ATDEPARTMENT OF HEALTH AND HUMAN SERVICES

 

FOOD AND DRUG ADMINISTRATION

 

CENTER FOR DEVICES AND RADIOLOGIC HEALTH

 

 

 

 

 

 

 

 

 

 

 

GENERAL AND PLASTIC SURGERY DEVICES PANEL

 

OF THE MEDICAL DEVICES ADVISORY COMMITTEE

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Wednesday, October 15, 2003

 

7:30 a.m.

 

 

 

 

 

 

 

 

 

Gaithersburg Marriott Hotel

9751 Washington Blvd.

Gaithersburg, Maryland


P A R T I C I P A N T S

 

Thomas V. Whalen, M.D., Acting Panel Chairperson

David Krause, Ph.D., Executive Secretary

 

VOTING MEMBERS:

 

Brent A. Blumenstein, Ph.D.

Phyllis Chang, M.D.

Michael A. Choti, M.D.

Ann Marilyn Leitch, M.D.

Michael J. Miller, M.D.

Amy E. Newburger, M.D.

 

CONSUMER REPRESENTATIVE:

 

Alisa M. Gilbert

 

INDUSTRY REPRESENTATIVE:

 

Debera M. Brown

 

TEMPORARY VOTING MEMBERS:

 

Benjamin O. Anderson, M.D.

Dennis W. Boulware, M.D.

Emily F. Conant, M.D.

Nancy A. Dubler, LLB

Ruth A. Lawrence, M.D.

Stephen Li, Ph.D.

Ellice S. Lieberman, M.D.

Barbara R. Manno, Ph.D.

Mary H. McGrath, M.D., MPH

Michael J. Olding, M.D.

 

Celia Witten, Ph.D., M.D., FDA

 


C O N T E N T S

 

Call to Order and Introductions,

   Thomas V. Whalen, M.D.    5

 

Open Public Comment:

 

   Virginia Silverman    11

 

   Dr. Marie Pletsch    13

 

   Dr. Philip C. Haeck    16

 

   Susan Schambeck    20

 

   Julie Godoy (read by J. Rosanna)    22

 

   Holly A. Feustel    27

 

   Dr. Elvin G. Zook    29

 

   Ruby Rahn    32

 

   Donna Sims (read by Nicole Rudick)    35

 

   Dr. Karen Becker    38

 

   Lale Goddard (read by Ruby Rahn)    41

 

   Teresa Hamilton (read by Erica Clare)    44

 

   Cheryl Robinson    47

 

   Linda Dintino (read by Stephanie Donny)    50

 

   Rebecca J. Smith-Miles    52

 

   Myrl Jeffcoat (read by Pam Dowd)    54

 

   Elaine Donnelly (read by Kathleen Witter)    57

 

   Rogene Schorer (read by Georgiana Hanson)    60

 

   Wanda Simison (read by Sibyl Goldrich)    63

 

   Lois A. Travis (read by Jan Erickson)    66

 

   Deborah Guillory (read by Jennifer Cook)    70

 

   Gerie A. Voss    71

 

   Susan Pope Helman    74

 

   David Helman    78


C O N T E N T S (Continued)

PAGE

Open Public Comment: (Continued)

 

   Dr. Christopher Batich    79

 

   Marilyn Malnack    87

 

   Leslie A. Rumsey    90

 

   Nikki Dollie    92

 

   Mike Dollie    96

 

   Dr. Ernest Lykissa    96

 

   Audrey Sheppard    108

 

   Dr. Elizabeth Connell    110

 

   Dr. T. Wade Clegg, III (read by Erin Hemstra)    116

 

   Lynda Roth, Coalition of Silicone Survivors    118

 

   Dr. Jane Zones, Breast Cancer Action    123

 

   Cynthia Pearson, National Women's

      Health Network    128

 

   Mary Dickerson    133

 

   Joe Kelly, Dads and Daughters    134

 

   Jama K. Russano, Children Afflicted

      with Toxic Substances    141

 

   Rodney Hayton, National Silicone

     Implant Foundation    147

 

   Dr. Carolyn Kerrigan, Plastic Surgery

     Educational Foundation    150

 

   Dr. James H. Wells, American Society of

      Plastic Surgeons    158

 

   Mary McDonough, In the Know    169

 

   Dr. Diana Zuckerman, National Center for Policy

      and Research for Women and Families    172

 

Open Panel Discussion     183

 

Sponsor Summation, Scott Spear, M.D.    228

 

Concluding Panel Deliberations and Vote    266


P R O C E E D I N G S

Call to Order and Introductions

    DR. WHALEN:  Welcome to the second day of the General and Plastic Surgery Devices Advisory Panel.  I would like to ask the panel members to give a brief reintroduction of themselves with their area of particular expertise as it relates to this PMA, starting to my right with Dr. Choti.

    DR. CHOTI:  Michael Choti.  I am a general surgeon in surgical oncology at Johns Hopkins Hospital, and my interest is in clinical cancer surgery.

    DR. BLUMENSTEIN:  Brent Blumenstein, biostatistician working independently.

    DR. CONANT:  Emily Conant, Associate Professor of Radiology, University of Pennsylvania.  I am a breast imager, chief of breast imaging there.

    DR. LIEBERMAN:  Ellice Lieberman.  I am an associate professor of obstetrics and gynecology, Harvard Medical School, and Associate Professor of Maternal and Child Health at the Harvard School of Public Health, and my expertise is in epidemiology.

    DR. MANNO:  I am Dr. Barbara Manno, from the Louisiana State University Medical Center, in Shreveport, Louisiana.  I am a professor in the Department of Psychiatry.  My background is toxicology and my sub-specialty within toxicology these days is forensic toxicology.

    MS. BROWN:  I am Debera Brown, the Vice President of Regulatory Affairs for Broncus Technologies.  I am the industry representative for this panel, and I have had over 20 years of experience in medical device development.

    MS. GILBERT:  I am Alisa Gilbert.  I am the consumer representative.  I am also a breast cancer survivor and founder of the Unbroken Circle in the Office of Native Cancer Survivorship.

    DR. WITTEN:  I am Celia Witten.  I am the Division Director of the Reviewing Division at FDA for these products.

    DR. MILLER:  I am Michael Miller.  I am Professor of Plastic Surgery at the University of Texas MD Anderson Cancer Center.

    DR. ANDERSON:  Ben Anderson, breast cancer surgeon, surgical oncologist from the University of Washington in Seattle.

    DR. LI:  Steve Li, President of Medical Device Testing and Innovations in Sarasota, Florida and my areas are biomaterials and biomechanics.

    PROF. DUBLER:  Nancy Dubler.  I am Director of the Division of Bioethics at Montefiore Medical Center, and a professor of Epidemiology and Population Health at the Albert Einstein College of Medicine.

    DR. NEWBURGER:  I am Amy Newburger.  I am in private practice in dermatology, in New York.  I teach at St. Luke's Roosevelt Hospital Medical Consortium.

    DR. BOULWARE:  I am Dennis Boulware, professor of medicine, University of Alabama, at Birmingham, and a rheumatologist.

    DR. LEITCH:  I am Marilyn Leitch.  I am a surgical oncologist and professor of surgery at the University of Texas Southwestern Medical Center, in Dallas.

    DR. CHANG:  Good morning.  I am Phyllis Chang, plastic surgeon and an associate professor in the Department of Surgery at the University of Iowa College of Medicine.

    DR. KRAUSE:  My name is David Krause.  I am the executive secretary of this panel and I am also in the branch that reviews these devices.

    DR. LAWRENCE:  I am Ruth Lawrence, University of Rochester School of Medicine, Department of Pediatrics and Ob/Gyn.  I am a pediatrician, clinical toxicologist, and my special interest is newborns and breast feeding.

    DR. WHALEN:  Thank you.  I am Tom Whalen.  I am Professor of Surgery and Pediatrics at Robert Wood Johnson Medical School and the Acting Chair for this Panel.

    There are brief housekeeping attention details that probably need to be presented in a little while when more people come in.  For those who did not stay until the end last night, the panel did conclude the scheduled day's business and did get through the FDA questions.  I will very briefly go over the results of those deliberations as we begin this afternoon's activities before the panel has final deliberations and voting.

    What we are about this morning is further public testimony that will probably take up the entire morning until the lunch break, which will be about midday or perhaps slightly later.  We will then have final summation and closing by FDA and then by sponsor and then the panel will deliberate.

    To reiterate something that I said yesterday, which apparently was not heard by many people, please either turn off your cell phones or place them on silent mode because it is extraordinarily rude to have them continuously going off when we are trying to hear people who have significant messages to give us from the podium, and the panel's deliberations as well.

    We now will proceed with today's open public comment session.  All persons addressing the panel are asked to speak clearly into the microphone as the transcriptionist is dependent upon this means of providing an accurate record of this meeting.  I would specifically now like to have the attention of all the individuals who are registered to speak to the panel today.  You have all been given a number corresponding to your order of appearance.  Please come to the podium area in advance so that we are not spending a great deal of time in transitions from speaker to speaker.  Specifically, we would ask that the speaker who is next to speak be in the corridor between the chairs, towards the end of that corridor, as the person is speaking at the podium.

    I would also like to remind you that we will have a timer to help you remain on time.  In view of the large volume of people who are going to speak to us today, it will need to be rigorously enforced and I apologize in advance for intrusions upon you if you extend beyond your allotted time.  At the 30-second mark there will be a yellow continuous light that comes on in front of you, and then a red light at the conclusion of that time.

    I would finally like to address the issue of financial disclosure.  Both the FDA 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, 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 interest 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, however, 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 request to present in the open session.  Speaker number one, please come to the podium.

Open Public Comment

    MS. SILVERMAN:  Good morning.  My name is Ginger Silverman.  I am from California, and Inamed provided me transportation and my accommodations for coming to the meeting.

    Twenty-four months ago I was diagnosed with ductal carcinoma in situ, breast cancer.  That is the bad news.  The good news is that I basically had breast cancer for about seven days.  Because of my familiarity with the disease, all the statistics, my knowledge of the options that were available to me and the possible outcomes, I chose the most aggressive treatment available to me at the time.  I had a double mastectomy two years ago, and that happened one week after my radiologist's phone call.

    As a result of my early diagnosis and my aggressive proactive choices, I now have silicone breast implants and did not need radiation or chemotherapy.  The discovery of, and subsequent process of ridding my body of breast cancer held many miracles.  Finding the right doctors is probably at the top of the list; embracing the love of my friends and family who gathered around to support me through the ordeal; and learning a lot about myself, my courage.

    Surprisingly, my ability to heal was facilitated in an unanticipated way, my selection of silicone breast implants.  My plastic surgeon recommended them because I chose immediate breast reconstruction and I wanted to have the most natural look possible.  I have no uncomfortable side effects and I could not be happier with the results.  They have actually helped me in my process of recovering my life.

    I have a five-year old daughter.  Her name is Eve, and she has just started kindergarten.  She looks at life through very impressionable eyes and I made it my life's mission to be a healthy role model for her as I made it through the past two years.  I wanted her to see that she had a choice in the way that she dealt with adversity, and choice is the operative word in that.  Women who choose or need breast implants for any reason should be allowed to make an informed decision on the type of implant they choose.  Silicone breast implants are available in many other countries outside of the United States but no woman should be forced to leave the country in order to satisfy her choice.

    Just as I teach Eve she can choose the way that she lives her life, I am asking you to please let American women have the choice of what implants to put into their own bodies.  They have a right to make the recovery of their lives the best that it can possibly be.  Thank you very much.

    DR. PLETSCH:  Dr. Whalen, advisory panel, my name is Dr. Marie Pletsch.  I am a board-certified plastic surgeon and have been in private practice in Santa Cruz and Monterey, California for the last 34 years.  I took care of my own expenses to come to this meeting.  My only connection with Inamed is that I have been an investigator in their core study for silicone gel breast implants, and I have also been an investigator for some of their competitors.  I am not a witness nor a party in a pending lawsuit regrading these implants.

    I am grateful for having had silicone implants available to me when I was diagnosed with breast cancer in 1988 and underwent bilateral mastectomies and reconstruction.  The original implants were replaced in 1991, using McGhan, now Inamed, anatomic or shaped implants, not because there was anything wrong with the first set of implants but because I was undergoing a revision of my reconstruction and I requested changing of the implants for a larger size and more anatomical shape.  Please note, reoperation is not necessarily an indication that there is something wrong with the implant.

    I may be the only presenter before this panel that can boast a unique combination of having implanted approximately 1,000 women with silicone gel breast implants and over 200 of these have been since the restrictions in 1992.  In addition to that, I have implanted approximately 500 women with saline implants.  Added to this, I am a female plastic surgeon with implants myself and this gives me a more intimate view of the situation both from a patient's and a surgeon's viewpoint.

    When asked by my patients and the press, are these implants safe?  I confidently answer yes.  If they were not safe, do you believe that I would keep these implants and would not have them removed, and why would I continue to use them?  I have implanted silicone gel breast implants since the mid-1960s and since 1992 I have used them every time the FDA protocol allows them to be used.

    What I believe is a tragedy is the harm that has come to American women in many ways because of these restrictions.  I will list several of them.  First, many women were falsely frightened about effects of silicone implants and many had unnecessary surgery to remove them.  Some did not replace them with anything and were consequently deformed, causing physical and psychological damage.  Others replaced them with saline implants, only to find out saline wrinkled and sometimes deflated.  Some of these women then requested replacement implants with silicone again.

    Secondly, some women with various diseases have erroneously been led to believe that their illnesses were due to breast implants when, in fact, they were due to other causes.

    Thirdly, women who could afford it left the country to go to other countries that allow these implants.

    DR. WHALEN:  Doctor, you need to conclude, please.

    DR. PLETSCH:  American women apparently do not have the right to choose the type of implants.  The rest of the world uses these 95 percent of the time.  I was in Germany in 1998 at the ECWON meeting and they were shocked and horrified by the actions of the FDA.  I ask you to look at the scientific facts and to encourage the FDA to lift the restrictions.  Thank you.

    DR. HAECK:  My name is Phil Haeck.  I am a board-certified plastic surgeon, practicing in Seattle, Washington.  I have been in practice for 18 years and I am a plastic surgeon without implants.

    I am the editor of Plastic Surgery News, the monthly news magazine of the American Society of Plastic Surgeons.  This organization has paid my travel expenses to be here today.  I have no financial interest in any device manufacture or their subsidiaries of affiliates.  Breast surgery accounts for approximately 20 percent of my practice.

    I am going to address the issue of reoperation in breast augmentation surgery since it has not been given an adequate airing here from the standpoint of the surgeon.  Plastic surgeons dealing with the challenges of a practice in breast surgery are not at all surprised at the reoperation rates reported here yesterday.

    So, this is what I tell my patients who have decided to undergo a breast augmentation procedure:  You are about to begin on a road to satisfaction.  To get there may mean more than just the one surgery, the one you and I have planned.

    There are only two reasons for immediately going back to the operating room in the first few days after breast surgery.  Severe bleeding is extremely rare but if it is severe and results in a collection of blood around the implant a hematoma may occur.  Most of those will need to be drained in a short second operation.

    Likewise, an infection around the implant will need a short operation to drain the liquids off and possibly remove the implant for a week or more.  It can then safely be replaced.  Both of these are extremely rare problems that happen in less than one percent of cases.

    All other reasons for reoperation happen later, over the time period of three to twelve months after the operation, or rarely, even years later when an implant fails.

    Capsular contracture can and does occur.  You should expect that it could occur anywhere from three to ten percent of my patients, but if it happens to you and you need reoperation, then it will feel more like it is 100 percent, and it may be painful both before and after reoperation.

    After this, the reasons relate to just two categories:  My skills in correcting your preexisting asymmetry of your breasts, or the way in which your body healed or didn't heal correctly after the surgery.

    It is a rare patient that arrives in my office requesting breast surgery who feels she has a perfect match between her left and right breasts.  Many have quite a different appearance from side to side.  You are probably expecting perfection and it is my intention to give that to you, but there is always the chance that what seemed like adequate correction at the time of surgery may not prove later to be to your or my liking.

    I tend to prefer to err on the conservative side since that is always easier to adjust later.  Complex intraoperative decisions about the modification of the infra-mammary fold, release of the pectoral muscle, re-positioning of a drooping nipple, and differential sizing of the implants may not turn out in the healing phase to have been exactly what was needed to provide a mirror image.

    The more extreme the preoperative differences from side to side, the greater the likelihood that a second operation will be needed.  Nevertheless, these secondary surgeries are not drastic operations and frequently can be performed with local anesthesia.  The patient usually returns to her normal routine within 48 hours or less, and I do not charge the patient a professional fee for these surgeries.

    The difficulty here, in my opinion, is that we look at any reoperation as a statistic.  But breast augmentation surgery is a unique situation in the realm of all surgical procedures.  Lumping and minor scar revision go into data that also holds statistics for implant failures and reoperations for ruptures--

    DR. WHALEN:  Doctor, you need to conclude.

    DR. HAECK:  --which gives a dangerously over-jaded look into this situation.  We are in a unique predicament here that does not have the morbidity precedent in another area of surgery.  As long as both the surgeon and the patient expect perfection from this operation, there will always be another patient on tomorrow's surgery schedule somewhere who is not undergoing her first surgery.  Thank you.

    MS. SCHAMBECK:  Good morning.  My name is Susan Schambeck.  I am the recipient of gel implants made by Inamed Corporation.  Inamed has provided my travel and lodging expenses here.

    I would like to share my story with the panel.  I decided to have breast surgery in 1995.  I feel that my decision was well thought out, and my research led me to Dr. Pletsch, in Santa Cruz, California.  I was 36 years old and the mother of a two-year old son, Norton.  I had nursed him for a little more than a year and felt confident that giving him that kind of healthy start in life was a gift.  I felt complete with having one child to leave my legacy to and it was time to give myself a gift.  Since I have always been athletic and outgoing, I saw an opportunity to get my body back into balance.  Dr. Pletsch was very helpful in that process.  I knew that I was a good candidate for breast augmentation.  I knew that it would be a significant boost for my self-esteem and personal image.  These are the best years of my life and it is very important to have choices.

    I had my surgery in February of 1995.  My only choices were to have saline implants or live with the effects of nursing my son.  I chose the saline implants.  The end result of that procedure was that I had severely wrinkled implants that looked and felt unnatural.  In July of 1999 one of the implants ruptured.  After discussing my options with Dr. Pletsch and my family, I was able to choose an upgrade to silicone gel implants.

    I realized the difference in the look and feel of the silicone gel immediately.  It was far superior to the saline.  I am convinced that if I had had a choice, I would have chosen the silicone gel over the saline.  I didn't like the feeling of wrinkled water bags in my body.  They caused me to feel self-conscious.  With the silicone gel implants I feel that I have a very balanced and natural shape.  Nothing about the silicone gel feels unnatural.  The consistency is as close to the real thing as it gets and I am very happy with the result.

    I sincerely wish that every woman who is considering an enhancement or reconstructive surgery could some day have real choices from the beginning of her journey.  I personally feel honored to assist in that process.  It doesn't seem fair to me to require two surgeries in order to achieve a choice.  I am very happy and healthy with the gel implants.  It is difficult for me to reflect back on the emotional and financial burden that I have survived simply because I didn't have a choice in the beginning.  Please allow us to have choices.  Thank you.  I have copies for the panel.

    DR. WHALEN:  Please go ahead.

    MS. GODOY:  Yes, my name is Julie Godoy.  I am a U.S. citizen, married to a Norwegian, living in Norway.  I paid my own expenses.  I am not a professional speaker.

    DR. WHALEN:  Ma'am, and for everyone, the microphones are very directional.  So, if everybody, when they come up, would just make sure that they are speaking directly into the mike, it would help us.

    MS. GODOY:  Shall I repeat?

    DR. WHALEN:  You can just continue; that is fine.

    MS. GODOY:  Someone is going to read by speech, Jama Rosanna.  I am having some eye problems.

    MS. ROSANNA:  This is Julie Godoy.  She is a citizen, married to a Norwegian, currently living in Norway.  She is a breast cancer patient, implanted with silicone breast implants in 1980.  Immediately following her surgery, she suffered from an adverse reaction from the implants.  Monday morning, on CBS the President of the American Plastic Surgeons Society stated that the implant seeking approval has been used in Europe for ten years.  Tuesday, we were told that the implant has been used for 25 years in the U.S.A.  Obviously they are speaking about the old implants.  What is new?

    Europe has united their efforts to protecting their citizens against adverse and debilitated effects of failed breast prostheses on their women and children.  I flew here to see what new developments are pending with regards to the implant problem, only to find that there is no new device.

    There is nothing more than a facade--the same device, old product, new name.  I am having difficulty reading, sorry.  Recently, Inamed Mentor and McGhan breast implant manufacturers submitted new patents on breast implants, outer breast prostheses, shells and breast implant fillers.  In their own words, each patent identifies the failure of the design of the silicone sacs, migration of silicone oil outside of the implant and the toxicity of the silicone oil to human tissue, along with the medical literature documenting the failure of the prior devices.  In fact, all 73 breast implants from 1958 to 2003 have identified in great detail, with medical documentation, the adverse severe problems.  All previous breast implant patents document the high failure rate.

    For an example, in 1995 the Payman second breast Implant patent claimed that the Avalon breast prosthesis was porous so that it would absorb blood and other body fluids and become invaded by blood vessels and living body tissue, with the result that a sponge implant surrounding the body tissue became so interwoven as to permanently retain the position in the body.  Also, because of the infiltration of germs directly into the sponge, the fibers became more absorbent.

    Dr. Frank Gerro, in 1987, wrote in detail, severe adverse reactions to silicone breast implants identified human adjuvant disease comparing a ruptured implant to free silicone injections.  Additionally, escape of the silicone gel from the envelope of the prosthesis is associated with other adverse consequences in satelliting of the gel into various parts of the soft tissue around the prosthesis pocket down or into the arm.

    Recent data also suggests that the risk of infection in the surrounding prosthesis is increased following its rupture and free silicone gel in the prosthetic pocket.  He was the first to also identify death from a breast implant.

    In 2001, McGhan Medical Corporation filed for a patent for a filler material for a surgically implanted prosthesis such as breast implants--

    DR. WHALEN:  You need to draw to a conclusion, please.

    MS. ROSANNA:  --whiiich have conventionally used silicone gel.  Moreover, adverse consequences have recently become associated with silicone implants because it has been discovered that the silicone oil can migrate through the implant shell, and silicone oil is not biocompatible with the other human tissue.  Therefore, the use of silicone-based filler materials have been discontinued in the industry.  Those are their words.

    Dr. David Kessler discovered the addictive--

    DR. WHALEN:  Excuse me, you will need to end your comments, please.  You are over time.

    MS. ROSANNA:  Well, can I just finish the sentence?

    DR. WHALEN:  The very last sentence.

    MS. ROSANNA:  Dr. David Kessler found in the patents the addictive tobacco through the manufacturers' patents.  To date, we need to know what implant we are dealing with.

    DR. WHALEN:  I just need to reemphasize to everybody, in view of the first few speakers, we very much want to hear everybody who signed up.  Over the two days, we have about 110 such individuals.  The only way we can do that within the time constraints that I think have generously been set up for the public testimony, is to have everybody fulfill the time requirements that have been set for them.  So, please, if we could do so?  Thank you.

    MS. FEUSTEL  Good morning.  I am Holly Feustel.  I am receiving no compensation for speaking here today.

    Just over two years ago I had both of my breasts removed during simple mastectomies.  While the initial surgery and reconstruction were terrifying, the process was not new to me.  At the time of my surgery, two of my older sisters had already had the procedure.  Unfortunately, my family is intimately familiar with breast cancer.  The disease has taken my maternal grandmother, my mother, her sister and my cousin.

    While I have spent the majority of my childhood watching women die of breast cancer, my mother's and cousin's death have had the greatest impact on me.  I spent years of my childhood watching my mother experience the slow, painful death of fighting breast cancer.  When she died she was just 42 years old and I was nine.  I spent a year of my adult life watching my cousin and her battle with breast cancer.  At the time of her death she was just 36 years old and I had turned 21.

    You may be thinking that while my experiences are tragic, how are they relevant to you?  Well, my experiences are relevant because they are about choice.  At the time I had my mastectomies I was not diagnosed with breast cancer.  It was an elective surgery, my choice as the result of watching others die of breast cancer and discovering that my two older sisters and I possess the genetic mutation BRCA1.

    When faced with the results of my genetic testing, I chose to have a mastectomy.  I chose to have reconstruction following and I chose silicone breast implants.  I assure you that a lot of thought went into each of these decisions.  Perhaps the toughest choice was silicone versus saline implants.  Fortunately, when the time came to make that choice I had a wonderful plastic surgeon, years of sound research and the personal experience gained from two older sisters who already had the procedure.  One chose saline implants and the other chose silicone.

    I firmly believe that choosing silicone implants was the right decision for me.  I have no medical problems from my implants and I am pleased with the natural feel and shape of my breasts.

    I have come here today at great personal expense.  My husband serves our country in the U.S. Army and is currently away.  I have four school age children and I have traveled a great distance to be here for just three minutes.  My motivations are simple and selfless.  I want other women and my four young daughters to have the same options and choices that I had, and I thank you for your time.

    DR. ZOOK:  Good morning.  I am Elvin Zook.  I have been Professor of Surgery and Chairman of Plastic Surgery at Southern Illinois University School of Medicine for the past 30 years.  I am board-certified in plastic surgery.  I have no affiliations or conflicts of interest with the implant device manufacturers, and I have paid my own travel expenses to present at this hearing.

    In my practice of plastic surgery, I use breast implants in performing both breast reconstruction and breast augmentation surgery, and I derive a portion of my income from this type of surgery.

    Prior to the 1992 decision by the FDA, I actively used silicone gel breast implants for cosmetic augmentation of the breast, and since then I have used them for breast reconstruction, as permitted by the FDA under clinical studies.

    One of the sharpest criticisms leveled at surgeons during the 1991 and 1992 FDA hearings, and still today, is the perceived lack of adequate information given to the women before surgery regarding the safety of silicone gel breast implants.

    When using silicone gel breast implants in my own practice, I make every effort to inform patients about what is known about the safety of the implants, as well as the risks of potential complications that could occur.  I have found it is helpful to have sample implants available for women to see and feel during their consultation.  I believe this effort has been responsible for my not being threatened with any breast-related lawsuits.  I personally think patients should be educated as fully as possible on surgical procedures and materials.  They can then be free to make their own choice for surgery.

    Nearly one year ago I was asked by the American Society of Plastic Surgeons to chair a team to develop a patient information document to provide women with information on the risks and potential complications of silicone gel breast implant surgery.  A number of patient information documents were studied before we created this document.

    The group worked diligently to create what is now an online brochure, which you have, covering what is known about silicone gel breast implants, expectations of breast implant surgery, risks and potential complications.  Options for surgical placement of the implant are explained, as well as financial issues related to treatment of complications.

    The brochure includes color patient photos to visually illustrate some local complications.  It is followed by a series of questions to evaluate understanding of the effectiveness of the information and its validation.  We have tried to be comprehensive in our approach, recognizing that no procedure is totally without risk.  In fact, we all could agree that nothing in life is totally without risk.

    We believe that women who read and understand this information and ask questions should be adequately educated to make their own choice.  The brochure is available on the website of the American Society of Plastic Surgeons.  It is available to members of the American Society of Plastic Surgeons with the recommendation that they use it to inform women about breast implant surgery.  Thank you.

    MS. RAHN:  Good morning.  My name is Ruby Rahn.  I received breast implants after being diagnosed with fibrocystic and micromastia disease.  I have a similar story to many women who have made statements here.  I got breast implants.  After ten years I got very sick and once my implants were removed my health improved.  When I got sick I wanted to find out what happened to me.  I wanted to take responsibility for my health so it seemed reasonable to start to look for answers.

    I have spent the last decade trying to find answers.  In my search I came across an advertisement for silicone in an issue of Plastic and Reconstructive Surgery in which they talked about the wonders of silicone products.  It showed pictures of breast implants and other medical devices made of silicone, and I wondered if other products had problems too and I discovered they do.

    Wear debris is a well-known and documented complication of a long list of medical devices, including breast implants.  Wear debris occurs when implants age and degrade inside the body.  As implants degrade they start to break down into small particles.  They can travel to the lymphatic and vascular system into regional and distant parts of the body.

    To illustrate wear debris, I have included some photographs of breast implants that were removed from a friend of mine.  One implant is still intact, while the other shell has broken down and disintegrated.  These breast implants were removed en bloc where the implant and capsules were removed in one piece.  While the scar capsules held much of the silicone gel inside the elastomer, the elastomer shell broke down inside the capsules and is no longer visible.  What happened to it?  Where did it go?  And, what are the long-term effects of having an elastomer shell break down and migrate inside the body?

    When our immune system detects these particles, it responds by creating a chronic inflammatory foreign body reaction.  A similar foreign body reaction can occur when a splinter gets in your hand or foot, only in this case the inflammation isn't visible on the outside of your skin; the process happens internally.  Compound this reaction by having multiple implants over the period of 10 or 20 years and there is no question that you will develop a chronic inflammatory syndrome from countless splinter-like shell particles or wear debris.

    It is important to note that once the immune system becomes chronically activated, it leads to an ever-increasing attempt to destroy a foreign object that cannot be destroyed by the weapons our immunity has in its arsenal.  Our immune system is designed for destroying biological entities, not indigestible, man-made chemical composites like silicone elastomer.  In an attempt and failure to destroy these particles, our immune system chronically activates macrophages that produce destructive cytokines.  Cytokines and the chemical cascade they produce are implicated in a long list of serious health concerns, including depression, and may be the leading reason why so many women who have had breast implants have committed suicide.

    I strongly urge this committee to recommend to the Food and Drug Administration to further require long-term studies to investigate whether a cellular response to particulate debris is causing the health problems that hundreds of thousands of women, who have already had breast implants, are currently experiencing.  I think those are important questions to ask and understand before making breast implants available.

    Thank you for giving me this opportunity to make a statement.

    DR. WHALEN:  Ma'am, before you leave the podium, are you also going to be reading a subsequent statement?

    MS. RAHN:  Yes, I am.

    DR. WHALEN:  Do you have that with you now?

    MS. RAHN:  No.

    DR. WHALEN:  Okay, fine.

    MS. RUDICK:  Good morning.  My name is Nicole Rudick, and I am reading testimony for Donna Sims because she was too sick to be here today.

    My life with and without silicone breast implants: I am a 47-year old woman with no conflicts of interest.  I had silicone breast implants put in, in 1983.  In 1998, 15 years after implantation, I felt that my breasts were getting hard and painful so I had a mammogram done both in 1999 and 2001.  Both mammograms indicated very dense, fibroglandular breast tissue present.  The mammograms were so painful, they hurt so bad that if my breasts weren't stuck in the machine I would have been on my knees.

    I knew then that there was something really wrong with my implants, and I tried in every way I know how to find someone who believed me.  Finally, I found a plastic surgeon who is very reputable and took my problem seriously.  My plastic surgeon said that I had capsular contracture, grade IV, and I needed to get my implants removed as soon as possible.

    This is where the real problem starts.  My husband and I live on a low fixed income and I have no insurance.  We tried everything to get the money together for my surgery.  Finally my family came through with the money I needed for explantation.

    The surgery was scheduled for New Year's Eve, 2001.  The surgery was very painful and I was slow to heal.  The surgeon said that both implants were completely ruptured.  I had drains in for over a week.

    In October, 2002, ten months after explantation, I found two lumps in my left breast.  They were very painful and growing larger every week.  Again, I had to try to find the money before yet another surgery and, again, my family had to come up with the money to pay for my surgery.

    I had surgery in October, 2002.  The hard lumps turned out to be left over silicone from my explant surgery that had migrated throughout my breast.  Since then I have found two more lumps on my right side.  I can't afford another surgery.  I don't have any insurance and my husband and I are so far in debt I don't think we will ever see the daylight again.

    With my having silicone breast implants, I have not been able to find an insurance company that will insure me because of my implants.  I have tried to get help from my state government welfare program but I have been turned down several times because my husband and I own our own home.

    My hair has been falling out.  I have skin problems, dental problems and vision problems.  My entire body aches with pain and inflammation of my joints and muscles.  My memory is awful.  I have been diagnosed with fibromyalgia, polyarthritis, Sjogren's syndrome and silica.  I just don't know what is next.  The bills for all these tests just keep climbing and so do the illnesses.  Will this ever end?

    DR. BECKER:  Good morning.  My name is Dr. Karn Becker.  I am the president of a scientific consulting firm here, in Washington.  I have 15 years of experience in the development and clinical evaluation of innovative medical devices.  I have not been compensated for my professional time or expenses today.

    I came here because I was, as a woman and a scientist, alarmed at the misinformation being put forward in the popular press regarding these devices.

    Over the years I have contributed to the design and approval of many original PMAs and, in 1991, I prepared one of the breast implant PMAs considered by this committee.  My knowledge of the science and clinical experience with breast implants is extensive.  I have spent approximately 20 percent of my professional time over the last 13 years on one breast implant project or another.  As a result, I have personally reviewed thousands of studies--chemistry, manufacturing, preclinical, clinical and epidemiology.

    The past decade of research on this device has been productive and has considerably narrowed the focus of our questions regarding the performance or silicone gel-filled breast implants for reconstruction and augmentation.  Clearly, the product can be reliably and consistently manufactured.  The materials of which this device is comprised are biocompatible.  The short-term complication rates at two and three years have been reliably estimated.      The concern that these devices may pose a risk of long-term systemic toxicity or reproductive toxicity has been resolved by affirmative evidence from numerous well-controlled studies.  This data and information comprises valid scientific evidence sufficient to provide a reasonable assurance of safety and effectiveness for this device when marketed with adequate instructions for use.

    The premarketing clinical data provided in this application you are considering today, with three-year follow-up, is more extensive than that typically required for an implanted device.

    The data on the long-term performance of this device is, however, limited.  Premarketing studies do not provide data on rare or uncommon complications, nor on the long-term performance of implanted devices.  This committee is aware that questions of long-term performance are evaluated in the postmarketing setting.  Postmarketing studies for innovative implanted devices, although not required, provide the opportunity to study the performance of the device in a broader patient population, in larger numbers of patients, and over a longer period of time.  This information is essential for continued safe use and for continued product improvement.  For the silicone gel-filled breast implants under consideration today, the sponsor has proposed postmarketing research to assess long-term performance.

    I respectfully submit that this committee consider the approval of this product be accompanied by a risk management program to include three elements, number one, a mandatory informed consent; number two, a postmarketing study to provide clinical data on long-term performance, in particular, the incidence and prevalence of complications and device failure over time.

    DR. WHALEN:  Conclude, please, doctor.

    DR. BECKER:  And, third, a device retrieval program to study the changes that occur in the product itself over time, and systematically investigate the failure modes for this device.  Thank you for the opportunity to comment.

    PROF. DUBLER:  Dr. Whalen, may I pose a question for a moment?

    DR. WHALEN:  Yes, Prof. Dubler?

    PROF. DUBLER:  We have heard that there is a new application and new patents that have been submitted by the sponsor.  In your work, have you worked on these patent applications?

    DR. BECKER:  I have worked on some but I don't know the ones that you are referring to, not for this sponsor.

    PROF. DUBLER:  We have been told by the sponsor that the product under consideration by this panel is precisely the same product that was discussed in '91 and '92.  But there is also the implication that a new product is being developed.  Have you worked on this new product?

    DR. BECKER:  With this particular PMA, I am only familiar with the publicly available information.  So, I couldn't say, myself, whether it is exactly the same as the submission made in 1991.

    PROF. DUBLER:  Thank you.

    MS. RAHN:  My name is Ruby Rahn and I am reading for Lale Goddard, who is too sick to be here today.

    My name is Lale Goddard and I have no financial ties with anyone.

    In 1997, my breasts were augmented with silicone gel-filled breast implants.  In the mid-1980s, I started having joint pains and depression with thoughts of suicide.  I was diagnosed with bipolar disorder.

    In 1987, my rheumatologist diagnosed me with definite asymmetrical inflammatory arthritis or possible rheumatoid arthritis with atypical presentation, with poly arthralgia but with little joint swelling.  My bone scans showed signs of inflammation and my bilateral hand and wrist x-rays showed non-specific bone irregularities.

    In 1988, my bleeding sediment rate went up to 85 and X-rays of my hands and feet showed multiple bone erosions.  I was also diagnosed with fibromyalgia, anemia and seropositive rheumatoid arthritis.

    In 1989 I had my breast implants removed and both implants had ruptured and the elastomer shells had deteriorated, and my left breast was deformed.  I have joint contractures, ligament ruptures and severe osteoporosis and my right hand is deformed.

    Silicone elastomer used in solid or bulk form is biocompatible.  However, transformation of silicone elastomer of an intact silicone gel-filled breast implant, into particulate debris and the capacity of the particles to induce excessive inflammatory cytokine synthesis by macrophages and other cells, could cause particle-activated arthritis that mimics rheumatoid arthritis.  Unlike silicones, inflammatory and anti-inflammatory cytokines are biologically active proteins.

    Orthopedic surgeons refer to bone destruction due to macrophage activation by particles as a cellular response or particle disease.  They do not refer to it as immune response or autoimmune disease.  Scientific literature states that elevated inflammatory cytokines can contribute to the induction of depression and depression can lead to suicide.

    The FDA has recognized, in vivo and in vitro, testing standards of biological responses to particles and both standards state the following:  It is well recognized that the biological responses to particles could be different from those to solid materials.  The interaction of the particles with cells in the tissue, notably macrophages and other phagocytic cells, is the key to the final biological response.

    Please recommend to the FDA to require Inamed Corporation to do preclinical testing for biological responses to elastomer particles, less than 10 microns in size, prior to the approval of the PMA because it is relevant to women's health.

    If you have any questions, call me anytime at area code 916.444.1967 or send me an e-mail at lalegoddard@msn.com.  For a copy of my statement, go to my website at www.lalegoddard.com.  Thank you very much for your time.

    MS. CLARE:  Hello, my name is Erica Clare.  I am reading for Teresa Hamilton, who is too ill to be here today.

    My name is Teresa Hamilton, and I am from California.  I have no conflicts of interest.

    In 1986 I was diagnosed with breast cancer at the age of 29.  My left breast was removed because of cancer, and a month later my right breast was removed since I was told I had a one in three chance of getting cancer in that breast prior to menopause.

    After radiation treatments, I had expanders put in to stretch my skin out so I could have implants.  These were removed and temporary implants were put in a few months later, in 1987.  I still had problems with scar tissue so stronger implants, made by McGhan, now Inamed, were used to replace the other implants.  I looked and felt great for maybe two years.

    After that, I started to get allergies to nickel in jewelry and allergies to pollen and penicillin.  I also had repeated yeast infections and seemed to get more and more colds.  Being a single parent, it was getting harder to take care of my elementary school-aged daughter.  She would have to stay at my parents' house while I would try to recuperate.

    A few years later I noticed my right implant was getting harder.  The infections and allergies seemed to get worse.  Soon I was housebound and stayed that way for over five years.  Still, I was told my implants were safe.  By this time, my daughter was living with my parents most of the time since I was too sick to care for her.

    In 1999 I thought I had better have my implants removed.  The left implant was weak but still intact.  The right implant had dissolved completely, shell and all, into a gooey mess.

    I have since had a hysterectomy due to numerous fibroid tumors.  I now have a lowered immune system, fibromyalgia, a low thyroid.  I am constantly tired despite medication to help my fatigue, asthma, and foggy thinking.  I am 45 years old now.  I am slowly detoxing but I am still so ill I can't work except when I feel up to it, just a few hours a week.  Consequently, my parents, who are in their 70s, are having to take care of me and pay for most of my medication bills and all of my living expenses.

    I was in the Dow Corning settlement but I have only seen $725 for years of pain and suffering.  My chest is scarred and disfigured as a result of all the surgeries I had to have to put in the implants in the first place.  I don't believe that I will ever get the justice I deserve from all the pain, suffering and expenses that implants have caused me and my family.

    I have been cancer free for over 14 years now but I am still chronically ill from my silicone/saline implants and the right one rupturing and dissolving into my body.  I never had any of these health problems before having breast implants, but I am sure that having these implants has not only lowered my immune system but will also lower my life expectancy as well.  After all, they have been slowly killing me for years.  Thanks for letting me speak my mind, Teresa Hamilton.

    MS. ROBINSON:  Good morning, ladies and gentlemen.  My name is Cheryl Robinson and I live in the Damascus, Maryland area.  Due to the enormity of this issue and the fact that the safety and quality of women's lives are at stake, I am obligated and compelled to share my story.

    I have no financial relationships with Inamed or any other of its competitors.  My decision to choose silicone augmentation was cosmetically motivated.  Initially I was very happy with my decision.  My breast implants enhanced my self-esteem and promoted my confidence.

    It wasn't until ten years after implantation when I began to suffer with complications.  I noticed that my right breast began to harden, exhibiting signs of capsular contracture.  I also began to notice my left breast was getting smaller.  I now realize that was an early indication that my implants were leaking silicone from my chest into my bloodstream and tissues.

    Over the years I became very ill, presenting with a host of physical and neurological symptoms, for example, the inability to concentrate; profound confusion; and short-term memory impairment.  Eventually it became impossible to resume my family responsibilities and I was unable to support our lifestyle, and had only my husband's salary and mounting medical bills.  Keep in mind that before all of these symptoms surfaced I was very physically active; actually one of the few female jockeys in my early 20s and continuing to maintain my active lifestyle through middle age.

    When I was explanted both implants were found to be ruptured and had probably been so for a long time, though there is no way to predict exactly when the ruptures occurred.  My implants were considerably lighter than when originally implanted and the silicone that couldn't be removed during my en bloc procedure is still migrating throughout my body.

    I have been diagnosed with fibromyalgia, chronic fatigue, Hashimoto's thyroiditis and autoimmune related thyroid disease, and degenerative disc disease.  At the age of 49, I am left with the fears and uncertainties of what diseases or conditions may continue to surface.  For me, there is no doubt had I not made the decision to be explanted, I would not be personally delivering this short speech to you today.  I am absolutely, unequivocally sure that my implants were the direct cause of my declining health.  Of course, I suffer with depression as I live my life in chronic pain and am forced to accept the fact that there is no proven or definitive way to rid my body of the silicone that has migrated from my chest, ravaging and polluting my body on a systemic level.

    The data being presented on behalf of Inamed to market silicone breast implants does not reflect the long-term studies that are necessary to assess the possible safety and health risks that these implants may impose.  Silicone breast implants do not offer women a choice but, rather, offer women a chance to play Russian roulette with their health.

    I respectfully ask you, members of the panel, would you allow or encourage your loved one to be the recipient of such a ticking time bomb?  I hope the answer to this question is a resounding no.  Thank you for your time and attention.

    MS. DONNY:  My name is Stephanie Donny.  I am reading for Linda Dintino, who is too ill to be here this morning.

    My name is Linda Dintino.  I had one set of silicone breast implants, implanted in 1980, at the age of 27, when my breasts were removed due to fibrocystic disease.  Silicone breast implants were in my body for 13 years, until I was explanted in 1994.

    Within two months of implantation I developed migraine headaches.  Every day of my life for the last 23 years I wake with a headache that does not go away.  I was a healthy woman in 1980.  I had two beautiful, healthy children without any problems.  I was athletic even after implantation.  I was a very active mother of two boys, a Cub Scout leader and a secretary of the PTA.

    In 1987 I was forced to give these activities up, along with enjoying my children growing up.  You see, I was just too tired and hurt too badly to do these activities any longer.  I could not lift my arms above my head, the pain was too great, and I had slowly been losing upper body strength for years.  I literally had to sleep with pillows tucked in between my breasts while sleeping on my side because of the burning hot pain involved.

    When the implants were removed from my body, I learned that my right implant was ruptured.  I was left with a big gaping hole in my right chest wall.  My body would not heal properly.  I walked around with this hole in my chest for four months.  My scars were open on both sides and would not close.  Even the drainage holes where the drainage tubes were took longer than they should have to heal.  I dressed these holes in my body twice daily for four months, while green oozing slime came from them.

    I am only one woman in a sea of thousands, all experiencing the same problems, and the only common denominator between us is the fact that we all had silicone breast implants.

    Studies that are being touted as proving that implants are safe have been bought and paid for by the very manufacturers that produce them.  These manufacturers are not studying what we have going on in our bodies, the very women that were affected.

    We need real research.  We need for this panel to take a stand and demand that thorough research be done, not just a short-term study aimed at putting money in the pockets of the manufacturer.  Thank you.

    MS. SMITH-MILES:  Good morning.  My name is Becky.  I am from northern Michigan.  I have not been paid or reimbursed, nor have any conflicts of interest.

    I had silicone implants put in over ten years ago.  I developed capsular contracture within two years and had intense pain.  I wanted to be more beautiful with implants.  Instead, my breasts became scarred, hard and ugly.  I hid my breasts from my husband.  I could not jog, walk fast or jiggle my implants without experiencing intense pain.

    Within eight years I was diagnosed with a neurological disease.  I went from being a very athletic, active person to being physically inactive.  I was a registered nurse.  I worked daily prior to my implants.  I have had fatigue, aches, spasticity with numbness and tingling in my calves, toes and fingers.  My headaches are severe and every day.  I started to stumble while jogging.  With the intense pain and general ugliness of my breasts, I became depressed.

    A mammogram confirmed I had ruptured.  I don't know for how long.  My skin developed rashes and reactions to different substances.  I started to have blister-like eruptions on my fingers.  These were intensely painful, with burning and itching.  I would scratch, and scratch, and scratch until the top layer of my skin would come off.  Then I found that if I used my teeth and bit into them, I could feel a little crystal on my tongue.  As soon as I got that crystal out, it healed and it stopped burning and itching.

    My gynecologist noted my depression and he ordered the MRI which diagnosed me with an autoimmune neurological disease.  My implants and capsules were removed.  My histology has shown giant cell incursions around my capsule.  My blood work has tested positive three times for ANA.  I developed partial facial paralysis and extreme gait disturbances.  I have had silicone leakage in my chest, in my axillary lymph nodes and down my arms.

    For the last five years I have been having silicone eruptions surgically removed and they keep popping up all over.  My life since getting implants has changed totally and forever.

    I lost my job and became disabled.  I suffer periods of being bed-ridden for days.  I can no longer jog, ski, exercise or even walk without the assistance of a cane.  I can't help my son's soccer team or his football team.  I can't ride my horses any longer, which was one of my big passions.  I can't shop or go for a walk in the woods--that is totally out of the question, or even pick up my grandchildren.

    I have lost most of my friends and all of my social life activities.  I beg you to think about my limited life when you make this important decision.  Thank you for your time.

    MS. DOWD:  Good morning, members of the panel.  My name is Pam Dowd and I am reading the story of my friend, Myrl Jeffcoat, from Sacramento, California.

    Hello, my name is Myrl Jeffcoat, Sacramento, California.  My purpose for writing this statement is to tell this panel a little of my experiences regarding silicone gel breast implants.

    On December 7, 1994 I was implanted with MgGhan 3M silicone implants.  I was very pleased at that time with the cosmetic outcome.  But in mid-1998 I began experiencing health issues that were diagnosed and tested for, subsequently being put on propranolol, a beta blocker, for severe daily headaches, gait problems, extremely low blood pressure and heart rhythm problems.  I also had developed an involuntary head tremor.  Propranolol has been a wonder drug in containing many of these symptoms but not the daily headaches, which I continue having to this date.

    Later that year I developed thyroid problems and was put on thyroxine, and I was diagnosed with cervical uterine cancer and was given a hysterectomy in early in 1989.

    In the early '90s I began a severe bout with chronic fatigue and fibromyalgia.  My hair began falling out and became thin.  I still have fibromyalgia symptoms often and the persistent daily headaches.  On my visits and testing with my medical professionals during the late '80s and early '90s implants were never mentioned as being a suspected cause of my health issues.

    In '92 or '93 I read articles written about my health symptoms and illnesses being associated with breast implants.   The medical community simply doesn't want to go there with our illnesses with breast implant association.   They continue to this day to be in total denial of it.

    In about 1994 I was seen by Dr. Eric Gershwin, of the University of California at Davis, and he classified me as a category B on the old global settlement grid.  It has been approximately nine years now that myself and nearly 440,000 women in this country have been corralled in this travesty of justice, some of us having been paid pittances from what we were originally promised; others not being paid at all; and some that will never see a dime for the pain and suffering they have endured.

    Our medical bills, sent to the MDA, are being hidden in a shroud of secrecy while cloaked in an exemption of the Freedom of Information Act.  Yet, in all of that the silicone manufacturers continue to believe they can turn a profit selling these harmful products to the women of this country and other areas of the globe.

    For 40 years there has been no FDA approval of these products.  There has only been a long and endless trail of meaningless studies while manufacturers continue, with FDA's blessing, to put human life and health at risk.  The reason for my comment here is to implore the FDA to perform the job the American taxpayers pay them to do.  I request that they perform their own studies and tests on silicone implants and not rely on the biased studies of manufacturers who stand to gain financially while putting human beings at risk.  Thank you for your time.

    MS. DONNELLY:  Good morning.  My name is Kathleen Witter, and I am going to be reading testimony from Elaine Donnelly, who is too ill to be here.  She has no financial interest in Inamed, nor any other competitors, nor is being paid to submit her testimony.

    My name is Elaine Donnelly.  I am 44 years of age, and I reside in Louisiana.

    I was augmented with silicone gel implants at the age of 19.  I was a healthy young woman who worked effortlessly as a health and exercise counselor and attended a local university.  I loved the look and feel of my implants and I felt, although expensive for me especially on a college student's budget, it was something I deserved and that I had earned.

    After my implantation I began to experience capsular contraction.  I returned to my plastic surgeon and a revision was performed.  Again within a few months, capsular contraction occurred but I didn't have any health problems.

    Nine years later I began having severe health problems that my doctors could not diagnose.  They believed that I had some sort of autoimmune disease developing.  I spent a total of 27 months in the hospital over five years, having tests performed and repeated, yet no treatment or cure could relieve the symptoms I was experiencing.

    In February, 1994 I suspected my implants were leaking since my breasts looked noticeably smaller each day.  I was told to have a mammogram done to see if there were any abnormalities to my breasts.  That is when I found out that both of my implants had ruptured.

    One week later I had my implants removed.  Much of the gel was gone from each breast implant and cannot be retrieved from my chest cavity.  Any breast tissue that was contaminated with the sticky, unstable gel had to be removed surgically.  As a result, I lost all my breast tissue in both breasts.

    My breasts are now deformed in appearance, and I am not among those who are fortunate to have had their health restored after explantation.  Perhaps because of all the silicone in my body, my health has continued to spiral out of control and I have become homebound.  Many days I am to ill to even get out of bed.

    As a result of having been augmented with silicone gel breast implants, my health has been destroyed and my body has been deformed.  It is imperative that breast implants be studied at least a decade, not only a few years.  Most women who might have problems will not begin to show their problems for at least seven to ten years.

    In addition, since some women who might have problems will not be able to obtain health care through the private health care industry because many health insurers will not cover a woman with implants even if she is in fine health, they might become dependent on Medicaid and Medicare programs.  That is why our government has successfully sued several breast implant manufacturers for tens of millions of dollars to reimburse Medicare for the cost of care of women who became ill because of their breast implants.

    I implore you to vote against the request made by Inamed to approve their silicone breast implant based on such a short research study.  In addition, I have much faith that some day you will have safe implants and I look forward to that day.  If we can put a man on the moon, we can put out a safe implant and women deserve that choice, but we will only have a safe implant once that implant has been studied thoroughly and researched for at least ten years.  Thank you so much for your time.

    MS. HANSON:  Good morning.  My name is Georgiana Hanson and I am reading for Rogene Schorer, who can't be here today because she is too ill.

    My health took a downturn within weeks of getting silicone gel breast implants, beginning with chemical sensitivity.  It wasn't until 15 years later that I realized that my implants might have anything to do with my scleroderma, my fibromyalgia and my cognitive problems.

    Ten years after having my implants removed, most of my health problems have been reversed and, as long as I am mindful and follow a fairly strict health program, I feel well.

    I have been an activist in the implant issue from the time I attended my first support meeting.  It was there that I watched a group of young mothers learn for the first time that the health problems their children were experiencing were shared by the children of other implanted women.  That awful moment, seeing the shock, guilt and horror on the faces of those young mothers, has been my driving force since then.

    After all these years, I ask why is there still no definitive study on the effects of breast implants on unborn and nursing children.  Over the years I have communicated with thousands of women looking for information and support.  One thing we all have in common is a pattern of symptoms that are destroying our lives.  These women are from all walks of life.  They could be your daughters, your sisters, wives and mothers, maybe even your sweet little granddaughter some day.

    The women are often desperate.  Some see suicide as the only solution.  They are sick but don't understand why.  They feel, as I did, that they are dying without knowing why.  They are frequently in pain, experiencing cognitive problems, mood swings, allergies, digestive problems and neurological problems but the doctors can seldom define their illnesses.  Many doctors, especially their implanting surgeons, have been rude and dismissive.

    In the meantime, women often lose their jobs, medical insurance, savings, and sometimes their home and family.  Many of them end up struggling to survive on welfare and Medicaid.  Of course, those numbers will increase if silicone gel implants are approved.

    The marking of breast implants usually targets young women, often before they have children, before they are mature enough to understand how much their decision could cost over their lifetime.  The costs are not only in dollars, but in health, careers, insurance and relationships.

    Few women will visit the FDA's very informative website to learn about the risks before getting breast implants.  This company has not proven that silicone gel implants are safe, and so they should not be approved.  However, if women are allowed to use them as part of clinical trials, as has been the case for ten years, a third party should counsel them on all aspects of the study.

    In closing, each new generation of implants promises to be new and improved but, to date, all have failed to be safe in the long term.  There is a huge population of women who have already received breast implants.  Before subjecting more women to studies for new and improved implants, we need to study what has happened to those who already have them.  This disaster has been going on too long.  Do you have the fortitude to stop it?  Thank you.

    DR. WHALEN:  As the next speaker is coming up, just so everybody knows, each individual speaker has three minutes.  People who speak for organizations have greater periods of time.  For anybody who has yet to speak who is anticipating that they will have more than that amount of time--that will be only if somebody else has yielded time to you.  So, if you come up and you have more than three minutes, you could perhaps just tell us whose time has been yielded to you to allow you that extra amount of time.  Thank you.

    MS. GOLDRICH:  Good morning.  My name is Sibyl Goldrich and I am speaking on behalf of Wanda Simison, who is too ill to attend.

    I was diagnosed with a precancerous tumor in 1987 and, after a mastectomy, I used McGhan, now Inamed, gel implants.

    I developed aches and pains, eye problems and a general feeling of unwellness within two years, and was diagnosed with fibromyalgia in 1992.

    I saw over 60 medical doctors in North Carolina, Florida, Texas, Connecticut and New Jersey who could not give me a definite diagnosis for my illness.

    I became blind in my left eye and my health rapidly deteriorated.  I have been bedridden with dozens of symptoms since June of 1993.  I have been diagnosed with MS and lupus.  I was hospitalized for ten days at St. Mary's Hospital, in Connecticut, where they found lesions on brain and spinal cord, and an ANA of 180.

    I was then transferred to a different hospital where I spent another 53 days getting stabilized and prepared for explantation.  My implants were removed in 1993, and the right implant was leaking.  I was hospitalized for a total of 180 days within a one-year period due to illness and toxicity from breast implants.  I was explanted on my birthday, September 22, 1993, and felt better within 24 hours.

    I spent $300,000 on treatments not covered by insurance, and relocation to Houston, Texas for 18 months.  Gradually my health has improved and most of my blood work is back to normal.  I have not developed new lesions on brain or spinal cord.  My brain fog improved greatly after explantation, but depression is still a huge factor.  I can't handle stress of any kind; my diagnosis of fibromyalgia was taken away.

    It is the FDA's job to approve medical implants that are safe and effective.  I understand that cancer patients need some form of reconstruction, but it should be safe, not almost safe.

    Meanwhile, the United States Department of Health and Human Services is suing breast implant manufacturers for Medicare costs of ill breast implanted women.  Where is the logic?  What information that the company provided would convince that breast implants are now safe?

    Wanda has asked that I take the remaining time that she has.  Last night there were a few questions that came up about gel migration and I would like to read to you from the panel memorandum, page 37:  Cases of distant migration of gel to breast axillary lymph nodes, abdomen, groin, arms and fingers have been reported, some with serious consequences and deformities, for example, extensive migratory granuloma, formation of contracture, and scarring from gel extrusion and ulcerations described as a result of gel migration.

    Inamed also reported on the results of a physician survey in which five cases of migration were reported out of 114.  I just wanted to point out the location of that to you.

    I also wanted to mention to you that this is really a matter of common sense.  We are asking for ten years of study.  Breast implants are available.  Women can get them.  Nobody is being denied the product.  But we are being denied the appropriate studies to prove that this product is safe.  I implore you to give us the ten years.  This company will survive.  They are selling their implants.  Please, ten years of study.  Thank you.

    MS. ERICKSON:  Good morning.  My name is Jan Erickson.  I have been asked to present the testimony of Lois Travis, who is not able to be with us today.  Lois lives in Houston, Texas.

    Her testimony reads, I was happily married and the mother of two beautiful girls, working part-time in the hospital as a registered nurse.  After mastectomies in 1965 and 1971, I was encouraged to have reconstruction surgery will silicone implants.

    Four months after implantation I began having vision problems and was told that I had cerebral edema, cause unknown.  My physical strength and endurance declined and I could not continue my active lifestyle of cross-country skiing, mountain hiking and tennis because of muscle problems.  I did try to play tennis but it was difficult because of muscles cramping up and shortness of breath, and I would have to stop the game to catch my breath.

    In 1976, a rheumatoid workup was done and the results mentioned possible early connective tissue disease.  I lost half my hair and was told I would possibly have to wear a wig.  I also lost some of my smaller nails and my entire body peeled.  To this day, I have very thin hair.

    The implants were changing and I would notice slight differences in the shape and then tightening around them that started to cause limitations in my reach and range of motion in my arms.  If I reached too high it was a sharp, burning pain and if I lifted something, like patients, it was sore for days.  The contractures around the implants became very hard, painful, asymmetrical and distressing to me, especially when trying to choose clothing.

    In 1987, because of the pain and limitations, I sought medical advice and was told I needed to have the implants removed and replaced.  I foolishly agreed to be re-implanted with double-lumen implants.  After surgery, I was told that the ones that were removed were taken out in pieces because they had ruptured.

    I later suffered suicidal thoughts and was hospitalized.  I was dysfunctional, mentally dull, unable to care for my business affairs and unable to read and comprehend what I had read.  I still have difficulty following instructions, reading and writing my thoughts.

    In 1994, I was explanted after seeing a rheumatologist.  If I had known the damage silicone would cause to my body I would never have agreed to have the first ones put in, let alone the second ones.

    I am somewhat better since my second explant but I am still plagued with muscle pains, headaches, depression, burning pain in my hands and feet, stabbing pains in the deep muscles of my legs, arms and hips and last, but very important, severe chemical sensitivity.  If I start to enter an elevator and it has just been cleaned it triggers my asthma.  Strong odors and most perfumes will trigger an asthma attack.  I must have my inhaler with me at all times.

    Now I know that there was not sufficient research done to back the claims of safety of silicone breast implants, and the new Inamed research shows that there is still not enough research to prove that they are safe for the long term.  I hope my story helps you understand what those statistics mean; what it is like to live with breast pain and pain throughout your entire body; what it is like to have your quality of life decline year after year.

    Thank you for your attention, and I hope you will give great thought to our testimonies before you allow other women to possibly be burdened with this kind of history.  It is no fun.

    Additionally, I would like to--

    DR. WHALEN:  You need to conclude.

    MS. ERICKSON:  Excuse me?

    DR. WHALEN:  You need to conclude, please.

    MS. ERICKSON:  All right.  I am also handing a letter over to the members of the panel that is co-signed by a number of national organizations.

    MS. COOK:  My name is Jennifer Cook and I am here on behalf of Deborah Guillory.

    My name is Deborah Guillory and I had silicone gel implants inserted into my body at the age of 19.  I was fine at first, but years later I could no longer walk a straight line and my concentration and memory were very impaired.  I also suffered from fibromyalgia-type pain.

    I had the implants removed in March of 1992, and at that time the left implant was only half the size of the right implant, half the size it had originally been.  This meant that a great deal of leakage had occurred over the 22-year period that I had my implants.

    I am glad to say that my ability to think and concentrate has improved after the implants were removed and I can now walk in a straight line.

    I have had to take antidepressants since 1992 because of low-grade depression, which is consistent with the three recently published studies of high levels of suicide among women with implants.  A forensics pathologist found that I have large levels of platinum in my body.  The pathologist explained that this platinum was contained in the silicone gel implants.  I still experience fibromyalgia-type pains, like the women in the FDA's study of leaking implants, and I have been disabled and unable to work in ten years.

    The silicone implants with the thicker gel were not expected to ever leak.  Current implants are made with thinner gel.  But perhaps most important, you can't tell what will happen to someone's health until at least ten years later.

    I am now going through a divorce, and attribute this largely to the fact that I am unable to lead a life of normal activity level and my husband would no longer tolerate this deficiency that I must live with.  Silicone gel implants ruined my life.  Sincerely, Deborah Guillory.

    MS. VOSS:  Good morning.  My name is Gerie and I am 29 years old.  I have come to address this panel today to explain why I believe the restrictions against silicone implants should be looked at based on my own positive experiences with them.

    I began my painful struggle with breast lumps and eventually breast cancer at the age of 20 after six years of having breast surgeries to remove these lumps, and fortunately learning they were benign fibroids.  I was not so lucky in the year 2001.  That year I learned that I had severe atypical hyperplasia in my left breast and ductal carcinoma in situ in my right breast.

    As a result, at the same time that I was planning my upcoming wedding for the following year, I was exploring medical options with breast surgeons, medical oncologists, radiation oncologists and plastic surgeons.  I eventually decided to have a  nipple-sparing bilateral mastectomy with immediate reconstruction, a decision that would change my life, and certainly for the better.

    During my recovery period I had several saline expander injections into my breast between October 2001, my initial surgery, and February, 2002, my follow-up cosmetic surgery.  I was surprised to see that the saline expanders were quite visible beneath my skin showing folds, creases and dimples.  My research explained, and my plastic surgeon confirmed that such an appearance was common using a saline-filled implant.

    When it came time to order my new implants for my follow-up cosmetic surgery I was a little nervous.  Like many women, I had heard that silicone breast implants may be harmful to my health.  However, upon further research I learned that there was actually no evidence that silicone implants were directly responsible for causing cancer occurrence.  I am so glad that I did that extra research and I was able to learn the truth about silicone implants.  It was a huge difference in my recovery process.

    In a couple of weeks after follow-up surgery I was back to work, cancer free and feeling better than I had before the surgery.  I took the liberty of taking a slightly bigger cup size and, with the help of my plastic surgeon, got two perfectly shaped breasts, much better than after my earlier surgical biopsies.  As a result, I was able to get married in the wedding gown of my choice; danced all night long and have a wonderful honeymoon, not ever wondering whether everyone thought that my breasts might not be real.

    I realize that not all women are as fortunate as I am to have caught my cancer so early; have active professional doctors and the freedom to carefully consider my treatment options.

    While I know that these options did not totally eliminate my risk for recurrence, it gives me the best possible chance to not ever have to worry again about those fibroids and hear the words "you have breast cancer" again.  It also did something else, it was extremely important to my overall recovery.  It helped me to restore the confidence that I had lost during the whole process.  I am proud of how I look again.

    Hopefully, not every woman will have to go through what I have gone through, but I strongly believe we need to allow women who want or need implants the choice to decide which is best for them.  While the appearance of the saline implants may be fine for some women, it is not fine for all women, especially those of us diagnosed with breast cancer in our 20s and 30s.

    Please let us make informed decisions as to what we want to do with our bodies.  Silicone implants were the right choice for me and they may be the right choice for other women like me.

    DR. HELMAN:  Good morning.  I am Susan Pope Helman.  I have no conflict of interest.

    As I speak, please pretend I am your wife or someone you love very much.  A little over 13 years ago I was normal.  I had two children and took care of my mother who had Alzheimer's disease.  I had two jobs and put myself through college.  I was a productive tax-paying mom who enjoyed golfing, swimming, bicycling and long walks on the beach and in the mountains.  I never missed a day of work.

    Then, September 6, 1990, I made the biggest mistake of my life.  I trusted my plastic surgeon who stated that silicone breast implants were safe and they would last me a lifetime and I would go to my grave with them.  I assumed the FDA had determined they were safe or they wouldn't be available.  Boy, how wrong that was!

    Within about six months I started getting horrible headaches.  I couldn't think right and noticed that I was dizzy and nauseated an awful lot of the time.  I would lose my balance and feel like I was going to fall over.  I couldn't figure out why.

    During the second year all of my hair fell out.  I was diagnosed with fibromyalgia.  I couldn't concentrate and I seemed to be in a fog most of the time.  When the pain would come I would thrash back and forth in bed and I couldn't see; I couldn't focus; I couldn't get up.  My life was destroyed.  I lost a wonderful job.  I lost my car, my salary, my home, my productivity and my sense of well being as a person.

    The illnesses began with a vengeance around 1997.  Both breasts burned like they were on fire and they throbbed with pain.  I had sores, blisters in my mouth and on my hands that would bleed, as well as on my bottom all of the time, and I wondered why I felt so bad and couldn't figure it out.

    I had the implants removed in 1992.  The implants were only in my body less than two years.  In 2001 I found out the reason.  The capsules which contained bacteria and T cells and silicone were still left inside my body and continued to make me sicker.

    I also found out both implants had ruptured and all of the silicone was never accounted for.  Testing revealed that silicone had migrated throughout my entire body.  I have had brain scans that show lesions.  I was told that I have the brain of an old lady.  Other tests showed other neurological problems.

    Two years ago a plastic surgeon removed the remaining capsules and the silicone that had spilled out into my chest.  She said she couldn't get it all and I had to live the rest of my life this way.

    I was treated like a guinea pig in a horrible experience that never should have been allowed to happen.  Without the grace of God and my husband, there is no way I could have made it through this.

    If the FDA approves these silicone gel implants, we know that women will be told that the FDA has decided that silicone breast implants are completely safe.  I really want this panel to seriously consider the experiences of women like me.  My hopes are that you will make it clear that a company that wants to sell breast implants needs to provide at least ten years of good data before expecting their implants to be sold and approved by the FDA.  Thank you.

    DR. ANDERSON:  May I ask the speaker a question?  Ma'am, a number of people like you have testified about the serious and terrible experience that you have had and then said we want ten years of data.  My question to you is if they came up with ten years of data that did not show a connection between the silicone implants and the illness that you are experiencing, would you accept it as being that, no, there really is no connection, or is your belief that there is no question that these two, regardless of the data, are connected?

    DR. HELMAN:  First of all, my belief is the guidelines for safety in any situation, and particularly for the FDA, are "do no harm."  My feelings are if they are proved safe beyond any reasonable doubt, then I believe they should be available.  Thank you.

    MR. HELMAN:  I don't have any problem pretending that I love her; she is a loved one.  She is my wife.  I am Craig Helman.  I am angry about all the things that she doesn't and does talk about, and have to take all the drugs that she takes with the hope of just staying alive.  I lay there at night, watching her in bed, jumping around, jerking uncontrollably with pain, and watch her face when she is grabbing her chest because she is in pain.  I have lived each day of this and enough of that.

    With all the modern technology, I think that the manufacturers could invent something that is safe.  It seems to me like, no matter what they do with silicone, it is still migrating through these people.  Maybe they will make a better wrapper and it can't get out.  I don't know what they have to do, but they need to do something.  Until silicone implants have been proven completely safe--I don't know what to say.  I would like to see more independent long-term studies before the FDA can make any decision.  That is it.

    DR. BATICH:  My name is Chris Batich.  I am a professor of material science and engineering, and also biomedical engineering in University of Florida.  In the past I have served as an expert witness for plaintiffs and defendants in the breast implant area.  I only work with plaintiff attorneys part time.

    The National Organization of Women has paid for my room last night.  I am up here for an NIH study section so they paid for my travel.

    I would also like to thank the panel for having such an inclusive meeting in covering this information, and I would also like to thank Mary McDonough for the three minutes that she has provided for me to expand to six minutes.

    DR. WHALEN:  Doctor, what was that name?  That yielded to you?

    DR. BATICH:  Mary McDonough.

    DR. WHALEN:  Just to clarify, I have taken the time off and you will have whatever time was allotted to you.  She has given you three minutes or her entire time since she was representing her organization.

    DR. BATICH:  My apologies for running through this very quickly.  Of course, there is not a lot of time for a technical presentation.

    [Slide]

    I am going to talk about the chemical composition, the uncertainties in that, and the changes in the chemical composition of the breast implants and what should be known about it.

    [Slide]

    If you are going to put something in someone's body that is going to continuously release material during its entire lifetime by gel bleed or, occasionally, by rupture as a bolus you want to know some things about it.

    First of all, what is being released?  This is highly variable.  It depends on manufacturing changes and it is frequently not documented.

    You would like to know how much is released.  This is highly variable, depending on the women.  For one thing, the type of surgery--it is not a well controlled parameter right now for both implant reasons and for physiological reasons and biological response.

    You would like to know where the material goes.  There are major uncertainties about where the material is distributed through the body, and some good radiolabeled studies would resolve a lot of these issues.  Some of them are starting to be done now.

    You would like to know whether it undergoes any chemical changes.  Silicone is a really complex material.  It is highly stable.  It is used in transformers because of its chemical stability, but part of that stability is because it has a reversible hydrolysis.  In a non-aqueous environment it reheals itself.  In an aqueous environment you are going to generate small molecules, low molecular weight molecules, continuously.  Because of this equilibrium, you can never extract them all out.  There is some concern, for instance, that there is a new shell that is being introduced, a fennel-based siloxane.  There is a real question about what its small molecules will do.  As far as I know, these have been very little tested, except perhaps internally by Dow Corning.

    So, you would like to understand the chemical changes and then you would like to know what kind of responses you might expect from those types of chemical changes.  Then, with that kind of data you can start making some reasonable estimates of the kinds of things you would look for.  It is obvious that this is not a very straightforward problem but it is clear that there are some very active species coming out.

    [Slide]

    If you look at this slide, this is from a book on immunology of silicone.  There was a symposium at NIH in 1995.  I presented one of the introductory papers on degradation reactions right after Dow Corning got up and talked about background of silicone.  There were a lot of papers on immunology presented.

    If you just look at this schematic diagram, you don't have a solid fibrous capsule.  You have a synovial type cellular layer, histiocytic.  Those things pick up the silicone that comes out through bleed.  They pass into the tissue.  So, at the very least, you have a part of the immune system that is picking up these tiny particles, carrying them somewhere, doing something, and a lot of that is not tracked, not known.

    [Slide]

    One example of the changes--this is a picture of the cover of the book and this is a histology slide.  So, it is processed in xylene and, yet, you see residual gel.  The residual gel indicates some cross-linking has probably taken place to allow that gel to stay in the slides.  The gels have been linked to adjuvant type reactions, and all, so it is interesting, provocative but it has not been followed up on as to what happens here.  Also, very tiny amounts, when they are distributed to very tiny particles, can create tens of square meters of surface area and that also has not been related to dose response.

    [Slide]

    If you look at this slide, particles of gel, even from oil when there is no rupture, also show that they become a gel.

    [Slide]

    One of the postulated mechanism is you could have oxidation.  It is well-known that lysosomes can produce things like hydroxyl radical or other reactive species which are known to oxidize silicone.  There are hydrolysis reactions that are well-known.

    [Slide]

    I tried to look over a little bit of the mass of volume of technical literature that came out.  D4 is one of the most interesting molecules.  I only found studies from D5 on up.  Again, there has been no discussion of what phenyl-containing coupling agents do, and there are silanols which are known to be very biologically active.

    [Slide]

    Here are summary points.  I see my red light flashing and I will just try to finish very briefly.  There are a lot of things that could be studied that are not being studied.  You need some independent investigators funded by organizations like NIH to get in here and look at some of these things.  I think you definitely need to keep looking at the data and try to do a better technology analysis before these things are approved for non-regulated use.

    DR. MILLER:  Dr. Whalen, can I ask a question of this presenter?  I wonder what you would suggest to us in terms of how to address all these questions and the relevance of all these questions, given the fact that there has been no evidence that has linked the implants to disorders.  I mean, you can raise lots of questions, and I share your concern about wanting to understand, as detailed as possible, everything that happens with the implants, but the quandary that I find myself in is are we going to find something in answer to these questions that will make us discover that there are health problems associated with it?

    DR. BATICH:  Well, one of the ways to miss important information is to put it in a lot of different situations.  In other words, there are very many different types of implants out there, very many different kinds of materials are releasing at many different rates.  If you put some good data in a lot of mixed bad data, you are not going to see certain relationships.  Sometimes it looks like there are no problems at all; there are very positive responses from implants.  Other times there seem to be a consistent--I don't know--group of symptoms.

    A lot of plastic surgeons I have talked to say they think there is something really there but they don't know what it is.  I think it behooves us to try to identify the kinds of things that could be coming out, and then you can study and see if there is a dose response.  The immune system is involved somehow because of the macrophages, but what it is doing I certainly don't know.  That is not really an answer but it is not a simple problem and there isn't good data to resolve it I think.

    DR. MILLER:  Thank you.

    MS. GILBERT:  I have a question.  Alisa Gilbert.  On your slide number seven you are asking the question what materials are released and you mentioned D4.  What is it about D4 that you think should be looked at?

    DR. BATICH:  Well, D4 is the monomer that silicone gel is made from.  So, when you make the shell and the gel there is frequently D4 present.  It is removed in different ways but it is a stable molecule in the sense that it is reformed again at very low rates by the gel itself and by the shell.  So, if you extract it completely and wait a while, especially in the presence of any kind of catalyst like sodium chloride or something like that, it will slowly reform.  So, there are a number of toxicological studies of D4 that have been published by other people.  D3 is more reactive and it is also interesting.

    MS. MALNACK:  Good morning.  I am Marilyn Malnack, from Gilbert, Arizona.  I am here to tell you about a successful surgery, and 25 years after I can say I am still satisfied with my implants.

    I had them in 1978, and the reason I wanted to have implants was to make my body a little more symmetrical.  I have nice hips and a nice waist but I was totally flat in my breast area.  I found a surgeon that did a wonderful job.  He told me about all of the risks that were associated with having a foreign substance introduced into your body.  I listened carefully and took a few months to think about it, and my husband agreed that it would be a great thing to have.

    So, I went in and had gelicone--gelicone!--silicone gel implants inserted in 1978.  I am still as active as I was then.  I am a healthy woman of 54.  I am very happy that I had them inserted.

    I don't know what else to say, except every person's body is different.  Your body is never static; it is always changing and when you make the decision to have this stuff done, you really need to look at all of the risks that are associated and decide whether you want to take those chances or not.

    Implants are a totally optional surgery.  Nobody has to have it.  Women seem to want to have these things done because we feel like we need to be more perfect than we are.  So, I think that is why a lot of women have it done.  Everybody has their own reasons.

    But I saw in the newspaper a small article by Inamed, that they were coming here, in front of the panel, to try to get silicone approved.  So, I e-mailed them and let them know that I had them for 25 years, and they called me back and asked me if I would like to testify, and I am doing that for my own self and for all the other women that have had successful implants and are happy with all of the results.  Inamed did pay for my travel expenses but that is all.  Are there any questions?

    DR. WHALEN:  I think gelicone is a great word and you ought to get on the web and trademark that right now before somebody else does!

    [Laughter]

    DR. CHOTI:  A question for you, how are you following up?  Are you concerned about leakage or rupture at this point, or what is your plastic surgeon telling you?

    MS. MALNACK:  You know, I haven't gone back to see my plastic surgeon because I had it done in Washington.  I am very aware of my body.  I am always looking at it, checking it and I think I would know if anything was leaking.  Some people are more in tune with their bodies and really, if you are going to have a foreign substance introduced, you really have to pay attention.  Even though it has been 25 years, I know that I can change and I am changing, and you always just need to pay attention to what is going on.  You can't just put them in and forget about it and go along with your life.

    DR. CHOTI:  What about mammograms?  Are you concerned at all about getting mammograms?

    MS. MALNACK:  Yes, I have had two mammograms and everything is normal.

    DR. CHOTI:  But it doesn't bother you about compression or worry about damage to the implants with the mammogram?

    MS. MALNACK:  No, but it does kind of hurt.  Ouch!  Of course, it does for all women.  It is not a pleasant procedure.

    MS. RUMSEY:  Hi.  My name is Leslie Rumsey.  I am from Pennsylvania.  I have no financial interest in this issuel; I have a very passionate interest in it though.  I had a little speech written but I sort of wanted to speak from my heart a little bit more.

    I was diagnosed with stage 0, non-invasive ductal and lobular carcinoma in situ in November of 2001.  Very delusionally, I thought at the most I would need was a lumpectomy and I would move on with my life.  I was told, however, that I needed a bilateral mastectomy and my world just came crashing down.

    I didn't even know how to deal with it.  I had two young children, two younger step-children, and there was no choice, breasts are removed and you go on from there.

    I researched on the Internet, talked to doctors, talked to nurses, talked to survivors about my choices for reconstruction.  They sort of dangle that out there for you, like everything else is minor--you are going to look great immediately after surgery.  I researched it all, and sort of wavered between saline and silicone implants until I had the expanders, and they were just very difficult for me to deal with.  They felt hard; unnatural.  My children couldn't nestle up to me.  I was used to them nestling up to me.  So, I made the decision to go with silicone implants.

    I had that done in June of 2002 and I have never regretted that decision.  They feel natural.  They look natural.  My children can lay against me.  It is just the most wonderful feeling.

    When you have seen yourself with breasts removed, and scars and the impact that has on you, it takes an hour just to get undressed for a shower, and in a short period of time, to look the way I look now, I can't describe in words how wonderful that is--to be able to show my daughter that you can have breast cancer and you don't have to fear it the way I feared it when I was growing up.  The movie of the week--you wake up; no breasts; your husband leaves you.  She doesn't have to face that.  She looks at me and she doesn't even see anything different about me.  So, that is something I really treasure.

    I have so much compassion when I hear what the women who have had negative results feel.  I listen to that and I would still make the same choice, and I would go through it, knowing that I am responsible; that I would need to go back to my doctor; I would need to know what is going on and take responsibility for my own physical health.  But it is something where I would still make the same choice for and go ahead with.

    In 2001 I was a victim of breast cancer.  When I had my bilateral mastectomy I became a survivor of breast cancer.  But I feel with all my heart that when I had the implants installed I became a thriver of breast cancer, and that is something I wouldn't change.  Thank you.

    MS. DOLLIE:  Good morning.  My name is Nikki Dollie and I am a silicone survivor.  I have no financial affiliations with anyone, except the next speaker that is my husband.  He drove 30 hours to get us here as it is that important for us to ask you to vote no to silicone.

    I have heard much talk of silent ruptures and that is a grave concern, but I talk of silicone gel as my personal, silent killer.  I was implanted in 1992 with silicone gel.  Had you observed me one year later or eight years later, you would have been observing a healthy, active, happy, trial attorney.

    I have developed a plethora of symptoms over a very short time span, and I was in a wheelchair with many symptoms identical to those experienced by what I call my silicone sisters.

    After explantation and removal of lymph nodes in my armpit and over my lungs in the year 2001, approximately six months after I first developed symptoms, I was out of the wheelchair within 72 hours of explantation.  I began immediate improvement in other areas as well.

    As a result of my gel bleed, my lymph nodes were saturated with silicone.  That is the pathologist's report.  No rupture.  My life was destroyed.  That is me, my victim's report.

    Today I am a shut-in, sharing many of the same diseases with which my silicone sisters suffer.  My life is a nightmare of illnesses and surgery after surgery.  Yes, that is one quick sentence but it is about the end of my life as I knew it.  This is the story of a gel bleed, ladies and gentlemen, and the devastation of my life and countless lives, my fellow implant survivors.

    I moderate an international support group for my wonderful women who can't be here:

    From Joyce in Pennsylvania--she asked me to tell you please do not approve the manufacturing of implants to kill the next generation as it is killing ours.

    From Kay in Oklahoma, we are the studies; the sisters.  I ask you to look at our bodies and consider the mail you have received about our pain and tell me how you can even consider placing a toxic killer back on the market.      From Rosanna in Florida, there is not enough research on these implants.  I have personally been very ill following a rupture.  I have worked with thousands of women over the last ten years that are sick and dying from the very same symptoms and diseases.  Why not study us?  I am the evidence.  We are the evidence, the women.

    From Colea in Washington, no one should receive silicone implants without being tested for sensitivity to silicone.

    From Susan in Texas, it is important for you to realize that despite suffering the ill effects of silicone, we represent someone's mother, child, sister, spouse, friend, etc.  We are important people and something horrible has been done to us with our exposure to silicone.

    From Michelle in Louisiana, please do not allow silicone to be the silent killer of the next generation as well.

    From Linda in Texas, having breast cancer at 29 was devastating.  Getting reconstruction surgery, recommended by my plastic surgeon, with implants--

    DR. WHALEN:  Ms. Dollie, you need to conclude, please.  Could you conclude, please?

    MS. DOLLIE:  Yes.  I just have two more.

    DR. WHALEN:  I am sorry, you need to come to your concluding sentence.

    MS. DOLLIE:  Ladies and gentlemen, based on what I have experienced with what was determined to be just a silicone bleed--and I say just a silicone bleed--very seriously, I ask you to vote no to silicone gel.  It was determined I had no rupture.  My pathologist's report showed that removal of the silicone in my lymph nodes is what allowed me to start breathing again.  I have had silicone removed, or about to be removed from my hands and my feet.  I don't believe this is a normal process of aging, and it took almost nine years for the first symptom to present.  Prior to that I was a happy, healthy, working attorney.  Had I known this would happen, had I been warned, I wouldn't be here today and I implore you to vote no.  Thank you.

    MR. DOLLIE:  Good morning.  I am Mike Dollie.  That was my wife, Nikki.  I have no financial affiliation with anyone.

    I don't have a clue what I am going to tell you.  I just want to speak from my heart here for a minute.  I have watched my wife go from a very athletic, very professional, vibrant attorney to a woman who is held captive in her own home, who can't get out of bed in the mornings until I bring her her pain meds.  Then, she is still there for a couple of hours till they take effect.  I have watched her go from somebody who is a published author to not being able to concentrate enough to read the newspaper.  I have watched her go from a woman who helped everybody do everything to somebody who now has to have someone help her.  It breaks my heart to see what has happened to her.  Everybody who knows her, knows what she used to be and what she is now.

    So, we ask jointly, as a couple, that you vote no in this situation.  Thank you.

    DR. LYKISSA:  Good morning.  My name is Ernest Lykissa.  I have been involved in the last--oh, since the years '89, '90 with silicone breast implant research.  Presently, I am involved in forensic and clinical toxicology in the city of Houston.

    When I was affiliated as a professor of clinical and forensic toxicology with Baylor College of Medicine in Houston, I was able to do extensive research with these particular devices.

    Oh, I forgot--my affiliations are that the National Organization of Women paid my ticket to fly up here and also paid for my stay last night in this hotel.

    In this Power Point that I present for you, I just summarize in the first four pages some research that was performed with mice at Baylor College of Medicine.  In order to remind you, this particular work was done at the time when we were told that silicone was inert, that there was no toxicity associated with it.  We were able to prove that there is an LD-50 associated with cyclosiloxanes.  We were able to prove, in our paper in Analytical Chemistry, that both the silicone and the platinum catalyst that is included in the low molecular weight silicone oil in order to polymerize that mixture and make it a good fill for the envelope so that it can be implanted in a human being, that material was passively leaking out of the porous envelope.  We were also able to show that there were toxic effects in the mice to the point where we also had death due to fatal hepatic and liver complications--hepatic and liver, I am sorry, I mean hepatic and pulmonary complications with the mice.

    As I said, in the second paper that I have there, we are showing also that platinum was being released in a very significant manner from those implants.  What we were saying was that the devices were depolymerizing with aging.  Remember, we worked not with brand-new, shiny implants.  We worked with devices that had been explanted from women after they had been in situ for a period of up to ten years, sometimes more.

    It seems that these devices, when they were manufactured, had convinced the manufacturers that they were a good device.  And, I agree with them.  They were looking at something very shiny, off the show room.  The problem is once you put it in a human body, once you subject it to the rigors that those ladies that were being implanted were subjecting them to, those devices were coming very quickly to a very high failure rate.

    I am not talking about ruptures now.  I am talking about where optically you can look at the device and you see nothing wrong with it.  Of course, you see some small tears.  If you put it under the microscope you see a lot of different things happening.  The fact that the capsule is formed by the body shows you a very strong reaction of the body.  It is rejecting it like a cyst.  It is encapsulating it like it was a cyst.

    So, we know that from day one that the body is not reacting very well.  In the old days the plastic surgeons were known to literally hit the women in the breast with a two by four literally to break the capsule because they would get hard.  Women obviously didn't want their breasts to be hard.

    After Baylor College of Medicine, in the laboratory, was able to test women that had been implanted and had been explanted, we were able to test their blood, their urine, hairs, nails, sweat and so on and so forth, and what we found was that there was still silicone.  Obviously, the silicone that had migrated in their body, in small foci throughout their body, was still releasing D4s, D3s, D5s, D6s, D7s, and so on and so forth.  These are the low molecular weights that get polymerized with the introduction of the catalyst of platinum and put in a gel form from the oil.

    So, once we had that situation, we found that these materials were still present in their bodies.  Some of them were worse than others.  Let's don't forget that it is not one breast implant out there, there are a lot of models.  There are a lot of batches.  When they were manufacturing them, if the batch did not gel properly according to the formulation, they went in and sprinkled a little more hexachloroplatinic acid or whatever else they needed.

    So, we are talking about a little bit of alchemy here.  We are not talking about chemistry; we are not talking about a controlled science.  Remember, these devices were not produced under strict controls.  I am talking about the early days.  Slowly, as we saw the symptoms being developed, as we saw women complaining, they went back and they used that as quality control.

    Of course, they attacked everything the scientists were trying to do by saying we have financial--you know, obviously I am not a millionaire and I am not going to make my living doing this, but what I am here to tell you is that my research has shown that these particular devices, with time they are like tires.  They have enough mileage on them and once they get enough mileage on them they will fail.

    So, I implore you, in your decision-making that you take that into consideration--that you ask the manufacturers to provide you with data that they have done stress testing on these devices.  I implore you, like you do with aspirin and like you do with vitamin pills, put an expiration date on these devices.  Demand that the manufacturer puts an expiration date on these things.  Just tell them, based on their studies, based on your decisions, I implore you that you do that because, if you don't do that, your names will be known to many of these women and somebody will be testifying against you.  Remember that.  You are handling here human lives.  I took an oath to cause no harm--I don't know about you--and I uphold that.

    In the last conclusive evidence that I am going to give you here so I can let other people talk to you about more important things, I think the recipients of these devices should be forewarned of the increased risk of the systemic toxicity with prolonged implantation past those expiration--

    DR. WHALEN:  Doctor, would you conclude, please?

    DR. LYKISSA:  I am done, sir.

    MS. GILBERT:  I have a question.  You don't have page numbers, but in the platinum in samples of women with silicone gel or silicone saline implants and their children, how long out did you do your studies?  I mean, how far away were the women from implantation and what about children?

    DR. LYKISSA:  As I said, you have to remember that these were not every case that we tested.  At the time we tested it, it was a custom case.  I mean, it was not like some type of--to answer your question, I will say that we tested these women with their implants, we tested them for a period of about two months to three months in vitro in order to see what they were releasing in our laboratory under the conditions that simulated the human body.  When we tested them, as I said, with the saline implant we did not find any toxicity to talk about that was, you know, very significant.  But with silicone breast implants, I can guarantee you.

    The Germans have confirmed our research.  So, I can stand up here and tell you that our research is valid and you can look at it with scientific criteria that has been published in Environmental Health Perspectives, American Journal of Pathology, Analytical Chemistry.  So, we are not talking here about, you know, something that came out of somebody's closet.

    DR. MILLER:  Can I ask you a question also?  Could you tell me about ExperTox?  How long has ExperTox, Inc. been a company?

    DR. LYKISSA:  ExperTox, as I said, is a clinical and toxicology laboratory and has been in practice now since the year 2000.

    DR. MILLER:  What percentage of your studies are done related to silicone problems?

    DR. LYKISSA:  I would say less than five percent.

    DR. MILLER:  So, you do toxicology testing--

    DR. LYKISSA:  We just do toxicology, sir.  We just have ICPMs, DCMs, LCMs, all the best technology.  You give me the samples; I give you answers.

    DR. MILLER:  And one other question, you know, you list a lot of toxic appearing things and you say that the longer the implant is in, the increased is the risk of toxic, you know, systemic effects.  Yet, we have no epidemiologic data that suggests there is a linkage between systemic illness and the implants.  So, how do you square these epidemiologic studies and the questions raised by this kind of information?

    DR. LYKISSA:  Well, the epidemiologic studies were not our concern.  We were testing patients, individual patients.  Obviously, the patients that had problems came to us.  The patients that did not have problems, they had no use for ExperTox.  The people that I see in my laboratory, sir, they are all suffering from some kind of toxicity most of the time.  The best news you can get out of my laboratory is that I found nothing and that happens very rarely, unfortunately.

    In these particular cases, the patients that I tested, they had been seen by rheumatologists, dermatologists.  They were suffering from silicone deformities.  They had sores on their bodies.  I mean, a very obvious disease state had established itself in their bodies for a long time.

    So, how do I square it off?  Believe me, I have seen enough people and enough sickness to tell you that I am so convinced of this, and I am very hard to convince, I promise you that--the people that I have seen have been sick, and I know that the fact that we have hexachloroplatinic acid release from those devices, which is an alchemist's product--it is platinum treated with aqua regia, for crying aloud, from the 1400s.  You know, we have this material released from the body.  I know that is the reason for the sensitizations and I know that the silicone, when it starts being released in the body, just adds to the burden and that is what breaks the camel's back.

    DR. MILLER:  Thank you.

    DR. LIEBERMAN:  I have a question.  You clearly have this data and clearly there is a lot of variation in the symptoms--

    DR. LYKISSA:  Oh, yes.

    DR. LIEBERMAN:  So, I wondered if you could help us to think about what factors might influence whether a woman has symptoms or not.

    DR. LYKISSA:  Okay, I will start by telling you that since all my graduate work up in Montreal, in medical school and following my graduate work with a Ph.D. and all these other things, what I learned was let's not forget the DNA.  Let's not forget the genetics here.  So, we have predispositions from the genetic factors.

    Number two, which makes it very complicated for any one of us in this room to have a clear understanding of what is going on, there were multiple models of breast implants.  There were the Dow Corning; there were the McGhan; there were this; there were that.  There were batch variabilities.  We went in and we tried to make ends meet.  So, this is another factor, what is the device you are talking about?

    We are all standing up here like, you know, the monkeys in 2001, trying to tell you that we know what the fact is.  We don't know what it is.  These are devices that were manufactured under different conditions.  So, these are the factors you want to look at.

    Then, number three, and very important, is the life of the woman.  What is she going to do with her body?  Where is she going to live?  Is she going to live in a cold climate?  We found out that as you turn the temperature up these materials depolymerize a lot faster.  So, if she is going to live in Florida with her breast implants versus Upstate New York, we are going to have different factors there.

    Also, we found out that lipophilicity--you know, the pores on the envelopes seem to allow this migration and depolymerization in the presence of stearic acid, for example, which is the human adipose tissue.  Also, unsaturated fatty acids seem to help that material.

    So, I can stand up here and tell you that I know but, you know what, I really don't know.  I wouldn't want your job.  Thank you.

    DR. LIEBERMAN:  I have one more question.

    DR. WHALEN:  I am afraid that is all we have time for right now.  We will try to maybe come back to it if we can, because we have multiple other speakers that are coming.

    I do want to let the audience know, especially the people who have spoken who wonder why different people get different periods of time, we have tried to make that announcement in advance but we weren't able to at that particular time.  But one of the subsequent speakers did donate five minutes of their time to the doctor.

    MS. SHEPPARD:  Good morning.  My name is Audrey Sheppard.  I live locally and have no conflicts.

    I headed the FDA Office of Women's Health for four years, from 1996 through '99.  Regarding silicone gel implants, these years produced an action-packed time.  My office worked closely with the Center for Devices to meet repeatedly with industry and women advocates to revise the breast implant booklet and place it on the web, and to sponsor FDA's rupture study and more.

    I left the FDA nearly four years ago.  Perhaps distance creates perspective.  So, let me summarize what I see as key considerations as you mull this critically important decision, whether to recommend that FDA approve the devices for widespread augmentation as well as reconstruction, releasing them into the bustle of the marketplace.

    One, as we have heard, over time silicone implants rupture and cause other significant local complications.  If approved for augmentation, considering the increased popularity of them, ultimately millions of young and middle-aged women are each likely to face a number of additional surgeries.  Based on the duration of the data submitted, it is certainly impossible to conclude this will not happen with the devices you are considering.

    Two, we are told various neurological diseases, perhaps atypical syndromes, can't be ruled out in a subgroup of implant recipients.  Here we have met and heard the personal stories of some of these women and their illnesses.  I would suggest that FDA has the responsibility to them and future women to apply a high standard for establishing reasonable safety.

    Three, FDA approval is the gold standard.  Should there be approval, consumers and physicians will take this as a clear indication of out-and-out safety.  You are well aware that augmentation is not a medical necessity which would justify a high degree of risk.

    Last, if FDA were to condition approval on rigorous post-approval requirements, this would be well intentioned but could not be successfully enforced.

    I see my time is getting short.  Inamed's proposed postmarket surveillance by mail seems less than stringent.  Placing much stock in hopes of meaningful postmarket data down the road is no substitute for a hard up or down decision now.

    I have been immensely impressed with the seriousness of these deliberations.  The health of millions of women rest in your hands.  Thank you.

    DR. CONNELL:  Good morning.  I am Dr. Elizabeth Connell.  I have been kindly yielded some time from Susan Lynch Hunt.

    I am currently Professor Emeritus in the Department of Gynecology and Obstetrics at Emory University School of Medicine, in Atlanta.  I appreciate this opportunity to present my experiences and views to this panel.  I have no financial relationship with Inamed and I have received no compensation or reimbursement for my appearance today.

    For more than 50 years I have had the privilege of practicing medicine and providing health care to women.  I began as a general practitioner in rural Maine, following which I received training in OB/GYN.  I then went into practice and also developed clinics for women in Spanish Harlem and at Columbia University in New York City.

    In addition to being a health care provider during these years, I also had the opportunity to conduct numerous research projects.  I have published over 200 scientific peer reviewed papers.  I also served five years as Associate Director of Health at the Rockefeller Foundation, and worked with the U.S. AID as a member of the agency's research advisory committee.

    I have also had a long involvement, starting in 1970, with this particular agency.  I have served on seven different advisory committees.  I have chaired three of them, including the first one dealing with silicone breast implants.

    To go back more than a decade now, I was invited to chair this panel when it was convened in November of 1991.  We were given two major charges by the then Commissioner, David Kessler.  First, we were to evaluate the PMAs of four companies who had submitted data on their breast implant products.  Then, we were to advise the FDA as to whether or not the PMAs were adequate for approval.

    Second, we were asked to determine if there was a public health need for silicone gel-filled breast implants.  In this context, we were to decide whether particular groups of patients, specifically those who had undergone major breast surgery mainly for breast cancer or for significant deformities, should be viewed as distinct from the larger group of women who were receiving implants for augmentation.

    Following three arduous days of hearings from dozens of witnesses, our panel deliberated and determined that the data from the four manufacturers were not complete enough to warrant approval at that time.

    However, I think it is critical to note that this was in no way a statement that we found these devices unsafe.  Nor did we determine that they posed a health threat to women who had received them.  Had we determined at that time that this was the case, we would have recommended that they immediately be removed from the marketplace.

    As to the second mandate, whether they met a public health need, we agreed there was ample evidence that they held a significant importance for both reconstruction and augmentation patients.

    Early in the following year, February of 1992, I again chaired this panel.  Before the follow-up meeting occurred, the FDA had asked for a voluntary moratorium on silicone breast implants pending evaluation of new evidence that potentially linked implants with autoimmune disease.  This time also Dr. Kessler gave us a mandate.  We were not to revisit the decisions regarding the PMAs that we had made at the previous meeting.  Because of the new information, he asked us to consider two questions.

    First, given several concerns, including leakage and rupture of the implants, what information should be given to women who already had them?  Second, given the new information, should these devices be allowed to be used in the future and, if so, under what conditions?

    After three more intense days of testimony and deliberation, we concluded again that although more research was necessary, there continued to be a public health need for these devices.  We recommended that women always receive the best available scientific information before using these devices.  We also concluded that there were no scientific data indicating that silicone implants posed a significant health threat to women, especially in the area of connective tissue or autoimmune disease.

    In summary, we determined that silicone breast implants should continue to be available, but that more study was needed to answer the remaining safety questions.  The panel also recommended that these implants be made available to all individuals who needed them for reconstruction, most particularly women who had breast cancer.

    Additionally, the panel recommended that some women be allowed to have these implants for breast augmentation so long as their surgery was conducted under clinical protocols, designed by appropriate agencies and organizations such as the FDA, NIH, plastic surgeons and other relevant groups.

    Over the past decade, I have continued to review the growing body of scientific evidence regarding the safety of silicone breast implants.  There, as you know, have been numerous studies, both here and internationally, carried out by recognized professionals seeking evidence-based information on this issue.  They have been conducted by such prestigious institutions as the Mayo Clinic, Harvard Medical School, the University of Michigan and Johns Hopkins, and the United Kingdom Independent Review Group, among others.  It is now 2003 and I believe that today there is sufficient valid evidence to answer the questions that we posed more than a decade ago.

    To put this issue into proper perspective, I believe that all of us have a stake in this matter.  We need to have confidence that medical and health policy decisions will be grounded in legitimate science.

    In conclusion, I believe that you are fortunate to have more than a decade of new research to consider, information that, unfortunately, was not available to us during our earlier meetings.  I continue to believe there is no evidence for significant health risks to women and that for many women the benefits will outweigh whatever risks there exist.  I think it is critical, and we said this very clearly in 1992, that women need to be given the best available evidence at the time that they are considering the use--

    DR. WHALEN:  Can you conclude, please, doctor?

    DR. CONNELL:  I am.  Also, I think we would be well advised to continue to monitor the situations, as we had recommended, in line with the current FDA protocol.  Thank you.

    DR. WHALEN:  Seeing no questions, we are on track to be a little bit ahead right now.  I can't reconcile that with yesterday, but we are.  I would hope that FDA and the sponsor will be prepared to make their final summations and comments prior to lunch, with the schedule we are presently on rather than after lunch as was originally designed.  We will take a 15-minute break and reconvene at 10:15.

    [Brief recess]

    DR. WHALEN:  We will have further open public comment.  We are left at this juncture with such comments coming from members representing various societies.  So, if the first of those speakers would, please, proceed to the microphone?

    MS. HEMSTRA:  Good morning.  My name is Erin Hemstra, and I am here to read the testimony of Wade Clegg, from Panama City, Florida, who could not be with us today.  Neither of us have any conflict of interest.

    Silicone gel breast implants break and leak.  When that happens, implants can cause pain and debilitating illness.  If FDA were to return this inherently debilitating device to the market it would be a very sad day in government oversight.

    Silicone gel implants allow for years of debilitation.  For healthy women, electing augmentation often assures that no insurance coverage will be provided to assist when problems occur.  The history of these devices clearly shows that any conclusions about safety need to be based on long-term testing of no less than ten, but preferably 15, years.

    The real question is have the risks and complications that have been seen in previous gel implants been eliminated by Inamed silicone breast implants?  Judging from the lack of long-term research data, the answer seems to be we don't know.

    If you recommend approval another group of teenage and young women face a future of debilitation.  Have any risks and complications been avoided by the implants that you are reviewing here today?  If the manufacturer claims that their product is better than previous gel implants, there is only one way to prove that--to study women who have had the implants for a long enough time to find out what happens when the implants break.

    It is not until the implants are in women's bodies for several years that it is possible to learn if they will break, leak or cause health problems.  Two years of research or even three, four or five years is not enough.  Thousands of women have had their lives diminished because they believed breast implants were safe.

    I hope that you will not repeat this fraud.  I plead for this FDA advisory committee to extend this process and continue to restrict access to gel implants while research continues, rather than approving implants which have not been proven safe for the long-term use.  Thank you.  Wade Clegg.

    MS. ROTH:  Good morning.  My name is Lynda Roth.  I am founder and director of the Coalition of Silicone Survivors, a group of over 10,000 breast implant survivors.

    I paid my own way here.  I received some help from friends and other implant survivors toward additional expenses.

    In 1990 I was diagnosed with breast cancer.  Understandably, I was in shock.  When presented information on silicone breast implants, I trusted that what my highly respected plastic surgeon and other doctors were telling me was true.

    I soon found out there were many risks that were not disclosed.  My implant hardened immediately, resulting in a great deal of pain and a very misshapen breast.  It spontaneously and silently ruptured within a few months.

    It was removed shortly thereafter, but much of the silicone gel was not.  I had a second implant removed a year after the first, and it was already sagging a great deal.  I had lost a lot of silicone.  My surgeon told me that silicone gel was inert and would not harm me.  I can assure you that my concern for having silicone implants was truly uninformed.  The pain and disfigurement that I suffered was immense.

    Within a year I was having problems with extreme fatigue, balance, memory, concentration, visual disturbances, fibromyalgia, etc., etc., etc.  In '94 I was diagnosed with lupus.  There is no family history of this or other related autoimmune problems.  Was it just a coincidence?

    It was certainly not a coincidence that I had small, hardened, rubbery lumps of silicone come out of my forehead for three years, or that I had silicone granulomas on my arm and leg.

    I still have neurological problems.  By the way, both neurologists who diagnosed this in '92 had never seen a silicone patient and both put in their notes that they thought silicone toxicity caused my problems.

    I have a masters in social work.  I lost my job because of my health problems.  I also lost my health insurance.  I am basically uninsurable.

    Women who want implants today are told they must waive the right to sue the manufacturer.  If the implant makers are so sure their product is so safe, why would they do this?  It may be acceptable to some that an implant can harden; that it can move; that their body may reject it; and an amount of pain may be acceptable to some.

    But please remember that silicone injections in the breast were banned by the FDA because women had serious health problems and died from injections.  A ruptured silicone implant is no more nor no less than a massive silicone injection.  All silicone implants will rupture in time.

    I believe many women could evaluate the risk of these devices if they had enough time and enough information.  Unfortunately, women who are told they have a life-threatening disease, such as cancer, are not in any objective shape to make these choices, especially when they are told by their plastic surgeon that these devices are safe, as I was.

    Reports to our group still show very few women are truly informed of the risks prior to these devices.  The studies that have been conducted by the manufacturers, supposedly monitored by FDA, are not run the way clinical trials are expected to run.  Many women report to groups like mine that they have never been contacted for follow-up in these studies.

    What good are these follow-up safety studies if many of the women are not contacted to see if they are problem-free and healthy?  I have been a group leader since 1991.  I am astounded at the fact that hundreds of thousands of women that registered and claimed injury from silicone implants in these lawsuits--that the rosy picture painted by Inamed and other people is not accurate.

    Studies that covered two years or five years inevitably will not find the kinds of problems that group leaders like myself have seen and heard about.  We all know from asbestos, dioxin, radioactivity, mercury, PCB, DVT and others take 20 to 30 years to manifest.  Why would silicone be different?

    If you now approve implants based on two years of data, while allowing eight more years to collect more, hundreds of thousands of women more will be exposed to these toxins before more evidence is in.  And, you have no way to enforce that the studies are done properly.

    Women receiving implants today may not be ill for 10 to 25 years.  What kind of future are we guaranteeing to them?  And, do we want 17-year old women to have these implants?  Is that a responsible decision for this committee to make?

    DR. WHALEN:  You need to conclude, please.

    MS. ROTH:  You have a very important decision.  I hope you will consider all the women who have been harmed by their silicone gel implants before you make your recommendations.  Thank you.

    MS. GILBERT:  Excuse me, can I ask you one question?

    MS. ROTH:  Sure.

    MS. GILBERT:  Are you the director?

    MS. ROTH:  Founder and director of the Coalition of Silicone Survivors.

    MS. GILBERT:  Do you guys actively--are you participating in any kind of research?  Are you collecting information on all these survivors?

    MS. ROTH:  You know, we would love to see a retrospective study of the people who really have had the problems but the manufacturers will never do that because there is too damned much evidence.

    DR. ZONES:  Good morning.  My name is Jane Zones.  I am a medical sociologist and I am here as a member of the Board of Directors of Breast Cancer Action.

    Breast Cancer Action is the first national breast cancer organization to refuse donations from any organization that would represent a conflict of interest and I have no conflict of interest here.

    Twenty years ago I sat on this panel as a consumer representative when FDA was considering whether or not manufacturers should be required to submit evidence of safety of silicone breast implants.  At that time, the only other woman in the room was the transcriber of the hearings.

    Things have gotten a lot more sophisticated since that time, but the one thing that hasn't advanced appreciably is our understanding of the long-term safety of silicone breast implants.  Twenty to thirty percent of women who have mastectomies choose to undergo reconstructive procedures with clear psychological and perceived appearance benefits, at least in the short run.  Many of these women are encouraged by their surgeons to have additional surgery on the unaffected breast in order to provide a better match. Women with high genetic risk of developing breast cancer also have been encouraged in many cases to undergo prophylactic double mastectomy, followed by reconstructive surgery.

    We have seen at these meetings that women who have reconstruction with implants after mastectomy experience much more complications than women who receive implants for breast augmentation.  Many women still do not receive detailed information about complications as part of the informed consent process.

    While the Institute of Medicine did an admirable job of compiling the accumulated evidence regarding the effects of silicone breast implants, they seem to have accepted the literature at face value.  To take a single example, one of the best and largest studies of silicone breast implants which shows no association of the devices to connective tissue disease, the Nurses Study, reveals considerable conflict of interest.

    Much of the research on implants is sponsored and carried out by those with a vested interest in the results, which is known to bias outcomes compared to independently sponsored studies.  Authors, including the lead and corresponding authors of the Nurses Study, variously received grants from manufacturers or payments from law firms representing manufacturers.  Two major investigators resigned from the project because of the appearance of conflict of interest, though one remained an author in the study.

    There are other concerns with the Nurses Study which were not addressed by the IOM committee.  The researchers report a mean follow-up after surgery of 9.9 years, with a range of one month to 40.5 years.  It is not clear how this was calculated since silicone breast implants have only been used since 1963, fewer than 30 years before the study cut-off.  Including even a small number of cases extending to over 30 years could inflate the mean follow-up substantially.

    Reported health problems of women with their breast implants occur with greater frequency as implants age in the body.  Long-term follow-up is a crucial variable in examining breast implant safety.

    As with other major studies of connective tissue diseases, the Nurses Study used only diagnosable diseases as outcomes and did not examine signs and symptoms.  Finally, although the sample size was very large, over 86,000 women, the prevalence of connective tissue disease in the population is very small, and the number of those with both connective tissue disease and breast implants, if randomly distributed, is extremely small.  The sample would have to be tremendously large, over 60,000 women with breast implants and twice that many controls, followed for ten years each, to have enough power to detect a doubling of relative risk of scleroderma, for example.

    The authors themselves conclude that because of the infrequency of occurrence of connective tissue disease, the study cannot be considered definitely negative.

    Recently, established medical perspective on two breast cancer related issues has been shown through randomized clinical trials to be completely wrong.  Doctors massively opposed randomization of their patients to control groups because they so thoroughly believed in the safety and efficacy of HRT and high-dose chemotherapy.  Tens of thousands of women were unnecessarily harmed because these beliefs were not true.

    It is unlikely that we will ever again get the opportunity we had 20 years ago to conduct sound and independent trials with long enough follow-up to answer the questions we continue to have about silicone breast implants.  We urge the panel to not recommend approval of this device which has still unknown long-term physical consequences.  Thank you.

    DR. ANDERSON:  May I ask a question?  First, in the study that you cited, I happen to have the abstract, and the issue about 40.5 years follow-up, what they are saying is that they had up to 40.5 years follow-up for the entire cohort.  They were looking at the connective tissue disease patients.  So, I don't think that that is an issue.

    But I think you made a very serious allegation against the authors of this study where you suggested that in the Nurses Study they were biased because of funding from private companies.  Do you have any data that they received funding prior to the publication of the study, as opposed to being--

    DR. ZONES:  Oh, it was in the disclaimer.

    DR. ANDERSON:  In the disclaimer of the Nurses Study?

    DR. ZONES:  Yes, the article is Sanchez Guerrero, in The New England Journal.

    DR. ANDERSON:  Okay.

    DR. ZONES:  Yes.

    MS. PEARSON:  I am Cynthia Pearson, Executive Director of the National Women's Health Network, an independent member-supported organization dedicated to safeguarding women's health rights.  We have no conflict of interest.

    We have reviewed the data that the FDA made available on its website on Friday.  We have listened to the sponsor's presentation yesterday, the FDA's review, and listened carefully to the panel's discussion last night.  Based on that information, I would like to use our time this morning to respond to four important points that I believe the panel has expressed over the last day.

    These points are that at least some panel members articulated very clearly that they believe that the large body of evidence looking at the health of women with implants, in general, is conclusive and is enough, and shows that long-term risks don't need to be worried about because of this literature.

    Two, I have heard some members of the panel say that the short-term increase in chronic tissue disease symptoms that were documented by the Inamed study is either not clinically meaningful or not clinically interpretable.

    Three, we have heard panel members say that they believe that it is important and possible to get more information after the approval of these devices, if they are approved.

    Four, some panel members have said that consent may make it all okay, good informed consent that lays out all the information, then appropriately allows a woman to make her own choice.

    I believe there are problems with each of those assumptions and would like to address them.  First, the issue of chronic tissue disease symptoms, there were questions, legitimate questions, in the absence of a control group, about to what extent are these increases in the symptoms, as we all saw posted yesterday, just a sign of normal aging, and as the night wore on to midnight there were jokes about maybe it is just a sign of normal fatigue because we would all score high on these now.

    We understand the problems with comparing to another study, but I would just like to point out that there are other studies that started with healthy women, that followed them over a period of years, that did not see these increases.  I will just take the Women's Health Initiative, which was a very large study that enrolled healthy women that were, on average, 30 years older than the average age of augmentation patients and, as reported in the last year, over a 4.2 year follow-up there was no worsening in mental health, general health, bodily pain, energy or fatigue.  I emphasize fatigue because to compare to the two-year follow-up in women at median age 34 years, that doubled in two years.

    So, we are concerned that these increases are at least worrying.  They certainly aren't conclusive because of the study design.

    Second, we disagree with the people on the panel who articulated that the literature gives us assurance that we don't need to really worry about silent rupture.  It would be nice to know why implants rupture; it would be nice to know how much of the silicone gets outside the capsule, but in the end we don't really need to worry because all these studies show that there is no conclusive cause and effect relationship between implants and harm to women's health in the long term.

    I just want to repeat what one panel member said yesterday.  If you look for a needle in a haystack by throwing the hay up and you don't find it, that doesn't mean that if you used a metal detector you wouldn't find that needle.  What that means in these women's lives is to do studies of long-term users with the power to find an effect.  Those studies have started to come out since the IOM review.  They have shown some troubling associations between suicide and other types of cancer.  They are not conclusive but they are troubling and post hoc speculation doesn't make suicide risk go away when it is shown repeatedly in three of these studies that have the power to find it.

    Third, we heard some panel members say that the need for more data will be remedied by what comes in post-approval, if the devices are approved.  The data that have been heard yesterday are from one to three years of a ten-year plan.

    I want to just remind the panel that while in this case the study from which you are hoping to get data post-approval was designed and begun pre-approval, I believe it is really crucial for you all to remember that the FDA's enforcement power to require post-approval data is very limited.  As far as we know, the FDA has never taken action against a product because of a sponsor's failure to complete post-approval studies.  If you believe that we need more data, you had better ask for it now, pre-approval.

    To respond to the fourth issue, the panel believes that women have the right to choose after excellent informed consent.  So do we.  But if important information does not yet exist, informed consent is inadequate no matter how long and detailed the patient information brochure is.  We believe that the right to choose is an illusion without the information to support a fully informed choice that has a full explanation of important and relevant risks and benefits.

    So, to conclude my remarks, I want to say that 12 years ago the FDA said there wasn't yet enough data to adequately evaluate the balance between risks and benefits.  Twelve years later we still don't have answers to women's important questions about the long-term effects of Inamed silicone gel-filled implants and women are counting on the FDA to take the right action to get those questions answered.  Thank you.

    MS. DICKERSON:  Good morning.  My name is Mary Dickerson.  In 1994 I was diagnosed with breast cancer.  Three weeks after my diagnosis I went in for a mastectomy.  I did have reconstruction.  My doctor used a tissue expander and about six months after that I had a saline implant put in.  I had that for six years.

    Three years ago, in December, I had a silicone implant put in and I just want to tell you a little bit about the differences.  I feel better with the silicone.  I look better with the silicone.  It is more natural.  It has a more natural feeling.  I can wear clothes better.  I just feel more comfortable with it.

    Having a saline implant inside of my breast was like having a tennis ball.  I couldn't wear a button-down shirt like this.  There were obvious differences, although we tried to make my other breast my reconstructed breast.

    I was 36 years old at the time and I knew I had no other choice but reconstruction.  My doctor worked very closely with me on what would be best for me.  I just want to say that for the past three years, with my silicone implant, my labs have all been fine.  I see my oncologist diligently.  I see my plastic surgeon diligently.  And, I am just here to ask you to give the women the right to choose.  Thank you.

    MR. KELLY:  Good morning.  My name is Joe Kelly.  I am from Minnesota.  I am president of the national, non-profit Dads and Daughters.  My organization paid for my trip here.  I have no conflict of interests.

    Everyone knows that silicone implants have risks.  You have to decide whether the benefits outweigh the risks.  I have never testified at an FDA meeting before but I am here today because of our very great concern about the growing use of implants among girls, and the unchecked cultural pressure on girls and boys to value how a girl looks more than who a girl is, and a woman also.  This pressure is toxic and too often fatal for our daughters.

    Under current FDA restrictions, teens under 18 cannot get elective silicone implants.  If you approve these implants, regardless of the restrictions you ask for, they will be available for off-label use, just like saline implants are today.

    Teenage girls in this culture are dissatisfied with their bodies and some will do anything to fit our culture's narrow, unrealistic genetic heritage-defying definition of beauty.  They will smoke to lose weight; use alcohol to numb the pain of not measuring up; spiral into depression and other mental illness; abuse a laxative and induce self-vomiting; and they will choose elective plastic surgery regardless of the risks.

    Girls' responses to the toxic beauty myth of our culture have serious, sometimes fatal health consequences.  And, that doesn't even touch on the social harm emanating from valuing appearance over substance in human beings.  We have a word for that phenomenon, bigotry.

    Perhaps most disturbing is the incredible number of people actively exacerbating this situation and selling our children's well being down the river to make money.  According to news reports, the most popular high school graduation gift this year in the U.S., in order of popularity, is cash, plastic surgery, cars.  The number of breast augmentations in girls 18 and younger has more than doubled since 1986.  Research shows that teenagers are the most likely age group to be dissatisfied with their appearance, especially features that do not meet culturally determined stereotypes emphasized in mass media, but that dissatisfactions lessens with age, as any parent with common sense knows.

    Although the FDA approved saline implants only for women 18 and older, there are no restrictions on the procedure so doctors perform on patients under 18 but medical associations, such as ASPS, apparently have no official position on teen surgery.  Breast implants have to be replaced when they break.  That is surgery that young women may not be able to afford and which may harm their health.

    Perhaps most outrageous to me as a father is the way that implants interfere with mammography, obscuring breast tumors.

    Finally, is it appropriate to perform cosmetic surgery on patients whose bodies are still maturing?  Unfortunately, no one has conducted studies or clinical trials on the safety and long-term risks of breast implants in patients under 18 or, if they have, the results have not been revealed.

    I think denying approval is your only reasonable response, though my argument might be a bit different than most that you will hear.  Even if it was the case, which it isn't, that no physical harm ever results from breast implants, your approval would endorse capitulation to an "appearance first" cultural standard that is dangerous and health-threatening to our daughters and, I might add, to our sons.  After all, would you tell your son that the size of a woman's cleavage is more important than the size of her heart?  Not unless you wanted to set him up for failure in life-long relationships.

    These "appearance first" cultural pressures have concrete negative consequences and I ask you to imagine your daughter's or your granddaughter's face in the story I am about to tell.  When we started Dads and Daughters we hired an immensely talented, committed young woman, named Heather Henderson, as our deputy director.  One morning, in September 2000, she did not come to work, which was very unlike her.

    I eventually went up to her house where I found Heather laying face down on the kitchen floor, dead of a heart attack at age 27, after an 11-year battle with bulimia.  It is obscenely ironic that Heather died of the very "appearance first" insanity she spent her life fighting.  But I think she died because there are not enough others of us out here, raising bloody hell about the waste of obsession with appearance that leads to deadly eating disorders; the waste of obsession with appearance that leads girls to smoke in order to lose weight and then develop breast and lung cancer as a result; the waste of obsession with appearance that leads girls to fall for elective breast enhancement and a lifetime of health risks, surgery and providing elective profits to implant providers.

    This is where you get to take your stand.  Please put your children's face in the picture and do what you know is best for everyone's health and say no.  Thank you.

    DR. WHALEN:  Mr. Kelly, can I ask you a question?  Your passion and the cogency of your argument is extremely well conveyed but, since you asked us as panel members to visualize your daughter, can I ask you a question in return?

    MR. KELLY:  Please, sir.

    DR. WHALEN:  If you visualize your daughter, or your wife or your sister a few years from now with breast cancer, does your argument change at all in terms of the reconstructive argument?  Or, is your off-labeling concern sufficient to even limit for that population of people not having silicone breast implants?

    MR. KELLY:  Well, first, thank you for your compliment about my age; I have adult daughters.  I have to say that, you know, my feelings are probably not quite as strong when it comes to reconstruction but they are not much less strong either.  I was talking about this, this morning with someone.  I have a mother who had severe polio when she was a young person.  It damaged her appearance.  It damaged her ability to get around.  It never bothered her; she went on with her life; she dealt with the imperfections of her experience and made amazing contributions to her family and to the world.  It is a challenge for all of us to deal with our imperfections and our disabilities and the struggles that we face.  I don't think it is worth endangering our future health to deal with something that is ultimately an internal struggle and decision that we have to make about how we live our lives.

    DR. WHALEN:  Dr. Miller?

    DR. MILLER:  Can I also ask a question?  I appreciate also all your perspectives.  I wonder, given your perspectives, do you feel that there is any amount of safety information which could be generated about the implants which would make them suitable as a procedure?  Or, is the mere principle of putting in an implant something which you oppose as a baseline?

    MR. KELLY:  No, I wouldn't oppose an absolutely risk-free implant, no.  But this certainly doesn't look or sound like a risk-free implant.

    DR. MILLER:  Just as a conjecture, if the implants could be proven absolutely with no risk whatsoever, zero risk, would the risk/benefit of the implants be suitable in your mind at that point to make them freely available?

    MR. KELLY:  You know, if I had my druthers I would say let's make them available to people who need them for reconstructive purposes.  I think the whole emotion of elective, trying to change our bodies from what they are genetically wired to be, is absurd and it is part of a larger cultural problem that is really harmful to all of us, and especially to our children.  I think it is important to see it in that context, that we are harming our children, and I think particularly marketers and people who are making money off our children's insecurities are hammering at our children with the notion that how they look is more important than who they are and what they can do.  And, that is just wrong.  No parent would tell their child that.  And, I don't think we should do things and make public policy that reinforces that negative message, that message that is, at its face, a lie, that someone's appearance is more important than who they are.

    DR. MILLER:  Thank you.

    MR. KELLY:  Thank you, sir.

    MS. RUSSANO:  My name is Jama Russano, and I am the founder of children Afflicted by Toxic Substances.  I was a child at 14 that received a silicone breast implant, in 1972.  I was born with a hemangioma tumor on my right breast and I never developed fully.  My left side was a little bit larger than my right.  I grew up in the '70s and I wanted to look like everybody else.  So, my mom, at age 14, took me to a plastic surgeon and he put in a silicone breast implant and said, you know what, the only reason that you would have to take this out is because you might develop a little bit larger on your left side than your right but, other than that, it will last you a lifetime.

    Six months later my right breast was like a baseball.  I went back to the plastic surgeon and they told me, you know what, that is just normal.  There is nothing wrong.  Just massage it a little bit; you will be fine.

    At 16 I started getting headaches.  I started having problems.  That breast implant remained in my body for 19 years.  I went to doctors.  I couldn't understand what was wrong with me.  I was finally diagnosed with systemic sclerosis.

    In 1989 I went to a plastic surgeon and I asked is there any way that this implant could be due to my health problems?  Oh, no; no, no, I don't think so.  I was diagnosed with systemic sclerosis.  I will give you a new, better implant, a new better silicone implant.

    I had the surgery.  Within months the implant fell into my armpit.  I got worse.  My health deteriorated.  I lost a high-paying job.  I couldn't take care of my kids.  My kids couldn't come up and hug me because of the scars.

    With all of those issues of dealing with young children, on top of all of that, I realized when the silicone issues started coming out what about my children?  Where are these studies?  The safety of silicone and breast feeding and pregnancy?  Are our children just anecdotal studies?  There are thousands.

    I decided that, you know what, this question needed to be answered.  I came from a manufacturing background.  Why weren't these questions answered?  They had 20 years to do this and they didn't.

    We started Children Afflicted by Toxic Substances and we had several main concerns.  One was a young girl getting implants.  We testified at saline hearings at FDA and we asked that young girls--if they were going to approve them, that they not be used under the age of 18.  A young girl cannot understand or comprehend this type of data.  Most normal adults can't understand it, and the data is not even half there.  They don't understand that when they have an implant put in they might lose sensation of their nipple; that they might not be able to breast feed later because their nerve endings were cut.  How do you tell that to an 18 or a 19-year old?  How do they understand that?  They don't.

    When it comes to reproductive issues, we have had many, many women who have complained and sent in questionnaires about infertility problems; about miscarriages.  And, when they got their implants taken out their problems got better.  They were able to have children.  Anecdotal?  Yes, you could say that.

    The ability for women to breast feed a child--in one study by the Hertz report, up to 64 percent of 42 women with implants were unable to breast feed compared to 7 percent of 42 women without implants.  This is the highest reported range in the literature, that having an implant may significantly affect the ability to breast feed.

    The health effects on children born to mothers with implants, concerning silicones and secondary chemicals, the catalysts, the benzine, the phalates, are we looking at that?

    It is so important that we understand and get MedWatch forms out.  We have tried.  We have collected thousands.  We have submitted many hundreds of MedWatch forms to the FDA and so far only 136 are reported by the FDA.  I know that number can't be right.

    As the director of CATS, we worked on a questionnaire with the FDA many years ago and, unfortunately, we didn't have the funds to be able to submit it to pediatric doctors or OB/GYN doctors.  We couldn't get funding.  Who is going to fund a children's foundation?  Our children are sick.

    I know I only have eight seconds, but this is a very important issue and I ask the Commissioner if I could just have another minute to be able to talk about the kids.

    DR. WHALEN:  That, unfortunately, is unfair to everybody else who wishes to speak so, I am afraid, you will need to sum up.

    MS. GILBERT:  Excuse me, I would really like to hear her testimony when it comes to children.  If we could just take one more minute?

    DR. WHALEN:  Are there any of the succeeding speakers who are willing to yield their time?  We will allow you 30 seconds and that is all we can allow.

    MS. RUSSANO:  I am going to quickly show some slides.  We had a number of children go to a doctor or specialist, an orthopedic specialist in the Midwest.  Each mother took their child and ask the pediatrician if their breast implants could be a cause of this rare bone deformity and the doctor told them no.  He did not report these to the MedWatch.  He didn't report it to the FDA.  He didn't write it in their health reports for the children.

    These children are one in two million, one in three million, and they have not been looked at.  They have not been studied.  I ask you, for the sake of our children, for the sake of our next generation, for the sake of your child, would you want to think about your child and what would happen to that child being exposed to this device that is leaking through your body?

    We need more studies.  We need fair studies.  We need studies by the NIH.  We need studies that are not manufacturer funded.  We need to come together as a group, as a society and take care of these kids.  They can't get health insurance.  Mothers are afraid to go to the doctors and say anything because their insurance company will drop them.

    I wish I had more time, but there are many, many children out there and there is plenty of evidence.  You know what, I have two boys.  My two boys have severe problems.  My young son had a bone cyst removed on his head, and I have about ten other kids that have the same thing.  So, I beg you, do not put these implants back on the market.

    MR. HAYTON:  I am Rodney Hayton.  I am the CFO of the National Silicone Implant Foundation.  I have paid for the complete expenses of this trip out of my own pocket.

    I know that Inamed says silicone implants don't cause disease.  That depends on your definition.  However, the impact of silicone implants varies from person to person according to leakage rate and personal immune system threshold.  Silicone overloads and damages the immune system.  Silicone allows a variety of atypical disease symptoms to develop.

    Silicone implants can harm infants because silicone crosses the placental barrier and goes into mother's milk, proven by what is referred to as the Scandinavian studies, funded by Dow well over quarter of a century ago, report number 39-89 Dow Corning research department, 1972.  I have provided a copy to the panel.

    In March, 1994, the FDA advised the Human Milk Making Association to screen for women who have or have had silicone implants.  The body tries to remove silicone with macrophages, nibbling off bits of the polymer chain.  Silicone is moved all over the body.  Wherever the macrophage is when it expires is where the silicone is deposited at these locations.  The body, through its wondrous chemistry, demethylizes the silicone which results in grains of sand all over the body.

    What has happened to some of these women with implants the SPCA wouldn't allow to be done to your dog.  A five-year old child does not need epidemiological studies to figure out "don't touch the hot stove."  They do not have to understand how and why.

    Actuaries for insurance companies know about silicone implants.  That is why Blue Cross and Blue Shield in Texas and other states will not provide insurance coverage to women with implants.  The Canadian FDA knows about silicone implants since Canada has socialized medicine and their actuaries know that silicone implant patients have a disproportionately higher morbidity and mortality rate as compared to similar women without implants.  United States centers of Medicare and Medicaid actuaries know the statistics because of women's health care and disability claims.

    Mme. Curie died of the effects of radiation toxicity from her experiments with pitchblende.  She discovered and separated uranium and radium from pitchblende.  This was back in the time when we did not know the dangers of radiation in the human body.  She died just the same.

    There have been silicone implants where the removed the shell was completely disintegrated.  What happens to these women?  We do not know because it has never been studied and researched.  It is illegal to inject silicone gel.  So, what is the difference between an injection and leakage?

    The manufacturers' own data shows a 35 and 45 percent complication rate after four years.  I have seen the complications first hand.  Not being a doctor, but being part of a support group, women have been fairly free to show what has happened to them.  Some of them just show pictures and that is downright disgusting.  How many lives have been lost or ruined from silicone in the body?  How many more before the FDA will step up to the plate to do the right thing without regard to financial gain?

    For those who plan to do so, I applaud you.  For those who do not, please step up to the plate also.  We need more longer, in-depth studies and a better product before approval so we do not ruin any more women's lives that may be mothers, daughters, sisters, wives, granddaughters.  I would hate to have eye surgery with a complication rate such as this.  The results are more devastating than to be blind but I would not even think about it.  Thank you.

    DR. KERRIGAN:  Good morning.  I would like to thank the General and Plastic Surgery Devices Panel for the opportunity to present today.  My name is Dr. Carolyn Kerrigan.  I am an officer of the Plastic Surgery Educational Foundation, and I am here today speaking for that organization.

    I am a Professor of Surgery at Dartmouth Medical School and Section Chief and Residency Program Director for Plastic Surgery at Dartmouth-Hitchcock Medical Center.

    In 1989 I wrote a report on polyurethane breast implants for the Ministry of Health of Canada, and in 1991 I testified for Surgitek at the FDA hearings on polyurethane covered silicone gel breast implants.  I have no current affiliations or conflicts of interest with any implant manufacturer, and the Foundation has paid for my travel to present at this hearing.

    In my full-time academic practice of plastic surgery, I am a salaried physician.  I do perform breast implant surgery, both for reconstructive and cosmetic reasons, and this surgery generates practice revenue for my multi-specialty clinic.

    The Plastic Surgery Educational Foundation represents the education, research and service arm of the American Society of Plastic Surgeons.  The Foundation, founded in 1948, has three main core purposes:  Education, research funding and international outreach and service.

    Critical to improving patient safety is continuing medical education of physicians.  The Foundation sponsors instructional courses and several annual symposia to provide in-depth review of safety and outcomes related to breast reconstruction and breast augmentation.  Learning opportunities in this arena have intensified since 1991.  The Foundation has also developed an innovative web-based outcomes data collection tool allowing for national benchmarking and comparison of an individual surgeon's outcomes against that benchmark.

    Our organization also monitors the scientific literature on breast implants.  This information is used to guide directed research projects in areas of identified concern and to support ongoing education of its membership.  A document summarizing the current literature has been submitted to the panel.

    Research, as sponsored by the Educational Foundation, includes both non-directed and directed research.  Over the past 13 years, the Educational Foundation has funded more than two million dollars in grants.  Many of these projects are related to aesthetic and reconstructive breast procedures.

    Our directed research studies are an important component of the Foundation's activities.  Our directed research policy does not allow any individual organization or corporate entity to direct or influence the selection, funding or design of any Foundation-administered study.

    In 1991, the FDA's call for the manufacturer's PMA for silicone gel-filled implants clearly identified the need for additional clinical research.  Consequently, the Foundation established a three million dollar breast implant research fund.  This focused effort, starting in 1991 and continuing to this date, has included 18 very specific projects to investigate multiple aspects of breast implants including autoimmune disorders, biochemistry of silicone gel implants, quality of life, device integrity, local complications, explantation and implant rupture.

    Eleven of the original 18 projects were acknowledged by the Institute of Medicine of the National Academy of Sciences in its 2000 report, "Safety of Silicone Breast Implants."  The IOM found, as most of you know, that women with silicone breast implants were no more likely than the rest of the population to develop cancer, immunologic diseases or neurologic problems.

    Building on members' positive response to directed research funding, the Educational Foundation took a giant step forward in 1994 and established the specialty-wide National Endowment for Plastic Surgery.  The goal was to create a perpetual funding source for research projects relevant to clinical practice and unanswered clinical questions.  One such project so far sponsored includes support of the Center for Implant Retrieval and Analysis, which determined and demonstrated the types of scientific analysis needed for each type of implantable device used by plastic surgeons.

    In 2000, the Foundation developed the National Breast Implant Registry for data collection on all implant types and procedures.  This has now evolved to a robust web-based data tool, with participation from more than 75 practices and over 5,000 women.

    Ten months ago the European Union mandated that its member countries implement breast implant registries by 2004.  Several countries have selected our National Breast Implant Registry as the model of choice.  The International Breast Implant Registry was thus formed to allow collaborative data collection and analysis between the U.S., European, South American and  Australian organized plastic surgery.

    In conclusion, our specialty has remained at the forefront of reconstructive and aesthetic surgery based on its commitment to education, innovation and sound clinical and basic science research.  The Plastic Surgery Educational Foundation is funding breast implant research to educate its membership, to ensure patient safety and improve patient outcomes.  The Foundation has been proactive in establishing the National Breast Implant Registry and has established significant international collaborations.  The Foundation believes that breast implants and informed choice offer health-related quality of life benefits for many women.  Thank you.

    DR. WHALEN:  Doctor, can I ask you a question?  You mentioned, midway through your presentation, that the corporations do not direct or influence what research the Foundation does.  Are you aware of any dollar amount contributions that Inamed may have made to the Foundation since 1992?

    DR. KERRIGAN:  I don't have any numbers at my fingertips.  Certainly, the substantial proportion of contributions to the saline implant research was through membership contributions.

    DR. WHALEN:  Are there corporate contributions?

    DR. KERRIGAN:  There are some, yes.

    DR. LI:  Dr. Whalen, I have a question for the speaker--Steve Li.  You mentioned that you support the Center for Implant Retrieval and Analysis.  Has this Center published any of their results anywhere?

    DR. KERRIGAN:  I believe they have.  We can get you those references.

    DR. LI:  Thank you.

    DR. MCGRATH:  Dr. Kerrigan, we were talking yesterday briefly about a registry.  Can you tell us a little bit about where you see this National Breast Implant Registry going, what this is, how it may grow or whether you intend to have it grow?

    DR. KERRIGAN:  We certainly intend to have it grow and develop in many avenues.  Right now the Registry is basically physicians reporting details of their surgery; types of implants they use.  As the numbers grow and we get more data, we will then be able to do an analysis and reflect.  It is very easy to add particular data fields so if there is a specific issue that we need to address, we can add that to the database.  Obviously, long-term we want to expand this so that women who go through this surgery have a chance to report on their outcomes and also their baseline health status before participating in this type of surgery.  I mean, it has huge potential.  It will take many years to grow but there is lots that we envision for it.

    DR. MCGRATH:  Are there any measures in place to protect the patients' privacy?

    DR. KERRIGAN:  It certainly would be HIPAA compliant.

    DR. CONANT:  May I ask a quick question?  What is the incentive to register your patient if there is a benchmarking that is a requirement?

    DR. KERRIGAN:  It is not currently a requirement.  It is currently voluntary.  But the development of this database and other web-based collection tools are very closely tied to some of the ongoing work by the American Board of Plastic Surgery which certifies plastic surgeons.  As many of you are aware, there is an initiative in place to bring on board maintenance of certification so that surgeons would have to continue to maintain some degree of certification, and this would be an obligatory participation, logging of all surgical cases you do which, obviously, then would include a subset of breast implant cases.

    DR. CONANT:  Any kind of auditing of one surgeon relative to the benchmark?

    DR. KERRIGAN:  Yes, I mean the tool is designed so that individual surgeons can reflect on their practice relevant to national benchmarks.  A group such as the American Board of Plastic Surgery would monitor how folks are doing, and if there are outliers, would have the capability to audit the practice.  This is what we hope is coming over the next five to ten years.  It is not there yet but that is part of what we envision.

    MS. GILBERT:  So, for the 5,000 patients you mentioned, is it accessible to patients?

    DR. KERRIGAN:  The Registry is currently not open to patients.  Those are some of the issues that we are addressing and would like to see it evolve to that.

    DR. WELLS:  Good morning.  My name is Dr. James Wells.  I am board-certified plastic surgeon and I practice in Long Beach, California.

    I am President of the American Society of Plastic Surgeons, the largest organization of plastic surgeons in the world.  On behalf of the 5,000 member surgeons, I want to thank you for the opportunity to present the perspectives of our organization.

    I have no affiliations or conflicts of interest with any implant manufacturer.  The Society has paid my travel.  I perform breast implant surgery as part of my practice.

    Breast reconstruction and breast augmentation are procedures that significantly improve the quality of life for many patients.  Both procedures give women a sense of normalcy.

    As a result of previous discussions with the FDA, the need for a document with photos which will fully inform the patient about risks and possible complications of surgery using silicone breast implants has been developed by ASPS, in cooperation with our sister society, the American Society for Aesthetic Plastic Surgery.  This is an example of such a document, and I believe you have it in front of you.  It includes a short quiz to validate the patient's understanding of the procedure which includes the risks and benefits.

    The choice of elective or reconstructive breast surgery has always been an individual choice for women.  Consultations may take 30 minutes to one hour to complete.  Most surgeons will continue to follow their patients indefinitely.  However, the satisfied patient without any problems is reluctant to return for routine follow-up.  This may account for the failure to obtain a higher percentage of follow-up sought by this panel.  Even the periodic manufacturer's payment to patients for follow-up is not a consistent inducement for patients to return in the absence of any obvious problems.

    Plastic surgery is often a series of progressive operations, following one another at intervals.  Breast reconstruction may require two or three procedures over a period of a year.  Are these reoperations?  Breast implant patients, other than reconstructive patients, may require some minor adjustments to achieve the perfection that they expect and the plastic surgeon hopes to achieve.  Many of these minor procedures are done under local anesthesia, at no charge to the patient with the expense absorbed by the physician.  In most cases, patients return to their normal activities in a very short time.  Are these reoperations?

    As plastic surgeons, we recognize that the public has come to expect perfect outcomes virtually all of the time.  How often do families insist that the plastic surgeon be called to the emergency room to sew up the simple lacerations, clearly within the capabilities of our emergency physician colleagues?  The breast surgery we perform is not different.  Patients and the public have come to expect perfection.

    Following this expectation of perfect, are we expecting or demanding that the breast implant achieve that same level of perfection?  Could it ever achieve that designation of being the perfect implant?  Or, is it reasonable to accept that, like all medical devices, it has its limitations, associated failures, needs for reoperations and, in some cases, is not indicated for all patients.

    ASPS believes that continued monitoring and tracking of these patients and devices should be part of the process.  An earlier presentation by Dr. Bruce Cunningham and Dr. Kerrigan outlined a concept and plan from an existing registry to accomplish this and we are prepared to work with the FDA and manufacturers to accomplish this, if this is the recommendation of the panel.  We are also interested in linking our new patient information document to the web-based registry and adding the follow-up patient satisfaction survey as a third component.

    The emotion of body image and its importance to all patients is what drives much of the demand for plastic surgery.  This includes the use of breast implants.  Every patient has a vision of themselves that may not be the same as others see them.  Once considered the domain of only the wealthy, aesthetic surgical choices are now available to all women.

    Unfortunately, the occurrence of breast cancer is age indiscriminate.  I can remember a 26-year old woman, faced with breast cancer, recently married, who was told she had to have a mastectomy.   She was devastated when she came to my office.  We agreed on a mastectomy, tissue expander and a gel implant.  That was almost 20 years ago.

    After her surgery, she was faced with a decision to have a child or not.  She consulted with me about that and, with encouragement, she and her husband had that child.  She was concerned she would not be here to see her child grow up.  She had the child. She beat the cancer.  She still has the same gel implant of almost 20 years ago, and I receive an annual Christmas card update.

    Should she have been denied a gel implant which helped her with a serious life decision?  The young woman with a totally male physique receives breast implants.  What emerges is a young woman, at a critical social time in her life, who now feels and looks like a young woman.  Was it wrong to give her gel implants after a long and detailed discussion?

    The picture I have tried to create for you is that of the typical plastic surgeon, consulting with patients, using implants which make a positive difference in their lives.  It is not a perfect device.  They all know it will have to be replaced at sometime in the future but, in spite of that, they make a choice which alters their life.

    During the implant terror of the early '90s, I answered the telephone on an 800 bank of phones with other plastic surgeons, answering questions of patients not understanding the decision reached then.  Many of these women were terrified regarding that decision.  I don't want to have to repeat that scene.

    The scientific process is a continuum.  What we learn today will be replaced by new technology and information in a matter of years.  It has become the responsibility of this panel to determine the safety threshold which the implant must achieve to make it available for general use by all women.  The tracking of outcomes, the use of evidence-based medicine, the follow-up and presentation of ongoing research would all be part of this discussion.

    On behalf of the members of ASPS, our current patients and future patients, we recognize your challenge and responsibilities.  We will continue to care for our patients regardless of the panel's recommendation.  We remain committed to scientific evaluation, the availability of a safe implant, and the patient's ability to choose the device she prefers.  Thank you.

    MS. GILBERT:  I have a question.  Is this the document you were talking about?

    DR. WELLS:  Yes.

    DR. ANDERSON:  I have a question--Ben Anderson.  You speak for a very large group.  We are not reviewing today all silicone implants; we are reviewing this one company's implant and the panel was quite surprised at the number of ruptures that occurred in a very brief follow-up period.  Do you individually, or speaking for your group, consider the rupture rate acceptable?

    DR. WELLS:  I am not sure that we have sat down to analyze that in any great detail.  We heard the numbers today, same as you.   Rupture rates are hard to evaluate.  Patients come to us with silent ruptures, as we heard about earlier today.  I have had patients personally who know they have had it for two years.  They are satisfied with the appearance but, under urging that this is not the way the device is intended, it is replaced at some point in time.

    I think you can do breast examination.  I think you heard from Dr. Spear that the breast has a different consistency and feel in the patient who has a ruptured implant.  If the physician does his job and continues to examine his patient who comes back on a regular basis--and that is always difficult to determine--I think you can detect it and take appropriate action.  Do we know the real number?  I don't think we do.

    DR. ANDERSON:  My question was, in your opinion, are these implants rupturing too frequently?

    DR. WELLS:  No.

    DR. LI:  Dr. Whalen--

    DR. WHALEN:  Yes?

    DR. LI:  This is Steve Li.  You mentioned your patient that has 20 years with her gel implant.  Knowing that there seems to be increase of the possibility of bad events as time goes on, what advice are you giving this patient?  Are you recommending that she replace her implants, knowing that the chance of rupture is going up with every year that goes by?

    DR. WELLS:  Well, you know, it is that old story of "if it ain't broke, don't fix it."  I think if you maintain contact with your patient and you see that there is an issue, that the breast examination changes, then removing a device at that point of time is a relatively straightforward procedure.  It can be done under local anesthetic.  The device is pretty much contained in that pocket, in my experience, and removing it and replacing it is a relatively straightforward procedure.

    DR. LI:  Thank you.

    DR. MCGRATH:  One of the speakers before, making a fine presentation about surgery in youngsters, mentioned that the American Society of Plastic Surgeons doesn't have an opinion about that.  Is that the case?

    DR. WELLS:  No, we don't encourage surgery in patients under 18.  There are situations where there will be some cases where a young woman has a congenital absence of a breast.  She is developing; she is living with her peers.  You can see dramatic changes in that patient if you afford them an implant after a long discussion with the parents and the patient.  The presumption that the parent should not be involved in these decisions is a wrong decision.  You have to have parental support in this kind of a thing.

    If you present that to the patient and suggest what if this device breaks, and you see the response from the patient, then the surgeon has an obligation at that time to say, no, you don't tell everybody yes because you have the tool in your box to fix the problem.  It doesn't fit for everybody.  At some point in time you are going to have to tell the patient the same thing--you have had a negative outcome; you have had a reoperation.  This implant is not designed for you; we are not going to put another one back in.  At some point you have to draw the line.  We are interested in a safe device; safe outcomes for patients.  It doesn't stand to reason to think that we are going to use a device that is going to put our patients in harm's way.

    DR. CONANT:  Just a quick question, I am still very interested in the concept of silent rupture and your ability to detect this by physical exam.  I understand that when the capsule has ruptured there is extracapsular silicone, potentially nodules or even softening of the implant as the capsule ruptures that can be detected by physical exam.  But I am wondering if you are aware of any study that compares physical exam with contained rupture.

    DR. WELLS:  I am not.

    DR. CONANT:  What do you feel your sensitivity is in detecting that on physical exam?

    DR. WELLS:  Well, again, it depends on the amount of capsule.  If you have a relatively soft breast--and it is interesting how many of them continue to be soft--there is a doughy feel to the breast instead of the kind of rebound phenomenon that the intact implants have.  I think you can detect that on physical examination.  You have to do the exam.

    DR. CONANT:  And do you feel that there is a continuum between intracapsular and extracapsular--

    DR. WELLS:  It can be very similar.  Again, it depends on the mechanism for the extracapsular.  If it is under trauma, sudden deceleration, if you will, of the implant, it may be a different situation.  Thank you.

    MS. MCDONOUGH:  Good morning.  My name is Mary McDonough.  I have no financial tie to Inamed.  I paid my own way here from California.

    I am here today as a survivor of silicone gel breast implants.  My story is very similar to the stories that you have heard over the last 24 hours.

    At first I was very happy with my implants, but after about five years I developed complications and symptoms.  When an MRI and a mammogram failed to detect a rupture, yet my symptoms progressed, I decided to have my implants removed.  It was only then that I learned that the shells of both of my implants had completely disintegrated.  I have been diagnosed with lupus, fibromyalgia and Sjogren's syndrome.

    I share the panel's frustration that despite 11 years of opportunity for research, Inamed has presented only one or two years of clinical data.  However, I feel that some members of the panel may believe that postmarket surveillance is the solution to this dilemma and in a perfect world the manufacturers would continue to diligently and thoroughly follow the patients, both in the clinical trial stage and in the postmarket surveillance phase of the research.  But the reality of the situation, and also listening to yesterday's data, leads me to doubt the ability of a postmarket study to answer any of the outstanding questions about safety that you and I have.

    Dr. Brown made a point last night that postmarket surveillance is not equivalent to a clinical trial.  Furthermore, the members of this panel have concluded that the adjunct study, which could have provided for at least five years of data on approximately 25,000 women, had such a low follow-up rate that it cannot be considered reliable.  So, the members of this panel should not be comforted by promises that postmarket surveillance will adequately answer the remaining questions of safety.

    In conclusion, the panel yesterday had a question about whether there were any published studies of degradation and breakdown of the implant shell in vivo.  I do want to point out that there is such a study, and it was given in the handout by Dr. Batich earlier today.  The study states, quote, exposure to the in vivo environment weakens silicone gel breast implants over time.

    Thank you very much for your time and consideration to this very important issue.  Thank you.

    MS. BROWN:  I just wanted to clarify, from a manufacturer's point of view, that there is a difference between post-approval monitoring of your commercial population as opposed to an obligation that the sponsor has to follow a clinical study, such as the core clinical study, out through ten years.  This particular sponsor manufacturer was complimented on its follow-up activities with respect to their population.  So, I actually have confidence in the sponsor's ability not only to monitor the adverse events in the commercial population but, in addition, specifically if they have an obligation to do follow-up for their core study population, they will, in fact, do that because they are legally obligated to do so.

    The second thing I wanted to mention is that I have heard a lot of comments about why is there so little follow-up at this point in time and, having gone through the product development process myself, I know that for companies doing validation it takes at least a year to do that.  It probably took one or two years to negotiate the study protocol with the FDA.  It probably took two years to enroll patients and another three years to do follow-up, and then another year to put the report together and get to this panel meeting.  So, if you add those numbers up, from the time you decide what your device is and set the design, it probably took nine or ten years to get here today.

    DR. ZUCKERMAN:  I paid my way here.  I am donating my time and I have no conflicts of interest.

    I am Dr. Diana Zuckerman.  I am president of the National Center for Policy and Research for Women and Families.  Our independent, non-profit organization is a think tank that gathers research information and uses it to improve the health and safety of women, children and families.

    It is hard to testify as the last public comment, although I am sure you are happy to have one that is last.  I will try to make this a grand finale.  Since you already discussed the key questions last night, I wonder how I can say anything that you haven't heard or might want to hear or might be willing to hear.

    I will express my admiration for all the hard work that you have done, and my sympathy for your very hard hours here, and just let you know that I didn't get home until one o'clock last night and then I had to rewrite all my testimony.  So, I may have actually stayed up even later than you did.

    I am speaking from the perspective of someone trained in psychology and epidemiology who is a university faculty member and researcher and taught courses in research methodology before moving to Washington where I worked in the U.S. Department of Health and Human Services, the White House Science Office and for non-profit organizations.

    As a researcher, I studied depression, women's self-esteem and body image so I find myself in familiar territory here.  I have read every published epidemiological study on breast implants and would like to very briefly discuss the Inamed studies in the context of those other studies.

    What do we know about the health effects of ruptured silicone gel implants?  The FDA study, described by Dr. Brown yesterday, is the best designed study ever conducted on this topic.  One reason for its superiority is that it was limited to women who had breast implants for at least six or seven years.  There are other studies that had women who had implants for an average of six or seven years.  That is very different from having studies where everybody had their implants for at least six or seven years.

    We know from hearing testimony of the women yesterday and today that many of these women were very happy with their implants, but then they had a rupture.  Often that rupture occurred well after seven years.  We also know that when epidemiologists try to figure out what is going on with what looks like some kind of new syndrome or disease, they do two things, they ask questions; they talk to people and they look at research.  Both of those things are very important.  You find your patterns when you talk to the people and then you look for your research to explain it and understand it.

    What do we know about the health risks of silicone implants more generally?  I have heard the Institute of Medicine report, the Mayo Clinic study, the Harvard Nurses Study, and the meta-analysis all cited here.  One thing I wanted to make clear, they are all about the same thing.  The 17 epidemiological studies in the Institute of Medicine report are the same ones that are in the meta-analysis and they lean very heavily on the Mayo Clinic study and the Harvard Nurses Study.  So, when you are talking about these as if they are independent, different proof of safety, they are not; they are actually quite the same thing.

    I would like to very briefly describe the shortcomings of some of the studies.  I think it was said yesterday, in the context of the panel describing the safety research on the Inamed study--I hope I didn't misunderstand, you said it was too small; too short.  That is exactly what is true of many of these studies.  They had rather small samples and they studied women who had implants for a short period of time.  I will give just one example.

    The Mayo Clinic study, one of the best studies, included only 749 women with breast implants; only 125 of them were breast cancer survivors.  To be in the study, women had to have had implants for at least a couple of months--months.  On average, they had implants for seven and a half years.  So, that means there were only about 375 women who had implants for more than seven years.

    Since diseases like rheumatoid arthritis and scleroderma take years to develop, there is no latency there; no time for them to develop.  Since rheumatoid arthritis is not very common in women in their 30s and 20s, as these augmentation patients were, you are really looking at a very small sample and there is no statistical power to find out whether there is a significant increase.  You don't have to take my word for it.  Just read the study.  The authors point that out themselves.

    So, while I agree that the Institute of Medicine report doesn't have sufficient evidence that there is a link between implants and disease, you can't conclude that there isn't, based on that report.

    In contrast to that study, the National Cancer Institute study also looked at women who had implants for at least eight years, another study that was really far superior to any other study, and they found women twice as likely to die from brain cancer; three times as likely to die from lung cancer; and four times as likely to commit suicide.  I was on the scientific advisory panel on that study and I know it really well and would be happy to answer any questions.

    I have some descriptions of the studies that I have talked about since I don't have time to go into it, which I will give to the panel.

    Now I want to talk about signs and symptoms.  Let's take another look at the signs and symptoms in the Inamed study.  Think about the testimony you heard from the women.  It took years for them to develop diseases but first they had symptoms that they didn't take very seriously.  We all feel fatigue--well, maybe it is because I am not getting enough sleep.  Maybe I am working too hard; maybe I am getting older.  There are a lot of good reasons.  But I also want to emphasize that there are a lot of women who couldn't come today who would have loved to tell their story, but they couldn't afford to get here; they couldn't even afford $150 to stay in this hotel.

    I now want to briefly talk about the cosmetic problems because I think that is one of the things that is most obvious, that when a woman has cosmetic results that are disastrous as a result of her implants, it is clear what is causing it.  I have some photographs that I want to share with you.

    Here is a photograph of a 29-year old woman who had her implants removed after seven years.  She had capsular contracture that was so painful she just had to have here implants taken out.  This photograph is from the FDA website.  That is obviously not a good outcome.

    Here is another woman that wasn't so lucky, Sharyn Noakes; you saw her photo yesterday.  Her ruptured implant had leaked into her healthy breasts and when the silicone was removed that is all that was left of her breasts.

    This last one is Cathy Nye, a breast cancer survivor who suffered from necrosis and her implant extruded through her skin.  We haven't talked very much about the complication rate in the Inamed study.  Six percent necrosis among breast cancer patients--six percent necrosis and that is a pretty serious thing to be worried about.

    Now very briefly, I will talk about the Inamed research and the quality of it.  I applaud Inamed's excellent response rate in their core study, as many of you did.  But, like Dr. Whalen and Prof. Dubler, I share your amazement of how little research the company has done in the last ten years.  Look at their 1990 study, 29 breast cancer patients and even then they couldn't keep hold of them so they didn't follow them up.  Several hundred augmentation patients disappeared into thin air; no follow-up.  That is the research that could have given us ten years of study.  It started in 1990 but they didn't follow up.

    Let's look at the adjunct study.  That was the opportunity to study thousands of women but they lost them all to follow-up.  Those data are gone and they could have been very, very valuable and helpful.

    One more thing, the core study is almost entirely white women.  Women of color might get breast cancer but only six African American women and five Asian American women are in that study even though we know that both groups have more problems with scarring and that African American women are more susceptible to autoimmune disease.

    What does approval mean?  If Inamed silicone gel implants are approved the company might be required to conduct research for another seven or eight years, but the FDA cannot enforce that.  They do not have the authority to make sure that those studies are done.  If they are approved, the FDA can try to enforce informed consent but they can't actually enforce it; they don't have that authority.  If they are approved, the women ages 18 and older, 17 and 16-year old girls, will still have access to them, just as they do to saline breast implants.

    Finally, most important, FDA approval is the seal of approval.  It sends a message, it says we think this implant is safe.  So, if it is approved, even if you talk about all your concerns, it will still be seen as an approval.  It will still be seen as a statement of safety.

    So, in closing, I agree that the FDA should have asked for more than two years but they didn't.  But that still does not excuse the company from not doing the research that they knew would really help us understand what the long-term safety is.  Thank you.

    MS. GILBERT:  Can I go ahead?  Dr. Zuckerman, I have some questions about some of the related cancer rates that you were talking about.  Can you just tell us a little bit about that?

    DR. ZUCKERMAN:  Sure.  The National Cancer Institute study was really important because it compared women with breast implants to other plastic surgery patients, and that is a very good control group because they are very similar in terms of their affluence, social class and lifestyle choices.  In this study where all the women had breast implants for at least eight years or the comparison group that had had plastic surgery without silicone, a different kind of plastic surgery eight years ago, what they found is that the implant patients were twice as likely to die from brain cancer; three times as likely to die from lung cancer or respiratory diseases; and four times as likely to kill themselves.

    They tried to control for smoking and they didn't have perfect data, but there were no differences among smokers in plastic surgery patients and breast implant patients.  They are equally likely to smoke.  So, there was no reason to think that smoking was the explanation for that.

    DR. ANDERSON:  Thank you.  That was a very helpful, interesting analysis.  You cited in the studies, the Harvard study and the Mayo study and that you can't conclude that this group doesn't exist, the women who would have these adverse effects, because the study is not large enough.  That is a type II error.  You can estimate, however, based upon the statistics that you got, how large that group could be.  Maybe Dr. Blumenstein could comment on this, but we know it is not 100 percent that have it and the hypothesis is it is not zero.  So, is it two percent?  Is it five percent?  Is it ten percent, based upon the data we do have?

    DR. ZUCKERMAN:  Yes, let me say that I think from the data you can conclude that the vast majority of women do not get sick quickly.  That is absolutely clear.  But because there weren't very many women who had implants for a long enough period of time to develop these diseases, I think it is really hard to make any kind of judgment about what might happen in the future.  You can make a judgment, you know, based on an average of seven years, or whatever, but it is very difficult.

    Just for example, if a woman smokes four packs a day of cigarettes and she has been doing that for eight years, she is not going to have lung cancer.  You have to study her for a longer period of time.  Lung cancer doesn't develop that quickly.  And, we don't know how long it takes to develop scleroderma but we know it doesn't develop in two or three years.  In fact, I would argue if a woman got scleroderma six months after her breast implants, it wasn't caused by the breast implants so you don't even want to look at those women.  That is why you want to focus on those who had implants for a longer period of time.  Personally, I think focusing on women with ruptured implants is really a very good way to study this, and cost effective.

Open Panel Discussion

    DR. WHALEN:  Other questions?  If not, on behalf of the panel, I would like to acknowledge all of the last day and a half's public discussants.  I would like to reassure them, as I did yesterday, that the panel, indeed, has heard each and every one of them and does not disregard the information that has been portrayed to us.  So, we appreciate all of that.  I think it is appropriate at this juncture to also acknowledge the yeoman's job that

Ann Marie Williams, from FDA does, in trying to corral 110 smart, passionate people up to the microphone in the way that she does.

    Before we proceed with the scripted activities, because of the subject at hand and because the moon was high in the sky when we had our deliberations last night, we are going to open up for a brief period of time to the panel if there are any glaring or exceptional issues that anybody would like to discuss at this particular juncture.  This is for discussion and not for questions at this particular point in time.  But if anybody wishes to do so, keeping in mind this horrible configuration where we are sitting at where I can't see 60 percent of you, try to get my attention and I will recognize you for discussion.  Brent?

    DR. BLUMENSTEIN:  Will we have a chance to make comments later?

    DR. WHALEN:  The last sequence of information exchange before a motion would be entertained and a vote would be taken upon would be that of the sponsor, following FDA having an opportunity to do so.  There will be some time at that juncture, following the time allotted to Inamed, for some questions and answers.  But if we are talking about comments per se, the only time that you will be making comments per se after this, if you choose not to do so, would be the justification for your vote as it was cast.  Prof. Dubler?

    PROF. DUBLER:  Dr. Whalen, I, at least, would argue that there are substantial issues to be discussed among the panel members, given their different expertise, before I would be comfortable voting, though I am not sure how to deal with that.

    DR. WHALEN:  That is what we are about right now.

    PROF. DUBLER:  Well, let me pose my questions and see if panel members have any response.  I am extraordinarily conflicted after all of the testimony and the data that we have heard and the passionate pleas between my concern that the data of one or two years is simply inadequate for us to determine safety, on the one hand, and the notion that there are certain women who clearly do want access to silicone breast implants.

    I think there is another tension that concerns me and that is, as I mentioned last night, between the notion of do no harm, which is the physician ethic, and the notion of buyer beware, which is the market ethic.  Every time I see advertisements in the newspapers and in women's magazines for breast augmentation it makes me suspicious that the people who will engage in the discussions with women will not be unbiased, which brings me to the notion that has been floated a number of times that a robust process of informed consent can, in some way, cure the defects in data and presentation that we have discussed.

    I would like to argue that that is not possible for numbers of reasons.  One, because I think of the physician perspective, and we have had a lot of physicians who have testified that they are in full-time salaried practice and--bravo, right?--I think that the impact on their group is unlikely to affect their judgment.  But if you are out there selling breast implants, I think that may affect your judgment.

    So, the process of informed consent begins on a tainted platform.  Moreover, the data on informed consent, unfortunately both in the clinical and the research literature, show it doesn't work, that, indeed, there is something called the therapeutic fallacy that says my doctor is telling me to do this; it must be for my benefit.  But there are serious structural problems with this notion of informed consent.

    So, I am faced with a problem, to which I would like other panel members to respond, that to approve something which doesn't have the data to support its safety seems to me to be irresponsible, but not to expand access seems, to me, to be mean to the women who want access.  So, a compromise, in the sloppy business of reaching compromise, might be to expand access substantially but leave it under the aegis of a clear protocol to ensure that we get the data.  So, I don't know how people with expertise would respond to that suggestion.

    DR. WHALEN:  If I could jump in and maybe ask Dr. Witten to correct me when I say something wrong here, I would simplistically abstract what you have just said, Professor, into what form of motion you might wish to bring forward post lunch when we do it.  To me, you are suggesting that that would be a motion to not approve because you feel that further study would need to be done before it is approved.  Am I misinterpreting that?

    PROF. DUBLER:  That would be my motion but I would be very interested, before I made that motion, in hearing whether those members of the panel who have greater expertise in research methodology and data analysis than I do are comfortable with the data that have been presented.

    DR. BLUMENSTEIN:  If I might go ahead--Brent Blumenstein--one of the comments that I wanted to make because it occurred to me as all of these presentations were made, and so forth, was on the utility of registries.  What I wanted to do is remind people that registries are not a replacement for randomized clinical trials or carefully conducted longitudinal studies.

    Registries do have utility, especially administrative utility, but registries are generally based on convenience sampling.  That is an insult in statistical terms, in case you don't recognize it.  And, convenience sampling doesn't lead to accurate estimates of incidence or outcome rates, especially when follow-up is also subject to volunteering to follow-up.

    Also, the lack of randomization and intervention assignment prohibits the valid comparison of outcomes with respect to interventions.  Therefore, you cannot use registries to compare interventions.

    As I have been sitting here, I have been thinking about other studies that could be done, that are really necessary that came up in all of this.  Some of these are in the form of questions that might be answered in the sponsor's comments and some of these might be ideas for studies that maybe somebody might want to consider. Especially when one considers all the resources being put into planning and implementing registries, I personally  would prefer some of those resources diverted into good clinical studies, rather than registries.

    So, let me just forge ahead.  One of the things that I wondered about was whether an analysis of the Inamed data included looking at outcomes, say reoperation or just time to bad things, by surgeon.  One of the things that came up here is how good are the surgeons; how much variability is there in the surgeon's performance.  And, you have an excellent opportunity here to explore that I think.

    Another question I wanted to pose was whether there were experiments with implants in large animals, large mammals as opposed to small rodents.  The idea here is that the physical characteristics of these larger mammals would more closely mimic the physical characteristics of an adult human or teenage human, as the case may be.

    Another example of a needed study that I saw was to evaluate the diagnostic performance of the physical examination for a silent rupture as compared to, say, MRI.  There was an assertion that maybe good, close follow-up by the surgeon with a physical examination might be sufficient.  Well, we need to know that, and here is an example of the kind of research that might not be sponsored by the sponsor, might not be funded by the sponsor but is certainly needed in order to carry forward with this.  That is all I wanted to say.

    DR. WHALEN:  Brent, in terms of how good are the surgeons, it is rumored that Denton Cooley was once asked to name the three greatest heart surgeons of all time and he could not think of the other two names!

    [Laughter]

    DR. LEITCH:  I guess the question I would ask is what kind of study are we saying would be sufficient to answer the questions that I think have been raised by the public that has spoken?  Are we asking for a randomized trial of saline versus silicone implants?  Are we asking for a study that would have follow-up of 20 years of a particular device?  You know, I think we have heard this theme over and over again about the long-term issues of follow-up and that some of these side effects that people are reporting appear late.  So, you are asking for a study with at least ten years of follow-up and maybe beyond that as the way of sorting out if this is okay.

    So, if you say that is the case, then, you know, you take an implant that is proposed at this time that would be implanted over a period of five years maybe, then you need the data collected on those patients for ten years beyond that.  What happens in that interval for research and development for implants that are better if the manufacturers anticipate that their way to get that to market is that they must produce a 15-year or 10-year follow-up experience before it comes to approval?  So, I think we have to say what kind of study are we saying we have to have to say it is okay.  I think that is one thing we need to know, and how could that be designed.

    DR. WHALEN:  We will go to Dr. McGrath and then to Ms. Brown.

    DR. MCGRATH:  I am a little out of sequence here because my response really isn't a scientific, technical one.  I really wanted to speak back to Ms. Dubler's questions when she mentioned her conflicts because some of those really revolve around questions of the ethics of the plastic surgeons involved in this and the researchers, and also the issue of self-enhancement which you actually brought up twice.

    I think we probably should look at those head on.  One of my other hats is I have served since 1982 on the committee of ethics for the American College of Surgeons, and I also chaired the ethics committee for the American Society of Plastic Surgeons, and these are issues that we talk about all the time.  Every physician is paid for their services when you do something for a patient and, yet, there is a concept of professional beneficence which we regard as the behavior of the physician that puts the good of the patient over the good of the physician.  This is something that we take very seriously and is practiced by, I think, the vast, vast majority of physicians in the United States.

    Obviously, there is a tension since physicians do get paid for what they do, but the goal is to always have that payment only secondary to doing the correct thing for the patient.  In this particular case, I don't think this is really such a pressing issue, to tell you the truth, because right now having this product available will have very little financial impact on plastic surgeons' practices.  We have saline implants available.  We use them for breast reconstruction and for breast augmentation.  So, I don't see this as a major issue.  Therefore, I wouldn't call into question, as you did, the testimony of the physicians before us today or the researchers before us today.

    The second issue that you brought up is self-enhancement and sort of you having a struggle with this.  You know as well as I that this is ancient and pervasive, the whole concept of self-enhancement.  I would ask everyone in the audience how many of their children have had orthodontia.  Orthodontia is a right of passage for teenagers nowadays.

    The breast surgery I do on teenagers, interestingly, is all on boys.  I see a large number of young males who come in with feminization of their breasts.  It is called gynecomastia.  Even as I was leaving San Francisco the other day, there was a 15-year old boy who essentially had D-cup breasts.  This is cosmetic surgery.  This is not covered by insurance.  I can do a procedure where I put this young boy under general anesthesia, with its attendant risks, and with a combination of liposuction and excision take away this feminization.  Is this trivial to him?  Is this something that I shouldn't do?  It has no functional effect on him.  There is nothing wrong with him hormonally.  He is simply embarrassed by the fact that he has girl-like breasts and he doesn't like to take his shirt off in the gym.  Somehow we don't have a problem with saying that that is okay, to correct that feminization for that boy but, yet, we struggle with saying it is okay to make a girl with a flat chest have A or B cup breasts with an implant.

    I think we really need to think about where our own acceptance of these procedures comes into play here.  Those are really my comments.

    DR. WHALEN:  Ms. Brown?

    MS. BROWN:  With respect, at this moment in time, to advising the sponsor to conduct a new randomized clinical study, a bigger study, a better study, a new study, as a manufacturer, I would ask what is a manufacturer to do who wants to get one of these devices approved?  They started this work back in--what?--1992, 1994, and they had to have embarked on a discussion with FDA on what was an appropriate IDE.

    The FDA never guarantees that when you conduct an IDE they are going to get approval from the data because you can't predict what the data are going to look like, but you do negotiate a protocol that you hope will lead to approval.  In this case the company was additionally guided by this guidance document that I printed off the Internet.  I don't know if it was in our packages.  It is called "Guidance for Saline, Silicone Gel and Alternative Breast Implants, Guidance for Industry and FDA."  It was recently updated, February 11, 2003 and it supersedes a document from August 13, 2001, and I don't know if there is a previous version of it.  But in this is a description of the preclinical and clinical testing that should occur in order to get to this point.

    Once again, it doesn't say what are the appropriate safety data that you absolutely need but I can tell you that the size of the study, the nature of the study, the nature of the analysis that have been done are extremely consistent with this document.  It also goes on to say FDA believes that a PMA may be filed with a minimum of two years of patient follow-up on a sufficient cohort of patients to evaluate the safety and effectiveness of the product.  Then it goes on to say that a total of a minimum of ten years prospective patient follow-up should be required.

    The company, I will say, has already demonstrated that if a PMA were to be approved they certainly would do ten years worth of follow-up.  I believe that they would do adequate patient follow-up and compliance because they have demonstrated they can do that already with saline implants that are on the market.  So, those are my comments.

    DR. WHALEN:  Dr. Choti?

    DR. CHOTI:  The concern that I have with that is that what we are learning is that the concerns don't really fit with this guidance document.  There is no precedent for asking longer than two years.  But we are concerned that there are delayed effects, delayed rupture, the performance issues that defy the recommendations of typical devices, at least this is what I am grappling with.

    I am having trouble coming up with a feasible study that would really answer the concerns that we have on these delayed problems.  So, I agree that it is a problem for the sponsor to tackle or to answer our concerns, but that still doesn't necessarily obviate the fact that these problems are there.

    MS.  BROWN:  I hear you, and I heard this morning somebody suggesting that we might need a treatment group of 60,000 patients and a control group of 60,000 patients.  If one were to need studies of that size, you might as well kiss the breast implant business goodbye.  I am not sure anybody will be able to do the study.

    DR. WHALEN:  But could I just interject, I couldn't get to sleep last night because, you know, that word "safety" keeps flashing in front of my eyes.  If that is, indeed, the case we can't say, well, you know, from a pragmatic point of view the study would be too difficult to do so to hell with it; we will approve it even though we haven't demonstrated its safety.

    I think the charge to the panel is to disregard the pragmatism and disregard the logistics of whatever the study would be to accomplish the goal; that the goal is, is it safe or isn't?  Dr. Miller?

    DR. MILLER:  I have tried for so long to understand why this is such a difficult topic, and why I can discuss controversial medical things with my colleagues and others and it is just a discussion about a disagreement but in this one, if I encounter somebody I disagree with my morality is questioned; my ability to think clearly is questioned.  I mean, it becomes a very personal thing.  Now, why is that?  I mean, what is happening with this problem?

    One thing we haven't discussed in all of our deliberations, and we had a unanimous opinion last night, was the effectiveness of the device.  I mean, our charge is to determine safety and effectiveness.  Effectiveness is universally agreed upon, that this thing changes the shape of the breast by making it larger or creating a simulation of a breast when there wasn't one there.  Nobody argues the effectiveness; that is a closed book.

    We are talking about the safety, the safety is a problem because it is a ratio of the benefit versus the risk.  The reason why we have such a difficult time describing acceptable risks is because we have such a different view of the benefits.  So, that ratio is different in everybody's mind.  We have had testimony here, in this hearing, from every part of the spectrum, from somebody who feels so strongly against the morality of enhancement surgery that a perfect safety record would be unacceptable because, by principle, there is no benefit but, in fact, there is only damage from these devices.  So, by definition, you could never have a safe device, given that perspective.

    There are different grades of the benefit.  What we have to avoid is getting into the business of deciding for people what the benefit is because the individual who wants this surgery has to go through this risk/benefit exercise in their own mind, and it is going to be different for every person.  There are those who perceive such an enormous benefit from having these devices that they would face enormous risk to have them.

    Now, there is a limit to what we should permit in terms of somebody doing that, but I don't know if we have hit that limit.  I don't think we are there.  I think that a large amount of latitude needs to be given to people to weigh for themselves the benefit and risk, and that is what is going to define safety for them.

    I think that is why we have such difficulty with deciding if these are safe.  It is not because we are not sure what the risks are.  I think the risks are really pretty clear.  I mean, we know the short-term complication rates.  We know what has to be done for those.  We know the long-term risks in terms of systemic diseases.  We haven't demonstrated a link with systemic diseases.  That is not to say they are not there but we haven't demonstrated it.

    Now, I have heard a lot of analogy to the needle in the haystack and I like that.  If I could try and attempt to use that for a moment, we have this giant haystack.  We know that needle is getting stuck--that needle is a bad thing, and we have had numerous examples of how bad it is to get stuck by the needle.  If there is a needle in that haystack, I want to know if it is there.  Okay?  But the needle is so small, is it appropriate to restrict any access to the hay because you might stick yourself with the needle that we don't even know is there?

    I mean, we have to have perspective on this.  I mean, if somebody says I am so afraid of being stuck by the needle that there is no way anybody should be stuck by a needle and I am not going to touch the hay if I can't be assured there is no needle there, that would require exhaustive knowledge of the haystack, which is impossible.  So, you could never say it is a safe device.

    But if somebody says, look, the needle may be there or may not be there.  My chances of getting stuck by the needle are so enormously small because it is a needle in a haystack, I am going to take some hay and take my chances.  They have weighed this risk/benefit thing in their mind.

    I don't think we should stand in the way of that.  I think we should permit them to weigh that in their mind.  Based upon the evidence I have seen, I am comfortable that, given the definition of safety and given the ability of the person to have the freedom to weigh this benefit/risk ratio in their mind, the risks are well defined, small; the benefit, the patient can decide.  My job is to inform them what the risks are and let them make the decision.  That is sort of how I would analyze it.  Thank you.

    DR. WHALEN:  I think it makes a difference whether you are the farmer or the horse.  Dr. Leitch?

    [Laughter]

    DR. LEITCH:  Again with respect to the study issue and how that would occur, whether a study would occur before market approval or would occur after market approval, I think one of the questions being raised by speakers to the podium and also on this panel is if the panel were to approve the product with conditions, what is the authority of the FDA to confirm that those conditions are lived up to and if, in the performance of those conditions, there is found to be a significant adverse issue what is the authority of the FDA to then bring that product back for reconsideration?  I think that is some of the concern that has been raised.  If you let it go, then it is gone and you can't do anything about it.

    DR. WHALEN:  Dr. Witten, would you like to answer that question?

    DR. WITTEN:  Well, I think what someone commented on previously is true, which is that we haven't pulled one of these products from the market because of something seen in the post-approval study.  But typically what we do is work with the manufacturer to make sure that that information, from that post-approval, becomes public and is made a part of the labeling, that the information is available to the physicians and the patients so that they can enhance their ability to make a choice as to their use of the product.  So, you know, that would be what we would do, whether it is adverse information or information that confirms longer-term durability or sheds some other light on the longer-term performance of the product.

    DR. LEITCH:  What about the idea that if you make the condition that they have do deliver on it?  You know, if you approve with a condition?

    DR. WITTEN:  Our ability to enforce that is limited.  We do work with sponsors to make sure that we get the information that we need but I think it would be accurate to say that it is limited.

    DR. WHALEN:  To extend that perhaps to what I would think might be an extreme example, if the panel were to stipulate and FDA were to accept the recommendation that the sponsor must continue the data acquisition with the same degree of rigor that has been done to this point in time, and if in a year the sponsor decided, well, we aren't going to do our mail-out surveys that we originally proposed; we don't really need to do that, what recourse would FDA have in that case?

    DR. WITTEN:  Well, I just say we hope it wouldn't come to that.  We would work hard with the sponsors to try to avoid that situation.  It is really hard for me to speculate on what action we could or would be able to take in that case.

    DR. WHALEN:  I hate to press you--maybe you won't ask me back and that is okay--

    [Laughter]

    --but, to your knowledge, in the Code of Federal Regulations what power is vested in FDA when posed with a circumstance such as that?  Make it generic, when a sponsor largely completely disregards the stipulations that have been made as part of the approval process, what power do you have to do something about that?

    DR. WITTEN:  I think it would be very difficult for us to do take action with respect to the application.

    DR. WHALEN:  Dr. Li?

    DR. LI:  I would like to speak a little bit about the biomaterials, biomechanics of this device.  I think the things that we are worried about here, short or long term to different degrees, is the fact that these implants rupture and that there is some silicone that makes it either intra- or extracapsular.

    From the materials mechanics standpoint, I find that it is amazing to me that we are still discussing this.  The preclinical testing is essentially irrelevant to those two questions, has been irrelevant for over ten years.  If you know that some percentage--we have been discussing what that percentage is but it is certainly something above zero and could be some alarmingly high number--you know some percentage is going to happen, if you have a laboratory test to show that none of them break, that laboratory test has no clinical significance.

    Worse than that, not only can we not assess this device, hopefully, some other company will come with a device that is touted to be more rupture resistant.  But in the absence of a clinical test to demonstrate that, how will we ever believe the next implant will, in fact, be more rupture resistant?

    So, as near as I can tell, there has been no data that has been presented or that I have seen in the literature that even makes kind of a passing attempt to try to mimic the clinical failures of rupture and gel migration.  In fact, we are still discussing just exactly what that gel is because a gel with a high molecular weight certainly is not going to migrate anywhere but, certainly if it is a D4 version of a silicone it is going to migrate somewhere.  We have no idea what percentage is coming out.  We have no idea where it is going.  And, a lot of these are essentially very basic--if I may take the liberty of saying that--basic biomaterials questions that neither the sponsor nor the industry seems to have directly addressed.

    I think retrieval studies are crucial to this understanding but I think what we have seen from this application is that a retrieval study will not get us there if the approach to getting that retrieval is not scientifically based or unbiased to essentially to assign blame as to why the implant fails.  It has to have the more basic failure mode approach to it that has been demonstrated in retrievals of other medical devices.

    So, my quandary is that the data that is presented for the mechanics and materials is absolutely no help to me to assess what the performance of this device is going to be.  I think that underpins our question in all these clinical studies.  If it is 15,000 or 60,000 some percentage is going to break and we are not going to know why.

    So, it is a little tough to me to describe how big a clinical study has to be if one of the things we are really worried about is rupture and we have no fundamental understanding of where that rupture comes from.  For as long as these devices have been around, I am shocked and I don't know what to do about it.

    DR. ANDERSON:  The argument was made by a number of people that if the FDA endorses the product the public will just accept this as, well, then it is without risk.  I want to challenge that idea.  I deal mostly with women who have breast health or breast cancer problems who, I must say, is a very educated crowd.  So, I may be biased by that.  But I think we may be selling the public short when we assume that proper informed consent cannot be performed.

    That being said, I think the question for the panel is do we have enough data that we can tell the patients what the risks are, because there are risks to everything that we do and this is not an exception.  If the answer is, yes, we can describe what the risks are, then I don't see why we, in a paternalistic way, would say, well, then you can't have the product, because there are risks that we do to everything we do in life.  If we cannot define what the risks are, if we don't really know what the worst-case scenarios are or the percentage likelihoods of these are, then that is the reason we need the study.

    I don't think we need further study to prove that this is a device without risk.  We need further study to clarify what that risk is so that we can really know what they are getting into.

    DR. WHALEN:  Is there anyone else on the panel who has any further comment at this stage?  Yes, Ms. Brown?

    MS. BROWN:  Once again as a manufacturer, I was actually unaware that post-approval requirements are unenforceable.  Most companies that get those letters from FDA take them really seriously and the regulatory people inside a company walk around to hammer people over the head for the entire year to get the data in to FDA.  Reputable companies, and I believe Inamed is a reputable company, take letters that they get from FDA extremely seriously.  We try to comply 110 percent.  So, even though there may not be apparent enforcement teeth to these letters, companies do take them seriously and the panel probably could make a requirement that those data get presented to this panel on some periodic basis.

    DR. WHALEN:  Ms. Gilbert, did you have something?

    DR. LI:  Dr. Whalen, just one other comment, if I may?

    DR. WHALEN:  Ms. Gilbert had something.  We will get back to you.

    DR. LI:  Sorry.

    MS. GILBERT:  Well, first I just want to thank everybody for their public testimony.  I am tremendously affected by what I have heard.  I just have this to add, if this product fails one woman it is not safe--one woman and it is not safe.

    [Applause]

    We can do so much better--we can do so much better.  I am not convinced that we have an explanation on long-term issues, side effects.  I know that when it comes to how doctors explain the complications and the cleanup of a mess from a rupture, it is varied.  When you are going in and you are discussing about personal choice, me, myself as a consumer, I don't think that that was really--I wasn't educated on the facts and I went through this surgery twice as a breast cancer survivor.

    You know, I am appalled when I hear this situation and how some of these circumstances women are going to have to live their life dealing with.  It is horrifying; it is horrifying.  And, I think if more women knew honestly what their choices were I think that they might choose something else.  I think it is our responsibility to make sure that we are giving them that option.

    It is not just the women who go through the surgeries but, also something I didn't think about before we actually made it here on this panel, are the children and the second generation exposure to this.  This is something that didn't even occur to me and it is so much bigger than what we are.  We have a responsibility to look into that and I don't think we have really gotten any indication of what some of those side effects are; what some of the long-term ramifications are.  I have children.  I had children after I had implants.  I am concerned.  I just wanted to bring that up.

    DR. WHALEN:  Dr. Li?

    DR. LI:  I just want to add one other thing, and I don't mean to lecture my clinician colleagues but I don't think that we should accept the rupture rate that you have got even if the fix is something that is clinically easy to fix.  I think the rupture rate is higher than I would like it to be.  It seems well within our materials and engineering knowledge to improve upon that rupture rate, to lower that rupture rate.  So, I think we need to think in terms of why is the rupture rate something that we are questioning after this point and are worried about--obviously because we are concerned that it is too high.

    So, I wouldn't be satisfied with just being able to maintain our current level of performance.  I think there is large room for significant improvement in that and I think we should aim for that somehow.

    DR. WHALEN:  Dr. Miller?

    DR. MILLER:  I could just say a word to that.  I agree--

    DR. WHALEN:  You are not going to extend the hay analogy, are you?

    DR. MILLER:  No, I would like to know why they fail.  It bothers me that the mechanical testing preclinically does not reflect what happens in vivo.  I mean that tells me there is a real problem with the preclinical testing.  I agree with that completely.  I may be naive but it would seem to me that you could contrive a test that would simulate what the implant experience is in vivo and try to refine that test until you begin to match the failure rate that we see.  I mean, it would help you make a better implant.  I mean, that needs to happen.

    That would make a better implant but we still have the safety of the current devices.  I mean, it doesn't necessarily change the question about current device safety.  We may not know the rupture rate but there are silent ruptures because they are asymptomatic and they don't seem to cause any problem.  I mean, if there was a problem caused by the rupture rate we would probably have known years ago why they rupture and at what rate they rupture, but because they rupture and they don't generally produce any symptoms or any harm and women sometimes don't even want to change, tells you something about that there may not be a clinical relevance to the fact that it ruptures.  I am uncomfortable with that but, again, I don't want to let my discomfort with the aesthetics of a ruptured implant just make me not want to have data that it actually harms people.  So, I want to avoid that temptation.

    We need to find answers to these things but I don't know if it is appropriate to make these things contingent upon releasing these to wider use given the criteria of safety and effectiveness that we have to work with.  I think it is holding the devices to a very high standard.  I heard applause for the idea that any failure is unacceptable.  That is a standard that is unachievable.  So, we have to have a balanced view on this I think.

    DR. WHALEN:  Dr. Choti?

    DR. CHOTI:  Just one point, I think one way to kind of think about it for the panel is, based on the data we heard, what is the concern about rupture, about free gel, intracapsular and extracapsular?  That is one way to distill the data.  I do think the performance of this device in regards to rupture is quite poor and the recommendations are basically to leave it until there is evidence of rupture.  So, one can then say, unless it is changed for other reasons, 100 percent of women will have a ruptured implant, who have them put in, basically.

    The question that you mentioned and that we are grappling with is how bad is free gel in the capsule?  Similarly, how bad is extracapsular extravasation?  That is something that we don't have good data on from the study but it is really an issue of how you look at the literature; how good is the literature that there is harm, both local and systemic, with free gel.

    DR. MILLER:  I like that.  I would like to know the answer to that.  I am not sure that requiring an answer to that is necessary to maintain a restriction on the use of the device.  I mean, I would like to know the answer and we need to find the answer but that is a pursuit that we will have for many, many years to come.  In the meantime, there are many women who don't have the devices available because of the restrictions.  So, some compromise has to be made here I think.

    DR. WHALEN:  Dr. Olding?

    DR. OLDING:  I would just like to echo that thought.  I think, for me, it is disturbing and I have said this already, the rate of rupture.  The endpoint of that is failure.  But the endpoint of the other medical devices is failure as well.  A perfect example is knee replacement.  They will not last forever.  The endpoint will be failure of the device.  The question is not will the device fail or really what percentage will will fail because sooner or later there theoretically will be 100 percent rupture.  The question is will that result in some short-term or long-term problem.  We know that, in fact, there are some/many short-term problems.  We at least have a fairly good idea from the data, the literature, that the long-term problems, if they exist, are small.  I think we need to remember that while we are thinking about these percentage rates.

    DR. WHALEN:  Dr. Li?

    DR. LI:  If I haven't done it already, I would like to kind of hammer home again another reason why we need to understand how these ruptures happen, and this is because if we don't know the mechanism of how these ruptures happen we are kind of at the mercy of the materials and design of the manufacturer through no fault of their own.  For instance, we heard that the device now is substantially the same as it was ten years ago and they have made some small changes to, they hope, toughen the material.

    Well, in the orthopedic world our history is littered by improvements that people have done that were logical and in time turned out not to be logical because we did not understand the mode of failure.  For instance, the simple example I gave the other day is that one would think that thicker would be better.  But thicker may not, in fact, be better if you don't know the mechanism of its failure.  So, the nightmarish thing that keeps me awake sometimes is suppose--I am not saying the sponsor is going to do this but this is a generic thing, if the sponsor decides, for instance, to change their sterilization method, if they change to a different gel, if they change some relatively small manufacturing detail that changes the material properties somehow, in the absence of understanding the connection between material properties and structure they could inadvertently put themselves in a place where they don't have to be.

    An example of this is a French company that makes ceramics for femoral heads in orthopedics.  The company has been in business--I don't know, 15 years or more and never had a problem, and they brought in new ovens, a new type of oven.  The first few batches in the new oven, which they swore would be faster, better, cheaper because of the temperature control in that oven--the first few batches of that resulted in so many failures that it was temporarily recalled by the government because we didn't really understand the subtleties of that particular step.  So, if we don't understand where the rupture comes from, in the nightmarish scenario, everything the manufacturer does to produce that implant potentially has an effect on the outcome.

    DR. WHALEN:  Does anyone else have comments at this juncture?

    DR. MILLER:  Can I say one more thing?

    DR. WHALEN:  As long as it is not about the hay.

    DR. MILLER:  I am sorry, I can't help myself.  I just have to say one more thing.  You know, part of the problem I think with why the device has not been improved so much, say, over the last ten years is an artifact in a way of what has happened with the regulation of the device.  I mean, before the decisions in the early '90s there were a dozen companies.  Now, competition basically has been destroyed amongst the companies and all the companies have just been trying to answer some legitimate questions about the devices but there is not much discretionary time and energy and resource for improving in that environment.

    I think one thing which we may see if we lighten it up a little bit--and I don't know, I have to ask if it is an all or none thing, do we say they are safe and then it is all over, or we restrict it at the current level, or can we do an in between sort of thing where we continue to monitor, and all of that?  We can discuss that I guess.  But I think a little liberalization to availability of implants and a little pressure off the companies will perhaps lead to better devices.  I could see that happening.

    DR. WHALEN:  Dr. McGrath?

    DR. MCGRATH:  I just want to go on public record saying that I don't agree with you, Dr. Miller, on that at all.

    [Applause]

    We are talking about using these devices in patients and I don't think we need to cut anybody any slack.  We want safe devices before we put them in people.

    DR. WHALEN:  Dr. Newburger?

    DR. NEWBURGER:  The device failure rate, I recall, is similar to the saline implant rupture rate that we discussed a couple of years ago when we were getting the follow-up on those devices, their post-approval progress report.  But when a saline implant ruptures the patient knows it immediately, obviously.  I mean, she wakes up one morning and it is just not there anymore.  So, she is going to replace that quickly.  With the silicone it is a different situation.  The gel is slow to extravasate.  So, it would be hard for the patient to detect if she has no symptoms, and if she has no symptoms she may not want to replace it.

    Since the silicone rate right now seems to be forever and it is not biodegradable--I have listed to the people who have given testimony and the silicone chemistry really isn't well worked out--it seems pretty clear to me that there is a small subset of individuals who have adverse reactions of one type or another to this.  Prospective studies really are the gold standard and the size of the current study means that we are going to be missing the 1/1,000, 1/10,000 events, and I really think that we have to hold this to a different standard than other devices by the nature of the filler.

    DR. WHALEN:  All right, I have once again masterfully mismanaged time so that my promise that we would have the FDA and sponsor before lunch was a complete bare-faced lie, for which I apologize.  We will adjourn for lunch and reconvene at 1:30.

    [Whereupon, at 12:45 p.m., the proceedings were recessed for lunch, to reconvene at 1:40 p.m.]


A F T E R N O O N  P R O C E E D I N G S

    DR. WHALEN:  Some who were here yesterday may recall that there was some discussion about the pronouncement or position of the American College of Rheumatology, and our subject expert in that matter, Dr. Boulware, has done some further investigation and has some comment.

    DR. BOULWARE:  The reason this was an issue for me yesterday is that in reviewing our conflict of interest with the FDA, we had to submit whether we had any financial interest which was obvious, but also whether we belong to any type of organization or professional society that has official policy statements about this.  I serve on the board of directors on the American College of Rheumatology and queried them directly about this.  I was given reassurance from them directly they did not have an official policy and, thus, I was a little distressed yesterday that maybe I either had wrong information or they had wrong information.

    I contacted them last night after the meeting, was able to get in touch with them and received a faxed letter from them today, which I will turn in to the panel but I will read to you briefly.

    The statement on silicone breast implants and the updated silicone breast implants statement--and there was one in July, 1996 which we were not provided and I have that up here--are not formal position statements of the College.  Rather, they are statements that were developed in response to media inquiries.  In addition, it is ACR policy that statements which are not reviewed and renewed within three years are automatically sunsetted.  Therefore, the ACR currently has no active official statement on the issue.  To clarify an issue I raised, the statement cited research studies that were completed at the time of this statement.  The College did not conduct any research nor has looked at the research available since July, 1996.  I submit this to the Chair.

    DR. WHALEN:  Thank you, Dr. Boulware.  At this time, I am going to attempt to very briefly summarize the panel discussions on the questions from last night to update individuals in the audience who may not have been able to be with us at the time that we went through them.

    For those who are M.D.s, I am sure you know how internists do this.  You are about to get a surgeon's discharge summary on the questions last night, but the entire discussion is, of course, a matter of public record that will be published.

    The first of the draft panel questions had to do with judging whether or not there is adequacy of information to determine the safety of the product as regards asymptomatic rupture.  There was consensus of the panel, overwhelming consensus of the panel that such was established for the short term, just one to two years, as was required by FDA but that long term that had not been established.

    The second question looked into the use of the historical published literature and asked whether or not that provided adequate justification to determine safety of the product with respect to long-term general health effects, and also the preclinical testing in that regard.

    Looking at the preclinical testing first, there was some persistent disquietude, among particularly the clinical panel members that may or may not represent a disconnect between the chemists and the actual testing that is involved, but the preponderance of opinion was that that preclinical testing did not translate in the way that one would like to an actual in vivo situation.

    There was a higher degree of assurance, however, by the majority of the panel members that there is long-term literature that judges general health safety.

    The third and fourth questions, although we ended up discussing them separately, had a very similar pattern to them and asked us to consider, respectively for the augmentation and the reconstruction groups, whether or not there is reasonable assurance of safety, taking into account core study, adjunct study and AR90 study, local complication rates, the asymptomatic silent rupture information in the core study and published historical literature.

    There was some considerable divergence of opinion among the panels members and really no consensus could be reached on either of these.  Although initially I, as the Chair, thought there would be a similar view in the augmentation and reconstruction groups, clearly there was some divergence of opinions, and there was also a particular concern raised in the augmentation groups as to the impact of implants upon patient attitude towards mammography and the potential effect that that might have in terms of screening for future neoplasia.

    The fifth question, shifted from safety to effectiveness and, as Dr. Miller and others alluded to this morning, there was fairly widespread agreement upon effectiveness having been demonstrated.  It asked if the instruments that were used in judging patient satisfaction and health status, quality of life, such as the SF-36, Body Esteem Scale, etc., were adequate.

    The consensus of the panel was that, yes, there was establishment of that, however, the caveat needs to be made that, once again, there is, just because of the imposed methodology, some question about whether or not that will remain so long term because there is a degradation in satisfaction with time, in part as might be anticipated, but also a trend that is as yet not fully plotted out.

    The sixth question had two arms to it.  Going back to the safety questions that were raised in question number one, we were asked, in respect to labeling for this device, how often and how we would recommend that there be screening for asymptomatic rupture.  Following from that, or at least attached to it, to comment upon the recommendations for the necessity of explantation of asymptomatic implant ruptures.

    As regards to that question, again there was no strong uniformity of opinion.  The preponderance of people felt that mere screening examinations--mere is not a word I should use; that is editorial--that screening examinations would be sufficient but there was a significant element that felt that more sophisticated screening should be utilized, and the most predominant one that was raised was magnetic resonance imaging.  The frequency of intervals of exam ranged from six months to two to three years, with a preponderance falling upon annual examinations.

    As to whether or not those asymptomatic ruptures should be explanted, there were seven of the panel members indicating they should; three indicating they should not; and three uncertain as to those who registered their opinions.

    The final question had to do with the outlined post-approval study.  In the PMA the post-approval study was outlined to be a two phase, one- to five-year, six- to ten-year, follow-up study which would be mail-out surveys.  There was a strong preponderance of opinion that that should be drawn to at least ten years, and at least a minority element felt that it should be beyond the ten years, and that a mail-out survey would be insufficient and there should be face-to-face contact, hopefully, with a physician, and also that the MRI study should be drawn out to ten years or more.

    As to specific endpoints which might be captured in a longer-term study, there were several that were mentioned, including the rupture rate, explantation rate, studies, if possible, histologically, biochemically and otherwise of the capsule and the extracapsular tissue, systemic problems being significantly and rigorously tracked, what other surgeries were performed, and the impact upon both pregnancy and offspring of those who have had implants.

    Now that I have finished it, it was more internal medicine than surgery.  I got on a roll; I apologize.  But, Dr. Witten, does that synopsis adequately, to FDA's regard, characterize our answering of the questions?

    DR. WITTEN:  Yes, thank you.

    DR. WHALEN:  Very well.  At this time, is there anyone from the FDA panel or from the FDA who feels they need to give any synopsis or closing information?

    DR. WITTEN:  Dr. Whalen, I don't think that we need to do so.

    DR. WHALEN:  Thank you.  We will then go to the closing comments from the sponsor.  I serve at the pleasure of the panel that I represent here as to whether or not you feel, before they go into their formal 20 minutes--we have, in view of everything that came up yesterday, extended the normal time from ten to 15 minutes to 20 minutes so that they may close.  But short of that actual formal closure, are there significant questions of the sponsor, hopefully focused questions towards one answering entity from sponsor that anybody needs to raise?  I am not going to preclude subsequent questions after their presentation as well by soliciting these questions.

    [No response]

    Then, if you would proceed, sir?

Sponsor Summation

    DR, EHMSEN:  Thank you, Mr. Chairman.  Again, I am Ron Ehmsen, Senior Vice President of Clinical and Regulatory Affairs for Inamed Corporation.  The sponsor's summation will be presented today by Dr. Scott Spear, who is our principal medical consultant.  Again, Dr. Spear is Professor and Chairman of the Division of Plastic Surgery at Georgetown University Medical Center, in Washington, D.C.  Dr. Spear?

    DR. SPEAR:  Thank you.  I almost get the last word in these hearings.  I am Scott Spear, and it is my privilege to deliver this summation statement on behalf of Inamed.

    To begin with, I want to thank each of you on the panel for your extraordinary efforts over the last two days.  Certainly the debate and discussion have been lively and informed, and all interested parties have had a fair opportunity to express their views.

    It is now my responsibility to summarize and, more importantly, to clarify Inamed's presentation.  First, I want to say to the panel that yesterday afternoon many of you asked some very important and difficult questions and, candidly, we don't believe all of our answers were as complete or as responsive as they should have been.  This was, frankly, unintentional, of course, and probably attributable to the pressures of the moment.  Nevertheless, we realize that we may have created some uncertainties, some questions, and I would like to use my time to address some of those outstanding issues.

    To begin with, a question was raised regarding the length of the study we conducted on silicone gel-filled breast implants.  Let us be clear about this.  The agency outlined in their guidance document the filing criteria for a ten-year study, designed for submission after two years, which the company closely followed.

    Inamed conducted the study with rigor, accumulated the data and filed the information in a modular fashion, as requested in the agency's guidance.  We remain confident in our data and of the timeliness for the study.  As you may recall, the company filed two-year data for its saline implants and received approval.  We believe that the two- to three-year data we presented over the last two days, coupled with the vast epidemiologic information from multiple studies that has been conducted over the past decade, has fulfilled the agency's guidance.

    Another important issue that was discussed, and this came up several times, was the question on whether we improved the quality of the product under consideration.

    We believe that confusion arose yesterday when questions came to us about whether this was the same product or not.  We answered that it was the same product because it is still a silicone shell and still filled with a silicone gel.  But there are crucial differences in the manufacturing specifications, and they are significant with regard to the device's safety and effectiveness.

    The difference is that the quality has improved in three important areas:  An increased minimum shell thickness, almost doubling in thickness; a change in the specification to increase the cohesiveness.  It is the same chemical composition, but the cross-linking increases the gel's consistency.  Third, a more consistent, predictable manufacturing process with tighter tolerances of quality assurance based on stricter validation standards.

    Next, many panel members had concerns about local complications, particularly reoperation.  Of the many possible local complications studied by the sponsor, the two most important that are implant related and are not cosmetic are capsular contracture and implant rupture.

    [Slide]

    Capsule contracture is shown on this overhead which, unfortunately, none of you can see.  It occurred in 8.3 percent of 494 augmentation patients, similar to the rate of saline implants.  It occurred in 16 percent of reconstruction patients, lower than the rate for saline implants.  You will note, those of you who can see on the projected graph, that the Kaplan-Meyer risk curve for capsular contracture is reasonably flat, particularly so for augmentation and revision.

    Complications such as asymmetry, malposition, bruising, scarring, hematoma, swelling, etc., are not implant related but surgery related complications.  These same complications occur at similar or even higher rates with saline implants, and occur in other breast operations even without implants, including mastopexy, breast reduction, mastectomy and even breast biopsies.

    While data was collected on reoperations, removals and replacements, these are actually not complications but are, in fat, simply a description of events that are a response to either a complication or, more likely, some other indication.

    As mentioned last night by one of the panel members, plastic surgery is different than other surgical specialties.  It is a process.  Some members of the panel were concerned that 20 percent of augmentations and 45 percent of reconstructions had a reoperation.  Well, it is widely known and accepted by plastic surgeons and their patients that 20 percent of rhinoplasties have a reoperation; most cleft lip repairs have a revision; the vast majority of flap breast reconstructions have a second operation; and any reconstructive or cosmetic procedure, if followed long enough, could benefit from a revision.  Reoperation and revision is part of what distinguishes plastic surgery from other fields of surgery.

    Looking at the primary reason for reoperations for breast augmentation, only one was for rupture, representing 0.2 percent of all patients, and 35 were for capsular contracture, representing 7 percent of all patients.  Less than 10 percent of augmentation reoperations were for these implant-related complications.

    Of the reoperations for breast reconstruction, 6 were for rupture, representing only 2.5 percent of reconstruction patients, and 15 were for capsular contracture, representing 6 percent of all reconstruction patients.  On the other hand, 71 were for surgery-related problems or cosmetic indications.  So, of the 127 reoperations in the reconstruction patients, 15 percent were device related but 85 percent were not device related.

    A fourth issue that came up yesterday was the European experience with silicone filled breast implants.  It is important to remember that in most countries in the European Union silicone gel-filled breast implants were never--and I repeat never taken off the market.  This gives these medical devices a 30-year or more track record in markets such as Italy, Germany and the United Kingdom.

    There were questions yesterday on whether there was any reliable data from Europe, but before I address that I would like to mention that the Europeans use silicone gel-filled breast implants over saline breast implants in a better than 9:1 ratio.

    To our knowledge, and I believe to the FDA's knowledge, there has been no cohort of women and no ministry of health to emerge and relate any serious health care issues concerning silicone gel-filled breast implants.

    All serious epidemiologic studies of the health outcomes of long-term silicone gel-filled implant use have come from the European countries, in particular in Scandinavia with their unique care and data registry systems.  The literature to date has addressed every health concern of the FDA.  Since 1994, these long-term studies have consistently shown that there is no evidence of silicone gel-filled implants having any long-term adverse health consequences.

    Now turning to probably the most talked about and most serious issue of yesterday is the issue regarding rupture and silicone gel-filled breast implants.  Let me clarify one point that was not clear to the panel yesterday.  Since our core study began in 1999, 318 patients, totaling nearly 600 implants, had had one MRI.  An additional 86 patients, totaling 170 implants, had a second MRI at a two-year interval.  Our estimated Kaplan-Meyer risk at three years of silent rupture is 2.7 percent based upon that data.

    The rate of rupture of silicone gel-filled breast implants overall in our core study, projected over a three-year period, was collectively 3.4 percent.  This result is consistent with a recently published, historic, prospective two-year randomized MRI-based rupture study.  For silicone gel-filled breast implants similar to the Inamed implants under review, the failure rate between three and five years was approximately one percent per year.

    If you extrapolate the data from our MRI study and the Danish study I just quoted, the rate of rupture for a five-year period would be expected to be no more than five percent and for a ten-year period we would expect it to be 10-15 percent.

    But what is the significance when a silicone implant ruptures?  In our data, with 26 reported ruptures with Inamed devices, there was no extracapsular silicone found either by physical examination or by MRI.  Historically, with standard, substantially inferior earlier generation devices, approximately 20 percent of ruptured implants were associated with extracapsular silicone, which includes an era when closed capsulotomies were commonly performed, which were a known cause of extravasation of silicone.

    On the question of are patients with ruptured silicone gel-filled implants at risk of disease, the best way to answer that question is not in a small clinical study such as ours but, rather, in a large epidemiological study or studies.  As has been shown in study after study, including a large scale recent Scandinavian study of over 8,000 patients, there are three key findings that the panel needs to be aware of:  There is no convincing epidemiologic evidence of systemic illness caused by silicone gel-filled implants, period.  Finally there is no convincing epidemiologic evidence of systemic illness caused by extracapsular rupture of silicone gel-filled breast implants.  There is no evidence for any of these concerns.

    Why do silicone gel-filled breast implants rupture?  While nobody knows for certain why silicone gel-filled breast implants rupture, it is certainly the opinion of many experienced surgeons and many bioengineers that long-term ruptures are related to repetitive folding and tears created by creases from that repetitive folding.

    A question was raised this morning concerning a patent for a Trilucent soybean oil-filled breast implant.  This patent was originally filed in 1994 by three individuals, not affiliated with Inamed, who were seeking a competitive alternative to silicone gel-filled breast implants.  That patent was subsequently acquired by two different companies before being acquired by the Collagen Corporation in 1998.

    In 1999, Inamed acquired Collagen Corporation for its facial aesthetics business.  In the course of that transaction, more than 600 pieces of intellectual property became the property of Inamed, including the soybean oil patent.  Clearly, Inamed would not state in a patent application that the use of silicone-based materials has been discontinued by the industry.  Clearly, this would have been a false statement at the time it was made.

    I trust that we have addressed the issues that were on your minds yesterday, at least many of those issues.  Now, what would Inamed do as a responsible company moving forward if the panel and FDA recommend approval of these devices for commercial use?

    Nancy Dubler gave us the correct formulation yesterday morning, one where we have an equal ethical responsibility with everyone else here today.  It is our responsibility to protect the public with the safest possible product and maintain a patient's right of choice.  In that process of choice, physicians and patients must have full access to an informed consent process that is reasonable and understandable.  In addition to safety and efficacy, we agree that it is medicine and not the marketplace that should guide the decision to use this product.

    It is the obligation of Inamed to continually pursue a better product and this is what we propose to help meet our obligation, the following:  Inamed agrees that a thorough informed consent form for the patient is essential.  We would ask that a small group of the panel members help develop such a consent form, along with the FDA.

    Inamed would develop and distribute a patient education booklet on breast implants.  This pamphlet will be built from the informed consent form and will be written for the woman who uses Inamed products.  We will utilize focus groups to develop such a book.  We want to make sure that every woman considering breast implants is as informed as possible.

    Next, we support this panel's opinion and will recommend to FDA that the patients should be followed up to ten years via physical examinations and MRIs at five, seven and nine years, and even longer if the panel so recommends.  We understand from legal counsel that the FDA has every bit of the authority to enforce this requirement.

    Next, as a condition of approval, Inamed will supply to FDA and this panel annual reports on the post-approval study, and have an independent third-party, on annual basis, audit that study.  Inamed will pay particular attention to any relationship between outcomes and rupture status.

    The company further agrees to conduct a device retrieval program to study the changes that occur in the product over time, and systematically investigate in a more aggressive fashion the failure modes for this device.  We agree that if this independent third party finds that the study is not in compliance with these conditions, Inamed will agree that our PMA will be withdrawn.

    Fifth, we recommend any patient with silicone gel-filled breast implants have regular physician follow-up as long as the woman has the device in place.

    Sixth, Inamed will produce a guide and establish a toll-free telephone number for women regarding how to monitor their breasts after implantation with a silicone gel-filled implant.

    Seven, Inamed is developing a surgeon education and certification program to train surgeons in this particular area of surgery using silicone gel-filled breast implants.

    Eight, an Inamed patient registry that exists today will continue to track patients who use breast implants.

    In closing, Inamed feels strongly that we have conscientiously met the FDA criteria for safety and efficacy as outlined in their guidance and consistent with longstanding standards for implantable devices.

    In addition, these devices meet or exceed the safety data for the FDA-approved saline breast implants.

    The evidence for the long-term safety for these devices is the reason why they are widely available around the world, approved in over 60 countries other than the United States.

    I personally feel strongly that these devices should be available to women who choose to have breast implants because they would be the best devices that would be available for women in the United States at the present time.  I encourage you to approve this PMA in light of the above conditions that Inamed has proposed.

    Finally on a personal note, let me thank the panel members for their attention, their obvious hard work and their personal sacrifice to take part in these proceedings.  Thank you.

    DR. WHALEN:  Thank you.  Are there questions of Dr. Spear while he is up at the microphone?

    DR. ANDERSON:  I have a question.  At the beginning of your summary and at the end you referred to FDA-approved saline breast implants.  I was not on the panel two to three years ago, but my understanding was that it actually wasn't approved without restrictions; it was approved under conditions.  Can you tell us what those conditions were, and what has the follow-up been?  Do we actually know that the track of Inamed is that it follows through on conditions when they are provided?

    DR. WHALEN:  Before you answer that question, let me just state to Inamed that we are going to have as many questions as the panel may have of you.  Although it has been my experience that FDA sort of guards this table zealously from sponsors, I think it might actually facilitate things if you want to identify the most probable answerers of your questions to come to this table so that you don't leave your plastic surgeon floundering alone at the podium.

    DR. SPEAR:  Poor plastic surgeon!  I can begin to answer that question but, obviously, a regulatory person would be better equipped.  Usually with approval comes labeling and conditions.  Now, there was labeling associated with the saline approval which I don't think is really that critical.  I think the conditions included long-term data collection.  For example, the PMA was approved in May of 2000 and I think in 2002 the panel was reconvened for follow-up data on saline.  I don't know how long that review continues out but I do know there were some conditions.  JoAnn, do you want to answer that?

    DR. KUHNE:  Yes, JoAnn Kuhne for Inamed Corporation.  Yes, the conditions of approval were to follow those patients out to ten years.  Six through ten years was with a mail survey; one through five years was with physician visits.  We are currently in our seventh year of follow-up.  We did present last year, in July, on those conditions of approval, identifying where we stood with those patients.

    Our follow-up was very good.  We captured capsular contracture, reoperations, standard types of complications that we would look at in the clinical trial to begin with, as well as patient satisfaction.  Those numbers, continuing out to five and six years, were consistent with what we had found earlier in the studies.

    Also, conditions of approval were a retrieval study, which we concluded last year and also presented in July on those implants as well as, as Dr. Spear mentioned, labeling.  We did a focus group to get lay persons' perspective on our patient brochure, making an informed decision for women for saline-filled breast implants to make sure that that information was readable and understandable to women.  We got various feedback from women, basically on having glossaries in that patient brochure, as well as having data segregated in terms of reconstruction in one area and augmentation information in another area because women having surgery for those separate indications didn't want to see all of the data combined.  They wanted to just focus on the data that was particular to their situation.  As well, we had follow-up fatigue testing that we also presented last July.

    DR. WHALEN:  Does that answer your question?

    DR. ANDERSON:  Is the data that you are describing available on your website or easily available to the public?

    DR. KUHNE:  The information that we presented to FDA last year was available on the website.  We did update our labeling.  I don't recall if the information is still available but we obviously could make that publicly available again.  We will be continuing to follow these patients up through ten years.  I don't know if FDA will require us to present to the panel again annually but, you know, we certainly are willing to do that and present that information publicly.

    DR. WHALEN:  Other questions?

    DR. LAWRENCE:  May I ask how you plan to follow the offspring, the women who were implanted and gave birth?

    DR. SPEAR:  Here I am giving personal opinions in part, but offspring, in my opinion, should be followed not by a small study of 900 patients.  Most of these women are just ending or past their childbearing ages.  That would need to be a much larger epidemiological study, looking at women who had implants and comparing them to a control group.  So, it would have to be an epidemiological study, not in a group of 900 patients.

    DR. KUHNE:  JoAnn Kuhne for Inamed.  I would also like to point out that we did do extensive animal testing in terms of reproductive issues and teratology.  If the panel wishes, we could have Dr. James Lamb, who is a toxicologist who was heavily involved in these studies, discuss that further.  Dr. Lamb?

    DR. LAMB:  I am James Lamb.  I am a paid consultant to Inamed, with BBL Sciences.

    As part of the submission, there were both literature studies and studies done specifically on the elastomer gel, two generation reproductive study.  In that case, they pulverized the gel elastomer, implanted it into the animals, mated those animals.  Then, the offspring were kept long enough to implant in them and mate the offspring.  So, you had an evaluation of not just the offspring early in life and also their potential exposure through lactation, but also then their own reproduction and development of their offspring.

    In all those studies they saw no difference in litter size; no difference in fertility; no difference in growth.  They did histological evaluations to address some of the issues that have been raised before about the potential estrogenicity of certain components in the silicone for example.

    DR. LAWRENCE:  Yes, I did read that material and I noted that in some of the experiments you actually sacrificed the animals before they were breast fed, and so forth.  I was speaking of human information because it is different.

    DR. LAMB:  Just to be clear, I am addressing just the preclinical animal toxicology studies.

    DR. WHALEN:  Other questions?  Dr. Li?

    DR. LI:  First, I think your improvement on the retrieval studies, as Dr. Spears described, is excellent.  I didn't see a commitment, if you will, to try to understand where the ruptures actually come from.  The retrievals are one way to access those mechanisms, but I didn't see a commitment to either develop or fund the development of more clinically relevant failure modes of the device.  Would the company care to comment on that?

    DR. SPEAR:  Can I start off commenting?  I have spoken to the bioengineers about this previously and within the last 24 hours.  To be frank, I think this is a subject that has frustrated not just this company's bioengineers of this device but other companies because the preclinical testing has not, as we have seen, been a great test of clinical conditions.  I think what they have committed to and, in fact, are excited about, frankly, is working harder to see if they can come up with something that better predicts behavior in humans versus in the lab.  It is a hard model to produce for a lot of reasons, a lot of biological variables, but I think they are committed to come up with a better model.

    DR. WHALEN:  Dr. Chang?

    DR. CHANG:  Dr. Spears, thank you for clarifying some of the issues raised last evening.  I would like to ask you to give me some advice since we have had so much public comment.  If one of the women who had problems related to a diagnosis of fibromyalgia came to my office seven years after having augmentation with silicone gel, sat in my office and was so convinced that these changes came after the implant, seven years after, what advice can you give me in terms of how I would counsel them?

    DR. SPEAR:  I guess I would give you the advice I would give the patient.  The advice I give patients like that--I mean, that is a clinical experience most of us have had--is to say the literature does not support causation between silicone gel implants and fibromyalgia.  It is a disease that is difficult to diagnose; it is difficult to get your hands around, but that a patient has options and if they feel strongly personally that they are linked, they have the option of removing the device totally or replacing it with a saline implant.  And, different women make different decisions with that information.  The minority, interestingly, remove the device.  Probably most would leave it and a significant number would switch to a saline implant which still, of course, has a silicone elastomer.

    DR. WHALEN:  Dr. Anderson?

    DR. ANDERSON:  One of the questions that was raised is if you do a cosmetic augmentation that a woman is paying out of pocket to do, and then she has a rupture, say it is a premature rupture, she is then obliged to come up with more funds, which she may not have, to pay for this.  How would the company in a responsible way handle this?  Is there a warranty that comes with your product?  Is there a period of time?  Or, is this the "buyer beware" approach?

    DR. WHALEN:  Could I please just interject, the transcriptionist requests that when all of us, but when Inamed is making responses, you start each time with your name.

    DR. SPEAR:  We include it each time?

    DR. WHALEN:  I am afraid so.

    DR. SPEAR:  This is Dr. Spear responding.  Inamed does have a warranty program for both silicone and saline implants, the precise details of which I am not aware but I know that it pays for a certain amount of dollars towards reoperation for a certain number of years, plus I believe it is a lifetime replacement of the device as long as the patient is alive.  So, there is some warranty process.  I don't think it totally obviates any expense.

    But interestingly, for many patients, fortunately, insurance takes the position that for whatever reason you got the implant, now that you have it, if you have a problem with it, insurance will pay, not in every case but in many cases.  I have an analogy.  You know, insurance companies, when you have an accident on your motorcycle, don't say we aren't going to cover it because you were stupid to get a motorcycle.  I mean, the fact is if you get an injury, regardless of the cause, if you have insurance it usually does cover it.

    So, there is a warranty program and in many cases if a patient does have a significant problem with an implant, it is often covered by their insurance.  Not inserting a new one.  I charge patients after many years for putting a new implant in, but insurance usually covers the removal, or whatever else is required.

    DR. KUHNE:  Excuse me, this is JoAnn Kuhne from Inamed.  I just wanted to expand on what Dr. Spear said.  The program that Inamed has is called the "Confidence Plus Program" and it does provide for up to $2,400 of financial assistance in addition to the replacement implants, as well as a contralateral replacement if that is needed in a situation.  These are both for our silicone gel-filled and our saline-filled breast implants.

    DR. WHALEN:  Debera?

    MS. BROWN:  I just wanted to bring up sort of a point of historical context.  There are testicular prostheses available that have been recommended for approval by another panel.  There are saline-filled testicular implants that were approved in July, 2002 based on one-year data.  There are also silicone gel-filled testicular implants that have been approved on two-year data.  Just so this panel is aware--they are probably smaller; I have never seen one--but there are similar type devices that are on the market that have been approved.

    DR. WHALEN:  I would hope they are smaller, or maybe that is just me!

    MS. BROWN:  No comment!

    [Laughter]

    DR. WHALEN:  Dr. McGrath?

    DR. MCGRATH:  I have a couple of questions about item number seven in your proposals.  The first question is, is this a recent idea that you are just putting out or is this a preexisting program, this idea of surgeon education, certification?

    Second question, would this be a required thing that would be a condition of purchase?

    Third thing, do you really mean certification?  As you know, it is very difficult for any medical body to provide certification, which is a statement of competence and incompetence about the individual's performance of the technical process.  It is one of the things we struggle with because it requires an examination process, and a proctoring and monitoring process while an individual is doing that surgery.  So, I would like you to elaborate a bit on what you mean by that word "certification."

    DR. SPEAR:  I can answer two of those.  I am not sure I can answer the middle one.  But it is not a new concept actually.  It has been in development for about six to nine months, the idea that if these products were approved, because they have been off the market in the United Sates for 12 years, there would need to be a reeducation program for surgeons to make sure, frankly, that we didn't go through what we did in the 1980s where people, who were not necessarily familiar with these implants, would be using them without proper training.  So, that has been in the works.  In fact, the first program was scheduled to occur in November, in Los Angeles, if there was an approval.

    Regarding certification, you can certify people.  I don't know what certification will get you.  I mean, the company could certify that somebody has had the program and has passed the training.  It is certainly not required to have a license in any given state.  The thing I can't answer is whether the company would require somebody to go through this program in order to be able to use the devices, and I am not sure that has been thought about.  Do we have a decision on that?  No.  I don't think the company has made a decision about that.

    DR. MCGRATH:  I think that would be a very important issue for us to have fleshed out before we accept this as one of the conditions.

    DR. WHALEN:  Brent?

    DR. BLUMENSTEIN:  Have you done an analysis by surgeon and on outcome to see how much variability there is between the surgeons that participated in your studies?

    DR. SPEAR:  I don't believe we have, although I am dying to do it.

    DR. WHALEN:  Let me follow that up though just from a practical standpoint, if you were going to do that, I would hope you would disclose the fact that you were going to do that.  If, indeed, you were going to do that, how might it impact upon surgeon participation in your studies, in your opinion?

    DR. SPEAR:  You are talking about analysis of the surgeons that performed?

    DR. WHALEN:  Yes, if you were going to, surgeon by surgeon, look at results, which physicians in general and probably surgeons in particular are not necessarily wildly enthusiastic about having done, might that impact upon your ability to have surgeons participate in your study?

    DR. SPEAR:  This is Scott Spear answering again.  It is sort of a new territory for us to address but, frankly, it would be in everybody's interest, including the surgeon's, that if that did occur it would involve retraining of the surgeon.  The surgeon, in the long-run, would be better off, having fewer problems, if he was identified as having a higher incidence of problems so that he would have fewer problems in the future.  So, I think it would even be in the surgeon's best interest, not to mention the public's best interest and the company's best interest.

    DR. BLUMENSTEIN:  This is Brent Blumenstein.  I just wanted to make it clear that my interest in this analysis isn't to identify particular surgeons but, rather, to estimate the variability across surgeons, which would give you a lot of information about how intense you need to be about training.

    DR. SPEAR:  Of course.

    DR. WHALEN:  Dr. Choti?

    DR. CHOTI:  Yes, Michael Choti.  You mentioned that the device was improved in the last decade, the thickness and so forth.  We still don't have clinically relevant criteria for determining whether those changes really improve the product.  For example, what about the rupture rate?  Any information that rupture is less with the new device than the older device?  I mean, just to show that these mechanical properties may be different, or the thickness may be greater, or the cross-linking may be different--how is the product any better?

    DR. SPEAR:  This is Scott Spear answering again.  What we are seeing is the maturation of the data that is going to give you that answer.  The study I referred to in Scandinavia, looking at patients who have had what we call a third generation or the same type of device as this one but available in Europe, are showing a significantly lower rupture rate at five and ten years as compared to data from the '80s, looking at the previous generation of devices.

    DR. CHOTI:  But it may be capsulotomy and other factors that are related to that and not the device performance itself.

    DR. SPEAR:  It could be but the fact that the rupture rate is lower is such good news that I wouldn't want to, you know, turn down good news.  Whether it is the surgical practice that has gotten better as well as the device--I mean, the device is being manufactured to much tighter specifications than it was.  That alone should mean that you would have less problems, less failures.

    The MRI data that the sponsor presented, with 600 MRIs at one year and 200 at the second interval, is actually good data.  The extrapolation of that data from the Scandinavian study gives you about the one percent rupture rate per year which, although it is higher than I would like, is not the doomsday scenario that people would have you believe.

    DR. BROOK:  Could I just pick up on that?  This is Michael Brook.  One of the issues that came up was this question of the compatibility before and after.  I think it wasn't mentioned this morning but, in fact, if you do the same mechanical tests on the explanted materials the mechanical properties had not changed.  They were within the specifications of the materials before.  This gets back to the question of the source of the rupture but those tests were done to show that the mechanical strength is there.

    DR. CHANG:  May I ask how old were these explants that were tested?

    DR. BROOK:  These were within the two-year study.

    DR. WHALEN:  Dr. Miller?

    DR. KUHNE:  JoAnn Kuhne.  I just wanted to clarify that the retrieval study included devices that were out to an average age of 6.8 years.

    DR. MILLER:  I have a question about how you would envision the education and certification program being conducted, and whether you think it would be appropriate to put in some criteria about what types of physicians would be permitted to go through this training program, where that is appropriate, and then there is going to be required some cooperation on the part of the practicing surgeon to deliver the devices back if they fail for a retrieval study and to follow-up patients and to register the devices.  Do you have a plan to enforce compliance on the part of the practitioner with these programs?

    DR. SPEAR:  I can answer some of that.  I may need some help with some of the other questions, but in terms of how the sponsor would go about putting this program together, the plan is to do these at local sites, such as Los Angeles, Dallas, New York, Washington in the vicinity of major national regional meetings, before and after.

    Regarding putting teeth into surgeon compliance, we all know, the surgeons on this panel or not on this panel, that that is a harder issue.  But, for example, the warranty program could be tied into surgeon compliance.  I suppose shipment of devices could be tied into surgeon compliance.  Am I going to get some help here?

    DR. CROTTEAU:  Crotteau, from Inamed Corporation.  In our "Confidence Plus Program" the patient or the doctor is not awarded the monetary remuneration until the explanted device is returned to us.  So, by associating the return of the device with the payment of the program we try to facilitate the return of devices so that we can perform analysis.

    DR. WHALEN:  Prof. Dubler?

    PROF. DUBLER:  Yes, do you think the company would be willing to consider making attendance at an education program and certification a pre-condition for receiving the implant to use?

    DR. SPEAR:  This is Dr. Spear.  I saw the appropriate nod from the responsible party of the company.

    DR. WHALEN:  Dr. McGrath?

    DR. MCGRATH:  I think, before we go too much further with talking about that, we had probably better step back a step and think about whether we really want to put all of these teeth in having physicians who use a product go through some sort of a mandatory process as a contingency for taking care of their patients and getting remuneration for their patients, not for themselves, because I am not quite sure that the best place to have the education and the "ascertainment" of competence is in the hands of a device manufacturer.  This gives a certain amount of control over access to the device that might prove in the long run to not be the best thing for the physician and for patients.

    So, before we go too much further with that, I would stop and really want to hear what we are talking about here.  Right now, it is a one sentence that seems to me very "loosey" and I would like to hear a lot more about this before we say that is a good thing to endorse.

    But my question really was on item two, your patient education booklet; item four, your discussion of the device retrieval program; item eight, the patient registry--I mean, all of these are things that you are also borrowing from the presentations that were made today by the professional organizations.  Do you see yourself interfacing with these non-industry groups that are already working in this direction?

    DR. SPEAR:  This is Dr. Spear answering.  I saw a nod from the responsible part from the corporation so I guess the answer to all those questions is yes.  But with respect to your question about industry education, I know there is precedent for this.  Certainly, there is precedent, for example, with the Midas Rex Drill.  That was a very powerful tool for craniofacial surgery and you could only use it if you were trained by the company to use that drill.  So, I am not sure it is necessarily a bad thing but there is a precedent for it.

    DR. WHALEN:  Dr. Leitch, did you have a question?

    DR. LEITCH:  Again on the education issue, I wonder if you have thought about education in terms of conduct of clinical trials because I think maybe some of your issues of maintaining follow-up of the patients and some of the violations, protocol violations that you had in the beginning of the study may be related to unfamiliarity of physicians or surgeons performing in a clinical trial, particularly if they are only admitting three or four patients into that trial.  I think what you are hearing is that this panel would be interested in rigorous follow-up, and the way to ensure that that happens is that your "investigators" are well educated about their responsibilities and how they are able to maintain follow-up of their patients, and that it is their obligation.

    DR. SPEAR:  This is Dr. Spear responding again.  I have two responses to that.  First of all, I think the FDA recognizes that the compliance in this trial, as in the saline trial that preceded it, was very good.  I think, in fact, the sponsor deserves to be congratulated, from my perspective, for the good compliance.

    The Catch-22 for the manufacturer in terms of the surgeons who are involved in the trial is that I think there was an effort made to hit the broad section of surgeons who would actually be using the devices which, by definition, is not always surgeon scientists.  So, you are trying to get real surgeons who are using these devices to report on their experience, which meant that you had to use people who were not necessarily academicians--in fact, I am not sure even a majority were academicians.

    DR. LEITCH:  And that is to be applauded.  I support that because they are ultimately the people who are delivering the majority of the care, and we are experiencing that in some of the other clinical trials, if they are using surgeons who, you know, have not previously had experience, they do need some education.  I think it would be a good idea to make sure that that happens.

    DR. SPEAR:  And let me add--this is Dr. Spear again--that the sponsor has had a very, very robust regulatory compliance program which audits all the sites at least once, if not twice, a year, reviewing all the data; trying to contact the patients.  They have been very proactive in this study, as in their other studies.

    DR. KUHNE:  JoAnn Kuhne, for Inamed.  I just want to comment to you that that is a point well taken, and we do refresher courses and have found that to be very useful, especially in our adjunct study where we are really trying to go after those sites and make sure that they complete their paperwork so that we get that paperwork and have more data and our compliance increases.

    DR. WHALEN:  Dr. Miller?

    DR. MILLER:  I have another question.  It has been suggested that if the FDA labels these as now safe, it will become a free-for-all out in the world and these will be used in everybody for indiscriminate reasons, and this sort of thing, because now they are safe.  Do you propose any steps--I mean, do you think the steps you have proposed are sufficient to prevent that sort of behavior?

    DR. SPEAR:  This is Dr. Spear answering that question.  I have personally struggled with the decision made by the FDA in 1992 regarding who could and who could not have these devices.  I still feel that it under-estimated women and was overly paternalistic.  I think a combination of labeling and conditions for approval should give people enough information that they can make a rational decision.

    For example, I have family members who have taken Accutane.  Anybody who has taken Accutane and read the disclaimers for Accutane should think three times before taking Accutane.  It has a lot of risks associated with it but it has benefits.  I think between labeling and public information this could be handled perfectly appropriately.

    The idea that there would suddenly be a windfall of silicone implants--as Dr. McGrath said earlier, women already have access to breast implants.  What we are trying to provide them is a better breast implant.

Concluding Panel Deliberations and Vote

    DR. WHALEN:  I would like to thank Inamed and ask that they perhaps retreat, and I then ask our Executive Secretary, Dr. David Krause, to read to us the voting instructions.

    DR. KRAUSE:  Please listen carefully.  These are the options for panel recommendation for premarket approval applications.

    Medical Device Amendments to the Federal Food, Drug and Cosmetic Act, as amended, allow the Food and Drug Administration to obtain a recommendation from an expert advisory panel on designated medical device premarket approval applications that are filed with the agency.  The PMA must stand on its own merits and your recommendation must be supported by safety and effectiveness data in the application or by applicable publicly available information.

    Safety is defined in the Act as reasonable assurance, based on valid scientific evidence, that the probable benefits to health, under conditions of intended use, outweigh any probable risk.

    Effectiveness is defined as reasonable assurance that in a significant portion of the population the use of the device for its intended uses and conditions of use, when labeled, will provide clinically significant results.

    Your recommendation options for the vote are as follows:  The first option is approval if there are no conditions attached.

    The second option is approvable with conditions.  The panel may recommend that the PMA be found approvable subject to specified conditions, for example, physician or patient education; labeling changes; full analysis of existing data.  Prior to voting, all of the conditions should be discussed by the panel.

    The third option is not approvable.  The panel may recommend that the PMA is not approvable if the data do not provide a reasonable assurance that the device is safe or if a reasonable assurance has not been given that the device is effective under the conditions of use prescribed, recommended or suggested in the proposed labeling.

    Following the voting, the  Chair will ask each panel member to present a brief statement outlining the reasons for their vote.  Thank you.

    DR. WHALEN:  Is there a motion?

    DR. BOULWARE:  Mr. Chairman?

    DR. WHALEN:  Dr. Boulware?

    DR. BOULWARE:  Based on the information we have had so far and the instructions, I move approval with conditions.

    DR. WHALEN:  It has been moved that there be approval with conditions.  Is there a second to that motion?

    DR. CHANG:  Second.

    DR. WHALEN:  Seconded by Dr. Chang.  Is there a condition that is moved?  Dr. Anderson?

    DR. ANDERSON:  I move as a beginning point that what was laid out in the sponsor's presentation just now be adopted as conditions subject to discussion and modification.

    DR. WHALEN:  Sorry, can you be more specific about what you mean about what they outlined?

    DR. ANDERSON:  I move that the eight points that were laid out by Dr. Spear be the conditions for approval subject to our discussion and modification thereof.

    DR. WHALEN:  Looking towards my FDA conscience who is ignoring me, is it appropriate to take those eight collectively or do we need to take the eight individually?  Okay, they may be taken collectively.  Is there then a second that those eight points be a condition?

    DR. BOULWARE:  Second--Dr. Boulware.

    DR. WHALEN:  It has been moved and seconded that the eight conditions, as outlined on pages four and five of the Inamed statement, be conditions.  That is open to discussion.  Would you care to start that off, Dr. Anderson?

    DR. ANDERSON:  I would like to discuss the informed consent form.  The proposition is that a small group of panel members, along with the FDA, help to develop a consent.  I would like to discuss how we would do that.  Is there any precedent to in FDA about how we might facilitate a proper consent development?

    DR. WHALEN:  Dr. Witten, would you address that?

    DR. WITTEN:  Yes, I am not sure what is referred to in this condition.  We do work on patient education booklets with sponsors, which is number two here, and we have asked panel members for input on that.  So, as far as informed consent, I am assuming what is meant here is surgical informed consent.  Is that what you all--

    DR. WHALEN:  Yes, right.

    DR. WITTEN:  Although we haven't done that in the past, I don't really see why we couldn't.  You are talking about having a model informed consent that would be part of the material that the sponsor would distribute to surgeons with the labeling?  Is that the idea?  I am just trying to understand what is being proposed.

    DR. WHALEN:  If I could interject, it would have to be a model consent form since even FDA, with all of its power, is not going to have the authority to tell every practitioner at every institution--

    DR. WITTEN:  Right.

    DR. WHALEN:  --what consent form they must use.

    DR. WITTEN:  Exactly.  Thank you for making that point.  I was going to explain that.  That is what it would be.  So, yes, I think that we could certainly--you know, the sponsor could certainly propose something and we could work with the panel to get input.  I mean, it isn't something we have done before but it doesn't look to me to be outside of the realm of something that we could do in conjunction with the sponsor and members of the panel prior to approval.  I think we would have to work out exactly how to do that.

    PROF. DUBLER:  Dr. Whalen?

    DR. WHALEN:  I will get to you in just a moment, Prof. Dubler.  Dr. Blumenstein and then Prof. Dubler.

    DR. BLUMENSTEIN:  Perhaps some of the people who testified in the public open meeting part of this activity would also have something to say about the informed consent.

    DR. WHALEN:  Prof. Dubler?

    PROF. DUBLER:  I am of that generation that needs something to hold in my hand that I read.  But it is clear that that is not the most effective way of communicating, and there have been some recent studies in The New England Journal of Medicine that demonstrate how woefully inadequate the written word is in communicating risks and benefits to patients.  This is a real opportunity, I would argue, to experiment with videos that would give all the voices an opportunity to be heard and, indeed, to be seen, and you might produce some patient education that really could incorporate some of the dialogue that took place at this panel.

    DR. WHALEN:  Other discussion on these eight conditions?  Dr. Olding?

    DR. OLDING:  I just wanted to make a comment about that.  There, in fact, are patient education videos made now by ASPS, and I would think that type of thing would serve well for what you have requested.

    DR. WHALEN:  Dr. Li?

    DR. LI:  Steve Li.  I think I would just like to perhaps add a little bit to number four, the retrieval program, as Mr. Krause suggested that we could do.  I think one of the things I would like them to do in addition to continuing the retrieval program is to perhaps work with the FDA and essentially reexamine the retrievals they have got already.  They have a substantial collection of retrieved devices and there quite possibly could be a lot of valuable information there perhaps if they extended the things they measured and examined.  I would want them to establish, as they suggest, perhaps a third-party consultant group that would ensure that the retrieval program would, hopefully, lead us to some conclusion as to where these ruptures come from.

    DR. WHALEN:  I would suggest that that may be substantive enough that it probably should be an additional condition that we will consider shortly, after dealing with these eight conditions, whether or not they are approved as conditions.

    PROF. DUBLER:  Dr. Whalen?

    DR. WHALEN:  Prof. Dubler?

    PROF. DUBLER:  There has been some discussion today especially about the visual examination of the field to see if silicone, in fact, exists outside the elastomer space.  Even the MRI might not be sufficient.  But someone suggested this morning that what is needed is a biopsy when the implant is taken out.  Now, I think this would be another condition and I am in over my head, for those clinicians who might like to rescue me, but is that something that we would like to see happen?

    DR. WHALEN:  As you, yourself pointed out, Nancy, that would be an additional condition, which is certainly going to be in order but is not presently.  So, if we could focus on condition number one, which is these eight conditions, for further discussion upon these?  Dr. McGrath?

    DR. MCGRATH:  Condition number five talks about recommending that the patient have regular physician follow-ups.  I assume that this is related to the detection of rupture as one of the reasons to have regular physician follow-ups.  I think this is the point of the correlation with the MRIs that you are doing, and that whole question the has so aptly been brought up by someone on the panel that there needs to be more information about the efficacy of physical examination in a ruptured gel implant and get some data on how that does correlate with your MRI findings at five, seven and ten years--nine years.  I would build that in as a condition, that that would have to be actually a piece of research that would be accomplished as part of that item five.

    DR. WHALEN:  Perhaps I am being subjective but I would incorporate that as a friendly amendment so that we could encompass it in the present discussion.  Dennis?

    DR. BOULWARE:  For that same number five, have we assigned a time period?  Annual or five years?  Can we strengthen that to say regular annual physical follow-up?

    DR. WHALEN:  I think while substantive, it is editorial to the changes at hand.  So, you are proposing that it be annual?

    DR. BOULWARE:  Yes.

    DR. LIEBERMAN:  Dr. Whalen, for number five, one of the things that is not done here, and I don't know if this is a separate condition, is to follow-up the women who have explants because these are the women with rupture and if we stop following them once they are explanted, then we don't find out their health outcomes.

    DR. WHALEN:  So, you would actually be proposing that there be deletion on number five past "follow-ups" and delete "as long as they have the device."

    DR. LIEBERMAN:  Yes.

    DR. WHALEN:  Would you have a suggestion as to how long that explanted population should be followed?

    DR. LIEBERMAN:  I think that that population should be followed for the length of the study, as long as they are following those women.  I think that that is the population that we are concerned about in terms of the effects of silicone that has been extracapsular and may cause a problem.  It doesn't necessarily have to be the same type of follow-up; we could work on that.  But I think we need to get the health status of those women and find out what has happened to them.

    DR. WHALEN:  Okay.  Dr. Miller?

    DR. MILLER:  On that same question number five, I agree with the point that was just made about needing to follow women.  Once they get the device, whether they have the device or not, they are followed for "forever" as possible.  Yearly I think is a good idea.

    I would like to have some mechanism to ensure compliance with this.  I mean, in the current study, of course, there is very intense compliance where you have to send reports and everything.  I think some kind of compliance could be ensured here where perhaps the physician could send in e-mail or send in a report of some kind that they have seen the patient.  What do you think of that?  I would like to see some way of enforcing it, even though I know how difficult it is.  I don't just want to have this become something that is very casual and is ignored.

    DR. WHALEN:  Do you have a concrete suggestion in that regard?

    DR. MILLER:  How about--I am just picking an idea, I don't know if it has ever been done before, but perhaps mandating some sort of form be returned to the company, either by e-mail or by mail, that needs to appear at the company's door every year, or something.  If it is not there, then the physician is contacted and if some explanation isn't made that physician is disqualified from receiving any more implants.

    DR. WHALEN:  Is there any more discussion on that?  Dr. Leitch?

    DR. LEITCH:  So, how many patients that would turn out to be?

    DR. MILLER:  I think it would depend on the surgeon.  I think some surgeons implant--

    DR. LEITCH:  But overall what would the company expect to receive?

    DR. MILLER:  In terms of follow-ups?

    DR. LEITCH:  Yes.

    DR. MILLER:  Oh, probably hundreds and hundreds.

    DR. LEITCH:  Thousands, wouldn't it be?

    DR. MILLER:  Yes, it would be a big job but I think that, you know, there is precedent with this for other devices.  Again, the thing that comes to my mind are things like pacemakers.  These are very heavily monitored and tracked.  You know, so much concern has been raised over the breast implants that I think an extra effort needs to be made to keep track of the patients, those who have received one of these devices, and some mechanism needs to be created to do that.

    DR. WHALEN:  Dr. Manno?

    DR. MANNO:  With reference to your tracking comments, I don't think the whole blame--usually I am hacking on physicians but this time I am not.  I think that not all the blame for lack of information should rest on the physician because there will be a component of women who will not, if they are not sick, go in for a checkup.  It would appear to me that it needs to be impressed on the women that this is equally as important as a yearly mammogram.

    Now, you realize that it has been an education process to get women to admit that they are vulnerable and go for their yearly mammograms.  We also have the problem of extending the age group downward rather than upward, and the young women are not used to having to go for these yearly exams as we older people are.  I think there is going to have to be some education of the patient, and I am thinking especially of the augmentation patient.  If you are sick you will go to the doctor.  If you are not sick you are not going to take the time.

    DR. CONANT:  I would just question who is going to pay for those visits.

    DR. WHALEN:  Sorry, can you say that again?

    DR. CONANT:  I would just question who is going to pay for those visits.  The young implanted patient isn't going to be paying for those visits unless they are not charged by the surgeon, and I wonder how many surgeons are going to no-charge an office visit.

    DR. WHALEN:  I see no further discussion right now.  Is there any further point to be brought up on condition number one, which subsumes the eight conditions with some changes that we have already made?  I will read these before we vote.  Is there any further discussion?

    PROF. DUBLER:  I didn't think we quite finished that last discussion.  I think that is a very hard issue.  Young women will need to go back for an annual visit.  That is expensive.  They probably haven't budgeted for it.  Some of them won't have health insurance.  I do think it is going to be very hard to get asymptomatic young women, who are not used to going for mammography, to come in and get checked and I just don't know what to do about that, and I don't think it is fair to make that a responsibility of the surgeons.  I think this is going to be a very difficult group to monitor.  So be it.

    DR. WHALEN:  Further discussion?

    DR. MILLER:  It is difficult in a forum like this to create a mechanism.  Could we just say that one of the things that has to be worked out with the FDA and perhaps the panel members is a practical mechanism to ensure follow-up?

    PROF. DUBLER:  Encourage.

    DR. MILLER:  Yes, encourage follow-up perhaps.

    DR. WHALEN:  I mean, you are basically asking can you stipulate a condition and the answer is obviously yes.  So, the reason we are here as resource experts to the FDA is to stipulate those conditions we feel are appropriate and to vote them up or down.

    DR. MILLER:  I would add that to number five, that there be some mechanism worked out to increase the rate of compliance with the follow-up.

    DR. WHALEN:  Further discussion?

    DR. BLUMENSTEIN:  Brent Blumenstein.  I am just going to blurt this out, but maybe the gynecologists could help in this.

    DR. WHALEN:  Phyllis?

    DR. CHANG:  A practical friendly amendment, rather than saying annual, knowing that this is going to be so difficult, the visits so far are one, three and five years.  Why not make it seven and nine years so that it may be achievable?  And the effort is education for women who don't have symptoms, and this is data collection that they have enrolled in a clinical trial so that they are assisting in establishing long-term safety records by showing up.  Given that education, I believe many participants would come back.  I don't know what kind of incentive program--I don't think we were privy to that three years ago in terms of how the sponsor was able to achieve a very excellent follow-up.  So, a similar model perhaps could be extended beyond the fifth year to nine years.

    DR. WHALEN:  I am sorry, just so I know what you are phrasing, for number five you are stating instead of annual that it be one, three, five, seven, nine?

    DR. CHANG:  Right, and that these details, I am going to also suggest, be worked out between FDA and the sponsor in continued discussion.

    DR. WITTEN:  Can I just clarify?  I had understood number five to be referring to any patient who was implanted with one of these products.  But are you talking about that, Dr. Chang, or are you talking about patients who were in the study?

    DR. CHANG:  These conditions are for patients in the study.

    DR. WHALEN:  No, these are conditions for any patient who gets an implant.

    DR. WITTEN:  Just for clarification, the study is annual.  The MRI cohort only gets MRIs on odd numbered years.

    DR. LAWRENCE:  Item number three does specify five, seven, nine years and longer if necessary for physical and MRI.  So, three and five are probably compatible.

    DR. WHALEN:  Dr. Leitch?

    DR. LEITCH:  Probably we need to clarify with the sponsor if number three refers to the planned study group patients versus this idea of follow-up of all patients.  Again, I think the requirements that we have on follow-up for all patients would be different in terms of the requirement to the sponsor than would be the study requirements, which I think would need to be stringent about and there is specific performance that is required of the sponsor on that part.  If you are asking them to be responsible for the monitoring of every single patient every year or one, three, seven and nine, then, of course, that is a much higher degree of responsibility in terms of the number of patients and the cost thereto.  So, I think those two points are separate.

    The point I would make about seven, as part of the patient education--I mean, we have talked about this idea of long-term follow-up of patients and, certainly, we heard from patients their concerns of long-term issues.  So, I think that is what needs to be expressed to patients in terms of motivating them for follow-up, that, in fact, they are receiving a service in the sense of coming for follow-up to assess for complications or problems which they, themselves, may be unaware of at the time of presentation, and that they would then potentially be benefited, as the MRI data matures, as to whether that should become a part the screening mechanism that would be undertaken as some degree of routine.  So, I do think we need to separate what we are talking about in those two groups.

    MS. GILBERT:  Alisa Gilbert.  I just want to say something about the recruitment or retention of the participants in the study group.  There has to be more work done in making sure that the women are following through and really tracking these women.  Can that be added somewhere within the eight, that there would be a motion for retention and recruitment?

    DR. WHALEN:  I am just trying to clarify what you mean since we are making conditions for all implants, when you say retention and recruitment, do you mean into the physician's practice who has implanted it, since this is no longer a study but, rather, a practice standard?

    MS. GILBERT:  Well, for the women who are in the study--I guess that is where I want to be clear about this too, is this just for the follow-up--

    DR. WHALEN:  This is for the entire population of patients who would be utilizing this device, were it to be approved.

    MS. GILBERT:  But there still will be an ongoing study, right, for the ten years?

    DR. WHALEN:  For the ten years there will be, yes.

    MS. GILBERT:  And there still needs to be more work done in getting more women to be actively recruited into the study to get accurate data.

    DR. WHALEN:  Well, are they going to be recruiting further patients or simply following patients--

    MS. GILBERT:  Following them better, yes.

    MS. BROWN:  You want adequate follow-up for study patients.

    MS. GILBERT:  Yes.

    DR. WHALEN:  So, you would like to have an additional recommendation that there be--help me here.

    MS. GILBERT:  More work to retain the patients that are actively enrolled in the study.  Because what are the numbers right now that we are looking at?  How many people are actively enrolled and what is the dropout rate and, you know, the loss of some of the women that were involved in the beginning but they then have kind of fallen out of the study?

    DR. WHALEN:  Just again to further clarify it, I would imagine, in terms of the study, it is almost always going to be the goal of those conducting the study to have as high a retention of the study population as possible.  So, if we are simply encouraging them to do what we already anticipate they will be doing, it doesn't take on a very strong dimension.  Do you feel that there need to be some teeth put into that?

    MS. GILBERT:  I don't know.

    DR. CHANG:  Dr. Whalen, can I ask the sponsor or Dr. Spears to clarify something?

    DR. WHALEN:  If it is a very focused question, yes.

    DR. CHANG:  The very focused question is for your proposals for follow-up on item three, is it your intent that "we support this panel's opinion and will recommend to FDA"--is it study patients be followed up for ten years via physical examinations?  It is study patients that should have MRIs at five, seven and nine years?

    DR. WHALEN:  If I could just interject, Scott, you were talking about what we talked about yesterday, that it be all patients.

    DR. SPEAR:  I apologize for the confusion.  I sincerely do apologize for the confusion, but number three refers specifically to the study patients.  The discussion was whether the mail-in would be a replacement for physical examination and whether the MRI is necessary for the five, seven and nine years.  All the others refer to all patients but number three is specific to study patients.

    DR. WHALEN:  Okay.

    DR. CONANT:  Dr. Whalen, I am not sure if this is an addition to or an amendment so correct me if I am at the wrong time here.  For number seven, the surgeon education, I would also like to see the sponsor develop an algorithm for surgeon evaluation by physical exam and then a system, if there is concern about rupture, for what the next step is--MRI evaluation if there is rupture; whether explantation is recommended.  I don't know if that is wrapped in number seven.  So, like a paradigm for how you deal with these patients and that part of the surgeon education.

    DR. WHALEN:  I think we need to take that separately so I will get back to you.  What I am going to do now is recognize Dr. Witten.

    DR. WITTEN:  Thank you.  Before you get to the vote on this, I just want some clarification from the panel on what their expectation would be for number eight.  In other words, what is the objective for number eight in the panel's mind?

    DR. WHALEN:  The subject of expectations of the registry is open for discussion.  Dr. McGrath?

    DR. MCGRATH:  I will go back to that, Dr. Witten, because I mentioned before that I thought number two, the patient education brochure, number four, the device retrieval program and the registry should all be done in coordination with a third non-registry party.  Such a group could be a university or a professional organization.  Certainly, those initiatives are under way out there.  But I would like to see partnerships with non-involved parties on those efforts.  I agree that it needs to be fleshed out.

    DR. WHALEN:  What I am going to do now is make my best attempt, with some of the changes we have just been discussing and changing some of the language to make it more appropriate, to go through each of these eight and ask the assistance of my fellow panel members to correct me when I goof up on any of them.

    Number one, Inamed will, in conjunction with FDA and any panel members they would deem appropriate, develop a model consent form.

    Number two, Inamed will develop and distribute a patient education booklet on breast implants.  This pamphlet will be built from the model informed consent form and will be written for women who use their products.  Inamed will utilize focus groups to develop such a book.  Inamed will make sure that every woman considering this product is as informed as possible.  Brent?

    DR. BLUMENSTEIN:  Can I suggest using the word "media" instead of "book" so they can do a videotape as well?

    DR. GILBERT:  I agree with that, media or packet.  A packet that would have a booklet, video and/or CD ROM.

    DR. MCGRATH:  Tom, before you leave that, you are either deliberately or inadvertently omitting my friendly amendment that this be done in conjunction with--

    DR. WHALEN:  That is why we are doing it this way, Mary, so you can keep me honest  If you could just rephrase that for us?

    DR. MCGRATH:  Well, it was just a codicil on the last sentence.

    DR. WHALEN:  I am sorry, say that one more time.

    DR. MCGRATH:  It was an addition to the last sentence or final sentence on that paragraph.  We are talking about number two, the patient education booklet--

    DR. WHALEN:  Correct.

    DR. MCGRATH:  The final sentence of this would be partner with other organizations such as professional organizations.

    DR. WHALEN:  So, Inamed will assure that every woman considering this product, in conjunction with partnered professional organizations--

    DR. MCGRATH:  Well, it would probably go up to the focus group.  We will utilize focus groups, partner professional organizations, and so forth, to help develop such a book.

    DR. WHALEN:  I assure you it wasn't intentional.  Number three, Inamed recommends to FDA that study patients should be followed up for ten years via physical examinations and MRIs at five, seven and nine years, and longer if deemed necessary.

    DR. LIEBERMAN:  I think that the recommendation about following explanted patients belongs there and not in number five.

    DR. WHALEN:  So, you would want to incorporate the MRI suggestions into the explanted patients?

    DR. LIEBERMAN:  I think we need to have the follow-up of the explanted patients as part of the study protocol, which it isn't currently.

    DR. LEITCH:  I would not suggest that the MRIs continue once they are explanted.  You know, if they are of the age to have mammography, they should have mammography at annual intervals but I would not say to continue MRI once they are explanted if they are not reimplanted.

    DR. WHALEN:  Would it subsume, both of what you are saying, to have it as I worded it but then to continue on to say that explanted patients will continue to be followed in the study at five, seven and nine years, not necessarily having the MRI part in it?

    DR. LEITCH:  No, I wasn't implying they should have MRIs.

    DR. WHALEN:  Mary?

    DR. MCGRATH:  A question, at this point we are talking about the study patients and their follow-up with physical exam and MRI.  Are we going to talk now or later on about other things that we might like to ask about those patients, ask them to look for in those patients besides doing a physical exam?

    DR. WHALEN:  I think that is dealer's choice but since I hold the deck, why don't we just make that a separate one and we will deal with it?

    DR. MCGRATH:  Thank you.

    DR. WHALEN:  Number four, Inamed will supply to FDA and, if deemed appropriate by the FDA the panel, annual reports on the post-approval study and have an independent third-party on an annual basis audit that study.  Inamed will pay particular attention to any relationship between outcomes and rupture status.  They agree to conduct a device retrieval program to study the changes that occur in the product over time and systematically investigate the failure modes for the device.  Inamed agrees that if the independent third party finds the study is not in compliance with these conditions that they will withdraw the PMA.

    Steven, was there anything further you wanted to put in there or do you just want to wait and add it to the discussion?

    DR. LI:  I will wait and add it to the next condition.

    DR. WHALEN:  Thank you.  Bear with me a second on number five--any patient with a silicone gel-filled breast implant will have annual physician follow-ups and there will be a mechanism to assure compliance with follow-ups.

    DR. CHANG:  I have a friendly amendment because I don't think that is a sustainable condition because it reads that Inamed recommends that any patient who has a silicone gel-filled breast implant have regular physician follow-ups.  Now, that can be specified, annually as long as they have the device but that is a recommendation and I don't believe it is a practical, achievable goal to say that Inamed will be responsible--

    DR. WHALEN:  Well, that is why I deleted "Inamed" and stated "any patient."  The context of Dr. Miller's suggestion was that it be annual on this particular item.  Clearly, that is why we are going through these and discussing them.  We can modify it any way that we want, but I deleted the Inamed part from this because this is what we are hoping FDA is going to recommend be a practice standard in terms of this device.

    DR. NEWBURGER:  Question, I am concerned about this, that if current trends are to continue within three years or so, this will be one million more women with breast implants and I find that a very unwieldy number.  Since part of the purpose of this I think is to also have access to this information on a more informal basis as well, I am wondering how those numbers would be managed.  Of course, yearly exams for a million people in three years is financially very difficult.  Is it fair to ask people to assume that burden, and is it fair to try to put that onto insurance companies to cover this?  So, I have a lot of trouble with number five.

    DR. WHALEN:  In view of what you just stated, would have a follow-up suggestion on what the frequency should be, or do you feel that we should not be stipulating that follow-up be part of this?

    DR. NEWBURGER:  I would like to see the follow-up less than once a year and perhaps every other year, and I would like to have some informal tracking mechanism for reports on these people.

    DR. CHOTI:  Another comment, first of all, a recommendation without any method--just putting it in as a guideline, it is unlikely to happen.  Second, regular physician follow-up doesn't specify that that is the plastic surgeon and, therefore, the gynecologist or the regular physician isn't going to be--if the goal is to detect rupture, and I assume that is the goal, and we have no other mechanism for doing it, no other imaging studies, then it needs to be a physician that is trained at detecting rupture.  So, this thing has no teeth.  I mean, we just want these women to be followed, not just to have these things put in and lost to follow-up.  But this is really not going to solve any problem.

    DR. WHALEN:  Do you have a counter proposal?

    DR. CHOTI:  Perhaps that the surgeon, the plastic surgeon putting it in--the recommendation should be that they should be the one to follow-up.  Then I don't know, as Dr. Miller suggested, how we can put a little compliance into that thing.  I don't know how to do that.  I don't think women will be followed up, many of them won't be.

    DR. WHALEN:  As it stands, I think we have three open issues on this particular item, frequency of follow-up, by whom, and the question of a mechanism for ensuring compliance, along with Dr. Newburger's concern about reporting data for all these patients.  Since that opens so many things, I think for this item we are going to have to go around the table.  So, we are going to start with Dr. Miller and ask how you would come on each of those items.

    DR. MILLER:  Do we have to resolve this at this panel or is this something we can leave to the work subsequent to the panel meeting that is going to go on with the educational material and informed consent?  Why don't we add this to that work?

    DR. WHALEN:  Well, it would be my contention that since we are stipulating a condition of approval, for this genre of stipulation we have to come in with some specificity to it.  Is there a particular type of specialist who needs to be involved, how often should it be, and the like?  So, I don't think we can simply say the condition would be FDA will work on some form of follow-up.

    DR. MILLER:  Okay.  I agree with the comments made about one-year follow-up.  Perhaps every two to three years is practical.  I think it should be examined by a person who is in the pool of surgeons who are certified to perform these procedures.  It may not be the same surgeon because people do move around, especially these younger patient populations, but there should be some effort to have that patient be linked to another surgeon who can do the examinations and is competent to do that.

    Then the enforcement part of it, that is a very difficult thing.  Yes, Mary?

    DR. WHALEN:  We are going to go around the table, Mary, and ask everybody to chime in with what they feel about this.

    DR. MILLER:  I think some sort of accountability mechanism, either just a mailed in piece of paper--even if a surgeon can't track the patient, just a statement from the surgeon that he has made an effort and this patient has now disappeared, some sign-off by the surgeon that he made a good-faith effort to follow these patients, maybe as simple as a mail-in thing.

    DR. WHALEN:  I am asking this as a question in regard to that last issue of a mechanism to ensure compliance, how is what you are suggesting different from a patient registry, or is it?

    DR. MILLER:  I don't think it necessarily is.  I think they both are coupled together.  You populate the registry by the follow-up from these physicians so they both go hand-in-hand I think.

    DR. WHALEN:  Dr. Anderson?

    DR. ANDERSON:  I see recommendations five and eight as being linked.  Number eight is the Inamed patient registry.  I would suggest that there is a recommendation made by the company and the FDA for annual follow-up, and we recognize that when we make a recommendation patients will have the option of following that or not following that.  Remember, we do have a study group that is being followed out to ten years.  So, it is not that we are devoid of data.  We have a selected subgroup that we are extracting data from.  I would suggest that we roll this into number eight, the registry, and this is a relationship between the company and the patient because patients move.  I think it is unrealistic to expect that the surgeons would track these folks.  It won't happen.  But if you make that relationship, there is a registry that is available and the patient understands this, and there is an annual card that is sent out, "how are you doing?"  We do this in epidemiological studies and that is how the registry data would be populated.

    DR. WHALEN:  Dr. Li?

    DR. LI:  I will generally defer to my clinical colleagues on the practicality of this, but as someone who might be interested in looking at that data to try to assess implant performance, it seems to me that you would have to know what information you want to be getting.  In other words, I don't know what I would do as a materials person to have a card that says this patient is doing fine.  So, I think if we are going to collect the data it has to be for a certain purpose, and if you aren't going to meet that purpose I am not really sure why all the effort and the expense is going to be put into that effort.

    DR. WHALEN:  Prof. Dubler?

    PROF. DUBLER:  Patients have authority and autonomy but they also have responsibility, and I think that number five gives us the opportunity to emphasize the patient's responsibility with physician best practice.  So, in the certification and training for plastic surgeons, I think that the notion that yearly follow-up is a part of the process should be an element.

    I think in the informed consent materials the notion that yearly follow-up is part of the process has to be an element.  Beyond that, I just don't think there is a lot we can do.  With one final note, which is that the cost of this is, of course, an issue and insurance companies should be encouraged to cover the cost of this yearly follow-up and physicians should be encouraged to make it financially available.

    DR. WHALEN:  Dr. Newburger?

    DR. NEWBURGER:  I think the purpose of this expanded registry then would be to detect the events that would occur in 1/1,000 cases, 1/10,000 cases, 1/50,000 cases, and without it we are not going to be able to see these.  I think one way that we can get higher compliance is to offer a financial incentive to patients who have received the implants.  The company has done that in the case of certain fillers.  I think that attracts more people to the process.

    DR. WHALEN:  We are looking here at all patients who receive implants.  Are you proposing that the manufacturer be providing financial incentives for all patients who receive implants?

    DR. NEWBURGER:  Perhaps with each card that would be sent to a patient, a reminder to see your physician for a follow-up.  If you do, here is a partial rebate.  I don't think it is appropriate for our insurance premiums to pay for covering the cost for an elective cosmetic procedure for other subscribers.

    DR. WHALEN:  Dr. Boulware?

    DR. BOULWARE:  Can you remind me again what the question is?

    [Laughter]

    DR. WHALEN:  We are trying to find a needle in a haystack.

    [Laughter]

    We are looking to see how often we are recommending, in number five, that patients are going to be followed; is there a specific breed of practitioner who is going to be following them; and are we going to propose that there be some compliance mechanism?

    DR. BOULWARE:  I guess my thoughts are that number five really is subsumed in number eight and for the patient registry we can come back with another condition to include the data we would like to have in that, which may include an annual physical exam and/or historical medical data that can be provided.

    DR. WHALEN:  So, you would say annual?

    DR. BOULWARE:  Yes.

    DR. WHALEN:  Dr. McGrath?

    DR. MCGRATH:  With regard to number five--before when I got all excited and was rising my hand out of turn, I was going to also suggest incentivizing with the manufacturer's rebate for these examinations for the patients.  However, I want to mention one other thing, if we are linking this, as I think three panelists have already, to number eight, the registry, again, I just want to comment that we are back to the same thing and I think the registry should be something that is managed by an independent party.  Ultimately, if we have a patient registry for breast implants we want something that can include implants from other manufacturers.  We want to have something that will live into perpetuity if companies change hands, and so forth, I think that this registry should be managed by an independent third party.

    DR. WHALEN:  Dr. Leitch?

    DR. LEITCH:  I would favor an annual follow-up with the idea because if you advise people for wider intervals they are, you know, likely to forget.  If you give them a two-year interval the chance is that they will do this in three years rather than two years.  So, I favor annual although I would defer to my plastic surgery colleagues in terms of some of the physical exam evaluations if they feel that every two years would be sufficient for that.

    In terms of how you get patients to do that, I also agree that there is some responsibility on the patient's part to have follow-up.  I mean, the patients here have told us that they may have long-term issues.  So, the way to address that and be certain that their surgeon is aware of that is that they have regular follow-up.

    While I think incentivization may be appropriate for the study patients, I think for the routine follow-up of patients it is not necessarily the responsibility of the sponsor to do that, unless they particularly wanted to do it.  But I think this is education of the patient that we have to focus on, that they do need to have some follow-up so that if they have issues they have a potential to be recognized.

    DR. WHALEN:  Dr. Chang?

    DR. CHANG:  I am going to be recommending that the sentence in item five that we are redoing be placed at the end of the patient information brochure, just as a general guideline.

    DR. WHALEN:  Dr. Choti?

    DR. CHOTI:  Well, as I said before, I think that the main goal of the regular follow-up is detection of rupture.  So, I think it needs to be a trained plastic surgeon with experience in identifying rupture.  That is part of the education of the surgeon, or certification perhaps.  So, that needs to be specified.  I don't think any physician, perhaps including myself--I wouldn't be able to detect easily what rupture would look like.

    I don't think it is the same as the registry.  I think the registry can track follow-up and can track issues such as rupture or any other problems.  So, I think the registry is linked to the follow-up to monitor follow-up, but it is distinct.  I think annual is probably reasonable for the reasons mentioned.

    DR. WHALEN:  Dr. Blumenstein?

    DR. BLUMENSTEIN:  No comment.

    DR. CONANT:  Just a comment, I think our trouble with number five boils down to the lack of long-term follow-up on this implant and we are trying to create that.  It bothers me that we will be doing that by this method.  However, I like the idea of the registry monitored by an independent group, but I think that the follow-up--it is incredibly unfeasible to think that young women with implants are going to be followed yearly by any physician, and they are going to be lost.  So, I think it is a combination of patient responsibility and I would love for physicians to feel some responsibility as well, but I would think that patients could answer quite a few questions regarding their implants.  They could be prompted potentially from a registry of some sort.  So, things like symptomatology, shape of implant, softening of implant, hardening of implant, things like that.  So, I think it might be a combination of patient response with and without physician exam.

    DR. WHALEN:  Dr. Lawrence?

    DR. LAWRENCE:  I would agree with those remarks and other comments as far as this stage of the recommendation is concerned.

    DR. WHALEN:  Dr. Lieberman?

    DR. LIEBERMAN:  I would like to echo Dr. Conant's comment.  I think that our angst with this has to do with our discomfort at the level of follow-up and feeling that there is this lack of information.  If we are considering this, I think we need to be realistic about the follow-up.  I think with all of those problems--financial--they are probably not going to be followed up regularly even if we recommend it and we should build into the registry some kind of regular mail follow-up that gets us at least symptomatology and serious outcomes.

    DR. WHALEN:  Dr. Manno?

    DR. MANNO:  I pretty much agree with what has been said, but I heard two things that troubled me.  One was that the company should consider offering some sort of incentive for follow-up in the general group of patients.  I question whether that is really ethical in today's climate.  That can perhaps be addressed by Dr. Dubler.

    The other thing that I heard that bothered me is that if there is a registry, as pointed out in number eight, which states an Inamed registry, they should not have to bear the burden of the other implants that I heard stated by a panel member.  I think that is over and above--beyond the call of duty.

    DR. WHALEN:  Dr. Olding?

    DR. OLDING:  I also agree that patients should be examined on an annual basis by one of the certified--if that is how you want to refer to them--plastic surgeons.  I also agree that there should not be a financial enticement for the patients to do that.  Finally, I certainly agree with Dr. McGrath that there should be a third-party participant, some professional organization, who monitors this or participates with this group, if for no other reason than to add a certain air of validity to it.

    DR. WHALEN:  Ms. Brown?

    MS. BROWN:  I have no further comments on this.

    DR. WHALEN:  Ms. Gilbert?

    MS. GILBERT:  I agree with what Dr. Olding just said, and I would encourage the patients to take the responsibility in getting annual examinations.  I think it is really important because of the rupture rate and because of the failure rate of this device for them to take the responsibility.

    DR. WHALEN:  In view of what I think all the panel members were contributing to this, I am going to give a shot at verbalizing the opinions that have been expressed and state that for number five it is very strongly encouraged that any patient with a silicone gel-filled breast implant have follow-up at least one- to two-year intervals by appropriate physicians conversant with the implants.

    The silence is deafening so we will go on to number six.  Inamed will produce a guide and establish a toll-free telephone number for patients regarding how to monitor their breasts after implantation with a silicone gel-filled breast implant.

    Number seven, Inamed will develop a surgeon education and certification program to train surgeons in this particular area of surgery using silicone gel-filled breast implants.

    DR. MCGRATH:  A simple wording change, Inamed will develop, with a professional educational organization, a surgeon education and verification program, and so forth.  I add that because I think a professional educational organization knows how to apply standards for physician training, also how to verify and test for some level of having acquired those skills, and also, if needed, to set up a proctoring program.

    DR. WHALEN:  Dr. Anderson?

    DR. ANDERSON:  That was the point.

    DR. WHALEN:  Dr. Manno?

    DR. MANNO:  Along with what has been said on seven, it might be feasible for the company, the company or the society doing the educating and certifying to keep a list of the currently certified physicians on their website so that, with the mobility of the patients, they can always have access to their nearest plastic surgeon.

    DR. WHALEN:  Dr. Olding?

    DR. OLDING:  I just would suggest perhaps a slight addition of a few words at the end of that, that would be as a requirement for utilization of the implants.

    DR. WHALEN:  We have three substantive changes.  I just want to try to recapitulate and ask if they are agreeable.  Dr. McGrath suggested that this be Inamed along with appropriate professional associations and that, instead of certification it be a verification program.

    Dr. Olding has suggested that it be as a requirement for utilization of these implants.  Brent?

    DR. BLUMENSTEIN:  It is really a physician registry, and then you can link the outcome to the physicians.

    DR. WHALEN:  Thanks!

    [Laughter]

    Very well.  We have already touched upon number eight a bit but I think we need to have some further discussion about this, as it reads, and it is verbatim from the sheet in front of you, an Inamed patient registry that exists today will continue to track patients who use the products.  Someone has suggested that it should be independent of the sponsor.  Comments and discussion upon this point?  Dr. McGrath?

    DR. MCGRATH:  Independently sponsored with, obviously, Inamed participating and joining into this also.

    DR. ANDERSON:  And I would suggest that the registry needs to explicitly track data regarding rupture, intracapsular and extracapsular.

    DR. CHOTI:  That is part of it.  I don't think that needs to be specified but one thing that can be emphasized is something like "for life."  It says patients who use the product so I assume that means forever.  Right?

    DR. WHALEN:  Well, I would differ.  I think you would have to actually stipulate that because "use the products" could mean till explantation.  Are you talking about life of the patient or life of the product?

    DR. CHOTI:  Life of the patient.  I think that is important, particularly the ones where there is rupture, but for all of them I think it is an important point and in the registry they need to be tracked beyond the time it is explanted or changed.

    DR. WHALEN:  So, it perhaps then should read that a patient registry that exists today will continue to track patients for the duration of their lifetime.

    DR. ANDERSON:  And there was one other point about a mail-in card type follow-up.  The registry can't just exist with no data filled into it.  There needs to be a good-faith effort to follow-up on patients, just as we would do in an epidemiological study.

    DR. WHALEN:  So, perhaps a patient registry that exists today will continue to track patients throughout their natural lifetime and strong efforts will be made to assure the highest accrual of data to that registry.

    DR. ANDERSON:  Yes, that is good.

    PROF. DUBLER:  I am just puzzled.  We want this to be an independent registry.  I agree it should be, but we want Inamed to fund it because I don't see any other funders stepping up to the line.

    DR. MCGRATH:  That is not true.  There is already a registry that exists in one of the professional organizations that has other manufacturers' implants already involved.

    PROF. DUBLER:  Oh, so there is one that exists that could be expanded to meet this purpose?

    DR. MCGRATH:  Well, we heard a presentation about that today.  I don't know the details.  I mean, I don't know about it but I heard them present that material, yes.  Dr. Kerrigan presented it.

    DR. WHALEN:  Dr. Witten?

    DR. WITTEN:  Yes, I just want to clarify something.  These are conditions on the sponsor, right?  These aren't conditions on another party?  Is that what we are talking about?  I just want to understand the relationship, if number eight is recommendation of another party, how is it a condition on Inamed?

    DR. WHALEN:  Dr. McGrath?

    DR. MCGRATH:  Let me respond, Dr. Witten.  I think, Dr. Witten, what we had before is this number eight and the question was do we support number eight or not.  My answer is no, I don't support number eight as it is written.  I do support Inamed participating in a patient registry process, but I don't think the patient registry process should be an in-house thing in their house.  I think it should be an independent registry, administered by a professional organization of some sort and eventually that might include other manufacturers, and so forth and so on.  I think this is for everybody's safety because manufacturers change and companies change, and so forth, and it is safer to have this in independent hands.

    DR. WHALEN:  Very well.  We are now at a point where we can look upon our first conditions, which is these now modified eight sub-stipulations of condition number one.  When I ask for a hand vote on this, I will ask you to please keep your hands up for a little while because it is difficult for me to see everybody and I will be ducking and darting a little bit to see that.

    All those in favor of condition number one, please indicate by raising your hands.

    [Show of hands]

    DR. WITTEN:  Just to clarify, who is voting?  Who votes on this?

    DR. WHALEN:  Everybody except the consumer and industry reps.  I only vote in case of a tie.  Dr. Krause does not vote and you do not vote either.  So, as I see it, it is unanimous.  Everybody is in favor of this condition number one.

    Very well, taking it in step-wise fashion, I believe we have consideration for potential four more conditions, at least.  As I recorded them, the first would be Dr. Li to talk about explants.

    DR. LI:  I guess this is a new condition because what I would like them to do, perhaps after they have worked with a third party in establishing what data to collect on retrieved implants, is that they reinvestigate the current implants they have in hand to see how much information they can glean from actually already a substantial number of retrievals.

    DR. WHALEN:  Further discussion?  You couldn't hear him?  I am sorry, would you repeat it, Dr. Li?

    DR. LI:  I was looking behind me, sorry.  My condition was that after the FDA and a third party has worked with Inamed to establish how they should collect and what type of data they should collect in their ongoing retrieval program, that those same criteria be applied to their existing 339 retrievals that they have in hand because it is a very difficult collection of implants to get and I don't want to miss that information.

    DR. WITTEN:  Just for clarification, I am assuming, since this is a condition of approval motion, that your recommendation is that they apply those criteria to those retrieval specimens after approval and you are not suggesting necessarily that we complete that and look at the data prior to approval, or am I wrong?  Because it makes a difference as to whether it is a condition or whether you are asking for new data prior to approval.  So, I just want to understand what you are recommending.

    DR. LI:  Good question.  Actually, in this particular case I think I would make it a condition for approval in the event that on reexamination of the 339 retrieved components they perhaps would find a factor that would leave to rupture.  So, I would hate to find that out after the fact.

    DR. WHALEN:  The only question I would have on that one is since this is really short-term sort of data that you are looking at in terms of these explants, and their short-term rupture rate was not as high--our concerns are really more with the long-term rupture rate--do we need to stipulate that as a pre-approval condition rather than a post-approval condition?

    DR. LI:  I suppose I could live with it either way but if I personally had my druthers, I would make it a condition for approval.

    DR. WITTEN:  Let me just say that looking at new data is not a condition for approval.  I mean, if you feel that you need to do that before approval, then that would be a not approvable recommendation, with the recommendation that they need to do that to put it in an approvable form.  If you think you can live with it after approval, it can be a post-approval condition.

    DR. LI:  I guess then I would vote for after approval.

    DR. WHALEN:  Dr. Leitch and then Dr. Anderson.

    DR. LEITCH:  I guess the question I would have is if these implants have already been analyzed in some way, are they susceptible and available to be analyzed again in a different way?  Or, have they been compromised in some way with the analysis they have already had and trying to apply a different set of criteria wouldn't work out?  I guess that is something the sponsor would have to answer.

    DR. WHALEN:  That is a specific question to the sponsor, so if you could give us a concise answer to that?  Are they still in a condition where they are analyzable, or are they beyond hope?

    DR. CROTTEAU:  These devices are available.  They have gone through standard analysis and may have been tested to some extent but are available for further testing.

    DR. WHALEN:  Thank you.  Dr. Anderson?

    DR. ANDERSON:  I do not feel that testing needs to be done prior to approval, the reason being that whatever information is gleaned from this in terms of whey these are rupturing, the company would like to know this too because they would like to come out with a model that doesn't rupture.  So, I don't think we have to be concerned that they wouldn't actively try to seek it.  I think that was an excellent recommendation that we made to try to answer the question that is so important.

    DR. WHALEN:  Dr. Miller?

    DR. MILLER:  Does this sort of fall underneath stipulation number four that we already voted on, where they will diligently investigate further modes?

    DR. WHALEN:  The Chair had exercised the prerogative to make it separate.  Obviously, they are tied together but number four, as we reworded it, was already approved as condition number one.  So, this is a separate condition although it is somewhat linked.

    DR. MILLER:  Could I suggest as well that a test be developed by the manufacturer, which goes beyond the ASTM tests that are done, that reproduces the fold flaw question, reproduces what happens to wall of the implant in vivo.  It is going to require a new test that hasn't been described yet but I think that needs to be a part of investigating the failure modes.

    DR. WHALEN:  The gist of the discussion that I captured in the past 36 hours is that they very much would like to find that Holy Grail of testing but it hasn't yet appeared.  So, if you are going to stipulate that that is a condition, it is not presently, as I understand it, an achievable condition.

    DR. MILLER:  I guess I will have to defer to the bioengineering experts here as to how achievable that is, but I would like for it to be pursued.

    DR. WHALEN:  Steven, can you comment upon that?

    DR. LI:  It is difficult for me to say if the development of the test would be easy or hard seeing as how the device has been around for a while and the test doesn't exist.  I think it would be difficult to strap anyone with the responsibility to develop a test in a certain time period that demonstrates clinical significance.  Can it be done in general?  I think the answer is yes.  Can it be done in six months?  I don't know.  A year?  I don't know.  Maybe it will take a couple.  You know, without knowing the mechanism of the failure, it is a little difficult for me to tell you how to simulate the failure.  So, I would have made this clearly a condition if I knew how to word it in some practical fashion but I can't think of how to do it.

    DR. MILLER:  I will just assume that what I am describing falls under the category of investigating the failure modes and just leave it at that.

    DR. WHALEN:  Dr. McGrath?

    DR. MCGRATH:  Steve, help me on this, but I think you could even broaden it a little bit.  It seems to me that what we are really talking about is that we want more material analysis, and we want to see more about long-term performance, not just in terms of rupture but also gel bleed and everything else.  So, what we are really asking for is additional studies over a period of time, in a more representative environment, that will give us this long-term materials analysis.  Am I saying that right, and can you word that better, Steve?

    DR. LI:  Actually, you said it quite well.  I think that is kind of a two-parter though, in my mind.  I think there are things we can glean out of the retrieval program but that might not, for instance, give us meaningful data for gel bleed as a for instance.  So, that would be like a separate area.  So, my current suggestion for a condition is that I basically would like them to reinvestigate their current collection of retrieved implants, with perhaps a new set of data to collect on them to see if we can't get a better fundamental understanding of the information they already have.  That would be in addition to item number four of the condition we just passed.

    DR. WHALEN:  Since you just reworded it for us or restated it for us because I stepped on my parliamentary left foot, that was a motion for condition number two which we should not have discussed until it was seconded. Is there someone that will second it?

    DR. MCGRATH:  Second.

    DR. WHALEN:  Thanks a lot.  Anything else, Steven?

    DR. LI:  No.

    DR. WHALEN:  Is there any further discussion on this second stipulated condition that we are discussing right now?  Dr. McGrath?

    DR. MCGRATH:  Just procedurally then, I would like to break it into two parts, the part that Dr. Li is mentioning should be the analysis of the ruptured implants and particles to look at the rupture cause, but also some other long-term performance parameters that would be looked at.

    DR. WHALEN:  I am sorry, when you say split the two parts, you want to split this into two conditions or are you willing to contain it as one?  Okay.

    Will all those in favor of this condition please indicate by raising your hand, and keep it raised?  All the voting members?

    [Show of hands]

    It is unanimously approved.  The next in sequence that I had jotted down as a possible condition would be Prof. Dubler in terms of the capsule.

    PROF. DUBLER:  Well, I would look for help to the clinicians and researchers, but there were a number of times over the last two days when certain of the people presenting testimony indicated they didn't think that a gross examination of the field told us enough when we explanted a device and that perhaps even the MRI did not tell us enough.  If that were to be the case, then I would think it would be incumbent to set up a study which attempted to get patient agreement to do a biopsy at the time of explant.  Now, that may make no sense but, if it is a possibility, I would like to hear the clinicians comment.

    DR. WHALEN:  I don't think we have yet reached the stage of a motion on that so I am not yet going to ask for a second.  So, is there any clinician help in terms of the phraseology of how this would be done?  Dennis?

    DR. BOULWARE:  I would like to move that we include in the retrieval mechanism biopsies in dependent and random areas within the capsule.

    DR. WHALEN:  Is there a second for that?  Dr. McGrath seconds.  Dr. Anderson?

    DR. ANDERSON:  What we are really talking about is creating a tissue bank of capsules, which actually is a very interesting idea.  In fact, you might find that there would be information that could be gleaned about why people get capsular contracture.  So, I think it is a valuable idea.  It is important to understand that tissue banks are not a minor issue.  They are a big deal to create.  You have to decide if it is fresh tissue or fixed tissue, and the biggest problem that we have right now is that it is not hypothesis driven.  You are just collecting the tissues just sort of hoping that some day you will come up with the hypothesis.

    It would not be a shock to see that there are minute amounts of silicone on the all of the capsule.  So, my concern with this is that just showing the presence of that doesn't necessarily tell us anything.  I am not discrediting the idea because actually it wouldn't even be a bad idea for the company if they could find something that didn't make such tough capsules and capsular contracture.

    DR. WHALEN:  Dr. Li?

    DR. LI:  Yes, I think it is an excellent idea but in orthopedics this is actually a ripe area for NIH grants.  This is a very scientific, not straightforward type of analysis.  For instance, we don't know exactly how much is there.  We don't know the species that is there.  And, the analytical techniques to analyze for silicone actually don't exist at the moment.  So, it is a little difficult for me to figure out how you would make this a condition for a company to be approved.  I think it is a great idea and needs to be done, I just don't see us approving--but I see Dr. Newburger with a question.

    DR. WHALEN:  Dr. Leitch and then Dr. Choti and then Dr. Newburger.

    DR. LEITCH:  This is sort of a great study question but then, as was mentioned, you have to know what you are going to look for, what you are going to analyze, how you are going to retrieve the tissue.  Do you just want a microscopic exam?  I think one of the concerns that Dr. Dubler had was is there extracapsular silicone.  So, what she is really asking for I think is a biopsy of the tissue that is outside of the capsule, not the capsule itself.  The problem with that potentially is a sampling error.  You know, if you take a sample from wherever the surgeon makes the incision to remove the implant, that might not be the spot where there would be extravasated silicone.  So, you might be misled by the results.  If you found something, you could say something about that but that would be the problem.

    I think what we have heard in discussions over the last two days are a lot of good ideas for research, but whether that is reasonable to have the sponsor do that, unless they were highly motivated and if they thought it would make a big difference for them and they had a hypothesis, then they could say this is how we want to receive the tissue--we want fresh; we want formalin fixed, whatever it is they want.  Fresh tissue, though, is a big problem and almost all the clinical trials that have tried to do fresh tissue collection perceive it as a big problem in implementation.  So, again, you have to be prepared for the repercussions of that, and are we prepared to require that at this moment?

    DR. WHALEN:  Dr. Choti?

    DR. CHOTI:  Yes, I agree.  I mean, it is interesting but I don't see any reason to make this a condition of the sponsor for approval.

    DR. WHALEN:  Dr. Newburger?

    DR. NEWBURGER:  My belief is that the Department of Environmental and Toxicologic Pathology at the Armed Forces Institute of Pathology has the ability to do Raman spectroscopy and Fourier infrared microspectroscopy, and they keep a registry there.  So, I think any issues in terms of handling tissue could be addressed by them in a very efficient manner.

    DR. LI:  Excuse me, as a response for that, it is my understanding that with that particular method though they will be able to say yes or no for silicone as an element, is it there or not, but they won't be able to tell you the form of the silicone or what molecule it is necessarily part of, or whether or not it makes any difference that you can find silicone.  So, it is not so much a matter of we don't have a way to detect silicone in a location, but it is the nature of the silicone and its chemical environment, and those kinds of things that I was referring to.

    DR. NEWBURGER:  Indeed, but the AIFP does have coincident histopathology done by more standard techniques so that you can get a real sense of what the reaction pattern is where it is found.

    DR. WHALEN:  Just remember down there, please, when you talk to one another, talk directly into the microphone so the rest of us can hear you.  The ones that are aimed at the angle of your mandible don't help too much either.  Dr. Choti and then Prof. Dubler.

    DR. CHOTI:  Again, we don't even know what we are going to study with this.  Why not look at serum samples?  I mean there is no evidence to suggest that capsular biopsy is any more valid or more informative than any other sample.

    DR. WHALEN:  Prof. Dubler?

    PROF. DUBLER:  This discussion did exactly what I hoped it would do.  It convinced me this is a bad idea.

    [Laughter]

    DR. WHALEN:  With that in mind, since it was a motion as a condition, we do need to take a vote upon it.  All those in favor, please indicate so by raising your hand.  It has already been seconded so I think it would be a better process to take a vote on it.

    [One hand raised]

    One.  Dr. Newburger votes in favor.  All those opposed?

    [Show of hands]

    Everybody else votes against it.  The next that I had written down I believe was Dr. Conant's, in terms of a potential condition.

    DR. CONANT:  Yes, I was interested in adding on an educational component for the surgeons in terms of follow-up and recommendations for management of patients about to have rupture, based on physical exam, some kind of paradigm for this evaluation.  What I would imagine, on exam if rupture was suspected--these are out of study patients--and MRI would be recommended and then the sponsor would state in their labeling or I guess in their data that if there was rupture, it would be recommended that the implant be removed, to take a stand on that.

    DR. WHALEN:  So, if I am getting it right, there are three components to this.  You feel that there needs to be an educational program so that surgeons are brought up to speed on clinical recognition--

    DR. CONANT:  Yes.

    DR. WHALEN:  --of potential extrusion of silicone.

    DR. CHOTI:  Yes.

    DR. WHALEN:  That an MRI be done if there is clinical suspicion and that, furthermore--you want to wrap all this into it--if there is silent rupture, the recommendation be made to remove the implant.

    DR. CONANT:  Yes.

    DR. WHALEN:  Have I got it right?  Is there a second to that motion?

    DR. ANDERSON:  I would suggest a modification to that.  I am going to defer to my plastic surgery colleagues, but I don't think requiring an MRI--if it is something that is clinically obvious--

    DR. WHALEN:  I am sorry.  I have already gotten chastised once.  I think this discussion would follow a seconding and we haven't yet had a seconding, if that is okay with you.

    DR. ANDERSON:  Sorry.

    DR. WHALEN:  Is there a second to this condition?

    DR. MILLER:  I will second it.

    DR. WHALEN:  Dr. Miller seconds.  I am sorry, Dr. Anderson.  Please continue.

    DR. ANDERSON:  I apologize.  Requiring an MRI I don't think is necessary.  Recommending and MRI is appropriate.  But if you don't need it, you don't have to get it.

    DR. CONANT:  Actually, I think that is a valid recommendation.  However, my concern, and the reason I do say MRIs, is that I think there is sometimes a difficulty establishing whether it is a contained rupture; whether there is actually flattening and softening of the implant; and whether there are actually small areas of extracapsular rupture.  I would think, and again I will leave this to my plastic surgery colleagues, that if there were extracapsular rupture you would like to know where it is; you would like to map that out, and the MRI has that more global capability for doing that.  So, removal could attempt to take out at least the localized free silicone.  That is my thought process.

    DR. WHALEN:  What about the recommendation for removal of silent ruptures?  Is there any discussion on that?

    DR. MILLER:  Was that a part of the recommendation?

    DR. WHALEN:  The motion was made that there be provision of clinical education and recognition of rupture; that there be a recommendation for MRI if rupture is suspected; and that, if rupture is confirmed, the implant be removed.  The recommendation is made that the implant be removed.  Dr. Chang and then Dr. McGrath.

    DR. CHANG:  Just in response to the last comment, if, indeed, on clinical examination I were positive by history and physical that a rupture had occurred, an MRI would not add substantive information to change the treatment.  I would look with due diligence for any areas of palpable silicone.  So, I don't believe that the cost would outweigh the benefit gained of additional information, and would not change my treatment plan.  So, I don't think it would be wise to require MRI as an algorithm.

    DR. WHALEN:  Dr. McGrath?

    DR. CONANT:  Can I just comment on that?

    DR. WHALEN:  Dr. McGrath and then we will get back to you.

    DR. MCGRATH:  I think your motion is a bit broad.  Can we just take part one, about the education of physicians and the recognition of rupture, and perhaps could even include that in what we already voted on before because it is really very close to it.  We talked about surgeon education and verification in this area of surgery using silicone gel-filled implants.  Certainly, the recognition of a ruptured one would go with that.

    I think it is a totally different issue to bring up--I don't think we are ready to educate people about the use of MRI for explantation because, if I remember our voting and discussion from last night, we really hadn't gotten to a consensus yet about whether there is a utility for MRI or explantation.

    DR. CHOTI:  I think the consensus was, although the data is limited, there is a benefit and that we should recommend explant if there is evidence of a leak.  Is that not the consensus of the group?

    DR. WHALEN:  No, seven, three and three was the opinion registered, seven to take it out; three not to take it out; three on the fence.  So, it was a majority but not an overwhelming one.

    Other discussion?  If not, let me ask the pleasure of the panel.  Dr. McGrath has suggested that we divide this question and take the first part of it, which is the component of education of the implanting surgeons as to the subsequent recognition of rupture, and incorporate that back into the education program, which we have already stipulated as a condition and voted upon.  Is it the will of the panel to divide that out?  Is there any further discussion upon incorporating that aspect to the education program, into the overall education program that is being developed?  Seeing none, all those in favor, please signify by raising your hands.

    [Show of hands]

    Even Brent got his hand up so I know we approved it unanimously.  Good.  Very well.

    The divided question then leaves us with, in the face of clinical recognition of rupture, that there be a recommendation for MRI and that confirmation of rupture lead to explantation.  Any further discussion on that motion?

    DR. CONANT:  I am certainly willing to soften that to "consider" MRI.  My only concern about the MRI is, again, that free silicone isn't necessarily palpable nor is it visible.  Again, I would ask for plastic surgeons to comment on this.  In removing a ruptured implant with extracapsular extravasation, my impression was that it is ideal to remove as much of the silicone as possible.  So, I would like some comment on that.  I think "consider" MRI if indicated is fine.

    DR. WHALEN:  Dr. Leitch?

    DR. LEITCH:  Wouldn't it be the case though that with a mammogram, which is cheaper, you could see gross extravasation of silicone and that would be another way of mapping?

    DR. CONANT:  Actually, unfortunately, mammography doesn't always show the extent of disease because the silicone has such a high optical density.  If the area is superimposed over the implant you will not see additional areas of silicone.  You may see it tracking superiorly along the pectoralis or inferiorly, but you really don't have a three-dimensional mapping of it.  So, I don't think mammography is adequate.

    DR. WHALEN:  Dr. Olding?

    DR. OLDING:  Practically speaking, at the time of explantation--it sounds like you are potentially even talking microscopic.  The only practical part that we would remove would be the part that we could palpate or see.  So, although I would agree that an MRI would certainly be helpful, I don't think it should be required.

    DR. WHALEN:  Dr. McGrath?

    DR. MCGRATH:  When we discussed this last night, you know, we felt that a decision about whether to recommend a screening MRI and decision about explantation has to be data driven.  We don't yet have the data to make a clean recommendation on this.  Therefore, maybe what we really should do is turn this into another item and make that item a real hard plan, developing a plan for looking at this issue as a part of the post-approval study plan.

    DR. WHALEN:  Dr. Miller?

    DR. MILLER:  I think I have nothing to add to my comments that is relevant at this point.

    DR. WHALEN:  Dr. Leitch?

    DR. LEITCH:  Well, you do have the MRI follow-up study and I think that is an opportunity to generate the data to answer this question.  So, we can add that on as a clear goal of that study, to assess the value of that as a screening study.  Then, presumably, there will be outcomes for people in that study who identified they had a rupture and some of them are going to have the implants removed and some probably won't.  So, there will be data from those patients.  It won't be in a randomized fashion, as Dr. Blumenstein was suggesting, but it will exist as some data that could be evaluated, and that should certainly be an outcome that would be requested from that particular study.

    DR. WHALEN:  Dr. Anderson, did you have something?

    DR. ANDERSON:  Last evening we had this discussion about the removal of implants.  I think that we need to have it again here to make a decision whether we can decide or not.  I would like to make a proposal that the recommendation be when a ruptured implant is discovered, it is recommended to the patient that it be removed.

    DR. WHALEN:  Maybe I am just going to ask you what the difference is.  As it was worded, we said that the recommendation would be that it be removed if we find that it is ruptured.  Certainly, we can't require that.  That is a matter of informed consent and a decision between the surgeon and the patient.  So, I am not sure--

    DR. ANDERSON:  I am sorry, I didn't understand what our discussion was then.  Can I comment on that?  If we are not unanimous, because I heard some of my colleagues saying that they are not convinced of this, I think that in the absence of data showing the safety of ruptured implants, we have to recommend their removal.  A randomized trial or data demonstrating safety, until that is there, it seems to me that should be the position of the FDA.

    DR. WHALEN:  Dr. Choti?

    DR. CHOTI:  I guess it is a little like number five on the first condition, this would be a condition of the sponsor to recommend that in the literature?  That would be their position, to recommend removal?  Is that it?

    DR. WHALEN:  Basically, Dr. Witten, I would assume if this comes as a recommendation as a condition, it would be a labeling issue.  So, that translates to a sponsor recommendation.

    DR. WITTEN:  That is what we would assume.

    DR. WHALEN:  Dr. McGrath?

    DR. MCGRATH:  I am still struggling with this.  If we don't have a consensus among ourselves about whether it is appropriate to explant it just because it is ruptured, then how can we ask the manufacturer to put in educational materials that that would be a stipulation for their post-market approval.  I think we have to go back even further and make it one of the items that has to be part of a post-approval study plan.  That is, to start looking at patients with ruptured implants and to continue to gather this data in a formalized way so that we have a sense about what happens with these individuals.

    DR. WHALEN:  My read on that, Dr. McGrath, would be that, contrary to the way we have been voting today, rarely do you see necessarily unanimous votes on any of these recommendations.  Since this is a motion on the table, we will come to a vote on it.  As is FDA procedure, if it is a divided vote, we will read for the record those who favor and those who do not favor that particular stipulation of approval, which is an element of FDA subsequent consideration of what are only recommendations on our part if they are going to go forward with it.

    As to studying it going forward, I would entertain that as potentially yet a separate condition of approval.  Dr. Chang?

    DR. CHANG:  I will just make the comment that item one that was passed incorporated bullet four, where the sponsor said we will pay particular attention to any relationship between outcomes and rupture status.

    DR. WHALEN:  Dr. Olding?

    DR. OLDING:  As one of the panel members who disagreed with the treatment alternative when there is a verified rupture, intracapsular rupture, I would certainly be in favor of your statement if it said extracapsular rupture because we certainly have the data to recommend that.  But it would be difficult for me to agree with the intracapsular rupture.

    DR. WHALEN:  Before we advance to voting on this condition, let me read for the record and announce that Dr. Lawrence, one of our panel members, had to leave us and there are, therefore, now 15 voting members remaining, although if there is an abstention and a tie breakdown among those 15, I become a voting member to break the tie.

    What I believe we are about to vote on, and correct me if I am wrong, is a recommendation as a condition of approval that in the face of clinical suspicion of rupture, there be consideration of performance of an MRI examination, and that, by whatever means, if rupture is confirmed that there be explantation--a recommendation of explantation.

    Before we get to the actual vote, have I articulated that condition correctly or does anybody object to how I just stated that?  Seeing none, on that condition of approval, would those who are in favor please signify by raising your hands?

    [Show of hands]

    For the record, Dr. Miller, Dr. Anderson, Dr. Li, Prof. Dubler, Dr. Newburger, Dr. Leitch, Dr. Chang, Dr. Choti, Dr. Conant, Dr. Lieberman and Dr. Manno have voted in approval.

    Would those who are opposed, please signify, and abstention is allowable.

    [Show of hands]

    Dr. Blumenstein opposes this, as does Dr. Olding.  Those who abstain?

    [Show of hands]

    Dr. Boulware and Dr. McGrath.  Thank you.  The next in order of potential conditions of approval was an issue raised by Dr. McGrath.  I am sorry, I only wrote down your name and not exactly what the issue was.

    [Laughter]

    DR. MCGRATH:  Tom, I am disappointed!  As the next condition of postmarket approval, that the manufacturers be charged with evaluating the patients with ruptured implants, and monitoring the effects of this rupture both locally and systemically in these persons.

    DR. WHALEN:  Is there a second for that condition?

    DR. LIEBERMAN:  Second.

    DR. WHALEN:  There is a second by Dr. Lieberman.  Is there any issue, Dr. Witten, in terms of that?

    DR. WITTEN:  No, was that just in general or in the study, because that is already part of the study?

    DR. MCGRATH:  In the study.

    DR. WITTEN:  Pardon me?  In the study?  That is already part of what they are proposing.  So, I am just wondering what else you are suggesting.

    DR. MCGRATH:   It is number four, I believe, that you are referring to, where it says we will pay particular attention to any relationship between outcomes and rupture status.  I didn't know what "particular attention" meant and I would like this to be a formal study protocol.

    DR. WHALEN:  It has been moved and seconded.  Further discussion upon that?

    DR. CHANG:  Dr. McGrath, could you just clarify "formal study protocol?"  Do you mean incorporate these patients who are found to have ruptured implants?

    DR. MCGRATH:  Dr. Chang, I don't really want to rate the protocol right now but I can think of a lot of ways that these patients really need to be looked at very closely, and I am sure that can be written up.

    DR. WHALEN:  Seeing no further discussion on the motion as a condition of approval that the sponsor, in study patients, evaluate them for ruptured implants and monitor effects thereby, both locally and systemically, would all those who are in favor of that, please indicate by raising your hands?

    [Show of hands]

    It does pass unanimously.  That is the sequence that I jotted down during our discussion of the first condition of approval of other conditions of approval.  I will now entertain any further conditions of approval that anybody would like to make.  Dr. McGrath?

    DR. MCGRATH:  Last night when we were talking, when we got to question 7(b), it was please describe any other specific endpoints which should be captured as part of the post-approval study.  We talked about a number of those and we had a fair list