and what you have learned, your recommendation remains that we classify this as a Class I device?

MR. FALLON: Yes, on hypertrophic and keloid scars, yes. Yes, definitely. I mean, I don't see any safety issue. You could call Dr. Brawer. His number is right there. He is an expert. He is fairly articulate and you can ask him directly. He is more of an expert than I am.

DR. WHALEN: Dr. Dubler?

DR. DUBLER: Therefore, you have no other data but for the article that is numbered 9 that would demonstrate any danger from use on scar tissue? MR. FALLON: Yes. No, I don't have any other data, no. DR. DUBLER: So, if article number 9 is extinguished, then we are--

DR. MILLER: Yes, it also supports the fact that this should be used only on intact wounds.

DR. CHOTI: Although we still don't know the mechanism of action.

MR. FALLON: That is the proposed mechanism of action.

DR. CHOTI: Well, I think there is hydration, there is temperature, there are other modes of action. The real answer is whether you discount this article or not, we don't know how this works.

MR. FALLON: Yes.

DR. WHALEN: Thank you, sir. I think we are getting around to Dr. Chang.

DR. CHANG: I would use that same analogy of latex gloves, long history of use, relative safety, low percentage of side effects although there has been in certain populations, such as those with spinal cord injury meningomyelocele, certain increased risk for development of latex allergies. So, that is not to say that with increasing use of silicone gel products individuals having this type of reaction may come forth. So, I would use that analogy to say, yes, there remains the potential, particularly if there is shedding or potential for absorption of silicone products with long-term use, that we may see this increasing prevalence. But I believe, looking at the data presented by both FDA and industry, that there has been a long record of relative safety in the face of efficacy for this product. So, I would emphasize that it is intended for intact, closed skin and that it should be put into Class I.

DR. WHALEN: We haven't heard the words t-test today. Dr. DeMets, any comments?

DR. DEMETS: I just want to second what Dr. McCauley said. When I looked at the articles that were in our tab, I was struck by sort of two things. One, these studies are small and, therefore, whatever the effectiveness is, is going to be determined somewhat imprecisely, and some of them were uncontrolled and those that were controlled have a lot of missing data. So, I was less than overwhelmed with the benefit side of the equation. Because these were small, I was sort of pondering the side effect side because if it is a low but serious event the number of patients in these studies would be way too small to detect that. Now, maybe there are registries or the FDA database that could address that, but based on that literature I reviewed, I did see that we have enough numbers of patients exposed to really say too much about the safety. I am coming to this totally cold but that is just what I reflected when I read it.

DR. WHALEN: Ms. Brown? MS. BROWN: I would support the Class I classification. As I understand, these have been regulated under 510(k)s since 1976. Is that correct, David?

DR. KRAUSE: They are considered pre-amendments. So, they have been around since before 1976. I don't think we had our first 510(k) for them until sometime in the '80's but they were, you know, identified as a pre-amendments device by that submission.

MS. BROWN: But it sounds like there has been a fair history of marketing with the product, and there is a medical device reporting mechanism so if there are problems they do get reported to FDA. And, from what Sam Arepalli said, it sounds like there have only been two. So, it sounds like the risk is very minimal.

DR. WHALEN: Dr. Doyle, anything further on the first question? No? All right, the second question then that Dr. Arepalli has posed to the panel is still projected. Please discuss the risk of possible adverse skin reaction due to lack of biocompatibility for the scar management device and identify any other risks to health for these devices. Dr. Dubler, any thoughts?

DR. DUBLER: I have one question about the devices we haven't talked about thus far, which is they aid in the resolution of certain complex or difficult scar tissue. Would that scar tissue heal on its own over time, or does this do something that will create a different outcome?

DR. WHALEN: Yes, there might be multiple answers but I think the answer is yes to your question, both because it can both expedite and change outcome. But the primary beneficial effect, I think, has been to ameliorate the degree of hypertrophy within the scarring process so outcome would be changed. Any of the plastic surgeons like to have another opinion on that?

DR. DUBLER: Since there can be a beneficial outcome which would not occur but for the use of this, and since there doesn't appear to be any documented negative reaction but for two cases, and since I don't know what to do with article number 9, it seems there are no serious adverse health reactions that would argue against classifying as a Class I. DR. WHALEN: Dr. Choti?

DR. CHOTI: I agree.

DR. WHALEN: Dr. Newburger?

DR. NEWBURGER: I agree as well.

DR. WHALEN: Dr. Miller?

DR. MILLER: I agree.

DR. WHALEN: We are on a concise streak. Dr. Chang?

DR. CHANG: I agree. The caveat is in the usage. In one of the two examples a patient had the product on for over 30 hours. So, I believe that in labeling patient education has to be very important to limit to to 12 hours, I believe, the consecutive hours that this product should be applied to try to decrease the amount of skin rash as a result of excessive moisture from overuse of the product. But, otherwise, I agree that this should be a Class I product.

DR. WHALEN: Dr. DeMets?

DR. DEMETS: I agree with the previous comments.

DR. WHALEN: Ms. Brown?

MS. BROWN: I agree with the previous comments.

DR. WHALEN: Dr. Doyle?

DR. DOYLE: I agree.

DR. WHALEN: And, Dr. McCauley?

DR. MCCAULEY: Same, I agree.

DR. WHALEN: Now that the panel has discussed the FDA questions and our deliberations seem complete, we have time for any final remarks. Dr. Arepalli, is there any final comment from FDA, or anyone else on behalf of FDA?

DR. WITTEN: I just want to clarify that the second question was to discuss or identify any other risks that you all see. I think some were noted and if those are all the risks, that is fine but I just wonder if there are any other risks that haven't been discussed that anybody wants to comment on.

DR. WHALEN: I think we have hit them. Is there any final comment from anyone in the silicone elastomer for scar management industry? If so, would you please raise your hand? Yes, sir? Would you please again, even though you have spoken to us before, give your name and affiliation and any financial interest in the devices being discussed?

MR. DILLON: I am Mark Dillon. I am the president of Bio Med Sciences and, obviously, I have a financial interest in the company. I have a couple of comments. One is that I am aware of one paper that was done by Dr. William Monofeld where he looked for traces of silicon metal in skin biopsies taken, and I believe from a control source as well, underneath the treated area. If I recall correctly, he saw a fairly high baseline content of silicon metal in the skin which he concluded could be from a number of different sources--the fact that silicone is often coated on capsules to make them easier to swallow and on hypodermic needles and so forth--and he concluded that there was no increased amount of silicon in the skin treated with silicone sheeting. So, I thought I would share that with the panel. I would strongly agree with the idea of not indicating this product for use on open wounds. For one, the obvious reason is it is unknown and there is a classification for that already. Secondly, these products are always reusable and after the first application they are no longer sterile, even if they were provided sterile and most of them are not. So, I think with strong labeling to indicate against use on open wounds, that issue would be largely put to rest. I would be willing to share a theory on mechanism of action if the panel would like to hear some of my experience. I have noticed clinically that with the use of these products on hypertrophic scars, particularly in contractures over a joint, you can see a benefit in range of motion occur with a period of hours of use. To me, this is an indicator that there is a hydration mechanism and that this effect will reverse itself if the use is discontinued. Secondarily, we see over a longer period of time a remodeling of the scar, which may or may not be due to hydration, but that second effect is what is more permanent.

DR. WHALEN: Thank you, Mr. Dillon.

MR. DILLON: Thank you.

DR. WHALEN: Mr. Fallon, do you have any final remarks?

MR. FALLON: The trace of silicon in in vivo models will probably not come up because it is the job of the CD36 and scavenger cells to take those away. So, I really can't see how one could set up an experiment, besides in vitro, to show that it is getting into the skin. So, I just wanted to clarify that.

Classification Questionnaire and Vote

DR. WHALEN: Thank you. Now we will complete the classification questionnaire and supplemental data sheet. Ms. Marjorie Shulman, in the Office of Device Evaluation Classification, Reclassification, will assist us as we go along. After the formal panel discussion of each question we will note the answers for each blank on the data sheet as Ms. Shulman reads them out, and she will record it on the overhead for all of us to see. The voting members of the panel will vote then on the completed questionnaire and supplemental data sheet and this will then constitute the panel's recommendation to the FDA. Procedurally, are there any questions on what we are about to do next? [No response]

MS. SHULMAN: Are we ready? the first part on the sheet is just your panel name and you can fill that out. That is administrative, and the date; the generic type of device. Then the first question, is the device life-sustaining or life-supporting? DR. WHALEN: We can just go around the table, and this is for voting members. So, we can start on this first question, please, with Dr. McCauley.

DR. MCCAULEY: The answer to the first question would be no.

DR. DUBLER: The answer to the first question is no.

DR. CHOTI: No.

DR. NEWBURGER: No.

DR. CHANG: No.

DR. DEMETS: No.

MS. SHULMAN: The first one is no. Is the device for use which is of substantial importance in preventing impairment of human health?

DR. WHALEN: Just to stagger the way we answer them, Dr. Dubler?

DR. DUBLER: No.

DR. CHOTI: No.

DR. NEWBURGER: No.

DR. CHANG: No.

DR. DEMETS: No.

DR. MILLER: No.

MS. SHULMAN: The second one is no. Number three, does the device present a potential unreasonable risk of illness or injury?

DR. WHALEN: Dr. Choti?

DR. CHOTI: No.

DR. WHALEN: Dr. Newburger?

DR. NEWBURGER: No.

DR. CHANG: No.

DR. DEMETS: No.

DR. MILLER: No.

DR. MCCAULEY: No.

DR. DUBLER: No.

MS. SHULMAN: The third one is no. We now go to number four, did you answer yes to any of the above three questions? That answer is no. Then we go to number five, is there sufficient information to determine that general controls are sufficient to provide reasonable assurance of safety and effectiveness?

DR. WHALEN: Starting with Dr. Newburger?

DR. NEWBURGER: Yes.

DR. MILLER: Yes.

DR. CHANG: Yes.

DR. WHALEN: Dr. DeMets?

DR. DEMETS: I will vote no.

DR. WHALEN: Dr. McCauley?

DR. MCCAULEY: Yes.

DR. DUBLER: Yes.

DR. CHOTI: Yes.

MS. SHULMAN: The answer to that one is yes. On your sheets, you may mark w