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**
>
> Tuesday, October 14, 2003
>
> 8:00 a.m.
>
> Grand Ballroom
>
> Gaithersburg Marriott Hotel
>
> 9751 Washingtonian Boulevard
>
> Gaithersburg, Maryland
>
> PARTICIPANTS
>
> Thomas V. Whalen, M.D., Acting Chair
>
> 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. Newberger, 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., DR PH
>
> Barbara R. Manno, Ph.D.
>
> Mary H. McGrath, M.D., MPH
>
> Michael J. Olding, M.D.
>
> FDA
>
> Celia Witten, Ph.D., M.D.
>
> [C O N T E N T S]{.underline}
>
> [PAGE]{.underline}
>
> Conflict of Interest and Opening Remarks:
>
> David Krause, Ph.D. 7
>
> Panel Introductions:
>
> Thomas V. Whalen, M.D. 10
>
> Welcome Remarks:
>
> CDR Stephen P. Rhodes 16
>
> Dr. David Feigal 18
>
> Open Public Comment
>
> Introductory Remarks: Thomas V. Whalen, M.D. 20
>
> Public Speakers
>
> Susan Scherr, National Coaltion
>
> for Cancer Survivorship 23
>
> Shery Henderson, Silicone Solutions Outreach 28
>
> Carolyn Kittle 31
>
> Elizabeth Anderson 34
>
> Arlene Nicole Cummings 37
>
> Michelle Colombo 40
>
> Dr. Thomas Joiner 42
>
> Susan Cunningham 45
>
> Anne Stansell 49
>
> Rosella Rust 51
>
> Kathy Pate 54
>
> Nancy Bruning 57
>
> Jill Fallows 63
>
> Elizabeth Santoro 65
>
> Evon Peterson 69
>
> Elizabeth Weber 72
>
> Ed Brent 73
>
> Dr. Bruce Cunningham 76
>
> [C O N T E N T S]{.underline} (Continued)
>
> [PAGE]{.underline}
>
> Open Public Comment (Continued)
>
> Margaretha McGrail 78
>
> Gail Hamilton 80
>
> Audrey Moritz-Ciancutti 84
>
> Cynthia Teague 87
>
> Pamela Dowd 89
>
> Lisa Bordelon 92
>
> Jessica Forman 94
>
> Diane Fjelstad 98
>
> Dr. Frank Vasay 101
>
> Marcy Gross 104
>
> Dr. Marga Massey 109
>
> Carolyn Wolf 113
>
> Dr. Vicki Hofnagel, (by conference call) 117
>
> Virginia Gallagher, (by conference call) 121
>
> Dr. Mark Jewel 124
>
> Mary Ann Richards 127
>
> Lisa Bancarz 129
>
> Eileen Wright 132
>
> Lisa Lowenstein 134
>
> Kathleen V.F. Nye 138
>
> Betty Buikema 140
>
> Dr. Caroline Glicksman 143
>
> Dr. Edward Melmed 147
>
> Dr. Paul H. Wooley 152
>
> Nancy Gertner 157
>
> [C O N T E N T S]{.underline} (Continued)
>
> [PAGE]{.underline}
>
> Open Public Comment (Continued)
>
> Dr. Eugene Goldberg 160
>
> Mindy Tapscott 164
>
> Kim Gandy, National Association for Women 168
>
> Mary Ann Ward 175
>
> Marlene Keeling, Chemically Associated
>
> Neurological Disorders 180
>
> Vanessa Rose Ferelli 183
>
> Connie Wasserman 190
>
> Dr. Sidney Wolfe, Public Citizen 193
>
> Judy Norsigian, Our Bodies, Ourselves 203
>
> Dr. Deborah Bash 208
>
> Kathy Keithley Johnson, Toxic Discovery 212
>
> Dr. Paul Weiss, National Endowment
>
> for Plastic Surgery 218
>
> Dr. Laurie Casas, American Society
>
> for Aesthetic Plastic Surgery 223
>
> Dr. Leroy Young, Aesthetic Surgery
>
> and Research Foundation 229
>
> Dr. Martha Burke, National Council
>
> of Women\'s Organizations 233
>
> Dr. Laurie Young, Older Women\'s League 237
>
> Christine Lozier 241
>
> Anne S. Kasper, Finding My Way 244
>
> Dr. Shawna Willey, American College
>
> of Surgeons 249
>
> Margaret Volpe, Y-Me 252
>
> Regulatory Overview of Silicone Gel-Filled
>
> Breast Implants:
>
> Cilia M. Witten, Ph.D., M.D. 257
>
> [C O N T E N T S]{.underline} (Continued)
>
> [PAGE]{.underline}
>
> **Applicant Presentation**
>
> **Inamed Corporation**
>
> **McGhan Silicone-Filled Breast Implants**
>
> Introduction:
>
> Ronald J. Ehmsen, Sc.D. 264
>
> Preclinical Studies Review:
>
> Thomas E. Powell 267
>
> Clinical Studies:
>
> JoAnn M. Kuhne, MSN, RAC 295
>
> **FDA Presentation**
>
> **ODE and Office of Surveillance and Biometrics (OSB)**
>
> Introduction and Mechanical Testing:
>
> CDR Samie Allen 393
>
> Chemical Testing:
>
> Sam Arepalli, Ph.D. 399
>
> Toxicology Testing:
>
> David B. Berkowitz, Ph.D., VMD 405
>
> Clinical Data Overview:
>
> Sahar M. Dawisha, M.D. 413
>
> Statistical Testing:
>
> Telba Z. Irony, Ph.D. 439
>
> Medical Devices Surveillance and
>
> Literature Review:
>
> S. Lori Brown, Ph.D., MPH 448
>
> Postapproval Study and Labeling:
>
> CDR Samie Allen 465
>
> Open Panel Discussion 489
>
> Open Panel Discussion and FDA Questions 551
>
> [P]{.underline} [R]{.underline} [O]{.underline} [C]{.underline}
> [E]{.underline} [E]{.underline} [D]{.underline} [I]{.underline}
> [N]{.underline} [G]{.underline} [S]{.underline}
>
> **Conflict of Interest and Opening Remarks**
>
> DR. KRAUSE: Good morning, everybody. We are ready to begin this, the
> 63rd meeting of the General and Plastic Surgery Devices Panel. My name
> is David Krause. I am the Executive Secretary of this panel and I am
> also a biologist and a reviewer in the Plastic and Reconstructive
> Surgery Devices Branch.
>
> I would like to remind everyone that we request that you sign in on
> the attendance sheets which are just outside the door. You can also
> pick up an agenda, a panel-member roster and information about
> today\'s meeting out there on the table. The information includes how
> to find out about future meetings, future-meeting dates, through the
> advisory panel phone line and how to obtain meeting minutes or
> transcripts.
>
> Before I turn the meeting over to Dr. Whalen, I am required to read
> two statements into the record. One is the deputization to temporary
> voting status and the other is the conflict-of-interest statement.
>
> \"Pursuant to the authority granted under the Medical Devices Advisory
> Committee Charter, dated October 27, 1990, and as amended August 18,
> 1999 I appoint Benjamin Anderson, Dennis Boulware, Emily Conant, Nancy
> Dubler, Ruth Lawrence, Stephen Li, Ellice Liberman, Barbara Manno,
> Mary McGrath and Michael Olding as deputized voting members of the
> General and Plastic Surgery Devices Panel for this meeting on October
> 14 and 15, 2003.
>
> \"In addition, I appoint Thomas Whalen to act as temporary chair for
> the duration of this meeting. For the record, these individuals are
> special government employees and consultants to this panel or other
> panels under the Medical Devices Advisory Committee. They have
> undergone the customary conflict-of-interest review and have reviewed
> the material to be considered at this meeting.\"
>
> This is signed by Dr. David Feigal who is the Director of the Center
> for Devices and Radiological Health.
>
> The conflict-of-interest statement is as follows. \"The following
> announcement addresses conflict-of-interest issues associated with
> this meeting and is made a part of the record to preclude even the
> appearance of an impropriety. To determine of any conflict existed,
> the agency reviewed the submitted agenda for this meeting and all
> financial interests reported by the committee participants.
>
> \"The conflict-of-interest statutes prohibit special government
> employees from participating in matters that could affect their or
> their employers\' financial interests. However, the agency has
> determined that the participation of certain members and consultants,
> the need for whose services outweighs the potential conflict of
> interest involved is in the best interest of the government.
>
> \"We would like to note for the record that the agency took into
> consideration certain matters regarding Dr. Miller. He reported his
> institution\'s past and current involvement with firms at issue. The
> agency has determined, therefore, that he may participate fully in the
> panel\'s deliberations.
>
> \"In the event that the discussions involve any other products or
> firms not already on the agenda for which an FDA participant has a
> financial interest, the participants should excuse him- or herself
> from such involvement and the exclusion will be noted for the record.
>
> \"With respect to all other participants, we ask, in the interest of
> fairness, that all persons making statement or presentations disclose
> any current or previous financial involvement with any firm whose
> products they may wish to comment upon.\"
>
> At this time, I would like to turn the meeting over to Dr. Whalen.
>
> **Panel Introductions**
>
> DR. WHALEN: Thank you, Dr. Krause.
>
> Good morning. I am Dr. Thomas Whalen. I am Professor of Surgery and
> Pediatrics at Robert Wood Johnson Medical School. I would venture,
> based on my own experience this morning, there are others who are
> going to be at this meeting who are probably visibly aging waiting for
> the elevators to get down here because it takes so long, including
> some of our panel members. So we would hopefully tolerate some of them
> coming in a little bit later than we had anticipated.
>
> Today, the panel will be making recommendations to the Food and Drug
> Administration on a premarket approval application. Our next item of
> business is to introduce the panel members who are giving of their
> time to help the FDA in these matters and the FDA staff who are here
> at this head table.
>
> I would ask each person, starting at my left, to introduce themselves
> and for the panel members to specifically not only give the typical
> introductions with your names, institutions and titles, but to please
> give a very brief comment upon the area of expertise that you bring to
> this particular panel.
>
> Starting to my left, then, from the FDA with Dr. Witten.
>
> DR. WITTEN: I am Dr. Celia Witten, the Division Director at FDA of the
> Reviewing Division for these products.
>
> DR. MILLER: I am Michael Miller. I am a professor of plastic surgery
> at the University of Texas M.D. Anderson Cancer Center and I have
> worked with breast reconstruction and breast surgery and these types
> of devices for many years.
>
> DR. ANDERSON: My name is Ben Anderson. I am an associate professor of
> surgery at the University of Washington. I am a breast-cancer surgeon.
> I do not place implants but my patients do receive them and I am
> listening on their behalf.
>
> DR. LI: My name is Dr. Steve Li. I am the President of Medical Device
> Testing Innovations. My areas of expertise are biomaterials,
> biomechanics and failure of medical devices.
>
> PROF. DUBLER: I am 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. My
> expertise is in medical ethics.
>
> DR. NEWBERGER: I am Amy Newberger. I am a dermatologist in private
> practice in Scarsdale, New York. I teach at St. Luke\'s Roosevelt
> Medical Hospital Consortium in New York City. My expertise is that I
> have along experience with various forms of silicone.
>
> DR. BOULWARE: My name is Dennis Boulware. I am a professor of medicine
> at the University of Alabama at Birmingham. I am also a
> rheumatologist.
>
> DR. McGRATH: I am Mary McGrath. I am a professor or surgery at the
> University of California, San Francisco, and I am a practicing plastic
> surgeon, have been working with implants for almost 25 years. My
> research interests are in wound healing and biomaterials.
>
> DR. LEITCH: I am Marilyn Leitch. I am a professor of surgery at the
> University of Texas Southwestern Medical Center in Dallas. I am a
> surgical oncologist so I deal with patients having breast cancer and
> also breast-screening issues. That is the expertise I bring.
>
> DR. CHANG: I am Phyllis Chang. I am an associate professor at the
> University of Iowa College of Medicine, Department of the Surgery in
> the Division of Plastic Surgery as well as in the Division of Hand and
> Microsurgery. My expertise is as a reconstructive plastic surgeon.
>
> DR. CHOTI: My name is Michael Choti. I am an associate professor of
> surgical oncology at Johns Hopkins University and my interest is in
> clinical surgical oncology.
>
> DR. BLUMENSTEIN: I am Brent Blumenstein, a biostatistician working
> independently.
>
> DR. CONANT: I am Emily Conant. I am an associate professor of
> radiology and Chief of Breast Imaging at the University of
> Pennsylvania. My expertise is in detecting and diagnosing breast
> cancer with breast imaging.
>
> DR. LAWRENCE: I am Ruth Lawrence from the University of Rochester
> School of Medicine and Dentistry, Professor of Pediatrics and OB-GYN.
> My particular area of interest and expertise is breast feeding and
> human lactation, its impact on both the mother and the baby, and the
> breast and its function and purpose.
>
> DR. LIEBERMAN: My name is Ellice Lieberman. I am an associate
> professor of obstetrics and gynecology at Harvard Medical School and
> an associate professor of maternal and child health at the Harvard
> School of Public Health. I am also Director at Brigham and Women\'s
> Hospital of the Center for Perinatal Research and my expertise is in
> epidemiology.
>
> DR. MANNO: I am Barbara Manno. I am from the Louisiana State
> University Medical Center in Shrevepoint, Louisiana. I am professor in
> the Department of Psychiatry. My specialty is toxicology. I have been
> trained as a general toxicologist. I have worked in poison-center
> activities from management down to answering the phones. So I come to
> you with quite a few years in medical-toxicology support and my
> subspecialty is forensic toxicology.
>
> DR. OLDING: My name is Michael Olding. I am an associate professor of
> surgery at George Washington University in the Division of Plastic
> Surgery. I have had a long interest in plastic-surgery devices in
> general and, in particular, breast reconstruction. I bring that
> experience to this panel.
>
> MS. BROWN: My name is Debera Brown. I am the Vice President of
> Regulatory Affairs for Broncus Technologies. I am the industry
> representative for the panel. I have worked in medical-device
> development for over twenty years.
>
> MS. GILBERT: Good morning. My name is Alisa Gilbert. I am the
> co-founder of the Unbroken Circle and Director of Office of Native
> Cancer Survivorship and the consumer representative today. I am also a
> breast-cancer survivor of seven years and I have intimate experience
> with implants and this whole process. So I am delighted to be here.
>
> DR. WHALEN: I would like to thank all the panel members for their
> introductions and also thank them for the time they are giving these
> two days to help out the FDA.
>
> Also, because of the panel configuration going from Delaware to
> Virginia, you may need to not just raise your hand but speak into the
> microphone if you need get my attention at any time to ask questions
> or make comments, please.
>
> I would like to note for the record that the voting members present to
> constitute a quorum as required by 21 CFR Part 14.
>
> Next, I would like to introduce Commander Stephen Rhodes, the Branch
> Chief of the Plastic and Reconstructive Surgery Devices Branch who
> will make some introductory remarks. Commander Rhodes?
>
> **Welcome Remarks**
>
> CDR RHODES: Thank you, Dr. Whalen, and good morning. I am Stephen
> Rhodes, the Branch Chief of the Plastic and Reconstructive Surgery
> Devices Branch here at the FDA. Welcome members of the panel, members
> of the public and manufacturers to this important two-day meeting of
> the General and Plastic Surgery Devices Panel, important because it is
> the first FDA panel meeting to make recommendations on the
> approvability of a silicone gel-filled breast implant since 1992.
> Tomorrow, you will make recommendations and vote on Inamed
> Corporation\'s premarket approval application.
>
> Because of the high public interest in silicone-gel-filled breast
> implants, in addition to the regular public-comment periods for any
> PMA discussion, we have scheduled eight hours for public comment on
> general issues related to silicone-gel-filled breast implants.
>
> After the public comment period this morning, Dr. Celia Witten,
> Director of the Division of General Restorative and Neurological
> Devices, will review the history of FDA\'s regulation of
> silicone-gel-filled breast implants. Following Dr. Witten\'s
> presentation, Inamed Corporation will present the data in their
> premarket approval application followed by FDA\'s review of the
> application.
>
> While this afternoon\'s FDA presenters are in the Office of Device
> Evaluation and the Office of Surveillance and Biometrics, there are
> other offices in the Center for Devices and Radiological Health that
> are part of the FDA team and many are here today. These include: the
> Office of Compliance who have evaluated the sponsor\'s manufacturing
> facility and audited the clinical-study data; the Office of Health
> Industry Programs who provide assistance to consumers and review the
> program labeling; the Office of Science; and Technology and the Office
> of the Director.
>
> Additionally, the FDA team consists of reviewers from the Division of
> Pediatric Drug Development and the Pregnancy Labeling team in the
> Office of New Drugs in the Center for Drug Evaluation and Research. I
> also want to acknowledge the valuable assistance provided by the
> Office of Women\'s Health in FDA Headquarters.
>
> As a reminder, we will not be discussing saline-filled breast implants
> at this meeting and I request that panel members and the members of
> the public limit their comments and discussion to the products being
> evaluated, silicone-gel-filled breast implants.
>
> Panel members, we appreciate your commitment. The representatives of
> 27 professional organizations and 92 members of the public who have
> requested time to address the panel, we appreciate your comments. And,
> PMA sponsor, we appreciate your participation in presenting the safety
> and effectiveness data you have collected to the panel and answering
> questions that the panel may have.
>
> Thank you for your attention. I would now like to introduce Dr. David
> Feigal, the Director for the Center for Devices and Radiological
> Health.
>
> David?
>
> DR. FEIGAL: Good morning. I would also like to extend my welcome here.
> I wanted to take a moment to actually address a problem which we are
> trying to deal with. We have heard for a number of years that it is
> very difficult for people who have medical devices to get
> notifications and information about these devices.
>
> It has been suggested registries could be used for such a mechanism
> but registries track individuals by name, must keep track of their
> addresses. They are very labor intensive and beyond, really, the
> resources of the Center aside from any of the confidentiality issues
> and problems that that creates.
>
> What we have done in breast implants is a new program which we hope to
> extend to other medical devices where we will actually provide,
> through e-mail contact, information about products of great concern to
> the public. There is a brochure that is out on the table that people
> can sign up and all that is needed is an e-mail name. If you would
> like to also give us your name, that is fine, but we are not in any
> way tracking individuals. This will be an opportunity where we can
> communicate with people who would like information about medical
> devices, about medical devices that they are using, about such
> products.
>
> So, for example, the summary of this meeting, the web pages where the
> transcripts may be found, other kinds of information about these
> implants will be provided as a part of the updates that would be sent
> by e-mail. If there are organizations that would like us to load
> mailing lists and other lists of people who would like to participate
> in this and hear information from us, we can do that as well.
>
> One of the things that we particularly appreciate is the publicness of
> this process. We realize that it is at some expense that people travel
> here. It is certainly a commitment of people\'s time. We value very
> much the perspectives that we hear from people who will put a face on
> the use of these products and we value, very much, your expertise in
> considering whether or not these products meet the standards for safe
> and effective products.
>
> So, with that, let me conclude my welcome and wish you a successful
> two days.
>
> DR. WHALEN: Thank you. We now will proceed with the open public
> hearing session of this meeting.
>
> **Open Public Comment**
>
> **Introductory Remarks**
>
> DR. WHALEN: All those who will be addressing the panel are asked to
> speak clearly into the microphone at the podium as the
> transcriptionist is dependent upon this means of providing an accurate
> record of the meeting.
>
> I would specifically now like to have the attention of all those who
> are registered or who might be considering speaking to the panel
> today. You have each, if you have registered, been given a number
> corresponding to your order of appearance. We would ask that you come
> to the podium area in advance so that we are not spending a great deal
> of time in transitions from speaker to speaker due to the volume of
> individuals who will be speaking.
>
> FDA staff will direct you to the appropriate podium. Please remain
> within your time constraints as we will have a timer going to help
> people remain on time and please be aware that you will receive a
> flashing light when 30 seconds remain in your allocated time. If you
> go beyond that, I will try to, as unobtrusively as possible, remind
> you that you need to come to conclusion.
>
> 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 oral statement, to advise the
> committee of any financial relationship that you may have with the
> sponsor, its product and, if known, its direct competitors.
>
> For example, this financial information might include the sponsor\'s
> payment of your travel, lodging or other expenses in connection with
> your attendance at the meeting. Likewise, FDA encourages but does not
> require you at the beginning of your statement to advise the committee
> if you do not have any such financial relationships.
>
> If you choose not to address this issue of financial relationships at
> the beginning of your statement, it will not preclude you from
> speaking, which is a departure from the last time I chaired a meeting
> a couple of years ago.
>
> We will start with those individuals who have notified FDA of their
> request to present in the open session. I would tell you in advance,
> for those of you who will be lining up in your assigned order, that,
> at a particular point in time in mid-morning, I will be interrupting
> to take a break and then I also will be interrupting at a later point
> in early afternoon when we will be breaking for 45 minutes for lunch.
>
> If the first speaker would come to the podium, then, please.
>
> **Public Speakers**
>
> MS. SCHERR: Good morning. My name is Susan Scherr and I am with the
> National Coalition for Cancer Survivorship. There is no conflict of
> interest. I have not received any funds. This is a statement letter on
> behalf of twelve different organizations.
>
> To the members of the panel, the National Alliance of Breast Cancer
> Organizations, Y-Me National Breast Cancer Organization, the National
> Coalition for Cancer Survivorship and nine non-profit health and
> cancer organizations that share our concerns believe it is important
> that women requiring reconstructive surgery for because have silicone
> breast implants available as an option for reconstruction.
>
> Please note that we offer no opinion or comment on the availability
> and use of silicone breast implants for cosmetic or other purposes.
> Consistent with the missions and expertise of our organizations, we
> are not endorsing products from any manufacturer and the following
> comments are limited to the availability of silicone breast implants
> for women with breast cancer, breast disease or other medical needs
> and by qualified clinicians.
>
> All of the undersigned organizations support the right of each
> consumer and patient to consider options for selection and then
> receive individualized treatment and care that follows the approach
> she or he desires and believes is best. Furthermore, we encourage
> consumers to make healthcare decisions in consultation with an expert
> clinician after receiving and understanding in-depth information on
> the benefits, risks and unknowns and uncertainties of a range of
> state-of-the-art options for care.
>
> Consistent with these rights, we believe that silicone breast implants
> should be available as an option for women requiring reconstruction.
> About 20 percent of patients with breast implants receive them because
> of a breast cancer diagnosis or other medical need. Current options
> for post-mastectomy reconstruction are limited and not all are
> suitable or possible for every woman.
>
> For many women, an external prosthesis is impractical and
> saline-filled breast implants often cannot achieve acceptable
> symmetry, appearance or comfort. We emphasize that, because women
> differ by health status and by emotional, physical and personal needs,
> they require a similarly wide variety of post-mastectomy
> reconstruction options.
>
> A further important distinction is that women with breast cancer who
> choose implants do so with a different risk/benefit analysis than
> those who choose implants for other reasons. After breast cancer, most
> women with an implant consider it is necessary, not optional, or even
> crucial, for their healing and recovery.
>
> Despite the availability of implants over the past decade, in reality,
> it has been very difficult for women to get implants in controlled
> studies as many physicians are unaware of the studies or unable to
> offer them to their patients. After an extensive review of the science
> surrounding breast implants, the U.S. National Academy of Sciences\'
> Institute of Medicine reported there is no causal relationship between
> systemic illness and breast implants as these illnesses occur with the
> same frequency in women with breast implants and women without breast
> implants.
>
> The U.S. Federal Court\'s National Science Panel, the European
> Parliament\'s Scientific and Technology Options Assessment and the
> British Ministry of Health all reached the same conclusion. In its
> recent report to Congress, NIH reported that a large meta-analysis
> following the IOM review of the literature concluded that there was no
> evidence of an association of silicone-gel-filled breast implants with
> connective-tissue diseases or other autoimmune or rheumatic
> conditions.
>
> Women should receive accurate information and give their informed
> consent regarding the risks and benefits of silicone breast implants.
> No breast-cancer or any medical procedure is without risk. Neither are
> medical devices which do not last forever. These treatments and
> devices are not completely predictable or completely understood.
> Silicone breast implants for reconstruction should not be held to a
> different, higher standard.
>
> However, we feel strongly that women considering silicone-gel-filled
> or any type of breast implants must receive current detailed and
> accurate information about the device\'s risks, benefits and
> complications including incidence of capsular contracture and rates of
> rupture. In addition, we advocate ongoing data collection and
> reporting based on long-term follow up of all women who receive
> silicone implants for reconstruction.
>
> Follow-up mechanisms such as privacy-protected recipient registries
> and close physician tracking will be needed to facilitate medical
> professional education training and disclosure data compilation and
> analysis, regulatory oversight and prompt communication of significant
> findings to consumers, panels and providers.
>
> In conclusion, the undersigned twelve organizations recommend that the
> panel make silicone breast implants available for reconstruction use
> for women with breast cancer, breast disease or other medical needs.
>
> Do I have time to read the organizations?
>
> DR. WHALEN: No; I am afraid that is the end of your time.
>
> MS. SCHERR: Okay. Thank you.
>
> DR. WHALEN: Thank you for your comments. Just two technical notes
> before our next speaker. One is, apparently, the light does not flash
> at 30 seconds but simply turns yellow. So you can be aware of that. Or
> it will turn red at the end of your time.
>
> The other technical note for the audience, if you are in possession of
> cell phones or pagers, I give you three choices; silent mode, off or
> outside. Thank you.
>
> The next speaker?
>
> MS. HENDERSON: Good morning. My name is Sherry Henderson and I am from
> Bossier City, Louisiana. I came here today at my own expense with no
> conflict of interest. I had fibrocystic breast disease and
> precancerous cells which resulted in a double mastectomy and
> reconstructive surgery with implants. During my first year of the
> implants, I had chest pain and headaches. Within the next three years,
> I had hair loss, muscle spasms, irritable bowel, reflux, chronic
> fatigue and rashes.
>
> By the eleventh year, a sonogram verified a silent rupture I had and I
> had my third surgery with a tram-flap. That was a six-hour surgery and
> the medical cost was \$41,000. I was fortunate to see a doctor who
> studied implanted women for over 20 years. I was diagnosed with
> several diseases including lupus likeness, rheumatoid arthritis,
> fibromyalgia, myositis, organic brain syndrome, high blood pressure
> and autoimmune diabetes. I am now on disability.
>
> I would like to ask the FDA to have the implant makers to do at least
> ten years of study and research. They should be required to pay for a
> national implant registry and require all women in it to have yearly
> screening examinations for local and systemic complications. Let
> unbiased researchers do the screening.
>
> The Inamed research shows very high complication rates and an increase
> in symptom-like fatigue in just the first two years after getting
> implants. But to know the real consequences, we must have longer
> research. Breast implants are not life-saving devices. If they are not
> safe, they should not be approved.
>
> Like thousands of breast-implant women, I live in pain every day and I
> pray that my grandchildren and my nieces do not go through the pain
> that I have gone through. The higher rate of brain and lung cancer,
> more suicides and the study linking implants to fibromyalgia are
> warning signs that silicone gel should be made less available, not
> more available.
>
> We are tired of all the suffering. There are young women becoming 100
> percent disabled and the government is finally coming after the
> manufacturers. If the FDA refuses to approve this defective product,
> the implant makers should be better research and develop safe
> implants.
>
> In the past, the FDA ignored hundreds of thousands of adverse reports
> reported to them dating back in the \'70s. Breast-implant women have
> copies of these reports and would be glad to provide them for anyone
> to see. These reports document horrible health problems and
> unbelievable complications with these devices.
>
> Please make the right decisions for the sake of women who trust your
> opinion and whose lives depend on your trust.
>
> Thank you.
>
> DR. WHALEN: Thank you. The first two speakers representing national
> organizations were each allotted five minutes, for audience knowledge.
> The next set of speakers for some time will be individuals and each
> will be allotted three minutes.
>
> The next speaker, please.
>
> MS. KITTLE: Good morning.
>
> DR. WHALEN: You can take advantage of our setting it up and just go
> ahead and take a few extra seconds.
>
> MS. KITTLE: What did you say?
>
> DR. WHALEN: You can go ahead and start.
>
> MS. KITTLE: Oh, I\'m sorry. My name is Carolyn Kittle. I am from
> Shreveport, Louisiana. I came here at my own expenses. I have no
> conflicts of interest.
>
> I am here today to testify about seeing a loved one experience pain
> from breast implants. I have two sisters that have had breast
> implants. My younger sister had breast implants for cosmetic reasons.
> After having two children, her breasts were sagging and her husband
> wanted her to have bigger breasts. She was only 22-years old.
>
> She immediately starting having problems. They became hard. Five
> ruptured and she has had at least five breast surgeries. Her health
> has deteriorated. She has been diagnosed with chronic fatigue,
> fibromyalgia, muscle pain, MS and many strokes and white lesions on
> the brain. She is only 46-years old and cannot work due to her pain
> and the MS.
>
> My other sister had fibrocystic disease and cancer cells, had to have
> a mastectomy with reconstructive surgery and implants. She soon was
> debilitated by headaches, muscle spasms, muscle pain, irritable-bowel
> syndrome and reflux. She had a silent rupture and three surgeries. I
> have seen her go from a vibrant wife, other and professional to a
> woman coping with lupus, fibromyalgia, thyroid disease and autoimmune
> diabetes. She has had three breast surgeries.
>
> I grieve to see both my sisters go through what they have gone through
> as a result of a product that, even today, has never been tested for
> long-term safety. My sisters have to travel hours away from their home
> to be seen by a knowledgeable doctor to treat their medical problems.
>
> Inamed\'s own research shows very high complication rates and they
> only studied women for two or three years. Just imagine what the data
> would have looked like if they followed the women for another few
> years.
>
> I am asking the FDA to please make the manufacturers study women for
> at least a few more years before considering approval. If you approve
> the implants first and tell the company to continue to study
> afterwards, the FDA has no authority to make them complete the study
> and you see, from the company\'s study so far, they won\'t do more
> than required.
>
> The European Union, on September 1, 2003, has reclassified all breast
> implants from a moderate risk category to the highest risk category
> for medical devices. Now is not the time to lower our standards here
> in the U.S. Scientists have found breast-implant women have higher
> rates of suicide and are more likely to die from brain cancer and lung
> cancer compared to plastic-surgery patients who smoke just as often as
> implant patients do.
>
> The FDA\'s own study shows the risk of leaking implants and those
> leaking implants are difficult and very expensive to remove. I urge
> the FDA to reject approval until further research and long-term data
> are available. We need to know what implants do to the human body year
> after year. I ask the advisory panel to the FDA to listen to all the
> ill women, make manufacturers do better research before you consider
> approval.
>
> Thank you and God bless.
>
> DR. WHALEN: Thank you.
>
> MS. ANDERSON: My name is Elizabeth Anderson and I come here from
> Florida at my own expense. I have no conflicts of interest.
>
> Until last month, I was director of an on-line health hotline and I
> have spoken with hundreds of women who have had breast implants or who
> wanted to get them. They wanted to know if implants were safe and if
> implants could make them sick. Many wanted to have their implants
> removed but they either had no money for the surgery or needed to find
> a doctor who would take their problem seriously and who would treat
> them.
>
> Many of the women I spoke with were sick with problems ranging from
> mild to devastating. While some got sick shortly after getting
> implants, most were fine for ten years after implantation and then
> they started getting sick at that point.
>
> Women told me they were suffering from multiple illnesses and of
> doctors who were unresponsive to any suggestion that their problems
> could have been caused by their silicone implants. Their doctors
> sometimes told them that they were depressed and that was why they
> were so ill, but it seems more logical that, because they were so ill,
> they were depressed.
>
> When you hear so many stories of ruined lives, you understand this.
> Some became so sick they could no longer work which, of course, meant
> the loss of income and health insurance. Can you imagine believing the
> medical device you have chosen is perfectly safe and thinking you are
> going to feel better about yourself only to become so sick that you
> lose everything, even your spouse.
>
> I have spoken with numerous women who have gone through this and I
> know women in their 30s and 40s who are completely disabled from their
> breast implants. I believe that women who have had mastectomies should
> have a choice for reconstruction, but what kind of choice do implants
> offer?
>
> There is no long-term reliable research proving the safety of breast
> implants, not the Mayo study, not the Harvard study, and not the IOM
> report that is based on them. Epidemiologists will tell you that these
> often quoted are seriously flawed because so many women in them had
> implants for only a few months or years. Diseases like scleroderma and
> MS take a few years to develop and to be diagnosed.
>
> Breast-cancer patients have suffered enough but, according to
> Inamed\'s data, these women will have more complications from their
> breast implants than those who receive implants for augmentation. So
> not only does a woman have to worry about a recurrence of because but
> she has to worry if her breast implants are going to make her sick.
>
> I am sure everyone here realizes the only thing most people need to
> hear about a medical product is that it is FDA approved. That is the
> seal of safety. People believe the FDA protects them from untested and
> unsafe products. To be approved, silicone-gel breast implants should
> be proven safe for long-term use by research on a large cohort over a
> long period of time, at the very least, ten years.
>
> The FDA is mandated to make decisions based on science but using all
> long-term research that is available is a hollow statement when there
> is no solid long-term research available. Everyone knows that three
> years of research is not sufficient. Since all Inamed\'s silicone-gel
> breast implantees since 1998 should have been enrolled a study, we
> should have at least a four-year study by now. But, where is it?
>
> The study that Inamed started in 1990 could have been an excellent
> study but they neglected to include more than a few cancer patients
> and then most of the augmentation patients were lost to follow up
> making the study useless.
>
> DR. WHALEN: Can you conclude, please.
>
> MS. ANDERSON: Yes. The FDA did not want to ban silicone-gel breast
> implants in 1992, allowed them to remain on the market to still be
> studied. I ask, where are the data from those women?
>
> MS. CUMMINGS: Good morning. My name is Arlene Nicole Cummings. I came
> here at my own expense and will not be reimbursed.
>
> At the age of 12, I had a benign breast tumor removed from my right
> breast. This left me with an asymmetry problem that only got worse as
> I got older and had my children. Fixing my breasts was something I had
> thought about for years. After I was done having my children, I felt
> the time was right.
>
> I did a lot of research on line and found a great deal of information
> but nothing personal. This is what prompted me to start
> implantinfo.com back in 1998 after I had my own surgery. implantinfo
> is now the largest community website for breast-augmentation patients
> where women can read the pros and the cons about breast implants and
> go through photos and stories of thousands of other women.
>
> I am here today primarily because I am a satisfied breast-augmentation
> patient. However, I never had the option of choosing silicone back in
> 1998. After talking to women and doing my own research, I would choose
> silicone now over saline if it was available to me.
>
> On my website, I have corresponded with countless women who, for many
> reasons, probably should have had the silicone option but did not.
> They were denied silicone implants, had an unsatisfactory result with
> saline, and then had a second surgery to replace the saline implants
> with silicone. So they actually had to have two surgeries to get the
> result they wanted the first time.
>
> I am also aware of the frustration that surgeons feel because they
> can\'t give a patient what they know, in some cases, will produce a
> better result for them. The risk of a second surgery, in my opinion,
> is far greater than the risk of silicone implants.
>
> Ironically, breast-cancer patients already have compromised immune
> systems but, for the most part, receive silicone implants. Are they at
> less of a risk of the supposed risks of silicone implants? I believe
> silicone implants provide a far better result for reconstruction. If
> these patients get breast implants and get a better result with
> silicone, shouldn\'t they be available to all of us?
>
> Women, along with their surgeons, should be allowed to choose silicone
> or saline. We are neither ignorant nor shallow and we are not seeking
> breast implants with informed consent. We have researched the
> procedure for years. The average age of a woman on my website is 34.
> Most of us are married with children and just want to get back what we
> lost after pregnancy and nursing.
>
> I believe in informed consent and women should be told all the risks.
> But, in the end, after we receive that information, let us decide,
> along with our surgeons, silicone or saline.
>
> I have passed out to a handful of testimonies from other women who,
> for many reasons, could not physically be here. There are thousands
> more on implantinfo.com and I encourage you to read about them and
> give us back the choice of saline and silicone.
>
> I think you for your time.
>
> MS. COLOMBO: Good morning. My name is Michele Colombo and I come here
> on my own behalf and I have no conflict of interests,
>
> I am 34-years old and married. For many years, I have been
> dissatisfied with the size and appearance of my breasts. I am very
> self confident and I am an educated person but have always seriously
> considered improving my appearance by undergoing breast augmentation.
>
> I have been researching breast augmentation for approximately five
> years including reading the FDA website as well as other resources on
> the Internet. In doing so, I have satisfied myself that silicone
> implants are a safe alternative for my breast augmentation.
>
> Unfortunately, in the early 1990s, silicone breast implants were
> banned for sale to people like me in the United States. If I lived in
> Europe, I could get silicone breast implants. If I traveled to Europe,
> I could silicone breast implants and come back to the U.S. and live
> here with them even though they are unavailable here. If I had breast
> cancer, I could get silicone breast implants. What\'s more, if I were
> a man, I could get silicone testicular implants and if I required a
> shunt for medical reasons, it would also be silicone.
>
> But, unfortunately, for me, I am just a woman seeking to undergo a
> cosmetic procedure. Moreover, what I seek is a procedure using a
> product which has been shown in numerous studies to have no more
> long-term heath risks than saline breast implants or other silicone
> devices.
>
> My problem, it seems, is that the FDA, up until now, has viewed people
> like me as unable to decide what it best for me. I could make that
> decision if I had cancer but simply because I want to improve my
> physical appearance, that is not enough to justify the risks, in
> someone else\'s opinion.
>
> I think it is time to reevaluate the true motivations for the ban in
> silicone breast implants. The fact that breast-cancer patients may
> obtain them and cosmetic patients cannot exposes the true reason for
> the ban. What is at stake is a moral judgement rather than a medical
> one. If my breasts are completely deflated from breast feeding, weight
> loss or age, improving my appearance with breast implants is deemed
> unacceptable because it would be for vanity. If I had had a
> mastectomy, it would be acceptable because it could be justified as
> medically necessary. The difference is a moral one and not the a
> medical one.
>
> I urge you to remove the ban on simply breast implants and let women
> make informed decisions about their bodies the way millions of people
> do every day with countless other devices and medicines that are
> approved by the FDA.
>
> Thank you for your time.
>
> DR. JOINER: Good morning. I am Dr. Thomas Joiner, the Bright-Burton
> Professor of Psychology at Florida State University. I have authored a
> peer-reviewed paper on the association between breast augmentation and
> suicide as well as six books and over 200 scientific articles on
> topics related to mental disorders including suicide.
>
> I was awarded a Guggenheim fellowship for research on suicide and was
> given the Schneidman Award for Excellence in suicide research from the
> American Association of Suicidology. My travel expenses to this
> hearing were paid by the American Society for Aesthetic Plastic
> Surgery. I have no financial ties to any implant manufacturer and no
> involvement in a pending law suit related to breast implants.
>
> I thank the panel for the opportunity to address the relation between
> breast augmentation and suicide. To date, there are four studies
> indicating that women who undergo breast augmentation have higher
> suicide rates than women in the general population. It is crucial to
> note that breast-augmentation patients are not representative of the
> general population and the ways in which they differ from the general
> population are very relevant to suicide risk.
>
> The crucial point it this. Breast-augmentation patients should be at
> relatively high risk for suicide for reasons that have nothing to do
> with breast augmentation. Given the demographic and other
> characteristics of breast-augmentation patients, their suicide rate
> should be higher than that of the general population.
>
> Consider race, for example; virtually 100 percent of
> breast-augmentation patients are white whereas the general population
> of women is, of course, more diverse. This is relevant because white
> people are more likely to die by suicide than non-white people.
> Breast-augmentation patients\' risk for suicide is increased partly
> because of the simple fact that they come from a racial group with
> relatively high suicide rates.
>
> This same exercise can be repeated with the same conclusions for each
> of the following factors; age, marital status, alcohol use,
> personality and symptoms of mood and other disorders. In each case,
> breast-augmentation patients appear to differ from the general
> population of women and, in each case, the difference is such that
> suicide risk is increased.
>
> I calculated the expected suicide rate in breast-augmentation women
> given their demographic and other characteristics. A conservative
> calculation produces an expected suicide rate among
> breast-augmentation patients that exceeded the population rate by
> fourfold. For reasons having nothing to do with breast augmentation,
> the subgroup of women who undergo the procedure should have relatively
> high suicide rates because their demographic and other characteristics
> put them at high risk.
>
> Given that expected rates are fourfold the population rate, and actual
> rates are lower in every study to date, the possibility arises that
> breast augmentation actually confers protection from suicide a
> possibility that squares with the finding that vast majority of
> breast-augmentation patients report high satisfaction with the
> procedure.
>
> A safe conclusion appears to be that actual suicide rates are no
> higher than and may possibly be lower than expected suicide rates
> among women who undergo breast augmentation.
>
> Thank you.
>
> MS. CUNNINGHAM: Good morning. My name is Susan Cunningham. I came here
> at my own expense. My biggest concern is that these implants do
> rupture and there is still no medical information on how to recognize
> a rupture and what to do about it. It is a frightening experience to
> be so sick and not have a clue what is wrong with you.
>
> Many women cannot afford an MRI to check and, even if they find out
> their implants are ruptured, they don\'t have the money needed for
> surgery. My own experience began after I had breast-fed both of my
> children. I decided on implants and arranged for a consultation with a
> highly respected plastic surgeon. I had concerns, but the surgeon said
> the implants would last a lifetime.
>
> I was fairly pleased with the results, but it didn\'t last long. I
> began to experience loss of nipple sensation and numbness. Then I
> experienced capsular contracture in the right breast which is very
> painful. As the years went by, I was plagued with sinus and
> respiratory problems. My health continued to decline.
>
> Finally, in 1993, I consulted my plastic surgeon. As he wrote in his
> notes, \"I reassured her concerning this and advised her to leave her
> implants in place unless there are further difficulties because they
> look very good.\" My body was wracked with joint pain. I was diagnosed
> with Raynaud\'s and suffered from constant muscle spasms.
>
> My breathing and chest pain were severely affected and I had been in
> the emergency room several times. Finally, tests indicated remarkable
> changes in my immunological system characterized by an unexplained
> decrease in the total CD4 or helper cells. I was getting sicker and
> experienced a fatigue so devastating that I would weep from the
> smallest effort.
>
> My concentration was zilch and I started having huge gaps in my memory
> like pulling out of my driveway and then wondering where I was going
> or what I was doing in the car. It was frightening and it became
> worse. Finally, I was forced to quit a career that I loved. At this
> point, it became necessary to sell our family home.
>
> I sought out Dr. Feng whose practice was 120 miles away. She informed
> me that at least one implant was ruptured. They were removed in 1995,
> both ruptured, and I promptly noted relief in the chest pain I had
> been experiencing for years. Within a few months, my bloodwork, which
> for many years had been abnormal, returned to normal except for IgE
> levels and a positive antihistone antibody which took an additional
> two years to return to normal.
>
> My overall physical condition has taken a few years to improve. I
> still suffer from fibromyalgia-like symptoms although attacks are less
> frequent and of shorter duration. At the ripe old age of 61, my mind
> is much sharper and my body much stronger than it was just a few years
> ago.
>
> Today, I live a far different life than I could have lived if it were
> not for ruptured implants and their devastating effects to my life. I
> am on disability which was granted on silicone rupture and related
> problems. It was a very black day for me to finally accept the fact
> that working is no longer an option for me.
>
> I am not looking for pity because I have been blessed with many other
> things in my life. But, if there is anything I could do to help
> another woman to avoid these devastating effects of ruptured or
> leaking implants, then I must try. That is why I am asking you to not
> approve silicone-gel implants until the company provides long-term
> safety data proving that leaking silicone and immune diseases can be
> avoided.
>
> The company\'s application for silicone-gel breast implants was
> rejected in 1991.
>
> DR. WHALEN: Can you conclude please.
>
> MS. CUNNINGHAM: Thank you. They had twelve years to collect data but
> they only collected three. They will only do better research if
> approval is denied until they do.
>
> Thank you.
>
> MS. STANSELL: My name is Anne Stansell. I came here from New Mexico at
> my own expense. I am a breast cancer survivor. I was diagnosed at age
> 39. The doctors said I needed a mastectomy, radiation therapy and
> breast implants. Implants were just part of the treatments. No
> discussion.
>
> I trusted the doctors who I felt had just saved my life. I didn\'t
> know there was no safety study of breast-cancer survivors with
> implants. That had never been done. I was all right for the first few
> years. Then I became very ill. I was diagnosed with Graves\' disease,
> fibromyalgia. My eyes were so dry that one of the retinas tore.
>
> My implants were taken out about two years later. I had to fight with
> my insurance company to cover the removal. Half of one of my implants
> was gone. Where did the silicone go? I don\'t know. Even with silicone
> left inside of me, almost immediately, I began to feel better. My
> family really noticed a difference even before I did.
>
> I am still recovering, but I can work some now. I thought of my own
> experience when I heard about the Inamed study of breast-cancer
> patients. I had many of the same local complications. I can\'t even
> remember how many surgeries I suffered. Silicone was found in my side
> where it migrated from a broken implant.
>
> Inamed cancer patients also had an increase in some autoimmune
> symptoms during the first two years. I think my symptoms started at
> the third year or so so it is likely that those signs and symptoms
> will increase over time, just like mine did.
>
> It doesn\'t do cancer patients any favor to give them the kind of
> choice I was given. The choice isn\'t a choice if it is not a safe
> choice. Informed consent isn\'t possible if the physicians think the
> FDA approval means a safe product. A recent NIH study shows a doubling
> risk of brain cancer and a tripling risk of lung cancer in
> breast-implanted women.
>
> Health Canada has now started a study in 1996 to determine the cancer
> risk in 40,000 breast-implant women who were implanted from 1974 to
> 1989. This data should be available later this month. It is outrageous
> to continue to allow the marketing of a device that may increase the
> risk of cancer in women who are recovering from breast cancer. Your
> job is to look at the research, but I hope you will listen to the
> patients, too. We illustrate the data. We are the examples of what can
> and what has happened to tens of millions of women around the world.
>
> MS. RUST: (Read by Beth Nichols.) My name is Beth Nichols and I am
> reading this on behalf of Rose Rust who is too ill to be here today. I
> have no conflict of interest.
>
> \"My name is Rose. I am 57-years old. After I remarried in 1990, I
> thought I needed to look younger so I opted to get silicone breast
> implants made by McGhan, now called Inamed. I had talked to a plastic
> surgeon and he told me they were safe and they would last my lifetime.
>
> \"Within four months of getting the implants, I noticed I was aching
> all over and had headaches. I went back to the surgeon and told him I
> thought they were making me sick. He told me I was listening too much
> to the media and he saw no reason to remove them. I believed him and
> left them in.
>
> \"I became more ill and the headaches became almost unbearable. I had
> so much pain that I had to quit my job. I had become so ill that I was
> put on Social Security disability. In the mid-\'90s, my nasal passages
> started burning and my nose was swelling shut in addition to the
> horrible headaches. My GP sent me to a neurologist who did many tests
> and sent me to an ENT.
>
> \"I ended up having three sinus surgeries. The three different doctors
> all told me that something was inflaming my nasal passages. They told
> me that if I didn\'t find out what my body was reacting to, they
> couldn\'t help me. I went to an allergist and he found no allergies.
> We had our house checked for any toxins. My husband checked our
> vehicles. By now, I was feeling much worse, dizzy and nauseated.
>
> \"Over the next few years, I went to many doctors including the Mayo
> Clinic, but nobody could find out what was wrong with me. The last two
> or three years, I have become so ill I am almost bedridden. My nasal
> passages burn all the time and my headaches are constant. My legs and
> feet burn, swell and hurt so badly, I can hardly walk. I am dizzy and
> nauseated. I have lost much of my short-term memory.
>
> \"Over the last few years, I have become intolerant of all chemicals.
> When I am exposed accidentally, my nose swells shut, nausea and
> headaches worsen and my heart acts up. In June of this year, I finally
> decided I was going to die if I didn\'t do something. In August, I had
> my implants removed. My left implant was ruptured and the plastic
> surgeon said most of the silicone had leaked out, migrating into my
> chest and into my lymph nodes. She described it as \'a sticky mess.\'
>
> \"She also removed the lymph nodes with silicone in them. At that
> time, she told me there was probably silicone in my liver, lungs and
> brain. The right implant was intact. I have no idea how long the left
> implant had been ruptured. I saw no difference in how I looked.
>
> \"Through the years, I have become unable to even take care of my
> home. Sometimes, I am not able to fix meals for my husband. I spend
> many days in bed. Long ago, I gave up on social events. My husband
> tells me I actually am much worse off than I realize. It is just a
> struggle to survive. If the doctors had not told me my illness was
> unrelated to my silicone implants, I would have had them out many
> years ago and perhaps avoided much of the silicone leakage.
>
> \"I think of how, in 1991, the FDA decided not to take silicone-gel
> implants off the market. It sent the clear message that silicone-gel
> implants are probably okay. I feel many of us have been the guinea
> pigs and I feel we have proven that silicone is not safe because the
> implants can leak throughout our bodies. It is too late to do much for
> women like me, but let\'s please save the next generation.
>
> \"It is your responsibility to protect us and hopefully you can
> restore my faith in our FDA.
>
> \"Thank you.\"
>
> MS. PATE: Hello. My name is Kathy Pate and I would like to thank the
> panel for the opportunity the speak today on behalf of silicone breast
> implants. I am a registered nurse in Albany, Georgia and I work in an
> operating room there. I have never had any financial relationship with
> any medical-device corporation or their competitors. I am here
> representing myself and I have paid my own way.
>
> I have breast-augmentation surgery in December of 1983 because I had
> difficulty buying clothes to fit. As many other women have stated,
> after I breast-fed my baby, I didn\'t have very large breasts to start
> with and then, after that, the problem was even worse.
>
> I became quite frustrated with this problem so I decided to have
> breast-augmentation surgery. At that time, the quality of saline
> implants was very poor. The possibility of deflation was very high. At
> that time, also, there was no discussion about the serious
> complications related to silicone implants when I had my surgery.
>
> My plastic surgeon did tell me that there were possibilities of
> localized irritation if the gel ruptured. He also said there was a
> possibility of capsular contracture. I went ahead and chose the gel
> because they looked more natural and they were lighter.
>
> When the media put out the information on silicone implants, and they
> were removed from the market in the early \'90s, I wondered what
> should I do. Should I have them removed? What should I do? So I
> pondered the thought and decided that the best thing to do was see if
> anything developed. I have not developed any problem with silicone
> implants and really have no concerns about their safety.
>
> I monitor my breasts with visual and physical exam and I have an
> annual mammogram. I stay in close contact with my plastic surgeon and
> we decide we would monitor for any changes in shape or consistency to
> detect an early rupture.
>
> I realize there are risks associated with all types of surgery and
> especially with any implantable device. Although it has been twenty
> years since my surgery, and I am sure at some point I am going to have
> to have those replaced, I would definitely do the same procedure again
> and I will go back to silicone.
>
> I believe firmly that women should have the option to choose saline or
> silicone and that they should have the risks and benefits outlined for
> each. The individual receiving the product needs to have confidence in
> the product, itself, and also in the surgeon who is performing the
> procedure.
>
> I believe women who are well informed will make the decision that
> works best for them. Given all the research and investigation of these
> devices, I feel certain that the product has been vastly improved to
> resist rupture and prevent complications. Breast-implant surgery has
> allowed me to be comfortable buying clothes and not reduced to buying
> bras with heavy padding to fill out my clothes, and even bathing
> suits.
>
> The real message I want to convey here is that I feel like the women
> need to have a choice and be informed of the risks and benefits and
> have the option to choose.
>
> Thank you.
>
> MS. BRUNING: Good morning. My name is Nancy Bruning and I have no
> conflicts of interest. I was told I had six minutes. Can I have six
> minutes, five minutes?
>
> DR. WHALEN: You are here with Ms. Peterson?
>
> MS. BRUNING: Bruning.
>
> DR. WHALEN: I know your name is Bruning. You are listed as being here
> with Ms. Peterson. That is why the two of you together were given six
> minutes.
>
> MS. BRUNING: I see. Well, I am wearing three hats, so\--thank you.
>
> I am wearing three hats. I am here today as a breast-cancer survivor.
> I am here as the author of a book about breast implants that is
> currently in its third edition. And I am here as a graduate student
> completing her Masters degree in public health.
>
> I became interested in breast implants because of my own experience
> with breast cancer and its aftermath. You would probably never suspect
> it to look at me or to hear me, but I have had my chest cut open seven
> times, twice for breast cancer and five times to fix what the
> breast-cancer surgery wrought on my mind and body.
>
> My most recent surgery was to remove the gel implant that had ruptured
> along with the entire scar capsule that surrounded it, and it was
> replaced with a saline implant. I am here to tell you that, although
> this could be dismissed by some as merely local complications, this
> surgery caused me more pain and disability than any of the other
> surgeries including the mastectomy.
>
> I am here because, if I had to do it all over again, you would have to
> tell me that, based on the studies that exist including the new Inamed
> study, breast-cancer patients have a very high probability of these
> things happening including a 46 percent chance of reoperation in the
> first three years.
>
> But can you tell me what the rate might be down the line? No; you
> cannot. I am here because, if I had to do it all over again, I would
> like you to tell me the odds that any silicone that escaped the scar
> capsule will cause systemic disease down the line. Can you do that?
> No; you cannot. Can you tell me the odds of that happening with the
> new Inamed implant? No; you cannot.
>
> The subtitle of my book is Everything You Need To Know About Implants
> and one of the first things I tell my readers that they need to know
> is that we don\'t know everything. Far from it. This was true when I
> first wrote the book in 1993 and it is only a little less true now.
> And what we do know is not good.
>
> During the process of writing and twice revising the book, I
> interviewed scores of plastic surgeons, breast-cancer survivors,
> implant patients, researchers and advocates. The one thing that is
> clear is that silicone breast implants were sold to almost 1 million
> women before any research on women was published in the peer-review
> journals.
>
> Currently, over a quarter of a million American women have breast
> implants every year. This could be a disaster waiting to happen if
> silicone implants become available without proper long-term study.
>
> We now know that silicone-gel implants break after about ten years, on
> the average. We now know that leaking silicone can migrate to the
> lymph nodes, lungs and all throughout the body. We know that, in
> several studies, women with breast implants were more likely to die
> from certain types of cancer.
>
> And we know that, in three studies, women with silicone implants are
> three times as likely to commit suicide. In the Inamed study, quality
> of life, including social interactions and self esteem, actually
> declined within two years of getting their implants. This certainly
> raises questions about whether implants make women feel good about
> themselves as promised. Results amy be even worse than the studies
> indicated. Let\'s remember that most women do not like to admit
> mistakes or to criticize their doctors to their faces.
>
> Regarding the research conducted by Inamed, in light of what we know
> already, I wonder why they thought two or three years of research was
> enough. Although the diagnosed rupture rate was low, 6 percent after
> three years reconstruction, we must assume that they are higher since
> three out of four ruptures are not apparent without an MRI.
>
> If you share my concerns that only half the breast-cancer patients
> were followed for even three years, especially since Inamed has been
> selling gel implants to cancer patients since the late 1990s.
> Breast-cancer patients deserve better. I am the living proof that they
> are living long lives.
>
> We deserve implants that don\'t result in additional surgery for 46
> percent of us in the first three years. We deserve long-term studies
> that can provide accurate information about the risks of developing
> serious implant-related health problems. We deserve to have a choice.
> Unfortunately, we do. Most breast-cancer patients can now choose
> lumpectomy, saline implant, silicone-gel implants or autologous
> construction. Choice is good but we deserve to have safe choices.
> Silicone implants should only be approved if they are proven to be a
> safe choice for all women.
>
> If there is a problem with the way studies are conducted and there is
> a problem with recruitment and compliance, then the answer is to fix
> that, not to make silicone-gel implants available.
>
> Since I received my diagnosis of cancer over 23 years ago and
> experienced the first inklings that breast implants were not as safe
> as I was led to believe they were, I have been living with two kinds
> of uncertainties. One, will I get breast cancer again and, two, will
> my implant cause me harm? I have seen studies that address the first
> question. Where are the good studies that address the second? Inamed
> has not provided them for the women who currently have silicone-gel
> implants or for the millions more who would if the FDA approves them.
>
> I have suffered more than enough and don\'t want other women to follow
> in my footsteps. We deserve to have better science than the implant
> companies have given us and it is your responsibility to use your
> power to make sure that they do just that before approval because it
> won\'t happen afterwards.
>
> Thank you.
>
> DR. WHALEN: Just to make it clear to the other speakers, to make sure
> that everything seems fair, the reason somebody would have six minutes
> as opposed to three is because two speakers who have preregistered
> with FDA have combined their time and one of those two individuals is
> addressing us. So, if you are wondering why you only have three and
> somebody has six, that is the reason.
>
> MS. FALLOWS: Good morning. My name is Jill Fallows. I am a nurse as
> well as an attorney. I do not have any financial relationship to
> Inamed or any of its competitors and, as a note of levity, as a trial
> attorney, I rarely find myself speaking before a group of such
> receptive physicians. I am appreciative of the opportunity.
>
> I will address the issue of choice this morning. It seems as though
> Inamed has framed its pro-silicone-breast-implant argument in terms of
> a woman\'s right to choose the device. But simply offering a woman the
> right to choose is a far reach from providing relevant, unbiased,
> sound medical information upon which a reasonable woman can make an
> informed choice.
>
> It is irresponsible to argue that a woman is entitled to choose a
> medical product while simultaneously glossing over the relevant safety
> data in the device\'s promotion and labeling. We want women to have
> choices. But we have learned from the Dalkon Shield and DES that they
> are not safe products and should not be offered to women simply
> because we cherish the notion of an individual\'s right to choose.
>
> This is particularly true at today\'s meeting because the silicone-gel
> breast implant does not purport to relieve the discomfort or pains
> commonly associated with diagnosed illnesses and conditions. Indeed,
> we don\'t want to offer women a choice of an implant knowing that it
> could rupture and leak silicone gel into their lymph nodes, lungs and
> other body parts where it cannot be removed.
>
> We don\'t want it leaking into their breasts so that removal results
> in a mastectomy to remove silicone rather than cancer. We should be
> mindful that breast augmentation is a completely elective cosmetic
> procedure and the risks to the patient should be clearly outweighed by
> its benefits.
>
> We need to empower women and their physicians with adequate, accurate,
> unbiased information broad enough to address the diversity among the
> 50 states informed-consent laws and yet specific enough to
> affirmatively warn women that they are buying a product with a litany
> of known serious risks.
>
> We take, as a starting point, the notion that a doctor or a patient
> must be apprised of information upon which a reasonable person can
> rely and make an informed choice about the safety of the implant. It
> would not be reasonable to minimize or hide the risks from the
> physician or the patients. The manufacturer\'s product literature
> should especially make mention of the rate of risks of complications
> and a black-box warning would be minimally acceptable if it stated
> that the manufacturer has not adequately completed five-year safety
> studies.
>
> I am most appreciative your time. Thank you.
>
> MS. SANTORO: Good morning. I drove here on my own expense and have no
> conflicts of interest. My name is Elizabeth Santoro. I have been a
> nurse for three years and I recently received a Masters of Public
> Health from Johns Hopkins. I will be discussing problems with data
> quality.
>
> A major area of debate is whether silicone breast implants cause
> autoimmune diseases such as scleroderma, lupus, rheumatoid arthritis
> and fibromyalgia. In 1999, the Institute of Medicine reviewed the 17
> studies available at that time and found that most research found no
> significant link.
>
> A year later, a meta-analysis of the same studies agreed with that if
> the largest study by Hennekins, et al., at Harvard was excluded. If
> the Hennekins study was included, there was a significant link between
> implants and these diseases.
>
> I would like to highlight some of the flaws in the studies that were
> both in the IOM report and the meta-analysis. First, not all the
> studies were published in peer-review journals. Second, many of the
> studies were based on hospital records. This is problematic because a
> lot of people who suffer autoimmune diseases are not hospitalized for
> symptoms such as pain and fatigue. Therefore, data from hospital
> records will not identify them.
>
> Medical records were also used as a primary source of information
> instead of a comprehensive medical exam. The absence of a medical exam
> creates the opportunity where valuable health indicators of adverse
> events can be missed. Often, vague and nonspecific symptoms can be
> present in the beginning of an autoimmune process. As a result,
> medical records may not be the best way to detect this class of
> disease.
>
> Most of the studies also included women who had implants for a very
> short period of time. Autoimmune diseases can take at least five to
> ten years to develop. So, including women with implants for only a few
> months or years cannot accurately capture all of the autoimmune
> diseases that might develop.
>
> I would also like to comment on the importance of sample size. Many of
> these studies had women with just a few hundred. That does not sound
> bad but a larger sample is needed when rare diseases such as
> scleroderma is being assessed. The research that has been conducted in
> the past and reviewed by the Institute of Medicine is not sufficient
> to draw conclusions about the safety of breast implants regarding
> autoimmune disease.
>
> And, by the way, those studies did not look at morbidity and mortality
> from other causes or from disorders that were not diagnosed diseases
> and therefore are useless for drawing any conclusions at all regarding
> cancers and other disorders.
>
> Also remember that the first Institute of Medicine on Agent Orange
> found no link to cancer. The first Institute of Medicine report on
> Gulf War veterans found no link to illness. Subsequent research found
> clear evidence of statistically significant increased risk of serious
> diseases that were not apparent to the IOM in their first analyses.
>
> I would also like to note how the data that was made available by
> Inamed is suggestive of a connection between silicone implants and
> autoimmune disease. Upon reviewing these data, FDA scientists found an
> increase in muscle pain, joint pain, hair loss, rashes and fatigue
> within two years of patients getting implants. During this same
> two-year period, it was also found that many patients reported
> decreases in both physical and emotional health. These signs and
> symptoms are characteristic of several autoimmune diseases in their
> early stages.
>
> In addition, FDA scientists noted previous studies found an excess of
> some cancers and leukemia among implant patients. These studies were
> published after the IOM report. The fact that implants may delay
> cancer detection via mammography is also troubling. Moreover, the
> FDA\'s own study found that silicone implants break within about ten
> years often with no warning signs and the clinicians and pathologists
> have reported numerous cases where silicone gel had migrated to the
> abdomen, groin, fingers and axillary lymph nodes.
>
> These findings raise grave questions about the safety of silicone-gel
> implants. They provide evidence that Inamed\'s implants are associated
> with many serious complications and declines in both physical and
> emotional health status even within the first two years.
>
> The data supplied by Inamed, combined with the limitations of the
> studies in the IOM report, show that there are many unanswered safety
> questions in regard to silicone-gel breast implants. As a result, they
> should not be approved by the FDA.
>
> Thank you.
>
> MS. PETERSON: (Read by Jennifer Brooks.) Good morning. My name is
> Jennifer Brooks. I am reading testimony for Evon Peterson who cannot
> be here today due to an illness. She has no conflicts of interest and
> neither do I.
>
> \"My name is Evon Peterson. Ten years ago, my silicone-gel implants
> were removed. I was an R.N. and had implants for reconstruction for
> following bilateral mastectomies. The doctors acted as if
> reconstruction was a given, something I should do. It wasn\'t
> presented as a choice.
>
> \"When I was explanted in 1993, the right implant was found to have
> ruptured and the left implant was severely leaking. Three additional
> surgeries in 1994, 1995 and 1996 followed to remove bilateral
> siliconomas.
>
> \"The first symptoms to appear after implants were the first to
> resolve or diminish when the implants were removed. A few weeks after
> reconstruction\--what an oxymoron that is\--the firmness and
> contractures began. The shape of my breasts became distorted and the
> surrounding tissue became inflamed. Lying on my right side or freely
> using my right arm was restricted. Searing pain invaded by back and
> neck.
>
> \"After that, more obvious systemic symptoms developed. By 1989, at
> age 45, I was totally disabled in my work and personal life. I
> experienced profound fatigue, insomnia, seizures, tingling and
> numbness of extremities, dizziness, nausea, skin discoloration and
> hardness, migrating joint pains, chemical sensitivities and balance
> disturbances. I felt like I was in a mental fog. I had contemplated
> suicide as an option to stopping the pain. I know if I had kept the
> implants in any longer, I would have committed suicide.
>
> \"One of the worst aspects of this experience has been in the
> continuing denial of manufacturers and the medical community. They
> fail to study implants and their related complications over a long
> period of time and then arrogantly claim that the products are safe
> for long-term use.
>
> \"Prior to explantation, I faced a paradox. I was too ill to have
> surgery and too ill not to have surgery. I am glad that, on the
> recommendation of three of my many physicians and also based on my
> increasing knowledge, I chose to improve the quality of my life by
> removing my implants.
>
> \"Despite living with multiple autoimmune processes and complications,
> my health has improved from about 10 percent functioning to 60 percent
> functioning. Considering that I have also aged ten years, I am
> delighted. I remain convinced that, had I not been explanted, I would
> have died within the year.
>
> \"I am unable to physically present today because of pneumonia.
> However, I petition you to require unbiased long-term studies before
> any decision is made about approval.
>
> \"Thank you.\"
>
> MS. WEBER: Good morning. My name is Elizabeth Weber. I live in
> Southern Maryland and I was not paid to come here today. The opposite
> is true. I asked to come today to share my story.
>
> My mother had breast cancer and had a bilateral mastectomy. I, too,
> had a bilateral mastectomy in June of 1999. I was aware of the
> controversy of silicone breast implants and, therefore, opted for the
> saline implant. I am a very active person. I trained for the Olympic
> Games since age of nine in the equestrian sport.
>
> Pain and perseverance is not new to me. The saline implants were very
> uncomfortable to me. Dr. Scott Spear did a wonderful job of my
> reconstruction and the outward appearance of the saline implants
> looked good, but I hated the way they felt inside. They were hard and
> hurt from the inside. I felt like I had a mass pushing against my
> chest.
>
> I stopped doing the sports I used to do and it was hard to sleep at
> night. One year later, I went to Dr. Scott Spear and asked to have the
> saline implants changed and replace by silicone implants. After I woke
> up from my surgery, I could feel such a huge difference. After I
> healed from the surgery, I felt like myself, a whole, natural and
> complete woman.
>
> The outward appearance was impressive and beautiful. But, even better,
> my breasts felt like mine from the inside. I now do everything I used
> to and more. I hope you give other women the same choice.
>
> Thank you for your time.
>
> ED BRENT: Good morning. My name is Ed Brent and I have received no
> funds nor do I have a sponsor that has helped me to fund this trip.
>
> Three years ago, my wife stood before you and did her best to convince
> you, the FDA, not to allow saline breast implants on the market. My
> wife had double-lumen implants, my daughter, Catherine, leg braces,
> and that was because of the silicone implants, carried one of my
> wife\'s implants to your table showing the black fungus growing inside
> of it.
>
> My wife was P.J. Brent. You may have seen her on CNN or other t.v.
> networks discussing breast implants. She was distraught after being
> here and learning that everything that she had said was anecdotal
> evidence and not to be considered by the panel. We were here March 1,
> 2000.
>
> On May 29, 2000, my wife committed suicide. She left behind seven
> children and I am here on behalf of my wife and children to urge you
> not to allow silicone breast implants on the market.
>
> There are three studies showing that women that breast implants are
> more likely to commit suicide compared to other women. Some experts
> think that these suicides mean that women with breast implants have
> lower self esteem before they got their implants as well as after. But
> the National Cancer Institute study, which compares implant patients
> to other plastic surgery patients, shows that the problem is more
> likely to be from the implants.
>
> My wife was not a woman with low self esteem. She was a vibrant,
> loving wife and mother. P.J. loved the way she looked the first few
> years after the implants. Then she started to get sick. Her joints
> hurt. Her fingers would swell so she could not wear her rings. She did
> not know what was happening and sought medical help. She had
> lupus-like symptoms and was diagnosed with fibromyalgia.
>
> She was explanted in 1992. P.J. breast-fed the two daughters she had
> after the implants. Catherine was born in 1985 and was diagnosed with
> chronic inflammatory demyelating polyneuropathy, CIDP, as well as
> esophageal-motility disorder. She spent years in leg braces to allow
> her to walk. Now, the braces are gone and have been replaced with a
> wheel chair and she has a special car with hand controls to help her
> drive.
>
> Christine was born in 1986 and also had esophageal-motility disorder
> and signs of the neurological disorder. After P.J. committed suicide,
> an autopsy was performed from her. Samples were extracted. Large
> amounts of platinum were found in her body. This came from the
> silicone. The high platinum levels, a doctor at CDC saw them and said,
> \"No wonder she committed suicide. She could not have been in her
> right mind.\"
>
> Hair, nail and tissue samples were taken from our daughters who breast
> fed and it was found that they, too, had elevated platinum levels.
>
> You have an awesome responsibility before you, a responsibility of
> conscience and doing what is right for the women and yet unborn
> children of these women who may be forever affected. Don\'t let this
> be a money issue, but a moral issue.
>
> Thank you.
>
> DR. CUNNINGHAM: Good morning. My name is Dr. Bruce Cunningham. I am
> Professor and Chair of Plastic Surgery at the University of Minnesota.
> I am speaking as an individual and have personally paid my way for the
> appearance today. I own no stock in any implant manufacturer and
> receive no compensation of any kind.
>
> I have, however, received peer-reviewed research grants from implant
> manufacturers and I have served as a medical director of a PMA
> breast-implant submission. I do use implants in my clinical practice.
>
> ASPS has recognized and acted on its responsibility to plastic
> surgeons and their patients. The American Society of Plastic Surgeons
> has already established a breast-implant registry within a larger
> outcomes data-collection activity. I worked on the development of
> TOPS, or Tracking Outcomes in Plastic Surgery, which collects
> plastic-surgery procedural data and clinical outcomes and can include
> collecting satisfaction data from patients, themselves.
>
> A breast-implant registry is embedded within the Internet
> data-collection tool of TOPS and can track things such as the number
> of implants placed or removed, clinical indications and type of
> facility, anesthesia and short-term complications. NBIR, or the
> National Breast Implant Registry, was designed to allow physicians and
> their highly mobile patients to track implanted and explanted devices.
> NABIR was, in fact, so successful in its design that it attracted
> international interest. It has served as the template for IBIR, the
> International Breast Implant Registry, which is poised to become the
> standard for the European community, Australia and South America.
>
> In the initial piloting phase of NBIR, this data-collection tool over
> the Internet, 9,000 surgeries were recorded including 14,912 implants
> and 2,084 explants. TOPS and NBIR, however, are hindered in their
> ability to provide benefit for patients and physicians by the
> stringent confidentiality constraints of HIPAA. They could be improved
> significantly to provide transparent tracking of devices, surgeon
> records and implant-related events.
>
> To do this, however, the breast-implant registry that we have
> established requires public-health authority status as a part of a
> Governmental Health Operations Act. The management, government and
> composition of the leadership of the NBIR could be changed to reflect
> the involved stakeholders by including the FDA, the public and
> industry representative members.
>
> Finally, TOPS could be enhanced to provide an interactive on-line
> patient-information and education process that could be linked, in
> turn, to verification and documentation of patient informed consent.
>
> In conclusion, ASPS, the American Society of Plastic Surgeons, is
> dedicated to providing the gold standard of outcomes data to benefit
> patients, the public and the profession. We look forward to a
> partnership. TOPS and NBIR can become a valid method for a registry to
> trace implant-related data and outcomes.
>
> Thank you for the opportunity to present.
>
> MS. McGRAIL: Hi. My name is Margaretha McGrail and I am not being
> compensated or paid in any way to be here. I live locally.
>
> Four years ago, I made a decision to have breast-augmentation. It was
> a personal choice. I didn\'t need the surgery. Years of running and
> age had caused my breasts to sag and shrink and it was affecting my
> self-esteem. Someone referred me to a local surgeon who specialized in
> breast reconstruction and I went in to speak with him about possibly
> having the procedure.
>
> After talking with him, I decided the procedure was harmless and that
> it was worth going forward with. While discussing the procedure with
> my doctor, my doctor mentioned that there was a study taking place
> that I could participate in if I wished. It involved the opportunity
> to have silicone implants rather than the typical saline implants.
>
> He explained that silicone implants were much more natural looking and
> feeling than the saline. Remembering vaguely that there had been some
> issues with silicone implants, I asked him about the hazards of
> silicone implants. We discussed the pros and cons of silicone and I
> was given a couple of articles about the topic.
>
> My surgeon felt it was a very safe procedure. It was my understanding
> that silicone implants had significantly improved over the years, that
> leakage was no longer an issue and that the past problems had been due
> to leakage. The articles I had been given were very positive and the
> benefits of my taking place in a study seemed to outweigh any possible
> problems. The study provided for regular checkups, periodic MRIs and I
> thought that was a benefit.
>
> I opted for the silicone implants. I can attest to the fact that
> silicone implants are, indeed, dramatically more natural looking and
> feeling than the saline implants. I have had no problems at all these
> past four years. I have been extremely happy about my decision to have
> breast-augmentation. I am very health conscious and take very good
> care of myself. I believe in a preventative and holistic approach
> toward my health, so the issue of possible problems with silicone
> implants is a concern of mine.
>
> I would do nothing knowingly to jeopardize my health. I have only had
> the implants for four years, so I cannot address the potential for
> problems after ten or fifteen years.
>
> MS. HAMILTON: (Read by Elizabeth Curtis Hamilton.) Good morning. My
> name is Elizabeth Curtis Smith and I am here of my own will and I am
> reading the testimony of Gail Hamilton who was too sick to be with us
> this morning.
>
> \"My name is Gail Hamilton. I got silicone implants when I was
> 24-years old. I had had two children and was very disappointed with my
> appearance after nursing. I was slim and healthy and was told by the
> plastic surgeon how wonderful these implants were and how they would
> improve my appearance and they would last a lifetime.
>
> \"Ten days after augmentation, the wounds opened up and there was no
> appreciable healing. The implants were removed along with very large
> blood clots. The implants were cleaned and reinserted. This time, the
> wounds healed. My body formed scar tissue around the implants causing
> them to feel like baseballs.
>
> \"Seven years after my initial surgery, the implants were removed. The
> troublesome scar tissue was taken out and the same implants were
> reinserted. By 1989, I was experiencing very uncomfortable pain in my
> right breast and visited the plastic surgeon again. He could find
> nothing wrong so I went home and tried to ignore the sore area under
> my right breast.
>
> \"In the summer of 1993, I started to feel a burning sensation behind
> the implants against my chest wall. It started with one side and the
> other one soon followed a couple of weeks later. The burning became
> worse and worse every day and I went back to the plastic surgeon
> again. I told him of the burning and how I was experiencing a shooting
> pain down my arms and legs and through my back.
>
> \"The surgeon told me that this pain could not possibly have anything
> to do with my implants but I would be able to have them removed if I
> wanted. I know this sounds dramatic and disgusting, but to try to
> explain the depth of this pain would say only that I felt like there
> was rotting inside my chest while I was still alive.
>
> \"The pain was so severe I felt I needed to have these things taken
> out of me. Nearly 20 years after I sat in the surgeon\'s office as a
> young, healthy woman, I was now desperately ill and in unimaginable
> pain. On November 16, 1993, I had another surgery and this time the
> implants were removed and not replaced.
>
> \"I had asked for the implants to be returned to me. Eventually, when
> I was able to look in the container, I found only one implant. The
> other one, the right implant, I was told was too ruptured and could
> not be returned to me. At home, I began having one crisis after
> another. I wasn\'t able to get out of bed myself or even sit up.
>
> \"I started asking questions. Why, after this surgery, had I been so
> ill? I had had numerous surgeries before and recovered in due time.
> Lying in bed, I wrote for the hospital records. I questioned my
> surgeon. One day, as I was lying there reading over the paper,
> something caught my eye. My surgery had begun at 1420 hours and was
> completed at 1443 hours. Those 20-year implants that I had been
> telling my surgeon had been giving me so much grief were removed, from
> start to finish, in a mere 23 minutes, less time than it takes for me
> to get a haircut.
>
> \"How could that be? More questions to the surgeon revealed that
> implants had ruptured and had been somewhat adhered to the chest wall.
> None of this was in the original OR reports and came out only after I
> continued to ask questions. Could some of that silicone have been left
> inside of me, I was so desperately ill?
>
> \"I owned a thriving hair salon and, no matter how hard I tried, I
> could not get rid of the terrible pain throughout my body. I
> eventually had to close my business, sell everything I had worked for
> my entire life. Life, as I knew it, was over. I was 43-years old.
>
> \"In February of 2002, a different plastic surgeon operated on the
> right breast and found a very large mass containing silicone. The
> pathology reports confirmed it was silicone within the scar tissue.
> Curiously, I asked about the size of it. Was it the size of a walnut?
> He said, no.
>
> DR. WHALEN: Ms. Curtis Smith, if you could conclude, please.
>
> MS. CURTIS SMITH: Thank you.
>
> MS. MORITZ-CIANCUTTI: Good morning. My name is Audrey
> Moritz-Ciancutti. I have come here from Pittsburgh on my own and I
> have no conflicts of interest.
>
> I had a bilateral mastectomy at Mayo Clinic due to fibrocystic disease
> with reconstruction with silicone-gel implants. My first rupture was
> two years later and both implants were replaced. Over the years, I
> started to become ill. I had a continuous burning in my chest and
> developed a very high sensitivity to any kind of heat and sun.
> Fourteen years after that rupture, and MRI revealed both implants were
> ruptured.
>
> The surgeon that removed the implants left some residual tissue
> behind. I think he thought he was doing me a favor because I opted not
> to have an additional implant put in that I would have some sort of
> breasts.
>
> My rheumatologist at Cleveland Clinic told me that, unfortunately, the
> surgeon didn\'t do me any favors, that in that tissue that was left
> behind were globules of silicone and there is silicone in my lymph
> nodes. She felt that this silicone has caused my condition. The
> silicone in my body explains why, immediately following the surgery, I
> began to have severe pain in my right arm and continuous swelling. I
> developed a cyst on my hand which had to be removed surgically and,
> after two biopsies, I was diagnosed with scleroderma.
>
> I continued to suffer with extreme fatigue and depression and my
> immunologist diagnosed me with atypical-tissue disorder, arthritis,
> cognitive dysfunction as well as asthma and allergic rhinitis. I
> suffer from recurrent bacterial infections and I go through monthly
> treatments of I.V. gammaglobulin.
>
> My body can no longer tolerate heat or sun and, two-and-a-half years
> ago, I had to leave Florida and move back to Pittsburgh because I
> could only tolerate a colder climate. Today, I am experiencing new
> scleroderma lesions on my chest, abdomen, my face and the top of my
> head and, once again, the chronic fatigue is reoccurring.
>
> The bottom line is that I have silicone throughout my body because
> these implants ruptured and the doctor is sure this has caused my
> condition and this silicone cannot be removed. There have never been
> any studies of the health of women with leaking silicone implants
> except for the one study conducted by the FDA. That one study found
> painful disorders such as fibromyalgia among women with leaking breast
> implants compared with women with implants that didn\'t leak.
>
> The results might have been even more dramatic if they had compared to
> women without implants but we don\'t know that because no such study
> has ever been done. If Inamed really wants to prove their implants are
> safe for women in the real world, they need to study the health of
> women with broken gel implants. Instead, they avoided that by studying
> women who only had implants for a very few years.
>
> Thank you very much.
>
> MS. TEAGUE: Ladies and gentlemen, my name is Cynthia Teague and I am a
> registered nurse from Baton Rouge, Louisiana. Inamed had sponsored my
> trip allowing me the opportunity to be here today. However, I am here
> because I am an individual recipient of silicone implants.
>
> I would like to address the panel regarding the use of silicone
> implants and encourage you to allow women to make the choice between
> silicone and saline implants for themselves. I would like to offer my
> personal testimony as to the safety of silicone implants and to their
> importance in improving my quality of life.
>
> I decided on breast-augmentation surgery due to the postpartal change
> in my body and after breast feeding my three children. I was feeling
> self-conscious, dissatisfied and eager for a change. My self
> confidence was suffering and my body image was low. I sought the
> consultation of a board-certified plastic surgeon and spoke with him
> at length about my concerns and desired outcome.
>
> My physician was very forthcoming with the benefits and risks of this
> surgery. At this time, women had the choice between silicone and
> saline implants. Ladies and gentlemen, I freely chose silicone
> implants. That was over thirteen years ago and, since that time, I
> have had absolutely no complications or regrets about that decision.
>
> My surgical results were excellent and I remain as healthy now as when
> I had my surgery. I attribute the remarkable improvement in my self
> esteem to the augmentation surgery. I attribute the remarkable
> surgical result largely, in part, to the use of silicone implants. In
> my consultation, I was able to handle both types of implants before
> making my final decision and I was also shown postoperative pictures
> of patients with both types of implants.
>
> I chose silicone because of their more natural look and feel. My
> excellent surgical results further validated my decision to use the
> silicone implants. Having the ability to choose what type of implants
> were placed in my body, was very important to me. I felt that I was in
> control and in charge of my own destiny.
>
> Not all women have that opportunity today. It is my belief that this
> choice should be extended to all women. Being able to make important
> decisions for oneself is crucial. Women in American have struggled for
> decades for this right. It is my request that the FDA reconsider its
> position on silicone implants and restore this choice to each
> individual.
>
> MS. DOWD: Good morning, ladies and gentlemen of the panel. My name is
> Pamela Dowd and I have traveled from Boise, Idaho yesterday to come to
> you at my own expense because my family felt it was vital that the
> panel hear from a 28-year survivor of breast cancer. Today, I stand
> before you totally breastless and I am proud.
>
> At the age of 27, I became a breast cancer statistic. I never had
> chemotherapy. I never had radiation. I was never sick before or after
> the mastectomy. But, in November, 1980, almost 22 years ago\--23
> years\--I began the road through reconstruction hell with a bilateral
> breast reconstruction that included a failed latissimus dorsi flap and
> three ruptured silicone breast implants. The first replacement was
> within 90 days.
>
> In June, 1987, when I experienced the third rupture, it sent me to the
> ER with a pain so excruciating, it felt as if thousands of needles
> were pulling and pushing through my body and I was literally pulling
> at my hair and screaming.
>
> After getting breast implants, I developed a constant cough and, at
> times, I choked on my own saliva. I have peripheral neuropathy and
> burning in the spine. I have IBS and photosensitivity. I have been
> diagnosed with Sjogren\'s and Raynaud\'s and considered lupus suspect.
> I have MS-like symptoms that cause me to fall at the drop of a hat.
> The silicone in my chest and vascular system will never go away. My
> chest constantly itches and burns from the residual silicone. My bones
> still scream with pain.
>
> In 1995, when I underwent explantation, my chest had to be scraped and
> cauterized to clean out the residue of the previous ruptured implants.
> The American taxpayer will, at some time, be responsible for the cost
> of my healthcare as they are now responsible for the healthcare of
> other victims of silicone-gel-filled breast implants.
>
> We are being asked one more time to trust the manufacturers. Their
> story is based on 41 years of corporate lies and we have no reason to
> believe they are telling the truth now. The manufacturer-funded New
> York study in the early 1990s didn\'t ask if anyone developed breast
> cancer autoimmune disease after breast implants. It asked if
> participants had ever heard of anyone who did, proof of nothing more
> than do people listen to gossip.
>
> In a federal depository in Birmingham, Alabama, lie 80 million
> documents of implant manufacturers, the ASPRS, FDA and others, telling
> the truth of this massive corporate coverup of the dangers of
> silicone-gel breast implants and I am a freelance researcher of those
> documents.
>
> I have survived breast cancer for 28 years and do not believe I
> deserve to have a faulty toxic product foisted onto me by corporations
> without a conscience. The implant industry has taken away my health
> but they will not take away my hopes and dreams. This, too I will
> survive.
>
> I ask you to please keep the ban on silicone-gel breast implants in
> place, not for my sake but the sake of generations of women to come
> who can and will become ill and disabled due to the toxins in the
> silicone gel.
>
> Thank you for your time.
>
> DR. WHALEN: If any of the speakers have handouts, could they bring
> them directly to Dr. Krause rather than to any other panel member.
> Thank you.
>
> MS. BORDELON: Good morning, ladies and gentlemen of the panel. My name
> is Lisa Bordelon. I am a registered nurse and I have practiced in the
> field of plastic surgery for fourteen years. I have also been actively
> involved as a study coordinator with both McGhan, Inamed, and Mentor
> adjunct studies from the inception.
>
> I have had silicone implants for some 20-plus years also. I am not
> here today because Inamed has sponsored my trip nor because of any
> business affiliation we may have but as an individual recipient of
> silicone implants. I am here to share my experience with and opinions
> of silicone implants.
>
> My decision to have implants initially was not unlike many others. I
> simply wanted to be more proportionate for my body and to appear more
> feminine. After the birth of my first child, I began to explore the
> option of breast-augmentation surgery.
>
> At the time of my initial consult in 1982, I was given a choice
> between silicone and saline implants. I chose silicone because of
> their more natural appearance and feel. The resulting surgery had a
> tremendous impact on my self esteem. I was more proportionate. My
> clothing fit better and I felt more feminine. Basically, I felt better
> about me.
>
> Many patients today do not have the choice of silicone implants for
> their breast surgery unless they meet certain qualifying criteria. For
> those select few that do meet these criteria, they often choose saline
> because of the prohibitive cost of silicone and because of the
> negative publicity received in recent years.
>
> As a plastic-surgery nurse, I see many patients with unacceptable
> results that may have been avoided by the use of silicone implants.
> Therefore, many patients are undergoing multiple procedures to achieve
> a result they may never reach with the use of saline implants.
>
> I cannot say that my experience with silicone has been totally
> uneventful. I have experienced encapsulation that has required
> surgical intervention. But this is a condition associated with saline
> implants as well. This response cannot always be predicted beforehand
> and makes no difference as to what type of implant is used.
>
> Great advances have been made in the manufacturing of silicone
> implants in recent years. I do not believe that the silicone implants
> are more dangerous than any other medical device but, like any other
> medical device, there are inherent risks involved. It then becomes the
> responsibility of the physician to inform their patients of these
> risks.
>
> I believe the decision to choose silicone or saline implants should be
> left up to the individual patient based on physician recommendations
> as to which result in a better outcome. For me, the correct choice was
> to have silicone implants. I would make this same decision again
> today. I believe silicone implants offer a good safe option to those
> considering augmentation surgery and I hope you will see fit to, once
> again, give all women this option. Thank you.
>
> MS. FORMAN: Good morning. I am Jessica Forman. I am a cancer survivor
> and I have no relation to any of the implant companies. I was here
> about ten years ago when FDA was holding its first round of hearings
> on silicone breast implants. I was then a breast-cancer patient
> scheduling surgery to replace the tissue expanders for permanent
> implants. I participated in that lobbying effort to persuade members
> of Congress and the FDA panel that silicone implants should remain on
> the market. I feel very differently today.
>
> I had my first mastectomy in 1990. I opted for immediate
> reconstruction and was actually in the hospital for surgery to
> equalize the normal remaining breast. It all came to a screeching halt
> because my oncologist re-read the latest mammogram and found another
> suspicious spot. Two weeks later, I had the second mastectomy and
> still wanted immediate reconstruction.
>
> Together, those two surgeries were a horror story, the first, for
> emotional storms, the second for physical problems. I had so many bad
> side effects that my doctor said to me, are you sure you are not an
> M.D.? This is only supposed to happen to M.D.s. Well, I am not. But
> all those setbacks explain why, two years later, I was still
> scheduling surgery.
>
> Ten years ago, I didn\'t care about the future. I wanted to look and
> feel as if I had never had breast cancer. I wanted to wear a bathing
> suit, wear sleeveless tops. I wanted to shop at Loehmann\'s in a group
> dressing room and not have anyone stare at my scars. And I wanted it
> right away.
>
> It didn\'t happen. It could not happen. Some days, I look in the
> mirror and I hate my scars. Other days, they are all right. I can\'t
> wear some clothing styles. They are simply too revealing. Sometimes, I
> can\'t lift my arms over my head. And I still can\'t find a bra to fit
> both parts of me.
>
> I know that the company testifying today provided data showing women
> with silicone or saline breast implants have a higher rate of
> complication than augmentation patients and I am upset to hear about
> that. I have an older sister who also had bilateral breast cancer. She
> got silicone-gel implants. She is suffering so badly from these
> connective-tissue immune diseases that she almost cannot work. She
> sacrificed everything to be able to work five hours a day.
>
> We don\'t know. Is this from her cancer or is this from the silicone
> implant. There is no way to find out. For myself, I know it takes
> longer to heal. I know I hurt a lot more and the fatigue factor has
> gone up tremendously. I can\'t get in to work like everyone else in my
> office. If I commute downtown for two or three days, I am exhausted. I
> am too tired to cook dinner, remember anything, can\'t solve problems,
> don\'t know what I am talking about. It is a lot easier if I can do
> this at home and cut out a two-hour commute.
>
> Hindsight is always twenty-twenty. If I had cancer today, I wouldn\'t
> opt for immediate reconstruction. I am not sure that I would have
> reconstruction at all. I would, however, take a long time to
> investigate my choices. There may be a better way than implants. There
> are tissue-flat reconstructions. They are not always appropriate.
> Given my weight and medical health, my doctor refused to do them. More
> power to him. I think it would have caused more problems.
>
> Recommendation; I think we need a big caution flag waved. There is a
> lot of information we don\'t have about cancer, the immune system and
> the safety of breast implants. I would like to see much more long-term
> research on silicone before your restrictions are lifted. I would like
> to make sure that they are long-term safe, not two years, not five
> years, but ten, fifteen, twenty years.
>
> I am not actually sure that gel implants need to be available since
> saline is. But, if they are available, I would ask you to restrict
> them and to insist on truly informed consent.
>
> Thank you.
>
> MS. FJELSTAD: (Read by Kathy Sachs.) Good morning. I am Kathy Sachs
> and I reading the story of Diane Fjelstad who is too sick to be here
> today.
>
> \"In 1978, I was encouraged by a team of doctors, including an
> obstetrician, a plastic surgeon and radiologist to have bilateral
> mastectomies to prevent breast cancer. I believed these doctors when
> they told me that the implants were perfectly safe, would last as
> lifetime and I would go to the grave looking better than most women.
>
> \"Although I had early warning signs, I didn\'t suspect the implants.
> There were unexplained blood disorders, a strange rubbery substance
> oozed through the skin of my foot, and a rash of new allergies
> developed which did not respond to treatment. I could not understand
> my continual fatigue in the late \'80s and \'90s. I was unable to
> drive to the next town, only fifteen miles away, without having to
> stop for a nap.
>
> \"This was very foreign to me as I had been a competitive athlete. My
> skin began to hurt. Worst of all, I feared I couldn\'t continue to
> work as a high-school teacher due to my memory lapses, fatigue and
> continual illnesses. In \'95, I noticed a dyslexia-like problem with
> words and numbers. Finally, I noticed that the left implant had
> seriously shifted and was pressing against my lungs. Breathing became
> difficult.
>
> \"I attended a conference on silicone exposure and discovered that
> many of my symptoms were classic; chronic inflammation,
> myofascial-pain syndrome, swollen glands, numbness and tingling, and,
> later, severe pain, early signs of Sjogren\'s syndrome,
> chronic-fatigue syndrome, muscle atrophy, low-grade fever, severe
> headaches, chronic sinus infections, lung problems and
> gastrointestinal problems.
>
> \"My condition deteriorated very quickly in the fall of \'95. I was
> explanted in late January, \'96. The explanting surgeon was furious
> that I had been allowed to get so sick and that the doctors had not
> picked up on my symptoms and treated them earlier.
>
> \"The simple explanting surgery turned out to take over five hours
> with black substances and school-bus yellow oil running all over the
> operating table onto the floor. What a stinking mess. The implants
> were filled with fungus and no sign of silicone gel remained in the
> ruptured shells.
>
> \"Since that time, I had a routine bunionectomy and asked the
> operating physician to do a biopsy testing for silicone. He was
> totally shocked to discover that there were, indeed, silicate crystals
> in the bunion. I also know that I have lesions on the brain from the
> silicone as revealed in an MRI. Who knows where else the silicone has
> settled since the body has few ways to rid itself of it naturally.
>
> \"My life has been disastrously impacted by silicone-gel implants. I
> have no breasts. I was no longer able to work as a high-school
> teacher. I had to go on disability. My husband of 40 years divorced
> me. My financial income has been reduced to one-fourth of what it was.
> My health has been compromised in many ways as I have mentioned.
>
> \"You will hear from some women who insist on being given a choice.
> Don\'t do us any favors by giving us the choice of an implant whose
> safety is unknown after just a few years.
>
> \"Thank you.\"
>
> DR. VASAY: (Read by Dr. Diana Zuckerman.) Hello. I am Dr. Diana
> Zuckerman. I am going to be testifying on behalf of myself tomorrow.
> Today, I am just reading the testimony of Dr. Frank Vasay who asked me
> to briefly describe his research. Dr. Vasay is Director of the
> Division of Rheumatology at the University of South Florida College of
> Medicine.
>
> Dr. Vasay did provide some testimony ahead of time. I hope you have
> it. He has personally evaluated approximately 2,000 symptomatic women,
> most of whom have silicone-gel-filled breast implants. He has been
> doing this work for over twenty years.
>
> He wants me to say for him that he has been satisfied that some
> women\'s immune system does not tolerate silicone breast implants. The
> syndrome remains undefined but recent information suggests that 10 to
> 25 percent of women are so ill approximately thirteen years after
> getting implants and that recent epidemiologic studies show
> statistically increased symptoms in women with breast implants
> compared to control groups.
>
> He has done some research and he asked me to describe it for him. This
> is published in various places. I had hoped his coauthor could do this
> for him, but she works at the National Cancer Institute and I guess
> that is a conflict of interest.
>
> He studied approximately 100 women who had rheumatologic symptoms as
> diagnosed by rheumatologists and who had silicone breast implants.
> Approximately half of them chose to have their implants taken out as
> was suggested to them and the other half, although it was suggested to
> them, and the other half, although it was suggested, decided to keep
> their implants. So that was his study group, obviously not randomly
> controlled.
>
> He followed them up for an average of 18 months. What he found was a
> remarkable number of women who had their implants taken out and not
> replaced showed slow steady improvement. The symptoms that they had
> were similar to fibromyalgia; muscle pain, chronic fatigue with
> multiple trigger points. He points out that, unlike classic
> fibromyalgia, exercise aggravated the muscle pain. So that was
> different from what one would normally see in fibromyalgia.
>
> He also found that some women got better and some did not, not
> surprisingly, but that most of the women who had their implants taken
> out did get better and most of the women who did not have their
> implants out got worse. By \"most,\" that was over 90 percent.
>
> There was a way to at least predict who would get better and who would
> not. Women who tended to have a bad prognosis and ruptured implants
> with silicone debris in their chest wall so that the silicone had not
> been entirely removed and could not be removed. He also found that
> women who had delayed removal where their implant had ruptured some
> years before but they hadn\'t gotten it out for quite a while also had
> a poor prognosis.
>
> He also found that the women who didn\'t do so well after getting
> their implants taken out tended to have an onset of problems very soon
> after getting their breast implants, usually within two years.
>
> He has, as I said, published some of this work and it will be made
> available to the panel.
>
> Thank you.
>
> MS. GROSS: Good morning. My name is Marcy Gross. I have six minutes
> having combined time with another potential participant. I am a
> health-policy consultant and a member of the State of Maryland\'s
> Women\'s Health Promotion Council. I retired in November of last year
> after 25 years at HHS most recently as the Senior Advisor for Women\'s
> Health at the Agency for Healthcare Research and Quality.
>
> During part of my tenure at HHS, I also participated in the
> Secretary\'s ad hoc working group on silicone breast implants. I give
> you this brief resume just to establish my familiarity with the issues
> you are considering today but I am here as a private citizen and I
> base my remarks on my personal views and on information available to
> the general public. I am not paid.
>
> One legacy of my six-year tenure at ARC is a good appreciation of the
> need for women and policy makers to have a strong evidence base for
> making decisions on healthcare issues. My concern today is that an
> adequate evidence base for the premarket approval of
> silicone-gel-filled breast prostheses does not exist and that the
> short-term assurances drawn from the applicant\'s study will override
> continuing gaps in the research on long-term risks.
>
> I can see from the information posted on the panel\'s website for the
> hearing that the FDA has done exhaustive background work including
> literature reviews, assessments of toxicology and chemical testing and
> extensive consideration of the clinical data. All this and more will
> come to you over the next two days.
>
> But some facts are simple and have not varied in the twelve years
> since silicone breast implants were pulled from the market. The
> studies available on the health aspects of silicone-gel implants are
> short-term analyses often involving mere handfuls of mice studied over
> the course of a few weeks in the case of toxicology and chemical
> testing and over a two-to-three-year period in the case of Inamed\'s
> core study being cited in this proceeding in support of a case for
> reintroducing silicone breast implants for unrestricted use.
>
> Yet, even these short-term assessments indicate that the rate of
> ruptures and other complications which lead to a reoperation remains
> unacceptably high, 20 percent plus for patients using implants to
> augment their figure and 45 percent plus for reconstruction patients.
>
> Thanks to our longer life spans, breast implants will stay in a
> woman\'s body for the rest of her life which can be 50 years or more.
> A two- or three-year study simply doesn\'t offer the kind of assurance
> of safety needed. It is a setup for future medical problems for women
> who have this type of device implanted, especially when retrospective
> studies show that, by ten years, most women with silicone-gel implants
> will experience at least one broken implant. At least these women know
> they have a problem and have further surgery. Silent ruptures are also
> a documented and recurring problem.
>
> Sometime in the next few days, I feel certain you will hear someone
> say that none of the several important studies of the possible risks
> of implants have shown that they cause long-term health problems. You
> may even hear it said that, well, we use silicone in other implanted
> devices such as heart valves, knee joints, hip replacements, so why
> should silicone from breast implants be different.
>
> My response is that having bubbles or globules of migrating gel
> floating through a human body into and around organ is, on its face, a
> health risk. As for silicone and other implanted devices, one doesn\'t
> expect bits of a heart valve to break off and migrate to the brain,
> liver, other organs.
>
> Further, patients who get hip or knee joint replacements are routinely
> warned that a small number of patients will have an immune-system
> reaction to the silicone fragments shed by newly implanted joints. How
> is it that orthopedic surgeons know this problem but the
> breast-implant community continues to doubt.
>
> There is no health imperative behind the push to reintroduce silicone
> breast implants. On the contrary, they are used in elective cosmetic
> procedures that often cause serious health complications associated
> with ruptures and the surgery, itself. Although there are other
> options available to breast-cancer patients that carry fewer risks,
> for some, silicone-gel implants is felt as important to their
> recovery.
>
> We know that this choice will make them more vulnerable to future
> illnesses and complications and will obscure future cancer screening
> procedures. But, again, we lack the kind of long-term studies that
> would allow their choice to be fully informed.
>
> This FDA panel will be making a decision that affects the lives and
> pocketbooks of women quite substantially. There are emotional issues
> involved in the decision and results. Implants are an expensive
> procedure especially when the cost of care for complications,
> reoperations, infections and other medical side effects are added in.
>
> About 250,000 new procedures were done last year at a cost estimated
> at approximately 5,000 each on average for a total cost of \$1.2
> billion to the healthcare system. While much of this is paid for by
> the patient, the cost for reconstructive procedures that many cancer
> patients elect to have is most often covered by insurance and, of
> course, follow-up care also would be covered most insurance.
>
> What is the policy recommendation here? The FDA found the middle
> ground twelve years ago. While I would still prefer to not have seen
> the fourfold increase in implants that has since occurred, at least
> the current policy sends a strong cautionary signal to women with
> choices. This should not change until we have more confidence that
> these implants are safe for long-term use and that will take time and
> more research, the kind of research that should have been initiated
> ten years ago. Let\'s not miss another opportunity.
>
> I thank you for your time and attention this morning. I see that you
> have an agenda which runs well into this evening so I wish you luck
> and stamina. Thank you very much.
>
> DR. MASSEY: Good morning. I am Dr. Marga Massey. I am an assistant
> professor of surgery and the Director of Basic and Clinical Science
> Research in the Division of Plastic Surgery at the University of Utah
> Hospitals and Clinics in Salt Lake City, Utah. I have no affiliations
> or conflicts of interest with any implant device manufacturer and have
> paid my own travel expenses to testify at the hearings today.
>
> I use breast implants in performing both cosmetic breast-augmentation
> and breast-reconstructive surgery. I am on a fixed salary as a
> University of Utah paid employee and receive no financial gain whether
> I perform breast-augmentation or reconstruction procedures utilizing
> breast implants.
>
> As an academic plastic surgeon involved in basic science research
> which occupies greater than 50 percent of my current time, I have
> restricted the majority of my clinical-practice interest to breast
> patients, both cosmetic and reconstructive. I have been impressed that
> cosmetic patients are very informed about their current surgical
> options to enhance the physical appearance of their breasts. This
> level of knowledge likely reflects the current availability of
> information regarding cosmetic breast augmentation on the Internet and
> through the mass-media coverage of this topic.
>
> Breast-cancer patients additionally master a very complicated variety
> of breast reconstructive options to include but not limited to tissue
> expansion with delayed breast-implant placement, immediate
> breast-implant placement in the setting of skin-sparing mastectomy and
> the use of autologous muscle flaps which may be augmented by the
> placement of the incorporation of a breast implant in order to restore
> the appearance of a natural breast after a mastectomy.
>
> Many speakers today will provide testimony regarding the safety of
> silicone-gel-filled breast implants. My personal review of the
> published information to date regarding the safety and efficacy of
> silicone-gel-filled breast implants supports their availability to
> cosmetic patients for breast enhancement. This availability would
> mirror that which is currently acceptable for breast-reconstruction
> patients.
>
> As a plastic surgeon practicing in an academic setting, along with my
> colleagues here today, we eagerly await review of this most recent
> evidenced-based investigation. We wish to continue collaborative
> scientific clinical investigations with the FDA and the device
> manufacturers to ensure patient satisfaction and safety.
>
> When the final review of this most recent evidence-based investigation
> becomes publicly available, I believe women will be empowered to make
> informed choices regarding the use of silicone-gel-filled breast
> implants.
>
> In conclusion, breast-implant device availability in clinical use
> should be based on sound scientific investigation. Public education
> should be based on sound scientific investigation. Implant-device
> availability and public education based on sound scientific
> investigation will ensure patient safety and will allow patients to
> make informed personal decisions regarding the use of
> silicone-gel-filled breast implants for cosmetic enhancement and for
> reconstructive restoration after mastectomy.
>
> I greatly appreciate the panel\'s time and consideration. Thank you.
>
> DR. WHALEN: Dr. Massey, would you entertain just one question? I
> appreciate your full discloser at the beginning.
>
> DR. MASSEY: Yes, sir.
>
> DR. WHALEN: But is it your contention, in your academic environment,
> that there is absolutely no relationship between any volume of
> procedures you do and present and future income?
>
> DR. MASSEY: I beg your pardon?
>
> DR. WHALEN: I am in an academic setting, as you are.
>
> DR. MASSEY: Yes, sir.
>
> DR. WHALEN: And certainly the number of procedures that I do will
> impact, at a divisional and departmental level, a revenue structure
> that does impact upon the income of I and my fellow faculty members.
> You said you are on a fixed income.
>
> DR. MASSEY: I am on an absolute fixed income that has no reflection on
> the number of surgical procedures that I perform.
>
> DR. WHALEN: So your department is able to remunerate you even if you
> do zero procedures or you do 200?
>
> DR. MASSEY: That\'s correct, sir.
>
> DR. WHALEN: Thank you.
>
> DR. MASSEY: Thank you.
>
> MS. WOLF: My name is Carolyn Wolf. I live in Virginia. I came here at
> my own expense. I have no conflicts of interest.
>
> In 1971, I had a double mastectomy and was reconstructed with what
> were then considered new and improved silicone implants. That was the
> time when breast implants were much thicker than they are today and
> were a rarity. Few women have had implants as long as I did. There are
> no published studies focused on women with implants for longer than 25
> years because so few implantees have lived so long.
>
> I would like tell you what happened to me. At first, I had no health
> problems and, even when they started, I had no idea they were related
> to the implants. But, after nine or ten years, I developed dozens of
> hard, burning blister-like growths on my neck and boils on my
> forehead. I have pain and numbness in my left shoulder, arm, hand and
> foot.
>
> By 1993, my family had noticed a distinct change of personality and I
> noticed cognitive changes. I am diagnosed with rheumatoid arthritis,
> Raynaud\'s, irritable-bowel syndrome, silicone-induced MS-like
> syndrome with neuropathy of the extremities. I have neurological
> damage to the left eye. My silicone level is double normal. This is
> two years after explantation.
>
> My brain MRI reveals more than 20 lesions. In March, 2000, a batch of
> silicone moved from my left breast into my armpit leaving an elongated
> swelling in its path with excruciating pain. On April 13, 2000, I lost
> vision in my left eye for 45 minutes. I had constant pain in that eye
> for six weeks but, after a long, thin greasy glob came out of it, the
> pain lessened.
>
> I have had two similar strings come out of my left ear in the last
> year. That is 30 years after implantation. Although I did not smoke, I
> was coughing up hard gold-colored globs and a lung X-ray showed
> chronic obstructive-pulmonary disease. Although the type of silicone
> implants that I had were thicker than those of today, MRI showed both
> implants ruptured. I went to three different plastic surgeons but they
> only wanted to install replacements.
>
> When my implants were removed three years ago, both implants were
> extensively ruptured, both much smaller than when they were implanted.
> The scar capsule surrounding the implants had cysts filled with
> chronic inflammation and foam cells containing silicone materials.
>
> Chest X-rays show that I still have silicone in the breast area. I am
> still exuding silicone from the nipples and have deposits of silicone
> in both armpits. Researchers at the National Cancer Institute have
> conducted the only studies of women who had implants for at least
> eight years. They found that women with implants were more likely to
> die from certain cancers and suicide.
>
> The FDA conducted the only study of women with ruptured silicone
> implants and they found they were more likely to have fibromyalgia. If
> implants are so safe, make sure that the implant makers prove it. The
> studies you will hear about today do not do that. Please remember
> that, whatever you do, if implants are approved by the FDA, you cannot
> control the advice given by plastic surgeons many of whom are still
> claiming that breast implants are perfectly safe and continue to
> insist that broken implants should be replaced.
>
> We beg you, please protect the younger generation. Thank you.
>
> DR. WHALEN: Thank you very much. I think that is an appropriate time
> that we will break for about thirteen minutes until 10:30. I need to
> remind the panel members, as difficult as it is, that any discussions
> upon the topic at hand need to be public, in front of the microphone,
> so refrain, outside of this panel room, from discussing anything at
> hand.
>
> \[Break.\]
>
> DR. KRAUSE: Let\'s continue, please. Thank you.
>
> DR. WHALEN: To try to keep on time, we are going to resume. Actually,
> the next public presenter is going to be via a conference call from
> the Hofnagel Group. They will have five minutes. Probably there will
> be people filtering back in because apparently the rest rooms were
> engineered by the same people who did the elevators. So we will have
> to have some forbearance for that.
>
> So the microphone is already rigged towards the speakerphone and we
> will initiate with the Hofnagel Group\'s discussion.
>
> DR. HOFNAGEL: Hello. We are speaking to the committee. We had
> difficulty hearing before. My name is Dr. Vicki Hofnagel. I have a
> group called the Hofnagel Institute. We came before the FDA previously
> on multiple issues. In 1994, I presented documents to the FDA showing
> that saline silicone breast implants still had migratory silicone into
> the chest wall of women.
>
> At that point of the purpose of that discussion and conference was to
> discuss the fact that surgeons who were removing implants were
> replacing implants and not taking tissue to study it from migratory
> silicone.
>
> At this time, we supported the decision by David Kessler because he
> was looking at life-long chronic complications not life-threatening
> complications. The implants that are being presented have not changed
> in their design, the manner in which the protocol for placement or the
> protocol for follow up has occurred.
>
> In this hearing, the availability to give public testimony is
> wonderful as it is in all hearings. However, that public testimony is
> usually not taken into consideration whatsoever as seen in the May,
> 2000 uterine-artery-embolization discussion before the FDA.
>
> We will be petitioning to the FDA to request that all FDA hearings
> will now be made public with public-television and also on the
> Internet. It is extremely important that this meeting be made known to
> women across the nation and throughout the world.
>
> The things that prompted the Dow Corning case are still existing
> today. I still see women every day with silicone breast complications.
> Virginia Gallagher will be speaking to that, the crystallization of
> silicone causing glass to cut into the chest wall, the implantation of
> migratory silicone onto the nerves, and things that have not been made
> public such as the common condition of chest-wall deformity from all
> breast implants being used today and that this chest-wall deformity is
> the cause of many of the complaints of pain, itching and heat
> discomfort that women have.
>
> This has not been known to the public. You can take chest X-rays and
> see the actual rib deformations in all of these women. Yet it is not a
> baseline study.
>
> There is much to be done. We need a national registry that will
> actually take in all of the complaints and look at them from the past
> if not looking on to the future. C-reactive protein, ANA, LE prep,
> complement fix, all of the routine studies still are not part of a
> strong protocol.
>
> We need to move forward and we should have seen a new design. We have
> technology to increase tensile strength. We have technology to
> encapsulate even a silicone gel. But the technology has not been shown
> in the new implants. Instead, we are given an implant now with a
> two-year shelf life. That two-year shelf life and the aspect of the
> life of an implant is still not given to patients. Informed consent
> and complete disclosure is absolutely a sham still today. We need a
> much better educational program for women.
>
> If we are going to move forward and reallow silicone to be used, then
> we need to change the design of the implant, make sure that it has
> radiopaque material to see when it leaks because so many women have no
> idea that they have leaks, by they have symptomatology and they are
> basically told, honey, go home. It is a little ache and pain. You are
> crazy in the head. And then, when we operate on them, we find that
> their entire chest wall has been destroyed.
>
> I am going to move on to Virginia Gallagher who is going to speak. We
> had two other women who wanted to speak. Those women are young and
> beautiful and, when they went to their physicians complaining of
> itching and burning and other difficulties, they were patted on the
> head because their breasts looked great. They looked great. These
> women were attractive. They were scared to death to have their
> implants removed because of chest-wall deformity.
>
> Our institute notified the FDA in 1994 and we have continued. We now
> have developed a plasma-state surgery using argon beam and liquids to
> actually prevent chest-wall deformity and the public is unaware of
> this.
>
> In the panel and committee, you should also have psychotherapists
> because of the reasons that women have implants and the reasons they
> do not present afterwards such as the two young women within our group
> and we will be forwarding documents.
>
> I conclude because of the time limitations. We will be sending a
> formal document because we cannot put all the data in such a brief
> discussion\--and move on to Virginia Gallagher. We will close with
> Denise Bennett who is the attorney and counsel for the Hofnagel
> Institute on illegal issues.
>
> Thank you.
>
> MS. GALLAGHER: Hello. My name is Virginia. I can\'t tell you in this
> short time the multiple problems that I developed, but I suffered many
> health problems and, within two to three days of surgery of having the
> implants put in, my back and chest area was completely erupted with
> red sores that left multiple scars all over and remain to this day.
>
> My implants became hard and lumpy, not only painful but socially
> embarrassing. Can you imagine what it is like to meet an old friend at
> your alumni and have them give you a hug, jerk back and look at you in
> shock at your chest because they have just hit a rock wall. That
> happened to me enough times so that I began to withdraw. It was
> embarrassing and humiliating.
>
> My lymph glands were very sore and felt like they burning. Within one
> or two months of the time my implants were put in, it was almost
> impossible\--well, was impossible\--to maintain totally normal range
> of motion with my arms. It was impossible, also, to find a comfortable
>
> DR. KRAUSE: Excuse me. Could you wrap up, please. We need to go on.
>
> MS. GALLAGHER: It was uncomfortable to find a position to sleep in. I
> asked the surgeon to remove them. He said, no, I would be
> psychologically damaged and that it would be an irreversible
> depression. The social situations were humiliating but the pain was
> terrible. My left breast grew to protrude from my body several inches
> more than the right breast and was inflamed and red.
>
> I was told by another surgeon that the implants didn\'t need removal,
> although they could be replaced with new ones. At the time of my
> removal, the burning lymph glands were free of pain when I came out
> from under anesthetic for the first time in 26 years.
>
> I am outraged that doctors have no concern for our health, that they
> deny the health problems that results, that insurance doesn\'t cover
> the removal of the implants and for teaching\--(operator
> interruption)\--is inorganic. It is not natural unless it is already
> there normally.
>
> I was told that these implants\--I was not told that they were not a
> lifetime procedure, that they would need to be replaced at any time in
> the future. When I got them.
>
> MS. BENNETT: This is Denise Bennett wrapping up. For a long time,
> manufacturers and regulatory\--
>
> DR. WHALEN: I am afraid that we need to move on because you are so far
> beyond the allocated time and I apologize for cutting you off.
>
> Let me just say to the rest of the people in the room as well, we try
> very hard to balance between the number of people who wish to speak to
> us and to try to allocate the time appropriately. So we are not trying
> to efface\--ignoring what people are saying by cutting people off but,
> rather, trying to balance that with justice towards everybody who
> wishes to be heard. Indeed, there are many people who do wish to be
> heard.
>
> On the contrary, I have to interject at this point to what I have
> heard now at least twice this morning. Having chaired the panel where
> we looked at saline breast implants, I can totally assure you that I,
> and our panel members, do not ignore what the public is saying. We
> very acutely listen to what the public is saying and we take that into
> account.
>
> The next speaker, please.
>
> DR. JEWEL: Thank you. My name is Dr. Mark Jewel. I am a
> board-certified plastic surgeon with over 25 years of experience with
> breast-implant surgery. I have no financial ties to industry or
> health-professional societies. I have been a clinical investigator for
> Inamed\'s core gel study and an investigator for Inamed in Mentor\'s
> cohesive studies.
>
> I am Vice President of the American Society for Aesthetic Plastic
> Surgery which will reimburse my expenses for travel and hotel. Today,
> I am speaking as an individual. I thank the panel for this opportunity
> to address the topic of patient informed consent and the management of
> expectations.
>
> I have a particular interest in this subject having researched and
> written the Patient Consultation Resource Book which is used by more
> than 40 percent of all board-certified plastic surgeons.
>
> With the Internet patients who see more information today than at any
> time in the past regarding breast-implant surgery, many arrive at the
> physician\'s office with a great deal of information including
> pictures of results from the websites, yet have an incomplete
> understanding of what will actually be their personal result of after
> breast-implant surgery.
>
> I believe we need to move beyond traditional approaches of informed
> consent to empower our patients to be actively involved in all aspects
> of the clinical decisions which precede breast-implant surgery. We
> must effectively educate patients regarding potential problems that
> may occur subsequently. In this way, the patient can better understand
> surgical risk, expected outcome, potential dissatisfaction and
> financial responsibilities of breast-implant surgery.
>
> Because the patient takes an active role in the entire process, she
> and whoever else she chooses to involve in her decision, are invested
> with a degree of responsibility and control over the outcome.
> Physicians have discovered that, even though patients may sign a
> consent form, that does not necessarily mean they will in the future
> remember being informed about potential complications or the
> possibility of dissatisfaction with results.
>
> Research into effective methods of achieving informed consent is
> ongoing and plastic surgeons have funded such research to help
> determine the extent of informed consent in breast-augmentation
> procedures. Informed consent means that the patient must be educated
> as to surgical alternatives and the probability of any unwanted
> outcome. Risk must be quantified in ways that patients understand and
> communicating risk effectively is a complex task.
>
> Patients must understand the limitations of surgery and the process
> involved with recovery. Patients need to understand this involves the
> potential for complications of the surgical procedure, itself,
> inherent risk of implanted devices and additional advisory information
> pertinent to the use of breast implants.
>
> It is essential for patients to understand that breast implants may
> need to be replaced over time. I have been involved in developing
> materials for breast-implant patients that I believe successfully meet
> all the criteria that I have discussed today. The FDA\'s ongoing
> regulatory process will ensure that sound science will determine what
> choices may be available for women going forward.
>
> Plastic surgeons welcome the current hearings which will determine
> whether silicone-gel breast implants can be available for general use.
>
> Thank you.
>
> MS. RICHARDS: Dr. Krause, and members of the panel. My name is Mary
> Ann Richards. My transportation costs and hotel accommodations have
> been paid for by Inamed. I have not been offered, nor would I accept,
> compensation for the time I have taken from my employment to present
> with you today.
>
> I am a four-year cancer survivor who chose to have a silicone implant
> after a mastectomy. Between the time it was determined I would need a
> mastectomy and actual surgery, itself, I did considerable research on
> the various types of breast construction available to me. After
> extensive research, I felt an implant would be my best option.
>
> The initial expander was put into place following my surgery on
> January 25, 2000, by Dr. Caroline Glicksman, an excellent
> board-certified plastic surgeon. It was a saline expander and, as it
> was filled with the saline solution, I found it extremely hard and
> uncomfortable, a constant reminder of my disease and loss.
>
> As part of a cancer support group, I knew several other women who had
> opted for the saline implants and they, too, found them hard,
> uncomfortable and disappointing. When I mentioned this to Dr.
> Glicksman, she said that I might be a candidate for a silicone
> implant. She gave me some literature and I did extensive research.
> After I did my homework, I felt that the silicone implant was the way
> I wished to proceed.
>
> I discussed this at great length with Dr. Glicksman and she gave me
> additional literature with both the advantages and disadvantages of
> silicone implants. I decided to proceed and, on May 26, 2000, I had a
> McGhan silicone breast implant inserted.
>
> Losing a breast because of cancer is not easy, but facing daily the
> reality that the cancer might reoccur was, for me, far more difficult.
> With my silicone implant, I am not constantly reminded of that
> possibility. My silicone implant is comfortable, soft, and feels very
> natural, unlike my original saline expander.
>
> I feel I am a responsible, informed consumer. I see Dr. Glicksman
> yearly. I am aware that silicone implant have a limited life
> expectancy, much as a pacemaker or artificial knee or hip and will
> need to be replaced in the future, much as they would.
>
> I have never, for one minute, regretted my decision with regard to my
> silicone implant and feel very strongly that other women who have to
> face the horror of breast cancer and the mastectomy should have the
> same options available to them that I have had. It is for this reason
> that I am willing to present before your committee about this very
> personal matter.
>
> Thank you for the opportunity to speak before you.
>
> MS. BANCARZ: Good morning. I\'m Lisa Bancarz, a 1982 graduate from
> Pacific Union College and resident of California who had
> silicone-gel-implant surgery in 1987. Following two pregnancies and
> breast-feeding both of my children, I found my breasts were
> asymmetrical. I was not happy with this change in my appearance.
>
> I decided to have breast-augmentation surgery and scheduled an
> appointment with a board-certified plastic surgeon. My surgeon
> discussed at length the pros and cons of the surgery. I spoke to
> several of my friends and acquaintances who already had this surgery.
> Some mentioned they were slightly more firm because of capsular
> contracture but they were happy and did not want them removed.
>
> I decided to proceed with the surgery and have never regretted it. I
> remember several articles and media programs regarding the issue of
> silicone and breast implants from the early 1990s. I spoke to my
> surgeon and he talked to me at great length regarding the silicone
> issues. He explained that, since I was not having problems with the
> implants, I should follow the recommendation of the American Society
> of Plastic and Reconstructive Surgeons and not have them removed.
>
> I obtained more information from articles given to me by my physician
> and what I personally read in the newspaper and magazines. It became
> evident, through my readings, that silicone had been, and still is
> being, used successfully for other types of implant procedures. I am
> offended that a woman\'s option to choose a silicone-gel implant was
> taken away.
>
> I feel comfortable with my decision to have silicone-gel implants and
> have never regretted it. Because of the controversy surrounding the
> silicone implants, I have attempted to keep up the studies and their
> results. Again, I feel I made the correct decision.
>
> I have several friends who have had the surgery. After seeing their
> results with saline implants, I am thrilled to have my silicone-gel
> implants. My breasts are soft and feel like natural breast tissue. I
> am extremely satisfied with the surgery and would not hesitate to have
> the procedure again.
>
> I would strongly recommend silicone-gel implants to friends and, yes,
> even my daughter if she expressed an interest at an acceptable age. I
> am very appreciative and glad that I was given the opportunity to
> choose silicone-gel implants. It is my strong belief that every woman,
> after consultation with her physician, should be able to determine
> which type of breast implants are best for her. Silicone-gel implants
> should be an option.
>
> Thank you.
>
> MS. WRIGHT: Good morning. My name is Eileen Wright and I want to thank
> the panel for allowing me to comment on my nearly 20-year experience
> with silicone breast implants. I currently work as a nurse manager
> within the Johns Hopkins Health System. I do not have any financial
> interest in the manufacturer or its competitors.
>
> I am a breast-cancer survivor. After my diagnosis and subsequent
> mastectomy, I chose to have breast-implant surgery. At that time, I
> was under the mistaken impression that my implants would last forever.
> I lost touch with the surgeon who performed my implant surgery very
> shortly after the procedure as he left the area to practice in another
> state. I truly felt any further follow up by a surgeon would be
> unnecessary.
>
> It was not until nearly 16 years later that I noticed, one, my
> implants had appeared to rupture; two, I discovered implants were not
> designed or meant to last forever. It was only through a conversation
> I had with a colleague who also had silicone implants that I learned
> implants, like any other medical device, may need to be replaced
> periodically.
>
> Needless to say, when I visited a local plastic surgeon in 2000, he
> advised me that the implants I had for 16 years needed to come out. He
> also told me about the various surgical options available to me after
> the implants were removed. As I look back on this process, it is clear
> to me that the science, along with the patient-education process, has
> evolved considerably since my first implant surgery in 1984.
>
> My plastic surgeon took the time to explain the range of
> reconstruction options available to me. He noted that I did not need
> to replace my implants with silicone-gel implants if I did not want
> to. He showed me, and allowed me, to handle examples of both saline
> and silicone implants and he detailed an exhaustive list of potential
> complications associated with the devices.
>
> When I expressed an interest in having the old gel implants replaced
> with new ones, he explained that rupture could occur again. He also
> confirmed that I understood that the implants might still need to be
> replaced at some point in the future. Until the time of the implants\'
> rupture, I had been very satisfied with the outcome of my initial
> surgery. Thus, I felt very comfortable replacing the old implants with
> new ones.
>
> It has been three years since my most recent implant surgery. I am
> very satisfied with the result and now consider myself a well-informed
> patient. It does not make sense to me that silicone-gel implants are
> only available to women for breast reconstruction.
>
> I think it is important that all women have the option of silicone
> implants available to them. I believe they provide a look and feel
> that is most natural.
>
> Thank you for your time.
>
> MS. LOWENSTEIN: Good morning. I am Lisa Lowenstein from Fremont,
> California. Inamed paid for my travel and accommodation to attend
> today\'s meeting.
>
> After breast-feeding and raising four children, I was not happy with
> the way my breasts looked and the way my clothes fit. I decided that I
> wanted to have breast augmentation to restore the look and the feel of
> my breasts. In 1997, I researched all the implants that were available
> to me. In August of that year, I met with my plastic surgeon and he
> informed me that my only choice was saline-filled implants.
>
> I was not happy with that choice due to a number of reported rupture
> incidents and an unnatural look that it had a history of. My next step
> was to have a mammogram done before the procedure. Within 30 minutes
> of having the mammogram done, I received a call from my doctor stating
> that he wanted me to retake the mammogram and that he wanted me to see
> him at his office.
>
> During that appointment, my doctor explained to me that what he and
> the X-ray technician found were decalcified starburst spots on both of
> my breasts. Considering the fact that my mother died from breast
> cancer, this was alarming to both me and my doctor.
>
> After discussing my options and the procedures, we decided it would be
> best to do a bilateral subcutaneous mastectomy, something that is
> rarely performed these days. The surgery took place in September of
> 1997. I was so scared of the possibility of having cancer. My doctor
> was quite pleased when the surgery was over and the tissue expanders
> were put in for healing time. The biopsy report came back negative.
> What a relief.
>
> My doctor knew that the silicone-gel implants would be out for testing
> and maybe in time for me to have them. He explained to me that if I
> was his wife, that he would want her to have the silicone-gel implants
> in this situation because they were, in his opinion, much more
> natural, softer, tier-drop shaped like real breasts, and feel like
> real breasts.
>
> He believed that there was less chance of leaking or rupturing and I
> trusted his opinion. In May of 1998, after qualifying to be a case
> study, I underwent my final surgery to insert the silicone-gel
> implants. My doctor informed me that these would be so much nicer than
> the tissue expanders and that, in time, would soften and drop into
> position like real breasts.
>
> I was ecstatic when the surgery was over. I hardly had any pain and my
> breasts looked beautiful. They were perfectly shaped, soft to touch
> and looked great in clothes. I never had any side effects or problems
> of any kinds with these implants and, as time went by, they softened
> even more and looked more natural than my girlfriends who had saline
> implants.
>
> Even though I had all my breast tissue removed, my implants looked
> much more natural with no wrinkles and no hardness. I am a very
> athletic women and work out at a health club very strenuously. I
> wanted to make sure that these implants could keep up with and not
> limit me in any way.
>
> Nothing limits me in my life by having these implants. I forget that I
> have implants most of the time and no one knows that these are not my
> own breasts and I never give my secret away. The best part for me is
> that I am healthy and these implants look great. I love being able to
> find clothes now that I fill out the top perfectly and evenly. It is
> important to me that I am proportional.
>
> The worry about breast cancer is erased from my mind. I would make
> exactly the same decision today if I had to. I wouldn\'t change one
> thing about my experience.
>
> In the dental field, which is my background, we let the patients
> choose what kind of filling to put in their mouth, whether it is a
> lesser material, veenamalgam\*, one-color silver, unnatural, or
> higher-quality materials such as a tooth-colored composite that is
> more natural and unnoticeable. Based upon my experiences, patients
> that care about their appearance will choose the higher-quality
> composite because it is more natural and aesthetically nicer.
>
> The key word here is choice. Women should have a choice of what kind
> of implant they want in their body from a list of all products deemed
> safe and effective.
>
> DR. WHALEN: Can you conclude, please, Ms. Lowenstein.
>
> MS. LOWENSTEIN: At the end of the day, I don\'t consider these an
> implant but part of my body. Thank you for your consideration.
>
> MS. NYE: Good morning. My name is Kathleen V.F. Nye. I rode in from
> Pennsylvania with friends and I have conflict of interest.
>
> I know from experience that silicone-gel implants will adversely
> affect the lives of many people if they are approved based on just a
> few years of safety data. Not only are the women who are implanted at
> risk but, also, there is a trickle-down effect affecting the whole
> family.
>
> Inamed says that their new and improved silicone breast implants are
> safe. I would like to relate my story of new and improved silicone
> breast implants. My first experience was in 1968. I was 22-years old
> and had a bilateral mastectomy. These new devices started to get hard
> in about six months. I also started having fatigue and joint pain and,
> in \'76, I found a doctor who would remove them. The new ones also
> hardened and were removed in \'81.
>
> At this time, the doctor told me there was a new and improved version
> and they would not get hard. I had the new and improved inserted in
> \'81. This new and improved silicone implant started to harden again
> in about six months. After three years of much pain, I went to a
> plastic surgeon and told him just to remove the implants. I did not
> want another set.
>
> But, again, I was told about a new and improved silicone breast
> implant. Again, the new and improved implant started to get hard in
> about six months. I started to feel lumps around the edge of the
> implant. There were three masses. The cancer was sandwiched between
> two masses of foreign material with giant cells.
>
> This started me on the road of more implant disasters. I had a total
> of 13 implants including devices made by McGhan, a company now called
> Inamed. In the early \'90s, the implant came through the skin and
> popped out on its own. I have a photo that I included in my
> presentation.
>
> I am sure you understand my concern when I heard the manufacturers are
> now trying to promote a new and improved silicone breast implant. Talk
> is cheap. It is easy to call an implant new and improved, but you
> won\'t know if it is really better until it has been inside a woman\'s
> body for five, ten or fifteen years.
>
> I urge you not to be as naive as I was when I was told that they are
> better than the old ones. Please do not put these new and improved
> implants, silicone-gel implants, back on the market unless they have
> been tested for a long enough time to really prove they are safe.
>
> Thank you.
>
> MS. BUIKEMA: (Read by Kirstin Hoskison.) Hi. My name is Kirstin
> Hoskison and I am reading for Betty Buikema. \"Every day has been a
> silicone day in my life for the last ten years. In 1993, I became a
> support-group leader with two other special women, Kay Dlugopolski and
> Peggy Pardo. We had the same thing in common, silicone breast
> implants. One was for reconstruction after cancer, one to keep from
> having cancer because of recurring cysts, and one for cosmetic
> reasons.
>
> \"We each became ill, have problems with the implants, had to have
> them removed and be reconstructed with our own tissue. Our medical
> records and history are similar to those we have heard over and over
> from so many women. Because we believed in the cause of fighting what
> happened to us, we began, at our own expense, to inform and educate
> ourselves and as many women as possible.
>
> \"We have had the opportunity to meet and talk to hundred, perhaps
> thousands, of women across America and the world. What we all had in
> common were silicone breast implants and the illness caused by them.
> That many women couldn\'t be a coincidence.
>
> \"When I heard that there are now three studies showing that women
> with breast implants are three times as likely to commit suicide
> compared to other women, I wasn\'t surprised. We knew women who have
> committed suicide, something I, myself, had considered when the pain
> was unbearable, when it doesn\'t seem like the pain will ever go away,
> and doesn\'t seem like you ever get better and, when you have
> mutilated breasts and you are broke, in addition to the pain, it can
> be hard to feel that life is worth living.
>
> \"The cost of having implants inserted is nothing compared to the cost
> of having them removed, not just in dollars but in health. This has
> cost me all of my savings for retirement. At a time when I should be
> enjoying life, all I can do is pay for pain-killing medications to
> survive. \"My own story started when I was 40 and had a double
> mastectomy because of chronic cystic mastitis and reconstruction with
> silicone implants. I immediately had a hematoma. A year and a half
> later, I had a small tumor near my rib cage which was removed a few
> months later. By 1990, my left breast was deformed, probably due to
> rupture. My implants were removed in 1992, but I was diagnosed with
> Sjogren\'s syndrome and later with atypical connective-tissue disease.
>
> \"Are Inamed\'s current silicone breast implants substantially
> different from implants I had. Will they leak or rupture, cause
> contractures? Will some women be allergic to silicone? Can you
> guarantee they will be safe this time? Are women going to be guinea
> pigs again? You know that silicone implants leak as they age. Why
> would anybody think a two- or three-year study is long enough when
> everyone knows that most women\'s health problems don\'t begin until
> seven to ten years after they get implants.
>
> \"I am not here to tell you what to do. I am here to beg you to base
> your decision on whether you would want your 17- or 18-year-old
> daughter to get these poorly tested implants. Remember that if
> silicone-gel implants are approved, teenagers will be first to line
> up.
>
> \"Thank you for listening to the women, but listen with an open mind
> and be sure they are safe before restrictions are lifted. You owe this
> to the women who are depending on your judgment.\"
>
> DR. GLICKSMAN: Distinguished panel members, I have no financial
> affiliation to any corporation. I have come to testify before you
> today as both a plastic and reconstructive surgeon and as a woman,
> wife and mother.
>
> I began my experience with breast implants in the late 1980s where, at
> Memorial Sloan Kettering, I performed close to 350 breast
> reconstructions and augmentations using both saline and silicone
> implants. In 1992, I began using only saline implants for augmentation
> and reconstruction and was an investigator in the McGhan saline study
> for five years.
>
> For seven years, I limited my patients to only saline implants while
> I, like my colleagues, followed the national and international studies
> on silicone and systemic illness. When, in 1998, the European nations
> declared silicone implants safe, I became an investigator in the FDA
> adjunct silicone study with Inamed.
>
> To date, I have implanted 130 women with over 300 silicone implants. I
> have followed these patients for close to five years with no reported
> systemic illness and a capsular-contracture rate of less than 1
> percent. You have before you the data, the science, but I would like
> to talk to you as a physician and a woman.
>
> I, like many of my patients, am a 40-something-year-old mother of four
> small children. We have all heard the arguments of the National
> Organization of Women. Women should feel good about themselves. Women
> don\'t need to diet and exercise. Women don\'t need to feel attractive
> to men. Well, I\'m sorry, but NOW does not represent me or the
> thousands of my patients whom I have treated over the last twelve
> years.
>
> We know the early detection of breast cancer and mastectomy saves
> women\'s lives. If we are to encourage women to undergo such
> procedures, we must be able to provide them with an aesthetically
> natural, soft and comfortable breast reconstruction.
>
> The majority of my patients seeking breast augmentation are in a
> similar position to myself, in their 30s and late 40s, have had
> several children and desire the fullness they have lost to pregnancies
> and breast feeding. They are not looking for the Baywatch look. They
> are well informed, educated, mature, American women who are seeking to
> restore their self esteem and improve their self image with a soft,
> comfortable breast implant.
>
> If you, as a panel, carefully review the last ten years of rigorous
> epidemiologic peer-reviewed studies, you will see no proven connection
> between silicone and systemic illness. Therefore, the final decision
> as to which implant to use should be made between the well-informed
> patient and her physician.
>
> No medical device can guarantee a lifetime of safety. Capsules, often
> tender and uncomfortable, form around neurostimulators, pacemakers and
> heart valves, and total joints do not last a lifetime. When I sit with
> my patients, we weigh the risks and benefits of any surgical
> procedure. Total joints may increase mobility and relieve pain and
> heart valves may prolong life, but both procedures carry considerable
> morbidity and mortality rates.
>
> But what are the benefits of breast implants? Who determines that the
> benefits of breast implants are not valid? Is self esteem and improved
> quality of life only reserved for men on Viagra? Are we protecting
> women in America or denying them the free choice that women in the
> rest of the world already have.
>
> I urge you to let the science of medicine speak, not emotions,
> hysteria, money or politics.
>
> Thank you.
>
> DR. WHALEN: Excuse me, Doctor. I don\'t believe you stated your name.
> If you could, please?
>
> DR. GLICKSMAN: Dr. Caroline Glicksman.
>
> DR. WHALEN: Thank you.
>
> MS. GILBERT: Dr. Glicksman, I have a question. Can you tell me how you
> followed these patients?
>
> DR. GLICKSMAN: I follow my patients at six-month intervals. I bring
> all my patients in, whether the study guidelines are at six months or
> a year or the three years and five years. I follow all my patients
> every six months. I bring all my patients back on an annual basis
> regardless of the study guidelines.
>
> MS. GILBERT: Is this done through MRI or is it physical examination?
>
> DR. GLICKSMAN: Physical examinations, mammography, annual mammography
> for those patients who are appropriate, unless there are problems,
> then ultrasounds and MRIs. But I have not had any problems that
> required those testings as of yet.
>
> PROF. DUBLER: Dr. Whalen, since the panel is arranged so that we
> can\'t see who is talking, could you ask panel members to who ask
> questions to please state their names.
>
> DR. WHALEN: And who were you? (Laughter)
>
> DR. EDWARD MELMED: I am Edward Melmed. I have no financial payment
> made to me but my trip was supported by NOW. I am a board-certified
> general surgeon and plastic surgeon. I am board-certified in England,
> South Africa and the United States. I came to the United States in
> 1973 as assistant professor of plastic surgery at the Southwestern
> Medical School in Dallas and I am currently in private practice.
>
> I did an enormous number of breast implants. I actually started in
> plastic surgery doing implants before there were implants. We used to
> use buttocks. I have seen the evolution of implants and I wrote
> extensively about it. In 1992, I changed and I started seeing women
> with problems. And now, when I counsel women and I want to tell you I
> have now done over 600 explantations, and if you include the miserable
> Pep implants, probably about 650 because every one of those ruptured.
>
> When I meet with women I tell them there are three problems with
> implants. The first is they rupture. Now, when you see an implant that
> is three-years old and you take out an implant that is three-years
> old, you are going to see a perfectly good gel implant that is not
> sticky. It does not cause any problems. The likelihood of capsular
> formation is minimal.
>
> When you get to four-and-a-half years, and these are implants that I
> have explanted fairly recently\--when you get to four-and-a-half
> years\--I beg your pardon. I don\'t do that quite as roughly when I
> explant. (Laughter) I will get to it eventually. I apologize\--the
> implant is now starting to get sticky and if I wasn\'t wearing gloves,
> I\'ll have a residue on my hands. Implants are porous. They have
> silicone bleed from the Day 1. But when they get to four-and-a-half
> years, we started to get significant tackiness to implant.
>
> A few months ago, I explanted a lady who I had implanted who had
> implants that I had put in seven years ago. What came out was the
> typical explanted mess. Now I have seen this hundreds of times and I
> am worried. I am very worried because we have an implantable surgical
> device. When I hear the last speaker make an analogy to a hip joint, a
> hip replacement, we are talking about a 70-year old who has got pain.
> We are talking about 17-year-old girls who are faced with a lifetime.
>
> One of my colleagues in Dallas said, This is a matter of informed
> consent. I, he says, put the silicone implants into my own 17-year-old
> daughter. I have lots of comments I could make on that.
>
> DR. WHALEN: Doctor, you need to conclude, please.
>
> DR. MELMED: I was granted six minutes, sir, because of another
> speaker. So, my first question to you, as a physician in practice, is
> tell me what is an acceptable failure rate of an implant. We accept
> that hip implants break. That is one thing. But here we are talking
> about putting an implantable device into a young person, and I, in
> practice, would like you to guide me and tell me what you consider an
> acceptable failure rate.
>
> We know it is upwards of 70 percent after a given time. And time is
> the factor that we are talking about in implants.
>
> The second problem that implants have is they form tremendous scar
> tissue and, perhaps, it is relevant to show a specimen of what it
> looks like at 15 years\--I am too efficient for the airport. I
> apologize again. This is a capsule that I took out after 15 years.
> This you could probably put on the soles of your shoes and wear for a
> while, it is so thick. It is full of silicone inside. This horrible
> tissue is in a human.
>
> Now, if you extrapolate that you are going to put implants into
> 17-year-old girls, at the age of 35, you are going to have these
> problems. So my next question to you is what do you consider a time
> element at which you consider implants must be replaced. Surely, you
> are going to replace them or you are going to just say, you can have
> this inside of you; we don\'t care.
>
> As my FDA, I want you to advise me what you consider a time element,
> first in terms of product safety and failure and, secondly, time in
> terms of scar contracture and its resultant problems.
>
> The third issue I don\'t want to dwell on because you have heard about
> it, but when it comes to symptomatology, I see an enormous lot of
> women with problems. Undoubtedly, a lot of psychological overlay.
> Undoubtedly, there are a lot of who real disease. The truth probably
> lies somewhere in the middle. I think our legal profession probably
> muddied the water by going after established connective-tissue
> diseases. We know it is not that. The Institute of Medicine is 100
> percent correct. This is not a problem that is classical.
>
> DR. WHALEN: Doctor, conclude, please.
>
> DR. MELMED: My last question for you is, then, if you are going to
> reintroduce this product, please tell me that it is safe. What do I
> tell me patients? Do you accept 1 percent, 2 percent? That is for
> 100,000 women.
>
> I think you, sirs.
>
> DR. WHALEN: Doctor, which of the other speakers yielded the time, just
> for our list?
>
> DR. MELMED: I beg your pardon, sir?
>
> DR. WHALEN: Can you just tell me which other speaker yielded to you
> for our list?
>
> DR. MELMED: I don\'t even know. I was sponsored by the National
> Organization of Women and they said that somebody had given up their
> time for me to talk.
>
> DR. WHALEN: Thank you.
>
> DR. WOOLEY: Hi. I\'m Dr. Wooley. I am also sponsored for travel
> arrangements by the National Organization of Women and I also have six
> minutes due to a donation from a breast-cancer survivor.
>
> I am a professor of orthopedic surgery, immunology and biomedical
> engineering at Wayne State University. One of the studies that I am
> going to describe to you was sponsored by Lifomatrix\*, the
> manufacturers of Trilucent.\*
>
> I am going to take the first minute to describe the findings of the
> scientific panel convened by the National Organization of Women in
> July of this year. This is a collection of scientists including those
> from the FDA, the NIH and academia.
>
> We are not anti-manufacturer and we are not anti-implant. However, our
> review of the literature and recent findings including some not
> published reveal three concerns to this group. The first, as you have
> heard, is device failure. It appears that elastomer shells are still
> experiencing a high rate of failure with recent studies suggesting
> about 17 percent rate of detectable leaks within five years of
> implantation.
>
> The second concern is local tissue reactions, capsular contracture,
> which you have just seen a sort of dramatic demonstration of, and
> tissue inflammation due to silicone exposure remain a viable concern.
>
> The third issue which I am going to speak to scientifically is latency
> issues. The study suggests that long-term exposure to silicone may
> result in an increase in both immunological and autoimmune
> connective-tissue disease problems, albeit not classic. That had been
> implicated during short-term testing. However, the consideration of
> the two years of clinical data, it is the panel\'s opinion, is
> woefully inadequate.
>
> I am going to move on to preclinical or animal testing and I would
> like to acknowledge the FDA for publishing, if not the whole technical
> report, summaries on their website. I would like to quote from Study
> 7. \"While a significant increase in total spleen activity was
> observed in high-dose animals implanted with the shell test article,
> the increase appears to be related to a low response of the sham
> control animals.\"
>
> I have heard far better explanations from recalcitrant graduate
> students trying to explain away data. This is a fairly reasonable
> explanation of what we believe is the adjuvant effect of silicone,
> something that the manufacturers are quite well aware of.
>
> If the panel would like to look at the handout that I provided them, I
> am going to contrast two studies, the first of which was done about
> ten years ago and looked at the implantation of silicone within an
> experimental model of autoimmune arthritis.
>
> Our finding in our first short-term was there were no adverse effects
> of silicone implantation of either the elastomer or gel on the
> incidence of this model Type-2 collagen-induced arthritis. There was
> no adverse influence of the elastomer or gel on the severity of the
> disease. However, immunological findings did reveal that a variety of
> proteins which had adhered to the elastomers were observed and
> autoantibodies unique to this type of implantation were detected. But
> I want to emphasize again, these autoimmune findings did not influence
> the disease. This is published in the leading journal of the American
> College of Rheumatology.
>
> A follow-up study to look at long-term effects was quite different.
> Long-term silicone elastomer\--by long-term in a mouse, I mean a year
> which is a considerable portion of a mouse\'s
> life-span\--significantly increased the incidence of arthritis in the
> mice and long-term silicone elastomer implantation significantly
> increased the severity in the immunized mice.
>
> So what I am afraid of is that the panel, by looking at only two-year
> data or short-term data is going to make the same misconclusion that
> we did with our initial look at short-term implantation and that
> long-term implantation must be considered. These autoantibodies that
> we see included anticollagen antibodies, particularly Type I. That is
> a protein that is inevitably going to bind to any elastomer.
>
> What is the significance of animal findings? Well, extrapolation of
> animal findings to the human situation is controversial, but this is
> an essential part of drug and device development and it is the
> panel\'s responsibility, of course, to consider that.
>
> The findings suggest that the implantation of silicone could
> exacerbate autoimmunity in susceptible individuals resulting in the
> development of autoimmune connective-tissue disease. We do, of course,
> predict that there are many other contributing factors particularly
> genetics which will influence the response to silicone in patients.
>
> I would like to thank the panel for their time.
>
> DR. WHALEN: Thank you. Before the next speaker, we apparently are
> going to take a brief unscheduled break of just five minutes. So,
> please, don\'t stray too far. Five minutes. A reminder to the panel,
> just talk about how the Red Sox are going to beat the Yankees today.
>
> \[Break.\]
>
> DR. WHALEN: We would like to resume. It may have been obvious to
> anybody who witnessed what just transpired, but, for future speakers,
> please, if anybody has any specimens that have potential as having
> biologic properties, please don\'t bring them to the podium or else we
> are going to be suspending activities once again. If we have to do
> that again, we may need to cut some speakers off and we certainly
> don\'t want to do that.
>
> Please.
>
> MS. GERTNER: Good morning. My name is Nancy Gertner. I want to thank
> the panel for hearing my testimony today regarding my experience with
> silicone implants. I am a retired attorney, a general surgeon\'s wife,
> and a five-year survivor of breast cancer. I am here representing
> myself. I have paid my own travel expenses to be here and I do not
> have any financial interest in Inamed or its competitors.
>
> When cancer was found in my right breast in a routine mammogram in
> 1998, I elected to have a double mastectomy. My choice to have what I
> thought was a prophylactic mastectomy on my left breast proved to be a
> prudent one as the surgery revealed cancer was also present in that
> breast.
>
> Before my surgery, I discussed various reconstruction options with my
> husband and my plastic surgeon. I knew I wanted to have immediate
> reconstruction following my mastectomy surgery and we discussed the
> options available including saline implants, silicone-gel implants and
> tram-flat reconstruction.
>
> My plastic surgeon reviewed the benefits and potential complications
> of each procedure with me. He showed me both pictures and actual
> implant samples. We discussed the advantages, disadvantages and
> likelihood of problems or complications with each option and I chose
> silicone-gel-filled implants because I felt they offered the look and
> feel most like my own natural breast tissue.
>
> I also knew other women who were satisfied with their
> silicone-gel-filled implants. I decided to have tissue expanders
> inserted at the time of the mastectomy surgery in November, 1998, with
> subsequent expansion. The silicone implants were inserted in February
> of 1999. I was immediately pleased and continue to be happy with the
> result. Because silicone implants were a viable option to me at the
> time I was diagnosed with cancer, I was much more able to cope with
> the loss of my breasts.
>
> As a woman, it was also important for me to have a choice and be able
> to make an informed decision. While every woman is different, gel
> implants were the best alternative for me and I am grateful my doctor
> was able to present them to me as an option. I felt then, and continue
> to feel, that reconstruction with silicone implants provided me with
> the best possible aesthetic result with a reasonable post-op recovery
> time.
>
> Having options and being explained my choices made me feel empowered
> as a woman and made me feel like I was not doomed to a single
> situation. I am happy with my reconstruction. I think it looks and
> feels beautiful and I have never experienced any personal or
> professional limitations as a result of my implants.
>
> I am frequently asked and glad to show other women my reconstruction
> and describe my experiences hoping to allay their fears when they,
> too, are diagnosed with breast cancer. I feel this because I was given
> many reconstruction options including gel implants. Breast cancer
> ended up being a small problem in my life rather than a big one that
> my body would have been a constant reminder of.
>
> I sincerely appreciate your time and appreciate the opportunity to
> share my experience. Thank you.
>
> DR. GOLDBERG: I am Eugene Goldberg. I am a professor at the University
> of Florida. I am going to try to provide some scientific information
> pertinent to this discussion. I have no financial interest. I have
> paid my own way here. I have worked in the past as a consulting expert
> in litigation on behalf of both defendants and, as well as defendants,
> plaintiffs. I want you to understand that clearly.
>
> I have some charts up there which about a half a mile down there you
> are not likely to see. But they are in a handout so that may help.
>
> My concern for this discussion will be\--and if my voice breaks up, it
> is not because of puberty, it is because of bronchitis. So please
> forgive me. My concern is with the risk/benefit issues and, listed
> here, are some of the safety risks that are associated and are well
> known from fibrous capsule contracture, pain, disfigurement and I am
> going to refer primarily to the question of shell failure and
> additional surgeries because that is really the substance of much of
> what we have done research on at Florida.
>
> I should mention parenthetically that several of the papers that we
> have published in Applied Biomaterials and in the Annals of Plastic
> Surgery are not discussed in your PMA nor is our failure analysis
> discussed in the PMA. The 1992 moratorium on silicone-gel breast
> implants was imposed due to inadequate safety data. The question is,
> do you have more safety data now in a relatively short two- to
> three-year period of evaluation, than you had at that time.
>
> Sound engineering-design criteria for gel implants and the mechanical
> and biochemical properties have not been available and no
> peer-reviewed large cohort prospective or retrospective clinical
> studies have been reported by manufacturers today, even though gel
> implants have been on the market for 40-ish years.
>
> The only peer-reviewed large cohort failure and safety analysis paper
> to date is from our laboratory and not discussed in the PMA. This
> analysis shows a statistically significant result for almost 10,000
> explanted devices from 42 separate studies. Some people have
> considered, in the literature and in private discussion, that this may
> be a biased study. If it is biased, it is biased in favor of having a
> large, the largest, cohort available from 42 studies and, therefore,
> represents a very wide range of different implants from different time
> periods, all of them gel implants, for which we have significant data
> in the literature.
>
> The results of that study can be represented qualitatively by some of
> the things you have just heard from Dr. Melmed where I show some
> examples from our laboratory examinations ranging from six-and-a-half
> years which are intact to 13-and-a-half years which is obliterated,
> literally, hardly there anymore.
>
> The high prevalence of shell rupture and the frequency of additional
> surgeries is something that we have tried to emphasize beginning
> around 1995, first in a letter to the New England Journal and
> subsequently in considerable research in our laboratory. We observed,
> as you will see on the failure analysis curve that goes up next, a
> shell failure prevalence at five years of 30 percent, at ten years, 50
> percent and 70 percent at about 17 years.
>
> This explant meta-analysis, not discussed in the PMA, substantially is
> confirmed by a noninvasive MRI study that has been provided to you by
> Dr. Brown and coworkers and essentially indicates that this curve is a
> reasonable representation of even what has been termed silent
> ruptures.
>
> If you look at two years, at the beginning of that curve, you find
> that it is extremely difficult to make any sense, whatsoever, out of
> rupture rates and reoperations. Our data from this study indicate that
> the reoperative frequency is of the order of one woman in three within
> six years and sometimes as many as two or three or four surgeries
> within the time frame.
>
> Two other points, quickly, I would like to make. One is that this is a
> new shell. This is not the old dimethylsiloxane shell. It is a phenyl
> shell and the phenylsiloxanes are associated with carcinogenic
> behavior as indicated in the PMA and there is also indicated the PMA a
> higher prevalence of both pulmonary and brain cancer which has been
> glossed over.
>
> DR. WHALEN: Dr. Goldberg, you need to conclude, please, sir.
>
> DR. GOLDBERG: I will conclude. To conclude, therefore, it seems to us
> that there is a need for much more scientific information before this
> new implant should be approved.
>
> Thank you.
>
> DR. WHALEN: As the next speaker is coming up, just for planning
> purposes of the speakers who are representing societies, it looks like
> we will probably be having some of you going after lunch. We will
> breaking for lunch at 12:30 for 45 minutes. If there is anyone towards
> the tail-end of the society speakers to whom that would impose
> difficulty, if AnneMarie Williams would raise your hand\--you probably
> already know her if you are speaking, in the back of the room\--please
> see her now so that some juggling of the speakers can be done.
>
> Yes, ma\'am.
>
> MS. TAPSCOTT: My name is Mindy Tapscott. I am 42-years old and I am a
> bilateral breast-cancer survivor. I would like to thank the panel for
> taking into consideration my experience with silicone breast implants.
> I also want it to be known that I am receiving no compensation from
> any group in any shape for form for my testimony.
>
> I was first diagnosed with breast cancer in 1989 and I knew I would be
> seeking reconstruction of my left breast following mastectomy surgery.
> After discussions with my surgeon, I elected to have reconstruction
> with a silicone gel-filled breast implant. I felt this option looked
> more natural than the other reconstruction options that were available
> to me.
>
> My surgeon provided and asked me to review and consider the insert
> that the manufacturer included with each implant. In addition, she
> reviewed with me the potential complications associated with silicone
> implants including capsular contracture and rupture. She informed me
> that some women are more prone to complications than others and that
> should could not reproduce what God gave me. I, nonetheless, felt
> comfortable with my decision.
>
> At my initial post-surgical follow-up visit, my surgeon advised me
> that massaging my breasts would help reduce the risk of capsular
> contracture but, I must confess, I did not follow through with that
> recommendation and, after about one year of my first implant surgery,
> I experienced significant capsular contracture in my left breast.
>
> I decided not to do anything about the encapsulation until ten years
> later, in 1999, when my implant was replaced. I requested that it be
> replaced due to the increased size of my right breast resulting from
> two pregnancies. After the procedure, my plastic surgeon specifically
> told me that the first implant was intact.
>
> One year later, the new implant also became encapsulated and, in the
> same year, I received a diagnosis of breast cancer in my right breast.
> Despite the complications I had experienced with my first implant, I
> also elected to have a silicone-gel-filled implant inserted after my
> second mastectomy.
>
> This, too, became encapsulated shortly thereafter. In January of this
> year, I decided to have both implants replaced once again. The latest
> procedure produced a terrific outcome and I have had no trouble at all
> since that time. Despite my history with local complications and the
> number of reoperations I have had, I still consider silicone breast
> implants the option of choice for me following my breast cancer.
>
> When you are diagnosed with breast cancer, you feel a loss of control
> because you don\'t know what you did to get the disease. Having
> choices made me feel like I got some control back. The many operations
> I have had do not bother me one bit. It was all worth it. Silicone
> implants have simplified my life. I am a mother of three small
> children and I can barely remember my purse when I leave the house,
> let alone my breast prosthesis.
>
> I don\'t have to worry if my breast is in before I answer to door or
> if my daughter has a friend sleep over. I never have to worry about my
> prosthesis falling out or coming out of position. The silicone-gel
> implants look and feel most like me and allow me to get on with the
> business of living.
>
> I am a carrier of the Bracca 1 mutated gene. The odds are great that I
> have passed this gene on to at least one of three of my daughters and
> I would want them to have the same choices.
>
> I thank you for your time today.
>
> MS. GANDY: Good morning. I am not Marlene Keeling. I just traded
> places with her. My name is Kim Gandy. I am President of the National
> Organization for Women.
>
> The National Organization for Women is the oldest and largest feminist
> activist organization in the United States advocating not only for
> women\'s equal rights, their economic and social well being but, also,
> for women\'s health. The National Organization for Women and myself
> represent only our own 501-C4 nonprofit corporation and no other
> party. My appearance today is underwritten by our 500,000 contributing
> members across the country.
>
> We have also asked three researchers and clinicians who participated
> in our May 8 symposium and our July 21 press conference to present
> testimony at this hearing as well.
>
> Thank you for the opportunity to present NOW\'s comments today on this
> very important issue. With hundreds of thousands of women from high
> school to retirees seeking breast implants each year and the number
> continuing to increase, a dangerous product will affect the health and
> safety of enormous numbers of women, individual women as well as their
> families.
>
> When a substantial number of these women fall ill, and depend on
> government healthcare systems for their medical care, the safety of
> their breast implants, a question you must determine here, will have
> become an important public-health question.
>
> But it is a personal health question for hundreds of thousands of
> women who need complete information in order to make informed choices
> about their medical care. Our organization has been contacted over the
> years by many women with silicone breast implants who are suffering
> from serious illnesses and disease that they associate with those
> implants.
>
> Their stories are heartbreaking. Many report having lost not only
> their good health but their husbands and partners, their jobs and even
> their life savings. We have also heard cases of suicide by these
> women, some of them mastectomy patients who became even more ill from
> their breast implants than they did from breast cancer.
>
> These women have reported a wide range of symptoms similar to
> fibromyalgia and lupus all the way to rheumatoid arthritis and other
> serious conditions. Most of them cannot afford the \$10,000 to
> \$15,000 and more that it costs to have their implants removed and
> they don\'t know where to turn for relief of their pain and
> uncertainty.
>
> Informed by the personal stories of these survivors, the assembled
> membership of NOW at two national conferences have adopted resolutions
> urging both independent research and long-term following of implant
> patients in addition to fully informed consent for all prospective
> patients.
>
> This spring, on learning that the FDA had been asked to consider
> returning silicone-gel-filled implants to the broad market, NOW
> sponsored a symposium on May 8 inviting more than a dozen researchers
> and government health officials from the Armed Services, from the
> National Institutes of Health, from the FDA and from private research
> institutes and universities to review their own findings and their own
> research with regard to the effect of silicone gel in the human body.
> Of course, you have heard already from some of those participants and
> will hear from more.
>
> We did this out of a conviction that government reliance on
> industry-supplied data, when special interests are involved, may have
> a result that is good for the industry but bad for the consumer. In
> reaching out to potential participants, we also learned that
> breast-implant manufacturers and plastic surgeons have made
> researchers and medical writers feel intimidated by spending great
> sums of money in persuasive campaigns to mislead breast-cancer-patient
> advocacy groups and the public regarding breast-implant safety.
>
> Women deserve the truth. They deserve to trust that what this agency
> tells them is a safe product to put in their bodies is, in fact, a
> safe product. When the information they are given is based on flawed
> or biased research, the result can be tragic.
>
> We know the breast implants leak and rupture and disintegrate in the
> body over time. We know that this causes a variety of problems, not
> the least of which is the promotion of systemic connective-tissue
> disease. I will refer you there to the research report which I have
> brought many copies of but particularly the research by Miller and
> O\'Hanlon of the National Institute of Environmental Health, part of
> the National Institutes of Health, the Environmental Autoimmunity
> Group which drew direct connections between silicone gel and systemic
> connective-tissue disease over the long term.
>
> Our symposium of researchers and clinicians have made numerous
> recommendations for future research and for improving the FDA\'s
> review process. These are included in the summary document which I
> would like to append to my comments for your review.
>
> If these preliminary findings do, indeed, lead to more conclusive
> assessments about silicone gel and immune-system pathologies, then we
> believe it will be clear that silicone-gel implants are not safe over
> the long term.
>
> We believe\--
>
> DR. WHALEN: Can you conclude, please, ma\'am?
>
> MS. GANDY: Yes\--that if it is in the interest of this industry to
> develop and promote a safe silicone-gel-filled implant that they would
> have done so by now. It is clearly not in their interest to do that.
> The only thing we believe that will result in a truly safe implant for
> women to choose is if the FDA requires that it be safe.
>
> If you permit them to continue to market unsafe implants to women,
> then they will have no motivation to make a safe implant for ourselves
> and our daughters.
>
> Thank you.
>
> DR. ANDERSON: Dr. Whalen, may I ask the speaker a question?
>
> DR. WHALEN: Yes.
>
> DR. ANDERSON: Ma\'am, you spoke of the symposium on May 8. When NOW
> put this together\--we are hearing two different viewpoints. Was NOW
> trying to present a discussion that included both sides or was the
> purpose of this to collect data that supported the view that implants
> are unsafe?
>
> MS. GANDY: We were trying to find out what was going on because we
> were getting very mixed messages. We heard from groups of survivors,
> groups that represent survivors, that they were told by doctors that
> these were safe and that there was no problem and that we would be
> doing a disservice to women by not allowing them.
>
> Then we had heard from so many groups of survivors and individual
> survivors that had terrible, terrible problems. The Co-Chair of our
> National Advisory Committee is a medical doctor and the dean of a
> medical school. And we knew that there was some unclarity over the
> long-term impact. So we thought it was important to reach out to
> people who were actually doing the work, who actually were doing the
> studies, themselves, who were looking at the women and who were
> engaged in the scientific part of it as opposed to the advocacy part
> of it.
>
> DR. ANDERSON: Did you have speakers that advocated for implants as
> well as speakers that had had these bad experiences?
>
> MS. GANDY: The speakers didn\'t advocate one way or the other. There
> actually was not a single speaker that advocated for or against the
> implants. That was a conclusion that was drawn from all of the
> research. What they did say was, and you will see the conclusions
> there\--they found that there were severe painful and debilitating
> local complications from the breast implants, capsular contracture,
> the kinds of things that you already know, that there was a very high
> failure rate and that, over twenty years or so, it approached 100
> percent and that there was substantial indication over a variety of
> the reports of the silicone gel, in particular, leaking into the human
> body had potential long-term consequences.
>
> They approached this from a variety of different directions, not
> making\--you are accustomed to dealing with doctors and researchers
> more than I, but what they did was they said, here are my findings and
> I have concluded that this seems to do this and we need to look at a
> longer sample, we need more information. That was the primary message
> that came from every doctor, from every researcher that testified, was
> this bit of information that we have leads me to think that there is a
> real problem here. But we don\'t really know until we have this much
> information.
>
> Every one of those doctors came to the same conclusion. As a result,
> we came to that conclusion, that this body should not be making any
> decisions on silicone gel until we had this much information and not
> this much information.
>
> DR. ANDERSON: Thank you.
>
> MS. GANDY: Thank you.
>
> MS. WARD: Good afternoon. My name is Mary Ann Ward and I am from Coco
> Beach, Florida. I am here representing myself and I have paid my own
> travel expenses to be here, have no financial interest in the
> manufacturers or its competitors.
>
> I appreciate the opportunity to speak with you today about my
> experiences as a breast-augmentation patient with silicone-gel-filled
> implants. I made a decision in 1978, when I was 29-years old, to have
> breast-augmentation surgery. I always knew my implants would need to
> be replaced at some point. My plastic surgeon was completely clear
> with me regarding that.
>
> Last year, that time came. The decision to have the implants replaced
> was solely my own. I was not suffering from any complications. I was
> not suffering from any disease or condition. I just thought, after 24
> years, I should have them replaced.
>
> After making the decision to have my implants replaced and have
> additional surgery, I consulted an experienced board-certified plastic
> surgeon and we reviewed different options including the type of
> implants available, the advantages and disadvantages of each option
> and I received a significant amount of medical information that I was
> able to apply in examining not only my health issues but my particular
> lifestyle and personal expectations.
>
> I am very proactive regarding my health as I believe most American
> women are, and I did research on my own. The two studies which were
> particularly helpful to me were the Mayo Clinic Study which was
> published in the New England Journal of Medicine in 1994 and the
> Nurses Health Study of 1995. Both studies found no association between
> breast implants and systemic diseases.
>
> My physician encouraged me in my personal education and discussed with
> me every piece of research I found. For me, having options was
> critically important not only from a health perspective but the
> implants needed to fit my lifestyle. You see, I am a 54-year-old woman
> who races sailboats competitively in the national and world arena. I
> race in bathing suits. I have to pull lines. I must be strong.
>
> It was important to me that my strength and ability to continue my
> sport would not be compromised. While there are no guarantees in life,
> my physician made sure that my education on the issues was thorough
> and that I was making a well-informed decision.
>
> Since my surgery, my physician has stayed close in contact with me
> requesting feedback on both process and results. I have been thrilled
> with the look and feel of my breasts. The gel implants have allowed me
> to have a natural appearance for a woman of my age while not
> interfering negatively or impacting my lifestyle. I continue to race
> sailboats. I work out. I play with my grandchildren and I do much
> more.
>
> I believe all women should have the choice I had. Given the science
> and research today, it is illogical to me that silicone implants are
> only available to women for reconstruction surgery. You have heard
> many compelling stories today, many of them very sad. My story is no
> less compelling because it is a happy one.
>
> Thank you for your time.
>
> DR. CHOTI: May I ask a question?
>
> DR. WHALEN: Sure.
>
> DR. CHOTI: What was your thought process or thinking as to why, after
> 24 years without a problem, you would get them replaced? Why not at
> ten? Why not at 15?
>
> MS. WARD: I actually was having no problems whatsoever. So I think I
> just kept putting it off. Finally, I had changed\--at the time that
> the tests were done regarding hormone-replacement therapy, because I
> had been through menopause and I am on hormone-replacement therapy,
> when all of that came up and I started having in-depth discussions
> with my doctor about that, I actually changed doctors at that time.
>
> The new doctor that I went to said, you know, Mary Ann, it has been 24
> years. You should have this looked at more thoroughly than your normal
> breast exams, than, you know, your annual mammograms, than examining
> yourself. It has just been that long. I think you ought to have
> somebody take a look at them. So I did.
>
> DR. CHOTI: But, at 15 years, you had the same thinking and decided, at
> that point, no need to replace them?
>
> MS. WARD: I really didn\'t. As I said, I am very proactive about my
> health so I was attentive to my breasts, most assuredly. But only
> really when I changed doctors and it was a new\--my new general
> physician said, I think you ought to at least go see a plastic surgeon
> and talk to him about it.
>
> When I saw my plastic surgeon, she was quite honest with me and said,
> you know, we see no real reason to replace them unless you just want
> to, which I made that decision because, when I had them put in in the
> first place, they said, these will not last you forever, Mary Ann.
>
> DR. CHOTI: And when they were removed, there were no leaks or
> ruptures?
>
> MS. WARD: They were fine. I was fine. I continue to be fine. Thank
> you.
>
> DR. WHALEN: A reminder to panel members of Dr. Dubler\'s appropriate
> request that we start off questions identifying ourselves.
>
> MS. KEELING: My name is Marlene Keeling. I paid my own way here and I
> have no conflicts of interest.
>
> I chose to get double-lumen breast implants in 1978 after my plastic
> surgeon assured me only 2 percent of his patients ever had problems
> and he could fix anything that happened.
>
> My health problems did not start until about seven years after my
> surgery. I developed weakness, fatigue, periodic swollen lymph nodes
> in my neck, depression, memory loss, peripheral and demyelating
> neuropathy. Since removing my implants, my ruptured implants, in 1994,
> all of my symptoms have slowly improved. However, the last time I had
> my natural killer cells counted, they were low. This is consistent
> with a finding of the Institute of Medicine report that states,
> \"Consistent with animal toxicology studies, it appears that natural
> killer cells might be affected by exposure to silicone gel.\"
>
> Inamed data has revealed the loss of natural killer activity in their
> immunotoxicity research. How can this panel approve a device for
> breast-cancer survivors that compromises the immune system by lowering
> natural killer cells which are the cornerstone of the immune system,
> are responsible for controlling tumor-cell growth and are involved in
> control of infection?
>
> In networking with other silicone-implanted women, I realize that many
> were being diagnosed with chronic inflammatory demyelating
> polyneuropathy and had memory problems or depression. In 1996, I
> became a founding director of Chemically Associated Neurological
> Disorders which is dedicated to information and research.
>
> German research by Flasseck et al., published 2003, found higher
> platinum levels in the fat tissue of breast-implanted patients when
> compared to control patients without implants. The same researchers
> report the data of this work clearly show that the use of elemental
> silicon as an indicator of migration from breast implants to the
> surrounding tissue is not appropriate.
>
> This becomes important because the Dow-funded Semple, et al., study on
> breast milk from implanted women used the inappropriate measurement of
> elemental silicon in an attempt to imply that breast feeding by
> implanted mothers is safe. In an e-mail, I asked the German
> researchers, could you comment on whether you believe that elemental
> silicon is an appropriate measurement for breast milk from implanted
> women to determine safety. Their response was, of course not.
>
> How can this panel vote to approve devices for augmentation and
> revision of young women of childbearing age without a properly
> designed breast-milk study for safety of children born after
> implantation.
>
> I have one final point. Two years ago, McGhan Medical, now Inamed,
> filed a patent which makes the statement, \"Silicone oil is not
> biocompatible with other human tissues. Therefore, the use of
> silicone-based filler material has been discontinued in the
> industry.\"
>
> How can this panel approve a device that harms human tissue, leaks
> silicone and heavy metals through the shell, ruptures at an
> underascertained rate, and the rupture may be silent. There is no way
> to remove all of the toxic and hypersensitizing chemicals once they
> leak into the tissues.
>
> Women with breast implants have not had informed consent. I say, loud
> and clear, you are the scientists in charge who must stop this
> experimentation on women and our future generations and must say no to
> corporate greed. I don\'t have a Ph.D. in suicide risk, but I can tell
> you, in networking with thousands of breast-implanted women, many do
> not have the money to have their ruptured and leaking implants
> removed.
>
> Many have constant pain. Many have declining health. Many have lost
> their health insurance or have been denied coverage. Many have
> children born after implantation with similar health problems and
> suffer guilt. Many are now no longer able to take care of their
> families and do not want to be a burden.
>
> Thank you.
>
> MS. FERELLI: Hello. My name is Vanessa Rose Ferelli. I have not been
> given any financial assistance from anyone related to this testimony.
>
> I am 29-years old and I was implanted on August 7, 2000, as part of a
> study from Port Jefferson in New York. I was misled about the truth of
> what the study really was about when I received the implants and I
> have been informed now that I wasn\'t even eligible to receive the
> implants at the time.
>
> Over the year and a half that I had the silicone implants, I was
> hospitalized many times. I was examined by a cardiologist,
> rheumatologist, my gynecologist and not once did anyone ever tell me
> that I could be sick or having some kind of a reaction to my implants.
>
> I experienced abnormally heavy periods that lasted several months at a
> time, fatigue so bad that I slept 16 or more hours a day, numbness and
> pain in my arms and my hands. I couldn\'t even hold a glass in the
> morning. I also had severe breathing problems. I lost my hair\--facial
> sores and a lot more.
>
> On December 1, I called my plastic surgeon from the hospital\--I was
> in the heart hospital having heart problems\--and asked them again,
> was there any possible way that this could be related to my implants.
> And he told me absolutely not.
>
> Finally, I met with a rheumatologist in New York that told me the
> truth about what was going on and he suggested I remove the implants
> as soon as possible. He said I was having something similar to an
> allergic reaction to them.
>
> On May 5, my implants were removed and they were sent to Inamed. The
> right one was totally ruptured and the report showed granulomous
> inflammation from the specimen sent to the lab. I didn\'t get a letter
> back from Inamed who received the implants right away until October
> 11. I didn\'t feel that they were really concerned about what had
> happened or studying anything since now I found out I was part of a
> study.
>
> Immediately after the implants were removed, I felt much better but I
> was still having breathing problems that were severe. I ended up going
> to another plastic surgeon who removed all my natural breast tissue,
> the surrounding tissue that was contaminated and that also had
> silicone in it.
>
> It has been about two-and-a-half years since this has gone on and I am
> much better now. I haven\'t had any of those symptoms again. The
> tachycardia and problems with my heart and the breathing problems are
> all pretty much gone. I still have some minor symptoms but nothing
> like what was going on before and it cost me about \$45,000 for the
> surgeries, the ordeal after the fact between the scans of my chest
> that never showed or revealed any kind of a rupture and I feel that I
> am lucky now to be okay, but I couldn\'t have imagined what would have
> happened if I didn\'t have the financial means to be able to take care
> of having them removed because a lot of things weren\'t covered under
> my insurance.
>
> I just ask that you please make sure that the implants are safe before
> they are approved. That\'s it. Thank you.
>
> MS. GILBERT: Ms. Ferelli, my name is Alisa Gilbert. I just have a
> question for you. You said you were part of a study. Did the study
> cover any of your expense when you had to go get the implants removed?
>
> MS. FERELLI: The only thing that they offered to me\--I called them
> when I talked to the rheumatologist and realized why I was sick. And I
> called them right away because I wanted a list of maybe chemicals that
> were now in my body, possibly. I was nervous about that.
>
> And they said that they would send me some information. All they sent
> me was a packet and a claim form and they said I could get my money
> back for the implants which I think were, like, \$1500. That\'s it.
> But as far as money\--and my insurance company wouldn\'t cover\--even
> if I wanted to go see if there was a rupture to get the\--I think it
> is a C-scan or something when you go to scan. Do you know what I am
> talking about? I\'m sorry,
>
> MS. GILBERT: An MRI? Are you talking about an MRI?
>
> MS. FERELLI: Yeah, something like an MRI but there is a special one
> that supposedly they could really tell to see if there was a rupture
> and they had me going into all of these different types of scans, but
> nothing revealed any kind of a rupture. But I had a lot of pain on my
> right side and burning. And I kept complaining about the right side
> and the burning.
>
> Then we didn\'t know until they removed it that the right one was
> totally ruptured. Thank you.
>
> PROF. DUBLER: Dr. Whalen, question. Could you come back to the podium
> for one minute.
>
> MS. FERELLI: Oh, I\'m sorry.
>
> PROF. DUBLER: I am Nancy Dubler.
>
> MS. FERELLI: Hi.
>
> PROF. DUBLER: Before your first implant, in your discussions with the
> surgeon, what did he\--he did not tell you it was a research protocol,
> involving a research protocol?
>
> MS. FERELLI: Actually, I went to two different plastic surgeons
> because I had saline implants first and they were ten-years old. And I
> wanted to have them changed because I was told that, in ten years, you
> should. Both of the doctors said to me that they just brought the
> silicone implants back on the market, that they did all these studies
> and tests and they have proven that they are 100 percent safe and that
> all the stories that you heard of people getting sick wasn\'t true. So
> I believed the doctors.
>
> PROF. DUBLER: You never signed a document that was labeled \"informed
> consent?\"
>
> MS. FERELLI: What I got\--
>
> PROF. DUBLER: What did you sign before your first surgery?
>
> MS. FERELLI: What I got from the\--which I found out now, all of my
> records and stuff, what I signed was one general release that I read
> that talked about anesthesia and stuff and another one, one page, that
> just said\--when they told me that they brought them back on the
> market, he said that I just have to promise to show up for several
> visits so that they can document and study my progress because they
> just brought them back on the market. So I said, okay.
>
> They never told me that you could get sick from them. If I did, I
> would have known a year and a half before\--when I had symptoms, I
> would have first realized that I could be having a reaction, but I
> went a year and a half of having these symptoms and nobody told me,
> not only the plastic surgeon that put them in. I was at St. Francis
> Heart Hospital in New York. I was at many different hospitals and I
> saw top doctors, cardiologists and nobody ever said that it could
> possibly be from that.
>
> Now that I know what happened to me, I have gotten\--
>
> PROF. DUBLER: Just a brief follow-up question. So the only research
> element you were aware of was your obligation to return\--
>
> MS. FERELLI: Right.
>
> PROF. DUBLER: \--for examinations following the implant.
>
> MS. FERELLI: Absolutely. That is why I called him from the hospital on
> December 1 to tell him that I couldn\'t make my appointment, because I
> had promised him I would be there. On the phone, he told me that this
> could have nothing to do with that and I have given documentation, and
> he also wrote up a letter and sent that to the study that said that I
> called from the hospital, I asked them if any of this could have
> anything to do with the implants, and he said, absolutely not.
>
> So he has even put in writing on two different occasions that
> absolutely no way could this have anything to do with the implants. So
> I believed him.
>
> PROF. DUBLER: Thank you.
>
> MS. FERELLI: Thank you.
>
> MS. WASSERMAN: My name is Connie Wasserman. I am a New York certified
> social worker. I am here on behalf of my niece, Vanessa Rose Ferelli,
> who I will refer to as Rose. I am not receiving any financial
> reimbursement of any kind for my testimony here today.
>
> My niece has been experiencing ill health since the end of 2000. She
> was experiencing heavy menstrual bleeding that left her body anemic
> and exhausted. Her gynecologist placed her on the pill hoping to
> regulate her cycle. She developed other symptoms such as hoarseness in
> her voice, paleness in her color, difficulty breathing and a chemical
> taste in her mouth.
>
> She would have episodes of passing out and was becoming progressively
> worse. I honestly did not know what to think. Doctors were attributing
> all these symptoms to extreme stress from the loss of her brother. I
> will never forget the terror in Rose\'s voice when she called me at
> 4:00 a.m. to tell me that she had figured out what her problem was.
> She was having a reaction to her breast implants.
>
> Was this all stress related? Something in her voice convinced me that
> this was real and she was very sick. I immediately contacted my
> physician for help when he told me that there was no evidence that
> linked breast implants with disease or illness. This was the same
> statement that we had heard from each of the other doctors.
>
> I indicated to him that I had heard this disclaimer from the other
> physicians, however, I wanted to know what he would do if this were
> his daughter. He then referred us to a prominent plastic surgeon who
> suggested removal.
>
> The doctor took X-rays and examined my niece. The X-rays did not show
> any leakage. The doctor blamed her chest pain and burning on the size
> of the implants and then recommended they be removed. He explained the
> details of the surgery with us indicating that there was a strong
> possibility she would not feel any better after the implants were
> removed.
>
> I counseled my niece by helping her to make a well-thought decision
> and not one in haste. I was concerned that if the implants were
> removed and she continued to feel sick, she might become depressed
> because of the scarring that could occur. She was adamant that, after
> being so sick for so long, she just wanted the implants removed and
> she did not care how she looked.
>
> Unlike many young women, Rose could afford to pay the doctor to remove
> the implants. Surgery proved what the X-rays did not show. One of the
> implants had ruptured. After the surgery, Rose began the slow road to
> recovery. Today, she is experiencing better health and more energy as
> well as elevated mood in spite of everything she has gone through.
>
> She is just grateful to be alive and feeling better. When I asked my
> niece what made her decide to get implants in the beginning, she told
> me that she was self conscious about her body and the doctor told her
> it was completely safe. My niece, along with many women who get breast
> implants, believe their doctors.
>
> In order to remove the implants, doctors had to carve out the scar
> tissue that formed around them. Many argue that it is important for
> some women who have poor body image and low self esteem. I cried when
> I saw the scarring that she was left with after the implants were
> removed.
>
> What about body image and self esteem now? Please, don\'t let this
> happen to other women. Please make sure breast implants are completely
> safe before they are approved.
>
> Thank you.
>
> DR. WOLFE: I am Dr. Sidney Wolfe. I do not get any money from Inamed,
> McGhan or any of the other companies and I drove out in my car today.
>
> Both the FDA approval standard for medical devices, \"reasonable
> assurance of safety,\" and the validity of informed consent, informed
> choice, are legitimate only if studies are long enough in duration and
> comprehensive enough to answer existing questions about safety.
>
> Instead of reasonable assurance of safety, there is now, more
> accurately, reasonable assurance of ignorance and, therefore,
> reasonable concern about safety. If the decision is to approve now,
> women will not get the information they need for truly informed
> consent before deciding whether to undergo silicone-gel breast-implant
> surgery.
>
> It is ironic that the clear evidence of certain danger such as local
> and regional complications, often from rupture, and remaining
> questions about other risks that led to the more-than-eleven-year-old
> moratorium on silicone-gel breast implantation, except for
> post-mastectomy patients, were based on much longer exposures of those
> women than now exists for the implants being seriously considered.
>
> Despite these deficiencies in the duration of the data being
> considered by the FDA, only the first three years of a planned
> ten-year study, there are many red-flag warning signals within the
> thousands of pages of documents put up on the Internet last week, more
> than enough to justify a decision to wait at least five more years to
> collect more information on the thousands of women who already have
> had implants rather than precipitously approving these unsafe devices
> for marketing to hundreds of thousands of women a year who will, once
> they are told by the government that devices have \"reasonable
> assurance of safety,\" opt for the surgery to insert them and,
> thereby, participate in a massive experiment.
>
> I think Dr. Krause gave you copies of my testimony because there are
> some charts which I just want to go through briefly. The first chart
> shows that the complication rates for the three-year data in the 1990
> Inamed study and the current core study are quite similar examining
> only the data on those implants in 1990 which Inamed is now seeking
> approval for. For example, for reoperation, it was 19.9 percent in the
> three-year 1990 and it is 20.6 percent in the three-year core.
>
> The next chart, though, shows the data from three years with that of
> five years in the 1990 study and shows the striking increase in the
> risk of various complications occurring just in the two years between
> Years 3 and 5. For example, the risk of removal/replacement increased
> from 6.3 percent to 11.5 percent in two years, capsular contracture
> went from 9.5 to 14.9 percent. The cumulative risk of breast pain
> which wasn\'t provided at three years in these data was already 25.8
> percent and loss of nipple sensation was 17.2 percent at five years.
>
> Since the five-year follow up in the 1990 study was not as great as it
> could have been, it is not unreasonable to hypothesize that, in the
> current core study, when\--not if; when\--the five-year data are
> collected prior to approval, hopefully, the risks will be as high or
> even higher than those found in the 1990 study.
>
> If you flip, now, to the third page, there are just four charts here
> that show, within the 1990 study, the effect of time on the increased
> risk of various complications, and this is in the face of having lost
> a number of people to follow up by the fifth year in that 1990 study.
> Breast pain goes from 14 percent at one year to 25.8 percent at five
> years, loss of nipple sensation from 11.8 percent to 17.2 percent,
> asymmetrical breasts increased from 5.9 percent in one year to 15.3
> percent at five years and the effect of the implant duration on
> whether the implant is actually palpable or visible, sort of contrary
> to the idea of a cosmetic operation, goes from 12.5 percent to 23.3
> percent at five years.
>
> Moving on to the next two charts, these are derived from the
> unpublished data from the SEER study funded by Inamed and Mentor using
> the NCI, National Cancer Institute, surveillance data. The most
> striking finding is that the Kaplan-Meier risk of implant
> removal\--this is projecting out on what you know, what is likely to
> happen\--was 21 percent at five years risk of removal in these women
> who had had post-mastectomy implants.
>
> But it has risen to 50.5 percent by ten years, more than doubling for
> those women with breast cancer who had a silicone-gel breast implant.
> In other words, by ten years, more than half of the women had their
> implants removed. This compares to 40.7 percent of those women getting
> saline implants. This is the only population-based study that we have
> on this topic with the advantages of better ascertainment to examine
> the problem of implant removal. It is noteworthy that, of the 6,563
> women with breast cancer in the geographic areas covered by the study,
> which are Iowa and Seattle, only 1, 159, or 17.7 percent of all those
> women had implants. The rest chose, I believe wisely, in most cases if
> not all, not to.
>
> There are in the study details for 1,012 of these; in other words, we
> have 87 percent ascertainment excellent follow up, much better than
> any of these studies. What it shows is, as I mentioned, it rises from
> 21 percent at five years, 27.4 percent at seven and 50.5 percent at
> ten years. I mentioned that rate was relatively, 20 percent, lower in
> the women getting saline implants.
>
> In addition to the primary deficiency of only having three years of
> data in the ten-year core study, according to the FDA, \"in the
> reconstruction study, only 59 percent of patients have reached the
> three-year follow-up visit. Worse, the follow up in the adjunct
> reconstruction group was only 53 percent at one year and 27 percent
> follow up at three years.
>
> Other problems noted by FDA reviewers were that, in addition to 92
> protocol violations in the core study, many involving a lack of
> informed consent as Vanessa Ferelli just mentioned, the adjunct study
> had even more egregious violations including 211 patients in whom
> informed consent was not obtained before surgery, 86 patients
> implanted in a facility without ethical review-board approval, and 25
> patients implanted by non-authorized investigators.
>
> According to another FDA medical officer who I think will present data
> this afternoon, Dr. Dawisha was very concerned about the lack of
> ascertainment of asymptomatic rupture since only a small fraction of
> these core patients had MRIs to detect rupture. This is particularly
> of concern because the FDA\'s own study, Dr. Brown\'s study, which she
> will talk about, based on 344 randomly chosen women who had had
> silicone-gel breast implants, found that 68 percent of the women had
> at least one ruptured implant using MRI. The median age of implant
> rupture was 10.8 years; in other words, half of them had ruptures
> after 10.8 year. 21 percent had silicone gel outside the capsule in at
> least one breast.
>
> Despite the concern about implant rupture and spread of silicone
> around the body, FDA stated that, \"Inamed provided no discussion of
> the significance of implant rupture,\" which includes published cases
> of lymph nodes, abdomen, groin and so forth.
>
> The final irony can be found in the section entitled Preclinical Shelf
> Life in one of the FDA documents. The document states, \"Based on all
> shelf-life data provided, Inamed supported a 2.5-year expiration date
> on their package label. The tests included gel cohesion\--obviously if
> it migrates to the body, the gel isn\'t terribly cohesive\--shell
> ultimate break force, shell tensile set and shell elongation. That is
> from the FDA document.
>
> Even though so many women are led to believe these implants will last
> at least ten years if not a lifetime, this 2.5-year \"expiration
> date\" is a further insult.
>
> The apparent unwillingness of the FDA to require silicone
> breast-implant manufacturers to provide longer-term data as a
> prerequisite to approval raises serious questions about whether the
> agency is enforcing the 1976 Medical Device Law to protect patients.
>
> The major precipitating event leading to the passage of that law was
> the disaster concerning the Dalkon Shield intrauterine device.
> Seventeen women died and thousands of women were rendered sterile
> because of the increased uterine infections caused by this device.
>
> Requiring adequate preapproval testing for permanently implantable
> devices such as breast implants was a major principle underlying the
> passage of the 1976 law. The agency appears poised to negate this
> principle as they consider the approval of breast implants.
>
> This year marks Sybil Goldrich, who generously gave me some of her
> time, twentieth anniversary since her battle with breast cancer. But
> that was only the beginning of her fight on behalf of women. After
> undergoing a bilateral mastectomy in 1983, she received breast
> implants. She, over the next couple of years, underwent seven
> operations, two mastectomies.
>
> During this time, she experienced excessive pain, capsular
> contracture, migration of gel to her uterus, ovary and liver,
> extrusion necrosis and rupture. Finally, she chose to have a tram-flap
> procedure. In 1998, Sybil cofounded Command Trust Network. I met her
> fifteen years ago when we originally got involved in silicone-gel
> breast implants, a national clearing house dedicated to providing
> thorough and unbiased information about breast implants.
>
> Since then, she has worked tirelessly to ensure government and
> corporate accountability with regard to breast implants. Her goal is
> to ensure a safe implant is available to all women. She does not think
> that the short-term data submitted for FDA approval begins to approach
> such a goal.
>
> Thank you. With three seconds to go.
>
> DR. WHALEN: Are there any panel questions of Dr. Wolfe? Seeing none, I
> would like to thank everyone who has testified this morning. We are
> going to break for lunch and resume activities precisely at 1:20 p.m.
> when other society testimony will be heard.
>
> \[Whereupon, at 12:35 p.m., the proceedings were recessed to be
> resumed at 1:20 p.m.\]
>
> A F T E R N O O N P R O C E E D I N G S
>
> \[1:30 p.m.\]
>
> DR. WHALEN: We are approximately 40 to 45 minute behind. I would urge
> everyone to try to keep within the time constraints as have been
> promulgated. As soon as the first speaker can come to the podium or is
> allowed to get at the podium, please feel free to begin.
>
> MS. NORSIGIAN: Thank you. My name is Judy Norsigian. I am Executive
> Director of Our Bodies, Ourselves and coauthor of the landmark book
> about women\'s health and sexuality, also titled, Our Bodies,
> Ourselves. Since the early 1970s, over 4 million copies in 18
> languages have appeared around the world and we include a section on
> breast implants which will be updated in our upcoming eighth edition.
> My organization has no conflict of interest with regard to this issue.
>
> Our interest in breast implants goes back to the mid-1980s when Ester
> Rome, my coworker, began to work with hundreds of women, both locally
> and nationally, who believed that breast implants caused them serious
> problems. Some of her interviews with women are reflected in the
> chapter that she wrote about breast implants in, Sacrificing Ourselves
> for Love, the book she coauthored just before her death from
> metastatic breast cancer.
>
> We still continue to hear from women, some of whom were initially very
> happy with their implants, that many of them have developed
> debilitating conditions after five or ten or fifteen years. Everyone
> knows that silicone-gel implants are more likely to break as they age,
> so it is essential that the FDA be concerned about what happens to
> women who have had their implants for at least five or ten or fifteen
> years.
>
> Inamed\'s own data show that, even in the first two or three years,
> there are substantial problems especially for breast cancer patients.
> I won\'t repeat them here, but I do want to underscore the fact that
> most of the 6 percent diagnosed with rupture had silent rupture and,
> therefore, leaking can continue for years without notice, as you have
> already heard today.
>
> Inamed also reported an alarming increase in many symptoms associated
> with autoimmune diseases for all implant patients including joint
> pain, fatigue, hair loss and muscle pain. If this is what is happening
> at two or three years using the best plastic surgeons that the company
> could find to participate in their study, what will happen to women
> across the country using less experienced doctors and with implants
> for ten or 20 or 30 years.
>
> One of the more disturbing aspects of the ongoing public debate about
> the risks of silicone implants has been the largely absent voices of
> physicians who have examined women with breast implants, those doctors
> who have looked more closely at the joint aches, fatigue, dry mouth
> and eyes and the masses of silicone that have hardened in up to
> 70 percent of the women\'s chests over time.
>
> To repeat Dr. Gary Solomon who has served as Associate Director of
> Rheumatology at New York University\'s Hospital for Joint Diseases
> Orthopedic Institute, \"Any physician who has seen a dozen of these
> women knows there are illnesses caused by implants.\"
>
> Unfortunately, as you have already heard, their symptoms and problems
> have not resulted in a clear clinical diagnosis. This difficulty with
> nomenclature has made it easier to discredit the women who have been
> suffering as well as their physicians who are trying to help them.
> Many experts agree that studies on silicone implants should include
> only women who have had implants in at least eight to ten years, since
> most leakage or rupture occurs after that period of time.
>
> Studies by the FDA\'s Dr. Lori Brown and her colleagues look at such a
> targeted patient population and show an increase in fibromyalgia among
> women with leaking silicone-gel breast implants. You will hear about
> that later.
>
> Let us also recall that three years ago more than 190,000 problems
> from breast implants had been officially reported to the FDA including
> 123 deaths. These complaints represented potentially more than 10
> percent of the estimated 1.5 million women who then had breast
> implants.
>
> We should also recall what happened in 1991 and \'92 when the
> breast-implant industry and the American Society of Plastic and
> Reconstructive surgeons spent approximately \$4 million in a PR
> campaign to try to downplay the potential risks of silicone breast
> implants and to block regulatory action by the FDA that might restrict
> access to these implants.
>
> A well-funded publicity effort underscored the greed of trial lawyers
> involved in breast-implant litigation referred to the medical
> literature indicating problems as junk science and urged women to
> phone and write the FDA to protest any regulation of the use of
> silicone implants. Rhetoric about giving women a choice was heavily
> employed and paid advertising spots featured women who wanted their
> right to choose breast implants.
>
> In the entire media flurry, what was often overlooked was the fact
> that breast-implant safety had never been demonstrated in over 30
> years of use despite the repeated pleas of women\'s health advocates
> and scientists at the FDA. In a climate where cosmetic surgery and
> breast-implant procedures are heavily advertised and promoted, it is
> not surprising that augmentation is on the rise despite the mounting
> evidence of harm.
>
> Many young girls are now given breast jobs as a high-school-graduation
> gift. With such a backdrop to these deliberations, it is especially
> important that FDA exercise extreme caution in the matter of approving
> a product that could have such long-term negative impact on so many
> otherwise healthy women.
>
> The FDA, which is charged to protect the public\'s health should deny
> approval of any breast implants until better data are available to
> resolve the ongoing debates about safety. Choices are great, but we
> need safe choice. What kind of choice is it to approve a product with
> very high complication rates and unknown health risks over time.
>
> I also want to give to you a letter from almost a dozen breast-cancer
> advocacy organizations who expressed similar views. They include the
> Mass Breast Cancer Coalition, other groups around the country.
>
> I just want to add a small footnote that, as a lapsed member of NOW,
> and I have not been following everything that NOW does, I can tell you
> that the representation of NOW as espousing a view that women ought
> not to care about their appearance is just pure hogwash.
>
> Thank you.
>
> DR. BASH: My name is Dr. Deborah Bash and I am a plastic surgeon at
> Mayo Clinic in Scottsdale, Arizona. I am here today representing
> myself. I have no financial interest in the manufacturer or any of
> their competitors. My travel expenses are reimbursed by Mayo Clinic
> for my travel today. I perform both reconstructive and cosmetic breast
> surgery with breast implants. I am paid on a fixed salary which is
> independent of the type and amount of surgery that I perform.
>
> I appreciate the panel providing me the opportunity to testify today.
> This is an important issue and I believe I have a unique perspective
> to offer for consideration. As a woman who has had a
> breast-augmentation surgery and a board-certified plastic surgeon, I
> can speak to both the clinical side and the patient side of these
> issues.
>
> I decided to have a breast augmentation in 1985 when I was a
> third-year medical student. At that time, of course,
> silicone-gel-filled implants were the most common device used for the
> procedure and that is what I had. As a medical student interested in
> plastic surgeon, I was a particularly well-informed patient.
>
> I knew what to expect and I was very comfortable with the decision
> that I made. I believe now, as I did then, that silicone-gel-filled
> implants are a safe option for women considering breast augmentation.
> I have not had any problems with my breast implants and, in fact, in
> 1999, I chose to have the original implants replaced.
>
> I knew when I had my first procedure that the implants would not last
> a lifetime, just as any medical device will eventually need a
> replacement. After 14 years, I chose to have my implants replaced with
> new silicone-gel implants rather than saline-filled implants because I
> had that choice. And, as a patient and a board-certified plastic
> surgeon, I knew silicone-gel implants would give me a better cosmetic
> result.
>
> Since my surgery in 1999, I continue to be a very satisfied patient.
> My experience as both a surgeon and a patient puts me in a uniquely
> credible position to discuss breast reconstruction and breast
> augmentation with my patients. I share with every one of my patients
> my history of breast implants and, in fact, my mother has also had a
> mastectomy and has silicone-gel implants at my recommendation.
>
> While my experience allows me to relate to patients at the different
> level, I am concerned because they do not have the same access and
> choices that I had. I believe it is important that patients understand
> the difference between silicone and saline implants. As part of the
> informed-consent process I use with all of my patients, I ask patients
> to touch and feel both types of implants.
>
> I explain the history of the implants and I tell my augmentation
> patients that, unfortunately, they do not have a choice for saline-gel
> implants. In my experience, it is rare that a primary augmentation
> patient prefers a saline implant after holding and touching both
> devices.
>
> It has also been my experience that, when I operate on women with
> aging silicone implants who desire replacement, that they chose to
> have a saline implant when they have a choice of silicone or saline. I
> believe they make this decision based on positive personal experience
> and informed consent.
>
> It has been my professional and personal experience that
> breast-augmentation patients should have the same options available
> that reconstructive patients have.
>
> Thank you very much for your time and consideration.
>
> MS. GILBERT: Doctor, this is Alisa Gilbert. Just out of curiosity, do
> you do any special protocol yourself in follow up or\--how do you do
> your own follow up? I mean, are you getting MRI, or you haven\'t had
> any problem whatsoever.
>
> DR. BASH: I have regular\--my annual breast exams and my mammograms,
> just like any women would for routine breast care. I am also on the
> Mentor silicone-gel adjunct study and I have done my follow up at my
> one-year, three-years, and then I have my five-years coming up.
>
> MS. GILBERT: Thank you.
>
> MS. KEITHLEY JOHNSTON: Good afternoon. My name is Kathy Keithley
> Johnson and I am the Executive Director of Toxic Discovery, a national
> consumer-advocacy organization whose primary goals are education and
> emotional support for individuals who have sustained injuries from
> silicone and saline breast implants.
>
> Toxic Discovery presently maintains a database of over 25,000 injured
> consumers with over 10,000 of those with breast implants. My expenses
> of my staff to attend this hearing were paid by private donations from
> our members and from the injured consumers. I also would like to
> submit to you today a collection of individual stories from the women
> called, We are the Evidence.
>
> My personal journey has well prepared me for my present position as
> Director of Toxic Delivery. I am a registered nurse. I am a former
> surgical nurse and I am former Director of Hematology Oncology. But,
> more important than my nursing background, I am yet another injured
> consumer.
>
> I am also one of the nurses in the Harvard Women\'s Study. I was
> implanted free of charge in Midland, Texas and was approached to
> become a spokesperson or poster child for the manufacturers. I so
> elected not to take part.
>
> During these hearings, the FDA will be determining once again whether
> or not to lift current restrictions on the use of silicone implants.
> We ask you, the committee, what restrictions have the FDA truly
> enforced? The breast-implant manufacturers and plastic surgeons of
> this nation would like to consumer to believe that silicone implants
> have been restricted over the years. We say there has never been a
> true restriction or protection.
>
> I ask you, who is minding the breast-implant store? The experts here
> today are not you, this learned committee member, nor are the experts
> the breast-implant manufacturers. The experts here today are not even
> the plaintiff attorneys or the defense teams. The experts here today
> and remain the injured who have suffered in the name of corporate
> greed.
>
> Mark McClellan, the FDA Commissioner, wrote a white paper a few years
> ago entitled, Protecting the Public Health; FDA Pursues an Aggressive
> Enforcement Strategy. In Mr. McClellan\'s paper, and I quote, \"The
> agency is committed to pursuing Food, Drug and Cosmetic Act
> violations.\" Toxic Discovery believes that violations are being
> committed daily via the route of the silicone breast prosthesis.
>
> In view of the supporting evidence and facts, silicone breast implants
> have never been approved safe. lifting restrictions would appear
> purely motivated by special-interest groups and organizations of
> plastic surgeons and of the breast-implant manufacturers. Lifting the
> restriction will allow the unchecked violations to continue.
>
> It was Abraham Lincoln from my sister state of Illinois that said,
> \"Sin by silence when they should protest make cowards of men.\" The
> breast-implant women of this world should no longer suffer in silence.
> The women and children of this continued medical experimentation will
> remain the evidence with or without the FDA\'s so-called approval.
>
> No committee including this one can change those facts. In Missouri,
> we were fortunate in January 2000 to pass a law concerning informed
> consent directly related to breast implants. The only other state that
> has such a law is the one I am visiting today, the Great State of
> Maryland.
>
> I stand before you as injured consumer but one that knows the truth of
> product failure and corporate lies. I hear you speak of research and
> yet you turn away from the truth. We, the injured consumers, continue
> to be your research. We, the injured consumers, are your evidence and
> we will remain just that, evidence that not medical device is totally
> safe but especially the new PMA application that Inamed would lead you
> to believe that is new and improved.
>
> Informed consent should being with informed individuals. Freedom of
> choice versus informed consent implies that women are aware of the
> consequences of their actions. But the women requesting breast
> implants are not provided the truth and continue to be the victims of
> social pressure and medical fraud.
>
> The right to choose is meaningless without the right to know. The poor
> unsuspecting cancer patient has received a double insult to injury.
> They have, in a large majority of cases, survived cancer to only learn
> in the years to follow that the very device that they believed would
> make them whole again would later cause further mutilation.
>
> Let us also not forget that the largest contributors to the majority
> of cancer organizations are the breast-implant manufacturers and
> corporations. As a former director of oncology, I know this very
> up-front and personal. Do you really want to hand over a legacy of a
> new generation of a breast implant to the\--
>
> DR. WHALEN: Can you conclude, ma\'am?
>
> MS. KEITHLEY JOHNSTON: \--to the consumers who were so irresponsible
> to thousands? May I say that I gave up five minutes for Allen Keithley
> this morning who was unable to attend.
>
> DR. WHALEN: Ma\'am, you have five minutes and you are 52 seconds
> beyond that now. If you could conclude, please.
>
> MS. KEITHLEY JOHNSTON: Women historically have been the cash cows of
> the medical profession. Women continue to be spoon-fed from the cradle
> to the grave how they should look by a media-funded,
> manufacturer-driven, silicone cartel. It is beyond time that we, the
> consumers, demand a safe breast implant.
>
> We, the breast-implant women, demand from the FDA that you do not
> approve Inamed\'s application and we ask you to defer approval until
> only a safe implant can be offered. The injured masses call on you,
> the committee, to save the next generation and the second generation
> of women that breast-fed their children. Do not allow the silicone
> holocaust to continue.
>
> MS. GILBERT: Ms. Keithley, I have a question for you. Alisa Gilbert.
>
> MS. KEITHLEY JOHNSTON: Yes, ma\'am.
>
> MS. GILBERT: How many of the you said 25,000 patients or consumers
> that you\--
>
> MS. KEITHLEY JOHNSTON: We have 25,000 members.
>
> MS. GILBERT: How many of those are breast-cancer survivors?
>
> MS. KEITHLEY JOHNSTON: Out of that statistic, I would say only
> probably 25 percent since I am an oncology nurse, or was a former
> oncology nurse. Most of that is known and we do open our doors. That
> is our first love is the cancer patient.
>
> MS. GILBERT: So you provide your main\--the support that you provide
> to the participants that you represent is specifically support or\--
>
> MS. KEITHLEY JOHNSTON: We are the only organization that I know of in
> the United States for breast-implant survivors and cancer survivors
> that had breast implants that failed that you actually get to speak to
> one of our people. All of our registered nurses that answer the calls
> all had breast implants, they all failed and they all had them
> removed. I have never received one nickel from the breast-implant
> manufacturer in any litigation nor, also, do I take a check from Toxic
> Discovery. I do this from a passion.
>
> DR. PAUL WEISS: Good afternoon. My name is Dr. Paul Weiss and I am a
> practicing plastic surgeon in New York City. I am here representing
> the National Endowment for Plastic Surgery and thank you for the
> opportunity to present today. I have no financial affiliations with
> the manufacturer, its product or its direct competitors.
>
> As part of my practice of plastic surgery, I perform breast-implant
> surgery both for reconstructive and aesthetic indications. I,
> therefore, derive a portion of my income from this type of surgery.
> The American Society of Plastic Surgeons is paying my travel expenses.
>
> The National Endowment for Plastic Surgery was established in 1994 to
> provide an ongoing secure funding source for specialty-based research
> projects. The Endowment was established by and is maintained by the
> Plastic Surgery Education Foundation, the research, education,
> domestic and international service arm of the American Society of
> Plastic Surgeons. The Endowment represents an unprecedented
> specialtywide cooperative effort and is funded solely through
> voluntary contributions of plastic surgeons and grateful patients.
>
> The National Endowment is very important to organized plastic surgery
> and was created to support initiatives that are relevant to the
> immediate day-to-day clinical practice of plastic surgery. In 1991 and
> 1992, the manufacturers faced the FDA\'s call for the PMAs for
> silicone-gel-filled breast implants. The impact of this request
> created a crisis for implant recipients. From that experience came the
> realization that, as a specialty, we needed to be much more proactive
> in our research efforts.
>
> With a commitment to our patients, sound science and quality research
> data, organized plastic surgery established the Endowment as a
> perpetual source of research funding for the specialty. Its mission
> includes supporting research directed toward defining the efficacy and
> safety of established plastic-surgical procedures, investigating
> innovative technology and plastic surgery, sponsoring research
> scholarships and fellowships and charitable programs in plastic
> surgery.
>
> The review process used by the endowment for awarding research grants
> is rigorous. The process and the application form are modeled after
> those of the National Institutes of Health. The grant awards are
> selected by an expert panel of clinical and scientific researchers,
> many of whom have served on NIH review panels or are recipients of NIH
> grants.
>
> While the Endowment is in the early years of awarding research grants,
> I would like to share with you information on the implant research
> funded to date. In 2001 and 2002, the National Endowment provided
> funding to establish and conduct research at the Center for Implant
> Retrieval and Analysis at Washington University in St. Louis,
> Missouri, and Bioaesthetic Plastic Surgery Center, also in St. Louis.
>
> The emphasis of this study was to determine the modes, causes and
> rates of implant failure. The study determined and demonstrated the
> types of scientific analyses needed for each type of implantable
> device used by plastic and reconstructive surgeons. The analyses were
> macroscopic, microscopic, mechanical, chemical and physical.
>
> A significant outcome of this research is that a standardized protocol
> has been developed which gives surgeons a clear approach for
> management of explanted breast implants.
>
> Another research project funded by the Endowment is a two-year study
> that measured the analysis of physical benefits of breast-reduction
> surgery. Plastic surgeons and our patients have faced numerous
> challenges in recent years. As a specialty, we are at the forefront of
> both reconstructive plastic surgery and aesthetic plastic surgery.
> Perhaps, most importantly, we are more strongly committed than ever to
> facilitating and conduction good research and being more responsive as
> advocates for our patients.
>
> In conclusion, the studies funded through the National Endowment for
> Plastic Surgery will provide information that will help determine best
> practices and deliver safe and effective care to plastic-surgery
> patients. We are confident that the FDA will review the scientific
> data on silicone-gel-filled breast implants and make its decisions
> based on the best interests of patients.
>
> Plastic surgeons want safe products for their patients and fully
> support the FDA\'s ongoing regulatory process for breast implants.
> Plastic surgeons want good quality research data to drive the clinical
> decision-making.
>
> Thank you.
>
> DR. McGRATH: May I ask you a question, Dr. Weiss?
>
> DR. WEISS: Yes.
>
> DR. McGRATH: You said that you founded the Endowment in 1994. Ms. Kim
> Gandy, this morning, from NOW, made the comment or the statement
> that\--I believe she said large sums of money have been spent by
> plastic surgeons to convince patients that implants can be used
> safely.
>
> Could you tell us how you have used Endowment moneys, plastic-surgery
> moneys, for that purpose, please.
>
> DR. WEISS: All of the Endowment funds are used to fund research
> projects and nothing more. There is no advertising or media money
> spent by the Endowment.
>
> DR. MANNO: Barbara Manno. Doctor, have these studies been published in
> peer-reviewed journals, any of the data?
>
> DR. WEISS: The one study on the effects of Betadine in breast implants
> has been published but mostly the work that has been done regarding
> breast implants has been to establish protocols for their study rather
> than reaching conclusions at this time.
>
> DR. CASAS: Good morning. My name is Dr. Laurie Casas. Before I begin,
> I would like to let the panel know that the relevant statistics for my
> testimony can be found stapled to the copies of my testimony.
>
> I am Dr. Laurie Casas. I have no financial ties to any implant
> manufacturer. I am neither a witness nor a party in an impending law
> suit. I am Communications Commissioner for the American Society for
> Aesthetic Plastic Surgery, also called ASAPS. My travel expenses to
> this hearing were paid for by ASAPS.
>
> I am an associate professor of surgery at Northwestern University
> Feinberg School of Medicine. I have published extensively on
> breast-surgery topics. I am currently participating in an IRB-approved
> multi-site prospective outcome study on patient satisfaction following
> cosmetic procedures. In addition, I am a board-certified plastic
> surgeon in clinical practice for more than 13 years. Therefore, a
> portion of my income is derived from breast-implant surgery.
>
> Plastic surgeons continue to fully support the FDA\'s ongoing
> regulatory process regarding breast implants. The FDA, the medical
> literature, plastic surgeons and their patients have raised valid
> concerns about these devices and, for the first time, we have data to
> respond to these specific concerns.
>
> The results of two surveys of more than 5,000 women with or
> considering breast implants will be published in the Aesthetic Surgery
> Journal, ASAPS\' peer-reviewed clinical publication. In these two
> retrospective outcome studies, these 5,000 women were anonymously
> surveyed in two separate questionnaires.
>
> The first study surveyed 2,129 women with implants of which 13 percent
> had silicone gel and 1,625 who were considering implants. They were
> asked questions related to their demographics, compliance with
> follow-up appointments, body image, motivation, reoperation and
> quality of life.
>
> The second study surveyed 1,359 women with breast implants of which 13
> percent had silicone gel. They were asked questions regarding why
> women may not return for follow-up visit, the adequacy of informed
> consent, their ability to get health insurance, and overall
> satisfaction with breast augmentation.
>
> The research was funded by the nonprofit Aesthetic Surgery Education
> and Research Foundation, ASERF. Each survey was posted on the
> independent website implantinfo.com over a period of months. The
> on-line surveys were implemented by professional research firms with
> protection in place to ensure respondents anonymity and to prevent
> multiple survey submissions. Neither ASAPS, ASERF nor implantinfo.com
> had access to the data before it was analyzed. The margin of error is
> plus-or-minus 3 percent at a 95 percent confidence interval.
>
> Both surveys showed that women\'s motivation for having their breasts
> enlarged primarily relates to their sense of self. In the first
> survey, the top reasons for choosing breast augmentation for 79
> percent or more of the respondents were; to look better in clothes, to
> feel better about themselves, to feel more confident and to feel less
> self-conscious. Pleasing others was one of their lowest priorities.
>
> Results of both surveys showed that women\'s expectations were met by
> the procedure. 92 percent said they were happy about their decision to
> get breast implants. 89 percent said the augmentation completely or
> mostly met their expectations and 94 percent said they would recommend
> breast augmentation to their friends or family. And if they choose,
> based on what they know today, would women with implants in this
> survey choose to get them again? 84 percent said they would very
> likely do so and 82 percent reported an improvement in
> self-confidence.
>
> The outcomes research also shows that women considering augmentation
> were not impulsive about their decision. 77 percent considered
> augmentation for at least a year before undergoing surgery and more
> than half thought about it for three or more years.
>
> The demographics from this data was very interesting. It showed that
> the median age of the respondents was 34. 75 percent are either
> married or in long-term relationships. 84 percent had at least some
> college education and 45 percent at least had a Bachelor\'s degree.
> And the respondents came from every state as well as Puerto Rico and
> the Virgin Islands
>
> The 2,800 members and candidates of the American Society for Aesthetic
> Plastic Surgery fully support the FDA\'s ongoing review of implant
> safety and efficacy and rely upon the agency\'s evaluation of the
> current science regarding silicone products.
>
> MS. GILBERT: Excuse me. I have a question. Alisa Gilbert. So you had
> 5,000 women in the study.
>
> DR. CASAS: Yes.
>
> MS. GILBERT: Where were they on this scale? A year after their
> surgery? I know that you said that some of them were considering
> surgery and some of them weren\'t. Do you have any kind of\--
>
> DR. CASAS: We have women from the \'80s to 2002 that were augmented.
>
> MS. GILBERT: Okay. How do these numbers reflect that? I mean, so 91
> percent wanted to look better in clothes or 92 percent said they were
> happy about the decision to get breast implants, but I guess what I
> want to know is how many of them were their first year out, their
> second year out, from implant surgery.
>
> DR. CASAS: We don\'t have the data broken up that way. We have
> it\--Dr. Leroy Young will complete the data for you and then, if he
> can speak to that, he will.
>
> MS. GILBERT: Okay. Thank you.
>
> MS. BROWN: This is Debbie Brown. I had a follow-up question. Of the
> questionnaires that you sent out, what was your percent respondents?
>
> DR. CASAS: It wasn\'t a send-out questionnaire. It was an on-line
> survey.
>
> MS. BROWN: And so did everybody respond or what was your percent
> respondents?
>
> DR. CASAS: Well, you mean the people that started the survey, did they
> finish the survey?
>
> MS. BROWN: Yes.
>
> DR. CASAS: Because once you sign on, then you complete the survey. I
> don\'t have that information.
>
> DR. YOUNG: Approximately 85 percent of people that started the survey
> finished the complete survey.
>
> MS. BROWN: Thank you.
>
> DR. YOUNG: I am Dr. Leroy Young. I have no financial ties to any
> implant manufacturer and am neither a witness nor a party in a pending
> law suit. I am testifying for the Aesthetic Surgery Education and
> Research Foundation, also known as ASERF. My travel expenses were paid
> by ASERF. The Foundation funded the research that I will be telling
> you about concerning two surveys of more than 5,000 women with or
> considering breast implants.
>
> I am a board-certified plastic surgeon and a portion of my income is
> derived from breast-implant surgery. In the past, I have received
> research funding from McGhan, now Inamed, and have served as a consult
> to breast-implant manufacturers. I am Chairman of the National and
> Co-Chair of the International Breast Implant Registries. I am
> currently Co-Chair of the Breast Surgery Committee of the American
> Society for Aesthetic Plastic Surgery also known as ASAPS. Results of
> my research will be published in ASAPS\' peer-reviewed clinical
> publication.
>
> Plastic surgeons have shared the FDA\'s concerns about certain issues
> raised in previous breast-implant hearings which is why I undertook
> the two surveys I will be speaking about today. One of the most
> important issues raised previously was whether breast-augmentation
> patients have been adequately informed about risk associated with
> breast implants.
>
> In the second survey, of 1,350 breast-augmentation patients, more than
> 90 percent of women remembered being provided with important
> information such as what to expect after surgery, specific
> complications, breast-implant deflation or rupture, and that breast
> implants do not last forever. 88 percent reported being actively
> involved in the decision about the size of their implants.
>
> We also explored the issue of reoperation. In the first survey of more
> than 2,000 women with implants, only 13 percent reported a revision
> and nearly all of them chose implant replacement, not permanent
> removal. Most of the reasons for revisional surgery were cosmetic in
> nature such as the desire for larger implants.
>
> Many women experienced breast pain associated with their menstrual
> cycles, nursing or other reasons. Surprisingly, a larger percentage of
> women without implants reported breast pain than women with implants.
> We also learned that 93 percent of breast-augmentation patients had
> all of their children before undergoing to procedure so nursing was
> not an issue. Of the small percentage who had children and nursed them
> after augmentation, there was essentially no difference in the rate of
> reported problems.
>
> There have been concerns about whether women with breast implants are
> being denied health insurance. The survey results indicate that more
> than 90 percent of women with implants have insurance. Of those who
> applied for insurance after receiving breast implants, 91 percent were
> able to obtain insurance. A small number of women were charged at a
> premium and a number of others had a two-year exclusion on their
> policy for breast-related problems. The margin of error of the surveys
> I am talking about is a plus-or-minus 3 percent at a 95 percent
> confidence interval.
>
> In the first survey, we have data covering the past ten years of
> patients\' experience with breast-augmentation. There were more than
> 2,000 patients with saline and more than 250 with gel implants. This
> is an expected distribution given that silicone was not on the general
> market.
>
> We have some preliminary data on comparisons between the devices
> regarding patient outcomes. For some findings, there are no
> statistically significant differences: fulfillment of expectations,
> whether patients would recommend the procedure, breast pain severity
> and frequency, asymmetry, skin wrinkling, hematoma and infection.
>
> Other data indicate statistically significant differences between
> saline and gel regarding patient outcomes. Examples are natural feel
> of the breast, capsular contracture and reoperation. We plan to make
> this data available to the FDA as soon as analysis is complete.
>
> Plastic surgeons are concerned that a small percentage of women say
> that breast augmentation does not meet their goals. We are gratified
> that these results demonstrate an overwhelming number of women report
> satisfaction with the procedure and we are constantly striving to make
> women\'s experience with breast implants meet their expectations.
>
> We fully support the FDA\'s ongoing scientific review of implant data
> and I thank you for the opportunity to present.
>
> DR. BURKE: I am Dr. Martha Burke. I am Chair of the National Council
> of Women\'s Organizations. We are the nation\'s oldest and largest
> coalition of women\'s groups representing 170 organizations and 10
> million women collectively. I have been paid by no one to appear
> today. I am here representing the American women from all
> socioeconomic, ethnic and income groups that my groups represent.
>
> We work on a wide variety of issues and, until now, we have never
> testified before the FDA. But, after hearing the stories of women who
> have been harmed by breast implants, we are here to show our concern
> for them and for women across the country who might be considering the
> implants.
>
> Some argue that breast implants have already been studied more than
> any medical device. If that is true, perhaps there is a good reason.
> More than \$2 billion in legal settlements might influence the need
> for research and the incentive for companies to fund such research.
> Unfortunately, even \$2 billion cannot guarantee good-quality
> research.
>
> I am here to let you know as panelists that American women who depend
> on the FDA to safeguard their health and safety are watching. We are
> not here to pressure you to vote a certain way but we are here to urge
> you to carefully scrutinize the safety of this product and answer
> these two key questions.
>
> If a product with high complication rates is approved, will the
> company that makes that product have an incentive to improve it? And
> if a company provides inadequate long-term safety data and the product
> is improved anyway, will the company have an incentive to improve
> their research?
>
> I would like to tell you about one of the many women who wanted to
> testify here today but could not come, one being Sharyn Noakes who is
> 55 years of age and she is too ill to be here. She had two sets of
> silicone-gel implants. The first was removed after only eight months
> due to extreme capsular contracture. When the surgeon opened her up,
> the implants were both ruptured. They were replaced with new implants
> that she kept for 24 years. And this is what she had to say.
>
> \"I had the implants removed when the pain and deformity became too
> much for me. The surgery that should have taken 90 minutes took over
> three-and-one-half hours. The implants had ruptured. The silicone and
> scar tissue had calcified and embedded into my chest. I was rushed to
> the hospital next door.\" This was apparently even outpatient surgery.
>
> \"I did not have cancer but I had to undergo surgery similar to a
> double mastectomy because of the silicone. I am forced to live
> deformed and I am very ill with several autoimmune disease. I believe
> there are many women like myself who will suffer when ruptured
> implants stay in their bodies.
>
> \"We are not like an automobile having our oil changed. Surgery is
> expensive and many women won\'t have enough money to have the implants
> removed. I am now on 13 different medications. Fortunately, my husband
> is retired military and I am able to get my medication free.
> Otherwise, it would cost me \$1,500 a month to stay alive.
>
> \"Would you like to see what your wife, daughter, mother or girlfriend
> could look like after having the implants for 24 years? Please look at
> my picture.\"
>
> Sharyn\'s story reminds me that the Center for Medicare and Medicaid
> Services is suing several breast-implant manufacturers to recover
> millions of dollars that Medicare had paid out in healthcare for older
> women harmed by breast implants. It doesn\'t make sense for one
> government agency to sue for healthcare costs while a different agency
> makes the same product even more available.
>
> I hope some of you will ask Medicare how they made this decision to
> sue. Do they know something that this panel needs to know? Women
> should have many options in their lives including safe medical
> products. Unfortunately, Inamed did not study the health risk or the
> cosmetic risk involved in this product. As Sharyn Noakes\' testimony
> shows, the cosmetic and health effects can be devastating.
>
> In closing, I remind you, if the FDA improves silicone-gel implants,
> they can\'t require informed consent because the FDA cannot enforce
> that. The FDA can\'t restrict the gel implants to cancer patients or
> to women over 18 because the FDA cannot enforce that.
>
> The FDA can only make meaningful restrictions on access if this panel
> decides that the company has not proven that the implants are safe. As
> you listen to testimony today, vote for approval only if you are
> confident that these implants are safe for long-term use.
>
> Thank you.
>
> DR. YOUNG: Good afternoon. I am Dr. Laurie Young, not to be confused
> with Dr. Leroy Young who preceded me.
>
> I should first clarify that I am not paid by anyone who is involved in
> any kind of litigation or involved in the promotion of anything
> related to silicone gel breast implants.
>
> I am the executive director of the Older Women\'s League. The voice of
> midlife and older women is the only national grass-roots membership
> organization focused solely on issues affecting midlife and older
> women.
>
> As you know, the risk of breast cancer increases with age and since
> our mission is to improve the lives of women over the age of 40, we
> are very concerned about the safety of silicone gel breast implants.
>
> We know that women with breast cancer want to have choices.
> Fortunately, however, these women have more options than ever before.
> Most will not need a mastectomy and if they choose to have one, saline
> breast implants and other reconstruction surgeries offer alternatives
> to silicone gel breast implants, so the standard for approval should
> be are these that are being considered by a panel today safe for women
> to use.
>
> We know that many women with breast cancer who were happy with their
> implants at first, have problems that arise and are entirely
> consistent with the high rate of complications that Inamed will be
> reporting to you today, such as 46 percent need additional surgery
> within two to three years, 25 percent have had their implants removed,
> 6 percent had a ruptured implant, 6 percent had moderate to severe
> breast pain, and 6 percent had necrosis which means that the skin or
> breast tissue around them died.
>
> Everyone knows that silicone gel implants are more likely to break as
> they age. When silicone gel implants break, the silicone can leak into
> the lymph nodes and other organs and unfortunately, Inamed did not
> study the health risks involved.
>
> If there are so many complications in the first two or three years,
> what will happen to women with implants for 10 years or more? Most
> women in their 40s or 50s, we know now will live another 25 to 40
> years.
>
> I would like to tell you about one of the many women who wanted to
> testify here today, but were unable to come. Susan Nicewonger lives in
> St. Louis. She received implants more than 20 years ago for
> augmentation. This is what she says:
>
> \"Over time, my breasts looked and felt as if I had two croquet balls
> for breasts. I will always remember how humiliated I felt when my
> gynecologist performed my annual breast exam. Her facial expression
> revealed disgust at having to examine my breasts. I actually had to
> request that procedure from her each year. Clearly, she wanted to
> avoid it.
>
> \"Sleeping on my abdomen was not an option, too painful. Soreness was
> a way of life. Anything that required air movement, hence, breast
> movement, was painful. It was when I began to notice a sound similar
> to scrunching cellophane when my right breast moved that I knew
> something was terribly wrong.
>
> \"A trip to the doctor and a subsequent MRI confirmed that I had a
> ruptured silicone implant and surgery would be necessary. My implants
> were removed this past May. Because of the leakage, breast tissue had
> to be removed from the right breast which has left me disfigured and
> unable to wear most bathing suits or any neckline that would reveal
> the sunken half of my right breast.
>
> \"I am, however, extremely grateful that those foreign, hard, painful
> objects have been removed from my body. I can\'t be certain of the
> path that migrating silicone has taken inside my body or how it will
> eventually manifest, but it is on my mind every single day of my
> life.\"
>
> I want to echo the comments expressed by Dr. Burke who said that the
> CMS, Medicaid and Medicare are now exploring legal methods to recover
> funds for the surgeries and medical treatments that women have had to
> experience as a result of these implants.
>
> Again, I ask you today to be concerned and serious, and not to make
> judgments based on inadequate or studies that are not complete. Women
> deserve complete information, if we are to be truly informed, it
> can\'t be on half-baked information.
>
> Thank you.
>
> MS. LOZIER: (Read by Nancy Nealand.) Good afternoon. My name is Nancy
> Nealand and I am here reading for Christine Lozier from Hackensack,
> New Jersey.
>
> \"My name is Christine Lozier and I am from New Jersey. I have no
> conflicts of interest. I got my first set of silicone gel breast
> implants in the 1980s, but my breasts hardened soon afterwards and I
> had to have them replaced two years later.
>
> \"Cosmetically, the results of the second implantation were very good,
> but then, five years later, I developed autoimmune symptoms and other
> health problems I had never had before, like asthma, Raynaud\'s
> syndrome, and fibromyalgia.
>
> \"After living with my debilitating health problems for over a decade,
> I decided three years ago to have an MRI. It detected that the left
> implant had ruptured and was leaking. When I went to a doctor to get
> both implants removed, it was discovered that my right implant was
> also leaking. As a result of the leak, I had to have a partial
> mastectomy in my right breast to remove silicone, not cancer.
>
> \"I bled severely and had drains for two weeks. Four months later, I
> underwent reconstructive surgery and had saline implants put in. The
> right one deflated two months afterwards. I had it replaced and two
> months later developed an infection and a rash on my left side.
>
> \"Because of the rash, I had to have both saline implants removed and
> replaced with new ones. It was during this surgery that my doctors
> discovered silicone that had escaped my left implant during my very
> first explantation and was still in my body.
>
> \"Since my first explantation, I have undergone a total of six
> surgeries, and each time I have needed to have drains put in because
> of severe bleeding and infection. It has been one year since my last
> surgery, and I still have pain in my left side from the silicone under
> my skin that cannot be removed.
>
> \"Each one of my reconstructions was paid for out of pocket and
> overall I have spent \$60,000 trying to get my body back to normal.
> Each time I have needed to be out of work for two weeks at a time and
> even though the silicone has caused severe health problems for me, I
> am stigmatized by my co-workers because I had implants and people have
> no sympathy for my condition.
>
> \"None of my doctors ever warned me of the possible effect silicone
> implants could have on my body and now that I am sick, they deny that
> silicone had anything to do with my illnesses. I feel betrayed and
> lied to and I am telling my story because I don\'t want future women
> to have to go through what I have been through.
>
> \"Please, don\'t allow silicone gel breast implants to go back on the
> market unless they are proven to never leak. If you require real proof
> of safety, I have no doubt that implant makers will develop a safer
> implant. If you don\'t, they will continue to sell the kinds of
> implants that have harmed so many of us.
>
> \"Thank you.\"
>
> DR. KASPER: My name is Dr. Anne Kasper and I came here at my own
> expense. I have no conflicts of interest.
>
> I am a partner in Finding My Way, a support service for breast cancer
> patients that is in Bethesda, Maryland. I am also the senior editor
> and an author of the book Breast Cancer: Society, Shapes, and
> Epidemic.
>
> Breast cancer patients have more choices than ever before and while it
> is important to have choices, and tell this to all the women in our
> practice, when a woman is diagnosed with breast cancer, the choices
> are often very difficult to make.
>
> The good news today is that three out of four women newly diagnosed
> with breast cancer can choose to have a lumpectomy with radiation
> instead of a mastectomy, and if a woman needs to wants a mastectomy,
> she can choose saline breast implants, silicone gel implants, or
> autologous tissue transfer procedures.
>
> How important is it that silicone gel breast implants be widely
> available to cancer patients? Under the current restrictions, the vast
> majority of women who want silicone gel implants for reconstruction
> are able to get them, but breast cancer patients are cautious, they
> want to live long lives and they have faced a life-threatening
> disease.
>
> They also, however, are concerned about cosmesis and how they will
> look after cancer treatment. Many will choose lumpectomy which allows
> them to keep their breasts, preserving their appearance and the
> sensory feelings of the breasts, but what women tell us\--and this is
> the take-home message from my talking with you today\--is that they
> only want silicone gel implants if they can be assured that they are
> safe.
>
> Women are often encouraged to choose implants and sometimes a rosy
> picture is painted about the benefits of implant reconstruction. In
> our practice, women are often disappointed to have reconstructed
> breasts that have none of the sensory, sexual, and maternal capacities
> of a normal breast and that often have complications.
>
> Many reconstruction patients who choose silicone gel implants are
> happy with their implants at first, but unfortunately, many then
> experience the kinds of complications that you have heard today and
> that Inamed has found, which include 46 percent will need additional
> surgery, 25 percent will have their implants removed, 6 percent will
> have a ruptured implant, 6 percent will have moderate to severe breast
> pain, and 6 will suffer from necrosis.
>
> In the Inamed core study of breast cancer patients, only 6 percent of
> the implants broke during the first two or three years, but over time
> we know that that percentage increases dramatically, and it is, of
> course, much more serious than when a saline implant breaks.
>
> As you know, when silicone gel implants break, silicone can leak into
> the lungs, the lymph nodes, and other organs.
>
> To determine the safety of silicone gel implants, Inamed should have
> studied the health of women whose implants broke especially since
> cancer patients may have compromised immune systems, unfortunately,
> they did not.
>
> Another shortcoming of the Inamed research is that it only included
> African-American breast cancer patients in the core study and only
> five Asian-American women. Obviously, this is not sufficient data on
> which FDA would make safety decisions for all American women.
>
> Both of those groups have approximately the same rates of cancer as
> white women, and African-American women are especially susceptible to
> autoimmune disease. All of these groups of women must be studied
> adequately to determine if implants are safe for them.
>
> The bottom line, though, is that the complication rates for breast
> cancer patients are very high in just the first two or three years.
> What is ahead for these women in five years, 10 years, or even 20
> years? Most breast cancer patients are living longer lives today and
> many choose mastectomy as a way to put the cancer behind them.
>
> With implant reoperation rates of 46 percent in the first two or three
> years alone, and higher rupture rates in the years to come, many women
> will not consider implants a satisfactory and safe choice at all.
>
> It is unusual to ask for more than two years of safety data for a new
> product, but silicone gel implants are not new. Inamed is asking for
> approval for an implant that has not changed much, if at all, in more
> than a dozen years.
>
> If FDA had strictly enforced restrictions on breast implants
> established in 1992, we would now have 10- year data rather than two
> or three years.
>
> If FDA approves silicone gel implants based on the data that has been
> provided, it sends the message they are not as concerned as women have
> a right to expect about the health and safety of breast cancer
> patients and especially women of color.
>
> If FDA allows silicone gel implants to remain on the market, but only
> as part of clinical trials, and this time requires a third party to
> monitor the studies, then perhaps breast cancer patients will finally
> get the information they need to make a meaningful choice.
>
> Thank you.
>
> DR. ANDERSON: I have a question. You have made the statement that
> cancer patients have these options and that silicone implants are
> widely available. I work in the Seattle community and actually I
> don\'t know of the availability of silicone implants.
>
> It would be an unusual plastic surgeon that would offer it as part of
> reconstruction, so I am curious what the basis of your statement that
> the silicone is easily available.
>
> DR. KASPER: Well, the ones that we see here in the Washington, D.C.
> area have been able to get the silicone gel implants when they wanted
> them. I am basing my testimony on our practice.
>
> DR. ANDERSON: Thank you.
>
> DR. WILLEY: Members of the General and Plastic Surgery Devices Panel,
> I am Shawna Willey. I am a medical doctor and a Fellow of the American
> College of Surgeons. I practice in Washington, D.C., general surgery
> with an emphasis on breast surgery. I am an Assistant Professor at
> Georgetown University.
>
> I am proud to represent the 64,000 fellows at the American College of
> Surgeons and thank you for the opportunity to offer a general
> surgeon\'s perspective on the issue of silicone gel-filled breast
> prosthesis for patients who are considering breast reconstruction or
> augmentation procedures.
>
> I have no financial relationship with any medical device
> manufacturers.
>
> Today, I would like to focus my comments on breast reconstruction and
> augmentation as procedures that improve the quality of life for our
> patients. Reconstruction of a breast that has been removed due to
> cancer is one of the most valuable surgical procedures available
> today. New medical techniques and devices have made it possible for
> surgeons to create a breast that can come close in form and appearance
> to matching a natural breast.
>
> Frequently, reconstruction is possible immediately following breast
> removal or mastectomy, so the patient wakes up with a breast already
> in place having been spared the experience of seeing herself with no
> breast at all.
>
> The availability of breast reconstruction gives the woman an option
> over which she has some control at a very emotional time. Both breast
> reconstruction and augmentation provide enormous benefits to women
> including an improved self-image and a sense of normalcy, but as is
> true with any operation, a patient must think carefully about her
> expectations and discuss them with her surgeon.
>
> The American College of Surgeons has a long-standing commitment to
> improving the quality of surgical patient care and to enhancing
> patient safety. Therefore, we are eager to hear more about the data
> collected by the manufacturer on the safety of silicone gel-filled
> breast implants and we welcome the FDA\'s review of these safety data.
>
> If these devices prove to be unsafe, we, of course, would not support
> their use in patients. Patient is always, and will always be, the
> primary concern of the College, but we also feel strongly that
> decisions that effectively limit patient options must be made on the
> basis of solid scientific evidence.
>
> We are concerned that procedures with benefits that are life-enhancing
> rather than life-saving are occasionally viewed by society as somehow
> less important. Breast implants should be regarded as any other
> medical device that is being considered by this panel. Further,
> distinction should not be made between the use for reconstruction or
> augmentation purposes. If the device is safe in one group, it should
> be safe in the other.
>
> Following more than 10 years of clinical studies and trials, if
> conclusive data are not found showing that these devices pose a
> significant risk to patients, we believe the choice to use them should
> be made by consenting patients.
>
> The College also agrees that it is vital for any woman considering a
> breast implant procedure to be well informed of all possible risks
> associated with the procedure, as well as with the device being used.
>
> Women must be informed, for example, that breast implants do not last
> forever, that complications can occur, and that additional operations
> may be necessary. Consequently, we support this panel\'s continuing
> efforts to ensure that breast implant patients have access to
> comprehensive and comprehensible material that can be used by patients
> to make informed decisions about these procedures.
>
> To conclude, let me reiterate that all surgeons are obliged to be
> scrupulous in ensuring their patients are provided with the
> information they need to give truly informed consent for any
> operation. We are certainly hopeful that the information collected by
> the manufacturer of these devices will contribute significantly to
> these efforts and help resolve the continuing uncertainty about the
> safety of these devices.
>
> Thank you again for the opportunity to speak today.
>
> MS. VOLPE: Thank you for allowing me to present this statement. I am
> Margaret Volpe, a breast cancer survivor with a silicone breast
> implant. I have no financial ties to manufacturers or health care
> providers and am not being reimbursed for my appearance here.
>
> I am a volunteer representing Y-ME National Breast Cancer
> Organization. Y-ME has received a minuscule amount of funding from
> manufacturers, but none in the past 18 months. Y-ME is committed to
> providing support and accurate information to empower individuals
> touched by breast cancer so they can select the most appropriate
> options in conjunction with their health care provider.
>
> W-ME\'s comments concern silicone implants for breast reconstruction
> or other medical need. We have no opinion on silicone implants for
> cosmetic purposes. We are not endorsing a product or manufacturer, but
> feel strongly that silicone breast implants should be more widely
> available as an option for women requiring reconstruction.
>
> When I was diagnosed with breast cancer in 1995, I faced fears and
> anxiety common to those diagnosed with a life-threatening illness. It
> was important to have reconstruction, to feel whole again, to not be
> constantly reminded of my breast cancer and to get on with my life.
>
> I have had no problems or complications with my implant since my
> reconstructive surgery in February 1996. Options for reconstruction
> are limited. There is tram flap reconstruction, major abdominal
> surgery with a painful recovery period, leaving us without our
> abdominal muscles. Women who are too thin do not have this option.
>
> If a woman has a tram reconstruction on one breast, she is unable to
> have a second tram at a later date. The latissimus dorsi
> reconstruction usually requires an implant. Saline implants are
> available, but for many they are unsatisfactory. A silicone implant
> gives a more natural look and feel.
>
> Y-ME emphasizes the need for a range of treatment options, so that
> each woman can choose what best fulfills her needs.
>
> The availability of silicone implants is important to women with
> breast cancer. It was difficult to get my implant because of FDA
> restrictions. I signed a lengthy and detailed informed consent. Even
> though a breast cancer patient theoretically can obtain silicone
> implants through a clinical trial, it is difficult for many women to
> enroll in a trial if the surgeon is unaware of or unable to
> participate in a trial.
>
> Please adhere to the science when evaluating silicone breast implants.
> The Institute of Medicine\'s exhaustive and definitive review of
> existing research found no evidence that silicone breast implants
> cause cancer or disease and no convincing evidence that silicone
> produces a immunologic response.
>
> The report states such diseases or conditions are no more common in
> women with breast implants than in women without them. U.S. Court\'s
> National Science Panel and several European Government Scientific
> Panels issued similar findings.
>
> NIH recently reported to Congress that a large meta-analysis published
> in the New England Journal of Medicine concluded there was no evidence
> of an association of silicone gel-filled breast implants with
> connective tissue diseases or other autoimmune or rheumatic
> conditions.
>
> Y-ME urges women to fully understand the risks and benefits of any
> medical or surgical choice. Women should understand that no medical
> device lasts forever. Shunts, pacemakers, and artificial knees and
> joints have an expected life span and possible complications including
> capsular contracture.
>
> Women must be aware of such side effects as capsular contractions,
> potential rupture, and the need for replacement. Doctors must provide
> accurate information about the risks and benefits of silicone implants
> because informed consent is key.
>
> As stated in the letter from several cancer and nonprofit health
> organizations, there should be long-term follow-up and data collected.
> Privacy-protected patient registries and physician tracking are vital
> along with timely communication of significant findings to consumers,
> patients and providers.
>
> In an effort to resume their life after a devastating disease, breast
> cancer survivors must be assured the right to select appropriate and
> effective medical therapies or devices.
>
> Y-ME urges you to consider the plight of these women, but in the end,
> to act based on the science alone.
>
> Thank you very much.
>
> DR. WHALEN: Thank you and on behalf of the panel, I would like to
> thank everyone who testified today for either their societies,
> organizations, or a individuals for taking time out of their schedules
> to talk with us. There will be further public testimony as we initiate
> our activities tomorrow morning.
>
> Before I go on to Dr. Witten, just briefly, there will be a slight
> change in schedule due to our lagging behind somewhat. Dr. Witten will
> be giving a presentation on Regulatory Overview of Silicone Gel-Filled
> Breast Implants and we will then take the afternoon break following
> which the sponsor will make their presentation.
>
> Dr. Witten is the director of the Division of General and Restorative
> Devices.
>
> Dr. Witten.
>
> **Regulatory Overview of Silicone Gel-Filled**
>
> **Breast Implants**
>
> DR. WITTEN: Thank you for the introduction.
>
> Good afternoon. I would like to welcome everyone to this meeting of
> the General and Plastic Surgery Devices Panel. I am Dr. Celia Witten,
> Division Director of the Division of General, Restorative, and
> Neurological Devices in the Office of Device Evaluation at FDA.
>
> I will talk about why we convened this meeting, what we are asking
> you, our distinguished panel, to do and provide the regulatory
> background for silicone gel-filled breast implants.
>
> We have convened this panel meeting to obtain your recommendations on
> whether there is a reasonable assurance of safety and effectiveness
> for the Inamed silicone gel-filled breast implant. We ask that you
> base your recommendations on the valid scientific evidence contained
> in the premarket approval or PMA application for this device and on
> your scientific and clinical experience.
>
> The FDA will listen to your deliberations and recommendations and all
> the evidence presented here today. After the panel meeting, FDA will
> continue to review the information contained in this PMA and we will
> consider the recommendations of this distinguished panel.
>
> Ultimately, FDA will make a decision on the approvability of this
> medical device.
>
> Now, I will move on to talk about the regulatory background for these
> devices. At the time of the medical device amendments in 1976,
> silicone gel-filled breast implants were already being marketed. FDA
> classified these implants as Class III in 1988, which means that they
> would require premarket approval in order to be sold.
>
> However, like other devices that were grandfathered under the 1976
> Medical Device law, they were allowed to remain on the market until
> FDA issued a rule calling for safety and effectiveness information.
> This occurred in April 1991.
>
> At that point, manufacturers had 90 days to submit PMAs with data
> demonstrating the safety and effectiveness of their implants. Several
> PMAs for silicone gel-filled breast implants were submitted.
>
> In November 1991, an advisory panel meeting was held to discuss the
> silicone gel-filled breast implant PMAs. A voluntary moratorium was
> issued after that panel meeting, requesting that it cease marketing of
> silicone gel-filled breast implants while FDA reviewed the safety and
> effectiveness information that was submitted.
>
> In February 1992, a second advisory panel meeting was held to discuss
> that new information. In April 1992, FDA announced its decision that
> no sponsor had submitted adequate safety and effectiveness data to
> support approval of their silicone gel-filled breast implant.
>
> Accordingly, silicone gel-filled breast implants became
> investigational devices at this point, however, FDA determined that
> there was a public health need for breast implants for reconstruction
> and revision patients.
>
> To address this public health need, FDA approved adjunct studies
> designed to allow for continued access of silicone gel-filled breast
> implants for reconstruction and revision patients.
>
> Inamed, in 1998, and Mentor in 1992, submitted protocols for an
> adjunct study and received approval. These studies currently remain
> active.
>
> At the current time, FDA has not approved any PMAs for silicone
> gel-filled breast implants. They remain investigational devices, which
> means that today, a patient must be enrolled in an adjunct study or an
> IDE study in order to receive one of these implants.
>
> I should add that in 1999, FDA issued a final rule calling for
> saline-filled breast implant PMAs, and in May 2000, two of these
> saline-filled breast implant PMAs were approved.
>
> FDA has provided guidance to manufacturers both in written form and
> direct discussions to assist them in developing the data needed to
> support a PMA. The FDA\'s guidance document provides manufacturers
> with information in several important areas.
>
> The Chemistry Section describes how to analyze the device, the
> Mechanical Section recommends bench testing, and the Toxicology
> Section includes a description of the types of biocompatibility
> information. All this preclinical testing is designed for evaluating a
> long-term implant.
>
> The Clinical Section details information regarding study design, data
> presentation, and information on presentation of literature review.
>
> So much for a brief summary of where we are with silicone gel-filled
> breast implants. Now for the task at hand.
>
> Inamed has submitted a PMA to the FDA for its silicone gel-filled
> breast implant, and that PMA will be the focus of our discussion over
> the next few days. This is the first PMA submitted for a silicone
> gel-filled breast implant since 1992.
>
> We are asking this panel to evaluate the information in Inamed\'s PMA
> and advise us as to whether there are sufficient information to
> provide a reasonable assurance of safety and effectiveness.
>
> Each panel member has been provided a list of questions to consider as
> he or she reviews the data. We have heard this morning a number of
> comments from the public and there will be an additional open public
> comment session tomorrow.
>
> FDA appreciates the effort our stakeholders have gone to, to provide
> us with input, and I want to assure everyone here that we will take
> these comments seriously as whether or not to approve this product.
>
> What follows after the break will be presentations from Inamed and FDA
> on this application. Following that, we will solicit the advice of the
> panel on what action we should take with respect to the application
> before us.
>
> The FDA very much appreciates your giving of your time and expertise
> to accomplish this important task.
>
> I will now turn it back over to you, Dr. Whalen.
>
> DR. WHALEN: Thank you, Dr. Witten.
>
> Are there any panel member questions for Dr. Witten in regard to her
> presentation?
>
> DR. ANDERSON: I have a question. Does FDA offer guidance as to what
> defines safety and efficacy?
>
> DR. WITTEN: There is a definition of safety and effectiveness which is
> in our law, which we will read during the voting process. It is
> something\--I can\'t tell you the exact wording\--but it is something
> like it is safe if there is a reasonable assurance that the benefits
> outweigh the risks in the target population for its intended use.
>
> DR. WHALEN: It is footnoted in your booklet. I can\'t tell you the
> exact page right now, but each of those definitions are in two
> continuous pages in the information that was provided us.
>
> DR. WITTEN: Actually, it is cited in the panel question, because the
> panel questions that you have, have the definition in there, because
> we wanted you to keep it in mind as you answered our questions about
> safety.
>
> DR. WHALEN: No other questions? Seeing none, we will take a 10-minute
> break. I would ask the sponsor to be ready to start at 10 minutes to
> 3:00 their presentation.
>
> \[Break.\]
>
> **Applicant Presentation**
>
> **Inamed Corporation**
>
> **McGhan Silicone-Filled Breast Implants**
>
> **Introduction**
>
> DR. EHMSEN: Members of the Advisory Panel, FDA staff, interested
> guests, I am Ron Ehmsen, Senior Vice President in charge of Clinical
> and Regulatory Affairs for Inamed Corporation. As such, I do have a
> financial interest in the company.
>
> My colleagues and I are very happy to be here today to have the
> opportunity to present a summary of the clinical and preclinical data
> that we believe supports our premarket approval application for McGhan
> silicone gel-filled breast implants.
>
> \[Slide.\]
>
> We are also joined by a number of consultants and experts in their
> various fields: Professor Donald Berry from the University of Texas
> and M.D. Anderson Cancer Center; Dr. James Brenner, who is our central
> MRI reviewer, he is a radiologist in private practice in Santa Monica,
> California; Professor Michael Brook, Professor of Chemistry and
> McMaster University; Dr. James Lamb, who is a toxicologist with the
> firm of BDL Associates in Virginia; Joseph McLaughlin, Dr. McLaughlin
> is President of the International Epidemiology Institute here in
> Maryland; Professor Kathleen Rodgers from the University of Southern
> California; Professor David Sarwer from the University of
> Pennsylvania; Dr. Howard Smith from Cleveland Clinic; and Dr. Scott
> Spear, who is Professor and Chairman of the Division of Plastic
> Surgery at Georgetown University Medical Center in Washington, D.C.
> Dr. Spear also serves as our principal medical consultant on the
> clinical studies that will be reported here today.
>
> For clarification purposes, Inamed Aesthetics, which is a business
> entity of Inamed Corporation, was formerly known as McGhan Medical
> Corporation, hence, the reference to the trademark McGhan in reference
> to our breast implants.
>
> Our PMA was submitted in December of 2002 for breast augmentation in
> women over 18 years of age, for breast reconstruction, and for breast
> implant revision, which includes removal and replacement of previous
> breast implants.
>
> \[Slide.\]
>
> This PMA covers seven device styles as shown in this slide, four
> smooth round, two textured round, and one textured shaped implant. The
> photographs on the righthand side of the slide show the smooth round,
> the upper photo, and the textured shaped in the lower photo.
>
> \[Slide.\]
>
> Today, we will discuss the preclinical and clinical findings that were
> submitted in support of our PMA, as well as review the peer-reviewed
> research that we believe adds a great deal of credibility.
>
> \[Slide.\]
>
> First, our key findings.
>
> \[Slide.\]
>
> Our data demonstrates that McGhan silicone-filled breast implants are
> safe and effective. Eighty-nine percent of the patients in the
> revision cohort, 93 percent in the augmentation cohort, and 96 percent
> of the patients are satisfied at two years follow-up.
>
> Lower rates were found for most complications in Inamed\'s
> Silicone-Filled Breast Implants compared to Inamed\'s saline-filled
> breast implants which were approved by FDA in 2000.
>
> \[Slide.\]
>
> The peer-reviewed research demonstrates that there is no increased
> risk of breast cancer, no increased risk of rheumatic or autoimmune
> disease, and no negative effect on children of women with breast
> implants.
>
> Tom Powell, our Director of Technologies, will now discuss the results
> of our preclinical studies. He will be followed by JoAnn Kuhne, our
> Senior Director of Regulatory and Clinical Affairs, who will discuss
> the results of our clinical studies.
>
> Let\'s begin with the preclinical. Mr. Powell.
>
> **Preclinical Studies Review**
>
> MR. POWELL: Thank you, Dr. Ehmsen. Good afternoon. I am Tom Powell,
> Director Technology at Inamed, and I have a financial interest in the
> company.
>
> I am presenting the preclinical data from evaluations performed by
> Inamed.
>
> \[Slide.\]
>
> The key preclinical findings are: Silicone materials employed in
> Inamed\'s gel-filled breast implant demonstrate biocompatibility and
> support the Institute of Medicine\'s report where the committee
> concludes that a review of the toxicology studies of silicones and
> other substances known to be in breast implants does not provide a
> basis for health concerns, and that silicone materials meet the
> physical property specifications for breast implants.
>
> \[Slide.\]
>
> Inamed\'s preclinical studies included toxicological evaluations,
> chemical evaluations, and the mechanical evaluations, meeting the
> requirements contained in the guidance for saline, silicone gel, and
> alternative breast implants, guidance for industry and FDA.
>
> For the purposes of this presentation, the findings are summarized.
> Complete documented results have been submitted to the agency.
>
> \[Slide.\]
>
> Toxicity evaluations demonstrated material biocompatibility as
> described in the FDA\'s guidance document for breast implants included
> pharmacokinetics studies, in vivo and in vitro standardized toxicity
> testing, and studies investigating special toxicological concerns of
> immunotoxicity, reproductive, and developmental toxicity,
> mutagenicity, chronic toxicity, and carcinogenicity.
>
> \[Slide.\]
>
> Inamed\'s pharmacokinetics evaluation was a scientific study tracking
> the movement of silicone gel implanted without an elastomer shell
> subcutaneously in rats. As shown in this gel study, the silicone gel
> is encapsulated and remains localized at the site of implantation with
> minimal distant movement.
>
> This result agrees with the IOM report which had similar findings
> where studies showed that deposit of gel, whether free or in implants,
> remained almost entirely where injected or implanted.
>
> Additionally, the submitted review of silicone distribution studies
> from literature further supported the IOM conclusion that, \"There do
> not appear to be long-term systemic toxic effects from silicone gel
> implants or from unsuspected compounds in the gels or elastomers
> detected by animal experiments.
>
> \[Slide.\]
>
> A battery of standard toxicological testing was performed on silicone
> elastomers and silicone gel. This battery investigated a variety of
> biocompatibility parameters including cytotoxicity where the silicones
> of breast implants were found non-cytotoxic, hemocompatibility
> demonstrating that silicones are non-hemolytic, pyrogenicity showing
> the silicones are non-pyrogenic, acute systemic toxicity demonstrating
> the implant materials are non-toxic, intracutaneous irritation finding
> that silicones are non-irritant, intramuscular implantation where
> silicones of breast implants are found non-toxic, and dermal
> sensitization where the silicones were found to be non-sensitizing.
> All testing demonstrated the biocompatibilities of these breast
> implants silicone materials.
>
> \[Slide.\]
>
> Additional toxicological studies were undertaken to evaluate areas
> described as special considerations in the breast implants guidance
> document.
>
> The immunotoxicity studies evaluating the test animals\' immune
> response to silicone elastomers and silicone gel were performed using
> National Toxicological Program methodologies.
>
> These assays investigated various immunologic parameters including
> antibody response to antigen, T cell, T cell subset, and B cell
> enumeration, mixed leukocyte response, and natural killer cell assay.
>
> In all testing, no adverse immunologic effects of silicone materials
> was found.
>
> \[Slide.\]
>
> The reproductive and developmental toxicity assessment included
> fertility/teratology and reproductive toxicity studies. The results
> from these studies sponsored by Inamed demonstrate that silicone
> materials used in breast implants are neither reproductive nor
> developmental toxins as there was no effect on parental, fetal, or
> offspring parameters.
>
> Additionally, the submitted review of silicone reproductive and
> developmental toxicity studies from literature further supported these
> results.
>
> \[Slide.\]
>
> A series of standardized mutagenicity assays designed to investigate
> the potential for genetic damage was performed on silicone elastomers
> and silicone gel. The studies used both bacterial and mammalian cell
> cultures and included Ames assay, forward mutation assay, mouse
> lymphoma assay, unscheduled DNA synthesis assay, cell transformation
> assay, and in vitro cytogenic/chromosomal aberration assay.
>
> In all testing, no evidence of mutagenic activity was found.
>
> \[Slide.\]
>
> Subchronic toxicity studies demonstrated that breast implant silicones
> again were non-toxic. Studies investigating potential for long-term
> organ or tissue damage and possible cancer development from exposure
> to silicone elastomers and silicone gel of breast implants were
> performed using the two-year chronic carcinogenicity tests in rats.
>
> The carcinogenicity testing demonstrated that incidents of carcinomas
> were similar to controls except for the expected occurrence of
> solid-state tumors. Rodent models for this testing are particularly
> prone to develop solid-state tumors at the site of implantation of
> foreign bodies. This well-known rodent response to implanted materials
> is not a physiologic reaction observed in humans.
>
> In this two-year chronic testing, the recognized gold standard to
> evaluate long-term toxic effects, no evidence of systemic toxicity or
> cancer other than rodent solid-state was observed in association with
> silicone materials.
>
> \[Slide.\]
>
> Overall, the extent of amount of toxicity testing performed has
> demonstrated that the silicone elastomers and silicone gel used in
> Inamed\'s breast implants are biocompatible and do not compromise the
> body\'s physiologic system.
>
> \[Slide.\]
>
> Looking at preclinical data, the preclinical chemical data
> characterizing silicone materials in breast implants support the
> findings of biocompatibility. The chemical evaluations focused on the
> silicone materials extent of crosslinking, extractable compounds, and
> heavy metals content characterization.
>
> \[Slide.\]
>
> The physical strength and elasticity of the silicone implant shell and
> patch materials are a result of the extent of crosslinking achieved
> during the vulcanization process. Physical property testing of
> elongation and tensile strength demonstrates the consistency across
> elastomer lots and that materials conformed to pre-established
> specifications
>
> Validation testing ensured that the process that is used by Inamed to
> produce implant shells are adequate to achieve a crosslink density
> that assures for every lot the strength and elasticity to meet the
> American Society of Testing and Materials Standard F703, Specification
> for Breast Implants.
>
> Every lot and every batch of silicone gel is tested to ensure the
> crosslink density conforms to predetermined specification using
> penetrometer testing prior to being released for use in the
> manufacturing of breast implants.
>
> MS. GILBERT: Excuse me. Can I ask a question here real quick?
>
> MR. POWELL: Certainly.
>
> MS. GILBERT: How do you measure the strength of an implant? Can you
> just give us an example of how you tell, I mean do you run a car over
> it, how do you measure it?
>
> MR. POWELL: There are number of physical tests that are run on the
> materials. Some are standard physical property testing of elongation
> and tensile strength run on a testing piece of equipment known as a
> tensile tester Enstron. They have various brand names.
>
> We actually will talk about, in the Mechanical Section, additional
> testing that is run on the devices themselves.
>
> MS. GILBERT: Thank you.
>
> \[Slide.\]
>
> MR. POWELL: Finished, sterilized devices were analyzed using
> techniques to detect extractable components including solvent
> extraction followed by gas chromatography using a mass spectrometer,
> ionization detector, and analysis by gel permeation chromatography.
>
> Levels of extractable silicone materials were determined and results
> of the toxicological testing of the implant materials demonstrated
> their biocompatibility and non-toxicity and support the IOM report
> where the committee concluded that a review of the toxicology studies
> of silicones known to be used in breast implants does not provide a
> basis for concern at expected exposures.
>
> \[Slide.\]
>
> Heavy metal analyses were performed with separate chemical analysis on
> the shell, patch, and gel. Metal concentrations were found comparable
> to approved saline-filled breast implants. Specific analysis with
> respect to catalyst platinum and tin were performed.
>
> Material toxicity testing demonstrated the biocompatibility of
> gel-filled breast implant materials and supported the IOM Committee
> conclusion that evidence is lacking for an association between
> platinum in silicone breast implants and local or systemic health
> effects in women who have these implants.
>
> \[Slide.\]
>
> Addressing the preclinical mechanical data, it demonstrates that the
> materials meet physical property specifications for breast implants.
>
> The mechanical preclinical evaluations included fatigue testing, gel
> bleed testing, and gel cohesiveness evaluations.
>
> \[Slide.\]
>
> Fatigue testing assesses the number of cycles at specific applied
> loads that a device can endure without the rupture of the shell.
> Smaller sizes of smooth and textured devices, representative of
> Inamed\'s gel-filled implants were compressively test.
>
> The testing was performed on individual worse case devices, those with
> a minimum acceptable thickness using load control equipment. For this
> testing, implants were tested at applied load levels of 20, 30, 40,
> and 55 pounds until either device failure was observed or 6 1/2
> million cycles was reached.
>
> In addition to cyclic testing, a test assessing the force to rupture
> from a single compression of an implant was performed. The minimum
> average force for this single compressive failure was 1,245 pounds
> force. This force is significantly greater than what would be normally
> experienced in vivo, such as the maximum 55 pounds force exerted by
> mammography equipment.
>
> Fatigue values from the applied load test cycles and the single
> compressive tests were used to generate applied force per number of
> cycle graphs and a threshold force, the force below which an implant
> can undergo an unlimited number of cycles without rupture failure was
> determined.
>
> The minimum threshold value was determined to be 30 pounds force which
> calculates to a safety factor of 8.1 compared to the expected maximum
> in vivo cyclic load of 3.7 pounds force. This means that implants can
> withstand more than 8 times the maximum expected cyclic load it would
> experience implanted in the body.
>
> PROF. DUBLER: Excuse me, I have a question.
>
> MR. POWELL: Yes.
>
> PROF. DUBLER: If that is the case\--and perhaps you will deal with
> this later on in your presentation\--and if the rupture rate is as
> reported, then, does the company have theories about what would
> undergird the rupture rate, if it\'s not a matter of force? You seem
> to be comfortable in all of the data that you are producing about the
> strength of the elastomer.
>
> MR. POWELL: The fatigue test is an in vitro test. There is a number of
> factors that are involved in the specific design of the fatigue test
> that may not be really predictive of an in vivo model.
>
> PROF. DUBLER: And is that true for other of the tests that you are now
> presenting the findings from?
>
> MR. POWELL: Yes, the gel bleed testing would be another in vitro
> assessment that really has no direct clinical correlation.
>
> \[Slide.\]
>
> Talking about the gel bleed testing, gel bleed testing assess the
> diffusion rates of silicone gel components through the implant shell
> and is a PMA requirement.
>
> The study design was consistent with ASTM F703 method and involved the
> use of a silicone disk technique and results have no direct clinical
> correlation.
>
> The calculated normalized diffusion rate value did not exceed 0.0019
> g/cm^2^/week.
>
> DR. WHALEN: Mr. Powell, this is Dr. Whalen with a question on that.
> When you assert that there is no clinical correlation to that, how
> would you then counter someone looking at that\--and I am engineering
> challenged, I will admit\--who wanted a sound byte to say, well, we
> have shown that it leaks, but it leaks slowly?
>
> To me, that would have enormous clinical import, but you say that
> doesn\'t have clinical implications?
>
> MR. POWELL: The silicone materials are really not readily soluble in
> an aqueous solution. This test methodology represents the worst case
> test method that can be assessed with some type of reliability in
> terms of a result.
>
> DR. WHALEN: Well, to follow up, I would assume that that standard is
> incorporated into the requirements for a device like this because of
> in-vitro concerns about leakage. If not, why else would it be done?
>
> MR. POWELL: This was a test method involved in the ASTM Specification
> F703 to get an assessment technique, so that different designs of gel
> implants could be assessed for different rates of gel bleed diffusion,
> more to be used as a comparative for different designs.
>
> \[Slide.\]
>
> Gel cohesiveness testing assesses the cohesion characteristics of
> silicone gel. Finished device gel testing was performed as per ASTM
> F703 methodology for gel cohesion.
>
> Cohesion result values were well below the accepted 4.5 cm maximum
> value identified in the ASTM standard for gel-filled breast implants.
> The results ranged from zero to 1.1 cm.
>
> DR. CONANT: A quick question. In terms of the cohesive testing, does
> silicone tenacity change at different temperatures? I assume these are
> done at room temperature versus body temperature?
>
> MR. POWELL: The testing is done at room temperature, that is correct.
>
> DR. CONANT: But how does the\--
>
> MR. POWELL: The crosslinking of the silicone is very thermally stable,
> so once it is crosslinked, it is not going to change with temperature.
>
> DR. MANNO: Excuse me, I have a question also.
>
> This gel bleed that you mentioned, was that the method that was
> presented in the material using the filter?
>
> MR. POWELL: The earlier drafts of the gel bleed was using filter paper
> and now we use silicone disk as the absorbent media.
>
> DR. MANNO: You are using a silicone disk to check for silicone gel
> leakage or bleed?
>
> MR. POWELL: We used an extracted silicone elastomer disk that is more
> absorbent to the silicone materials coming through the silicone
> implant shell than filter paper would be, so it\'s the worst case
> technology.
>
> DR. MANNO: How are you getting from to get to your amount of bleed
> from there?
>
> MR. POWELL: Over an eight-week course of study, weekly measurements
> are taken of the weight gain of the silicone disk that the implants
> are placed on and then replaced in exactly the same location.
>
> DR. MANNO: Okay.
>
> DR. MILLER: Dr. Whalen, could I ask a question? I think that you said
> something which caught a lot of our attention, that I just think we
> need to clarify.
>
> You said that the tests you are using have no clinical correlation or
> something like that, and I think that from the engineering point of
> view, what you are trying to say is that there are no comparable
> events in the body that are similar to the contrived test you are
> doing in a materials engineering sort of way, but the results you are
> getting have clinical implications because they are telling you
> something about the nature of the materials in the implants. Is that
> accurate?
>
> MR. POWELL: I would say that would be accurate if you wanted to
> compare between two devices, if you had similar experimental data
> between two different designs, then, you could make somewhat of an
> assessment in terms of a clinical outcome, but until you have a
> correlation between both the physical mechanical testing and the
> clinical outcome, it may not be directly related.
>
> DR. MILLER: There is a limitation\--I mean I just want to make sure I
> understand you\--when you do the tests, you get results. The results
> tell you something about the materials. How you move from those
> results to what is going to happen in a clinical situation is subject
> to some limitations.
>
> MR. POWELL: It would be correlated with the clinical studies, yes,
> sir.
>
> PROF. DUBLER: Dr. Whalen, I don\'t understand. I don\'t understand
> what you would like us to do with the data that you have just
> presented in terms of the sorts of deliberations that we are required
> to have.
>
> Can you tell us how you would like us to view the data that you have
> just presented?
>
> MR. POWELL: Let me refer to my colleague, Dr. Brook, maybe could
> better answer that question.
>
> DR. BROOK: My name is Michael Brook. I am a Professor of Chemistry at
> McMaster University in Hamilton, Canada, and I am a paid consultant to
> Inamed.
>
> I can understand the sense of confusion on the part of the committee
> and perhaps I can try and clarify the situation.
>
> When one is trying to do a materials test, you want reliable and
> reproducible tests that allows you to understand just how easily
> material is going to bleed, is going to leak out through this implant.
>
> We all know silicones are typically used for waterproofing materials.
> If you want to put shoe polish on that contains silicones, so that the
> water beads up, and if one was to try and design perhaps more
> clinically relevant tests, for example, into water, the problem is
> that the measurements are almost impossible to do. You don\'t get
> reliable data because so little goes into water or saline or other
> artificial materials that you can\'t get reliable data.
>
> So, the ASTM test is designed kind of like Kleenex in water. We all
> know that the water wicks up into the Kleenex. If you choose silicone,
> which is the material in which silicones will dissolve, you kind of
> get the worst case scenario. You learn how bad it could possible be
> under the worst possible case.
>
> You are essentially allowing it to go into a sponge that has exactly
> the same kind of properties. So, this allows you to develop a test in
> which you have reliable data, measurable data, quantifiable data, so
> you have good certainty, good numbers, and it counts as a worst case
> scenario. The problem is that you can\'t do that same kind of test
> into water, which is what you might like to do in order to make the
> clinical correlation. It is just so little that goes in, you can\'t
> use it as a reliable test.
>
> DR. CHOTI: Just a question. Do these preclinical tests, any
> differences between the smooth and textured, or the double lumen and
> single lumen?
>
> MR. POWELL: All these tests were done on both smooth and textured
> devices.
>
> DR. CHOTI: Are there differences in bleed in mechanical properties?
>
> MR. POWELL: Yes, there are differences in what I tried to describe
> here are the worst case scenarios.
>
> DR. CHOTI: If so, one useful correlate would be whether there are
> differences when you talk about the clinical data between leak,
> rupture, and so forth, between smooth and textured, for example.
>
> Does the textured have less of the stronger mechanical properties, for
> example, than the smooth?
>
> MR. POWELL: Actually, it has weaker, some of the break force values,
> however, in the fatigue test it was stronger, so it is not strictly a
> direct relationship with the testing that has been done.
>
> DR. CHOTI: And is the patch a weaker area or a stronger area?
>
> MR. POWELL: The patch is definitely the strongest area on the implant,
> and it is the same for both.
>
> DR. BOULWARE: Dr. Whalen, I would like to ask a question.
>
> Am I interpreting your gel bleed data correctly, 0.0012 gram/square
> centimeter/week, so if I extrapolate that out for 52 weeks, about 0.1
> gram/square centimeter, and assuming that it\'s about 6 inches across,
> two-sided, I just did it quickly here, about 150 centimeters, that is
> 15 grams per year bleed?
>
> MR. POWELL: In the smallest case, the calculated value in a year would
> be 14 grams of gel. We have never had any implant come back from a
> returned device analysis that has ever had that much.
>
> DR. BOULWARE: One more question. The permeability to water for the
> envelope, is it permeable at all to water?
>
> MR. POWELL: It is permeable to water vapor, but permeable to water, I
> don\'t believe that is measurable. Dr. Brook?
>
> DR. BROOK: No.
>
> DR. MANNO: On these numbers you are giving as normalized diffusion
> rates, I have noticed that you have given a single number, but should
> you not have associated something like a standard deviation in there
> someplace or a standard error, or a range of responses? This is
> normally how it is done in the biological community rather than the
> straight chemical community.
>
> Secondly, I would go along with the earlier question concerning having
> tested this, it\'s fine to test it at 25, but if you really want to
> see how it is going to work and you don\'t want to have to stand there
> and make a reference, that there is no clinical relevance here with
> this or correlation, then, it should have been done, I would think, at
> 37 degrees, which would be body temperature.
>
> MR. POWELL: Thank you. Again, this is following the ASTM methodology,
> which is fairly precise in the way they want it calculated.
>
> DR. MANNO: I would suggest that when you are looking at guidelines in
> developing a device and you are looking at safety, when guidelines
> should be considered to be a minimum requirement for testing, and
> anything else, while it may be costly and you may not think much of
> it, it is certainly icing on the cake to give us more to work with
> safetywise.
>
> MS. BROWN: That leads to a question that I had. Were you following or
> what was your understanding of the guidance that you were supposed to
> be using for the testing, is it the breast implant guidance?
>
> MR. POWELL: Yes, it was the FDA guidance that we were following.
>
> MS. BROWN: Okay.
>
> DR. OLDING: Michael Olding. I just want to back up for a second. You
> said this is the worst case scenario, and backing up to the mechanical
> evaluations, one would be surprised, given that information, that
> there would ever be a ruptured implant, but those values are really on
> just implanted implants, if you can relate them clinically, is that
> correct?
>
> They were obviously not in vivo, but they could have been removed
> after they had been in at a year or two and tested, so that it would
> have been more clinically relevant?
>
> MR. POWELL: Yes. We have accelerated shelf life studies that compare
> implants right after sterilization to those that would be on the shelf
> for five years, and find that the physical properties are not at all
> compromised in those particular comparisons.
>
> Then, in the initial retrieval analysis, looking at in vivo testing
> that we are doing, we find also that at this point, with the sampling
> that we have, that the physical shell strength requirements also have
> not diminished with the samples that we have tested in the retrieval
> program.
>
> DR. OLDING: How far out is that?
>
> MR. POWELL: The retrieval program has tested samples up to 11 years,
> but it right now is a small distribution.
>
> DR. OLDING: Thank you.
>
> DR. LEITCH: Could I use more clarification about the bleed? It sounds
> like on your retrieval studies, you have verified that the bleed rate
> has not ever been to this extent, the 14 grams per year?
>
> MR. POWELL: Correct.
>
> DR. LEITCH: So, what is it?
>
> MR. POWELL: What we evaluate when we have a returned product that
> comes back, we will look at the weight of the implant, we will weigh
> it and we will see if it\'s within the specifications for that
> implant, which is within 5 grams of the specified volume.
>
> To my knowledge, we have never had an implant\--
>
> DR. LEITCH: So, you have never had one that has been more than 5 grams
> difference?
>
> MR. POWELL: No, ma\'am.
>
> DR. LEITCH: Like how many would that be that you have looked at?
>
> MR. POWELL: In the report that we submitted, we had 339 returned
> implants back.
>
> DR. CONANT: Another quick question about gel bleed or the reverse, the
> solubility or the entry of things into the implant, how do you
> explain, with aging implants, the change of the internal contents, the
> opacifications, sometimes on imaging we may see water droplets or
> presumably serum within\--suggesting that things are also getting in
> as things are getting out?
>
> Have you noticed that in your retrieval program, they look different?
> I think we saw images this morning also of it.
>
> MR. POWELL: There is a tendency, I believe\--and, Dr. Brook, maybe you
> can help me with the potential for colorization of the implants?
>
> DR. BROOK: When one exposes any material to a complicated environment,
> everything is going to be soluble to different degrees, so, for
> example, alcohol in water are infinitely soluble in water, whereas,
> sand in water, sand doesn\'t dissolve very well in the water.
>
> So, those are the kinds of things that we also see with implants.
> Essentially, this outer layer is a membrane, and it\'s acting to
> prohibit some transport at some level, so that the rule of thumb is
> that things which are similar chemically, typically dissolve in one
> another.
>
> So, for example, lipids might be anticipated to dissolve to a better
> degree in the silicone than would water, for example. So, I don\'t
> know the answer specifically with Inamed, is it like that some lipids
> cross that membrane that go into the gel, yes, the answer is that
> there is going to be a higher solubility of lipids.
>
> Similarly, I should come back to this question of water. Absolutes are
> very dangerous. Small amounts of water are likely to go into the
> inside of the implant. The converse, the solubility of silicones in
> water is about 12 parts per million. It will be sort of comparable the
> other way around - small amounts can transform either in the gaseous
> form or in the liquid form.
>
> So, this is a membrane that is trying to keep the two parts of the
> body and the gel apart, but it doesn\'t work perfectly. It is
> extremely difficult to design a barrier that is a true barrier for
> everything, so there will be some transport in both directions.
>
> DR. MILLER: Could I ask one question, too? Do you have any theoretical
> calculation that could tell us, in the in vivo environment, what the
> bleed rate would be based upon the numbers that you get in your tests?
>
> MR. POWELL: No, I do not.
>
> DR. MILLER: Is it something that is possible to do, to make a
> theoretical calculation like that, or is that something that you just
> can\'t do?
>
> DR. BROOK: I don\'t think so. I mean first of all, this is my personal
> opinion, essentially, everybody is slightly different, what is the
> exact local environment, could you come up with a dummy solution that
> would be a very good mimic.
>
> DR. MILLER: Well, a physiologic solution of some kind, just an
> idealized solution, could you just put the numbers in a chemical, you
> know, some kind of equation for analysis and calculate what the bleed
> rate would be based upon these worst case scenario bleed rates?
>
> DR. BROOK: My opinion is that it would be very difficult to try and do
> that. Among other things, the environment around the implant is
> changing with time as you start to build up a capsule, and so at which
> point do you want to try and mimic the local environment.
>
> I guess by doing these tests into silicone itself, you know what the
> upper limit is, if you did it into saline, you probably would be able
> to measure, if you could, what the lower limit is, and it will be
> somewhere in the middle in vivo. But I don\'t know of any way to
> calculate that.
>
> I guess since we are out 40 years and people have been worried about
> this for a long period of time, I am not the only one who has been
> unable to come up with a reliable test to get at that number in vivo.
>
> \[Slide.\]
>
> MR. POWELL: So, just in summary, the preclinical evaluations performed
> in accordance to the FDA\'s guidance document demonstrates that the
> silicone gel-filled implant materials meet the physical property
> specifications for breast implants and the biocompatibility of
> silicone breast implants.
>
> I will now turn the presentation over to Ms. JoAnn Kuhne for the
> clinical discussion.
>
> DR. WHALEN: During that transition, let me just say to the panel
> members without any regard to where we stand on our schedule, I would
> like to strongly encourage the greatest possible scrutiny over both
> this presentation and FDA\'s. I don\'t want to restrict it in the
> least.
>
> However, I think it might make sense from a flow point of view that we
> let Ms. Kuhne and then each of the FDA presenters, or whoever is
> representing Ms. Kuhne, do their entire presentation, make notations
> of what questions you want to ask, and at the conclusion, at their own
> respective conclusions, we will take breaks and then ask some
> questions.
>
> Thanks.
>
> **Clinical Studies**
>
> MS. KUHNE: Good afternoon. I am JoAnn Kuhne, Senior Director of
> Regulatory and Clinical Affairs, and I do have a financial interest in
> the company.
>
> \[Slide.\]
>
> First, I would like to address the key clinical findings from our
> ongoing clinical trials. From my presentation, you will note that
> Inamed\'s clinical data demonstrate safety and effectiveness of McGhan
> silicone gel- filled breast implants.
>
> General patient satisfaction ranged from 89 percent in the revision
> cohort to 96 percent in the augmentation cohort with revision patient
> satisfaction falling within this range at 93 percent.
>
> There were lower rates for most complications for Inamed\'s
> silicone-filled breast implants as compared to Inamed\'s FDA-approved
> saline-filled breast implants.
>
> \[Slide.\]
>
> Now, let me briefly introduce what I will be discussing for the next
> 40 minutes. My remarks will encompass the scope of our clinical
> studies, the safety results obtained, the effectiveness results,
> comparison of the complication rates between the silicone gel-filled
> implants that are the subject of this PMA and our saline breast
> implants that have been FDA-approved for over three years.
>
> In addition, some highlights from published peer-reviewed clinical
> research, and finally, the conclusions from our prospective clinical
> trials.
>
> \[Slide.\]
>
> Now, for a brief overview of the three main studies Inamed has
> conducted on silicone gel-filled breast implants, which I may also
> refer to throughout the presentation as gel implants.
>
> All three studies were prospective, multi-center trials, but the most
> comprehensive clinical trial, and the one that will be the primary
> focus of my presentation here today, is the core study. The core study
> provided the primary data for this PMA submission.
>
> The study allows for evaluation of both safety and effectiveness of
> the gel implants. Our results include complete two-year follow-up
> data, as well as partial three-year data for those patients who have
> already returned for their three-year visit.
>
> The study includes women in three cohorts or groups with approximately
> 50 percent in the augmentation group, 25 percent in reconstruction,
> and 25 percent in the revision group.
>
> The adjunct study is a large ongoing safety study that also includes
> both reconstruction and select revision patients with a current
> enrollment of over 25,000 patients.
>
> The AR90 was a five-year study which included a small sample size of
> both augmentation and reconstruction patients.
>
> \[Slide.\]
>
> For a quick look at the scope of the three studies, we can see that
> the core study was initiated in 1999 and enrolled 940 patients.
> Patients are currently being seen for their three- and four-year
> follow-up visits.
>
> The core study protocol is designed to provide for 10 years of
> clinical follow-up.
>
> The adjunct study began in 1997 and continues to enroll new patients.
>
> The AR90 study began in 1990 and was completed after five years of
> follow-up.
>
> \[Slide.\]
>
> Our long-term post-approval studies for our core clinical study
> patients, should we receive PMA approval, consists of two phases. The
> first phase involves continuing to collect patient data via direct
> physician evaluation through five years post-implantation.
>
> This phase also includes obtaining MRIs through five years on the
> patients enrolled in the serial MRI portion of the study.
>
> Phase II of our proposed post-approval plan involves continuing to
> follow up on these patients through 10 years via mailed surveys. We
> have many measures in place to assure high compliance in mailed survey
> studies, such as premailings and follow-up reminder letters, as well
> as phone calls.
>
> \[Slide.\]
>
> Now, for more detail regarding the core study, which again is a
> prospective, multi-center clinical trial involving 940 patients
> enrolled at over 50 sites nationwide.
>
> Patients enrolled into the core clinical study with three different
> indications - augmentation, reconstruction, and revision.
>
> Augmentation patients are those patients who seek breast implantation,
> reconstruction, and revision. Augmentation patients are those patients
> who seek breast implantation to enhance the size and/or shape of their
> breasts.
>
> Reconstruction patients are women in whom one or both breasts are
> reconstructed after illness or injury. The majority of reconstruction
> patients choose to have breast implants placed after a mastectomy to
> treat breast cancer.
>
> Revision patients are patients who receive breast implants in a
> previous augmentation or reconstruction surgery and are having them
> replaced either due to cosmetic or complication reasons.
>
> The following slide show results of the augmentation and
> reconstruction procedures.
>
> \[Slide.\]
>
> This slide shows the before and after results of a cosmetic
> augmentation with McGhan style 45 silicone-filled breast implants. The
> patient was unsatisfied with the appearance of her breasts and opted
> for breast implants to enhance their shape and size.
>
> \[Slide.\]
>
> This slide shows the staged reconstruction results of a patient with
> McGhan style 10 silicone-filled breast implants. The patient
> previously underwent a bilateral mastectomy and desired to regain her
> shape.
>
> The picture in the top left shows this patient pre-mastectomy. Moving
> directly to the right, we see the patient post-mastectomy after
> placement of tissue expanders.
>
> The bottom left slide shows the patient after placement of breast
> implants, and immediately to the right, we see this patient
> approximately one year postoperatively.
>
> Again, the revision indication refers to those patients who have had
> previous augmentation or reconstruction breast implant surgery and
> have their implants removed and replaced either due to choice or
> complications.
>
> \[Slide.\]
>
> Now, for a description of the patient population. We see that the
> median age for augmentation patients is 34 years with those patients
> in the reconstruction and revision groups being somewhat older.
>
> Most of the women in this study are Caucasian and approximately half
> or more in each group are married.
>
> \[Slide.\]
>
> For augmentation patients, over 90 percent of the implants used were
> round with a smooth surface somewhat more common than textured. In
> reconstruction patients, 65 percent of the devices used were the
> textured shaped implants. Round implants were more common in revision
> patients with 71 percent choosing round devices fairly evenly split
> between smooth and textured surfaces.
>
> \[Slide.\]
>
> High compliance rates have been maintained throughout the study with
> 90 percent of augmentation patients returning for their two-year
> follow-up visit, 95 percent of reconstruction patients, and 87 percent
> of revision patients.
>
> Compliance rates are similar for our partial three-year data.
>
> \[Slide.\]
>
> Turning to the safety results.
>
> \[Slide.\]
>
> The complications we collected include reoperation, implant removal
> also referred to as explant or explantation with or without implant
> placement, rupture, capsular contracture, infection, and a number of
> others which we will discuss in greater detail shortly.
>
> The data are based on physical assessment of the patient through a
> physical exam. The method used to analyze these complications at three
> years was a cumulative risk analysis based on the Kaplan-Meier product
> limit method. This is the same method that was used for the analysis
> and presentation of our data for Inamed\'s FDA-approved saline-filled
> breast implants.
>
> \[Slide.\]
>
> Our protocol was designed to collect data on more than 30 different
> complications, all of which can be grouped into the following three
> categories: general breast surgery complications, breast implant
> related, cosmetic complications, and breast implant related,
> non-cosmetic complications.
>
> \[Slide.\]
>
> General breast surgery complications are defined as complications
> which are related to breast surgery in general regardless of whether
> the surgery involves breast implants. This category includes
> surgery-related complications, such as breast pain, swelling,
> infection, and tissue or skin necrosis.
>
> In the general breast surgery category, breast pain and swelling each
> occurred 7 percent or less in all cohorts. All other complications
> occurred at less than 5 percent. As you can see, infection ranged from
> 0.2 percent to 2.3 percent in the three cohorts, and tissue, skin
> necrosis ranged from 0.2 percent in the augmentation group to 4.3
> percent in the reconstruction group with the revision rate falling in
> between.
>
> \[Slide.\]
>
> Breast implant related cosmetic complications are defined as
> complications resulting from the breast implant surgery which are
> strictly related to the cosmetic appearance of the breast.
>
> This category contains the following cosmetic complications:
> Asymmetry, implant palpability, visibility, implant malposition, and
> wrinkling.
>
> In the cosmetic category, asymmetry is 2.8 percent for augmentation,
> 15 percent for reconstruction, and 5 percent for revision. Asymmetry
> could be expected to be higher in the reconstruction group because 37
> percent of this group underwent only unilateral implantation.
>
> All other complications are 5 percent or less in all groups with
> wrinkling ranging from 0.7 percent to 5 percent, and implant
> malposition ranging from 3 percent to 5 percent. Implant palpability
> is 2 percent or less in all groups.
>
> \[Slide.\]
>
> Breast implant related non-cosmetic complications are defined as
> complications occurring as a result of the breast implant surgery
> which are not considered strictly cosmetic in nature. This category
> includes the following non-cosmetic complications: capsular
> contracture, implant rupture, capsule calcification, and implant
> extrusion.
>
> For the non-cosmetic complications, capsular contracture is 8 percent
> for augmentation, 16 percent for reconstruction, and 9.8 percent for
> revision. Rupture is 1 percent for augmentation, 6 percent for
> reconstruction, and 3.6 percent for revision.
>
> Both capsule calcification and implant extrusion are less than 1
> percent in all cohorts.
>
> \[Slide.\]
>
> Regarding other complications in the core clinical study, silent
> rupture, meaning patients who may have experienced a ruptured implant,
> but have no physical symptoms of a rupture, was studies via a subgroup
> of 351 patients who are undergoing postoperative serial magnetic
> resonance imaging or MRI.
>
> These patients underwent routine MRI every two years. Of the 597
> implants, 317 patients that have undergone at least 1 MRI in the
> serial MRI portion of the study with 170 implants having undergone 2
> MRIs, 15 implants have been classified as having a silent rupture.
>
> The calculated Kaplan-Meier risk of silent rupture is 2.7 percent at
> three years. The risk of 2.7 percent includes 2 out of the 15 implants
> that have been classified as indeterminate for implant rupture meaning
> it has not been confirmed that these two implants are actually
> ruptured.
>
> It is important to note that because the patients are not experiencing
> any symptoms or adverse events related to the implant, some physicians
> do not recommend removing the implants that may have ruptured
> silently.
>
> \[Slide.\]
>
> Now, we will be presenting the reoperation findings from the core
> clinical study. It is important to note that reoperation is not
> synonymous with implant removal or explantation. Instead, reoperation
> means any surgery that occurs after implantation.
>
> As you can see on this slide, the three-year risk of reoperation was
> 20.6 percent in the augmentation group, 45.9 percent in
> reconstruction, and 33.4 percent for revision. Many different types of
> procedures are formed during reoperations as will be seen in the next
> slide.
>
> \[Slide.\]
>
> Presented here are some examples of the types of procedures performed
> during reoperation, such as aspiration, biopsy, capsule procedures,
> flap or pocket revision, mastopexy, and nipple procedure.
>
> As shown next in this list, removal/replacement of an implant is just
> one of the many types of procedures performed during a reoperation.
> Reposition implant and scar revision, wound repair are some of the
> last examples of possible procedures performed during a reoperation.
>
> Of all these procedures listed for reoperations, the most common were
> capsule procedures. A capsule procedure involves removal, suturing, or
> position manipulation of the capsule that forms around the implant.
>
> \[Slide.\]
>
> Within the augmentation group, 19 percent or 94 of the 494 patients
> underwent a reoperation. Of the 94 patients who had a reoperation, 32
> had an implant removed for a total of 60 explants.
>
> \[Slide.\]
>
> As seen in the pie chart on the left, of the 60 implants that were
> removed in the augmentation group, many were removed to treat capsular
> contracture; 18 were due to patient choice for a different size or
> style implant, and another 11 implants were removed for cosmetic
> complications, such as asymmetry or implant malposition.
>
> The pie chart on the right shows that the majority of explants, 39 out
> of 60, were replaced with another silicone gel-filled implant, and
> only 9 or 15 percent were not replaced. Twelve explants were replaced
> with other breast implants that are not part of this study, for
> example, with gel-filled implants that are part of another study or
> with saline-filled breast implants.
>
> Another significant finding was that upon explantation of these
> devices, there were no findings of extracapsular gel. These means that
> during the removal of these 60 breast implants, none of the physicians
> found that gel had migrated outside the capsule. This is consistent
> with feedback we received from plastic surgeons in general who
> indicate that it is not common to find extracapsular gel when removing
> an implant.
>
> \[Slide.\]
>
> Forty-two percent or 92 of the 221 reconstruction patients had a
> reoperation. Of the 92 patients who had a reoperation, 46 patients had
> an implant removed for a total of 56 explants.
>
> \[Slide.\]
>
> As shown in the pie chart on the left, of the 56 implants that were
> removed in the reconstruction group, 4 were due to patient choice for
> a different style or size implant, while 27 were removed to treat an
> unsatisfactory cosmetic result, such as asymmetry.
>
> The pie chart on the right shows the majority, 45 explants were
> replaced with another gel implant, and only 9 percent or 5 explants
> were not replaced.
>
> Furthermore, there were no findings of extracapsular gel during any of
> the explant procedures. This means that during the removal of these 56
> devices, none of the physicians found that gel had migrated outside
> the capsule. This is also consistent with our augmentation group. You
> will see in the next slides that our revision cohort did not
> experience any extracapsular gel either.
>
> \[Slide.\]
>
> Thirty-one percent or 70 out of the 225 patients in the revision group
> underwent a reoperation. Of the 70 patients who had a reoperation, 29
> had an implant removed for a total of 46 explants.
>
> \[Slide.\]
>
> Of the 46 explants that were removed in 29 patients in the revision
> group, many were due to patient choice for replacement with a
> different size or style implant or for an unsatisfactory cosmetic
> result, such as malposition, ptosis, or scarring.
>
> The chart on the right shows that 29 implants or 63 percent were
> replaced with another gel implant. Again, there were no findings of
> extracapsular gel at the time of explantation of the 46 devices.
>
> To reiterate, in this large controlled clinical trial, we see that
> none of the 162 implants removed showed gel outside the capsule
> formation upon implant removal. Plastic surgeons have shared with us
> that extracapsular gel is not a common event and is usually associated
> with a traumatic injury, such as a car accident or closed capsulotomy,
> which is a procedure that is not as common today as it used to be.
>
> However, it is important to note that if the surgeon had observed
> extracapsular gel, it is expected that the gel would have remained at
> the site as demonstrated in our preclinical experiments where free gel
> was injected into experimental rats and stayed at the site of
> injection.
>
> \[Slide.\]
>
> Moving on to other evaluations of safety - breast cancer, connective
> tissue disease, autoimmune disease, lactation, and reproduction.
>
> \[Slide.\]
>
> In the augmentation group, there was one report of breast cancer
> post-implantation. Reconstruction had 5 reports and revision had zero
> reports. It is important to note that all the reconstruction patients
> with post-implant breast cancer also had pre-implant breast cancer
> with 2 of these patients experiencing recurrent breast cancer in the
> same breast.
>
> \[Slide.\]
>
> Of the 494 augmentation patients, there was one diagnosis of
> rheumatoid arthritis at 11 months postoperatively. Of the 221
> reconstruction patients, there was one diagnosis of systemic
> sclerosis/scleroderma at four months postoperatively. Of the 225
> revision patients, there was one diagnosis of fibromyalgia at 11
> months postoperatively.
>
> These connective tissue diseases occurred in less than one-half of 1
> percent of all patients in the study.
>
> \[Slide.\]
>
> In the augmentation group, there were 5 reports of lactation problems
> primarily mastitis and inadequate milk production, and 8 reports of
> reproductive problems primarily spontaneous abortions. One of these 8
> patients had a planned abortion to treat a medical problem pre-implant
> and experienced a miscarriage post-implant.
>
> Reconstruction had no lactation problems and 2 reported reproductive
> problems. One patient experienced a miscarriage pre-implant and no
> menses post-implant.
>
> Revision had 4 lactation problems, the majority of which were
> inadequate milk production postoperatively, and 6 reproductive
> problems mainly spontaneous abortions and infertility. Two of these 6
> patients experienced infertility both pre- and post-implant.
>
> \[Slide.\]
>
> For the effectiveness results.
>
> \[Slide.\]
>
> Now, I will review the various components of our effectiveness
> results. Besides the endpoint related to increasing the breast mound,
> we examined three different measures: patient motivation, patient
> satisfaction, and psychosocial changes.
>
> Within our satisfaction measures, we captured general patient
> satisfaction at follow-up and patient satisfaction with the size and
> shape of the breast pre- and post-implantation.
>
> Within our psychosocial measures, we captured information pre- and
> post-implantation to assess any change in women\'s expectations of
> their breast implant surgery, self-esteem, and quality of life.
>
> \[Slide.\]
>
> One of the areas we explored was patient motivation for implant
> surgery. Therefore, we asked patients to rate their motivations prior
> to implantation. As the side shows, the vast majority of women were
> motivated to improve the way they felt about themselves or make them
> feel better about their physical appearance.
>
> It is interesting to note that motivations regarding partners and/or
> sex life were not a strong motivating factor for most of these
> patients.
>
> \[Slide.\]
>
> Patient satisfaction was extremely high with one year rates at 96
> percent for augmentation, 94 percent for reconstruction, and 87
> percent for revision. Satisfaction was 96 percent, 93 percent, and 89
> percent respectively two years after implantation.
>
> \[Slide.\]
>
> When measuring patient satisfaction with breast size and shape at
> baseline and at the two-year follow-up, a significant positive change
> was observed in all three cohorts or groups.
>
> \[Slide.\]
>
> In terms of patient\'s psychosocial changes, a questionnaire was
> developed by Dr. Julia Roland, the director of the National Cancer
> Institute\'s Office of Cancer Survivorship. This questionnaire was
> used to observe the pre-implant versus two years post-implant changes
> in general psychosocial concepts.
>
> This graph shows that self-image increased significantly in the
> augmentation and revision cohorts postoperatively while it remained
> constant in the reconstruction cohort.
>
> On the improved social relations subscale, there was a positive
> increase in all three groups.
>
> \[Slide.\]
>
> For the Tennessee Self-Concept Scale, scores for all patients started
> high and despite any postoperative complications that may have
> occurred, remained high. The scores show no change in the augmentation
> and reconstruction groups pre- versus two years postoperatively.
>
> We observed a statistically significant decrease at two years
> post-implantation in the way revision patients scored on this measure.
> This measure included aspects of how patients viewed their bodies and
> state of health, skills, their attitude about appearance, and
> sexuality.
>
> \[Slide.\]
>
> Similarly, the scores were high both preoperatively and two years
> postoperatively for the Rosenberg Self-Esteem Scale. The scale
> provides for a maximum score of 40.
>
> The scores obtained revealed a statistically significant decrease two
> years post-implantation in self-esteem for revision patients, whereas,
> no significant self-esteem changes were found in the other groups.
>
> \[Slide.\]
>
> Additional information was collected using the Body Esteem Scale. This
> scale measures body image based on three subscales. These subscales
> are sexual attractiveness, weight concern, and physical condition.
>
> The bar charts show the changes observed in the total score in the
> sexual attractiveness subscale. The bar charts on the left show that
> the total score does not change significantly in any of the groups,
> and the bar chart on the right shows significant increase in the
> sexual attractiveness scale in the augmentation cohort.
>
> \[Slide.\]
>
> Various SF-36 scales were measured. In all cases, the quality of life
> scores remained well above those of the general U.S. female population
> both at baseline and at two years. Although scores started high and
> there were no major changes overall, some of the individual measures
> decreased postoperatively.
>
> This may be attributed to ceiling effects seen at baseline, for
> example, 65 percent of the patients in the augmentation cohort scored
> 100 preoperatively, which is the maximum score indicating best
> possible quality of life at baseline for the role limitations due to
> physical health problems measure.
>
> Therefore, this 65 percent of the patients could not have had any
> increase postoperatively because they were already at maximum score
> preoperatively.
>
> \[Slide.\]
>
> In the next few slides, I will discuss the comparison of our current
> three-year core study complication rates to the three-year
> complication rates reported for Inamed\'s FDA-approved saline-filled
> breast implants which have been commercially marketed since May 2000.
>
> The protocol for the saline study was very similar to the current core
> gel study with similar endpoints collected and similar follow-up
> intervals. In addition, many of the investigational sites in the
> saline study are also enrolled in the core gel study.
>
> You will note that the complication rates for the silicone gel-filled
> breast implants that are the subject of this current PMA we are
> discussing today are comparable and, in many cases, lower than those
> same complications for our already PMA-approved saline-filled breast
> implants.
>
> \[Slide.\]
>
> For the augmentation groups, all complications with risks greater than
> or equal to 5 percent in either the current gel-filled breast implants
> or Inamed\'s previously FDA-approved saline-filled breast implants are
> listed.
>
> All the complications that showed gel-filled breast implants with a
> lower complication rate than those found in the saline study are noted
> in yellow. Almost two-thirds of the risks shown associated with breast
> implant surgery are considerably lower for gel-filled breast implants
> versus saline-filled implants.
>
> For instance, we see that wrinkling in our gel patients occurs at 0.7
> percent at 3 years, which is less than one-tenth of the risk of
> wrinkling in our patients with FDA-approved saline-filled devices.
>
> Furthermore, implant palpability, visibility showed less than 1
> percent risk with our gel-filled devices, while the risk of this
> complication was 9 percent with our saline-filled devices.
>
> It is also important to note that the complication of implant
> malposition presented in our saline augmentation group where the risk
> of 8 percent is more than twice as high as the same complication in
> our gel-filled devices with the risk of only 3 percent.
>
> Gel rupture is one-fifth the risk of saline deflation with gel rupture
> occurring at a risk of only 1.2 percent in the augmentation group.
>
> \[Slide.\]
>
> Now, with a similar list of complication rates for the reconstruction
> group, we see that asymmetry at 15.3 percent with gel-filled implants
> is half the risk seen with saline-filled implants.
>
> With the saline-filled implant, wrinkling and implant palpability each
> give a risk in the 20 percent range, while with our gel-filled
> devices, these two complications are dramatically lower.
>
> Implant palpability in the gel-filled implants is only 0.5 percent.
> The complications of loss of nipple sensation and skin paresthesia
> further the evidence supporting the gel-filled breast implant safety.
>
> In the saline-filled implant study, we saw that these risks were 12
> percent and 5.6 percent respectively, but the rates for these
> complications in the core gel study were zero.
>
> \[Slide.\]
>
> For the revision group, we see three complications that are displayed
> in yellow, indicating significant differences. All three are
> significantly lower with our gel-filled implants versus our
> saline-filled FDA-approved implants. Again, implant palpability shows
> a dramatically lower risk in the revision group. This complication was
> reduced significantly across all groups - augmentation,
> reconstruction, and revision.
>
> Asymmetry and wrinkling are also significantly decreased with the use
> of gel-filled breast implants versus saline-filled breast implants.
> While the risk with saline-filled implants are over 15 percent for
> each of these complications, gel-filled implants provide one-third the
> risk at 5 percent each.
>
> It is of interest that asymmetry and wrinkling were also significantly
> reduced in the augmentation and reconstruction groups showing that the
> gel-filled implants consistently reduced the concerns regarding
> asymmetry and wrinkling.
>
> To summarize the comparison of complication rates of silicone
> gel-filled breast implants to Inamed\'s FDA-approved saline-filled
> breast implants, the complication safety profile for silicone
> gel-filled breast implants meets or exceeds the complication safety
> profile for saline-filled breast implants.
>
> DR. ANDERSON: May I ask a very quick clarification question? I didn\'t
> hear you say what the follow-up time for the saline group was. We know
> for the gel, it is two years, but are these really comparable groups?
>
> MS. KUHNE: These are three years to three years. This is our
> three-year gel data, as well as our three-year saline data.
>
> \[Slide.\]
>
> Comparing our core study results to results reported in the medical
> literature, we find that with the exception of reoperation, all of the
> core study results fall at the low end of the rates found in other
> published studies with various lengths of follow-up.
>
> \[Slide.\]
>
> To summarize, the core study, conforming to FDA guidelines,
> demonstrates safety and efficacy of McGhan silicone gel-filled breast
> implants. We see that 89 to 96 percent of all patients were satisfied
> at two years follow-up. Lastly, we see lower rates for most
> complications for Inamed\'s gel-filled breast implants compared to
> Inamed\'s FDA-approved saline-filled breast implants.
>
> \[Slide.\]
>
> Examining the findings of peer-reviewed research, we have chosen to
> present findings from many independent reviews of published research
> by prestigious organizations rather than selectively citing individual
> published articles as you will see on the following slides.
>
> Although these studies are not specific to Inamed\'s silicone
> gel-filled breast implants, they are representative of the body of
> knowledge that currently exists on silicone gel-filled breast implants
> relative to systemic diseases.
>
> \[Slide.\]
>
> As a result of concerns raised in the early 1990s regarding the safety
> of silicone gel-filled breast implants, many government-funded
> agencies critically reviewed the available scientific literature
> concerning implants and disease.
>
> These agencies have been consistent in finding no evidence that
> silicone gel-filled breast implants are a significant health risk.
> Without exception, they have found that silicone gel-filled breast
> implants do not increase the risk of breast cancer or autoimmune
> disease, nor do they affect the health of children born to mothers
> with breast implants.
>
> \[Slide.\]
>
> With regard to cancer, many independent reviews of the literature have
> been performed to examine the relationship of breast implants to
> cancer. Specifically, an assessment of the toxic potential of silicone
> implants by the International Agency on Cancer found that there is no
> evidence that silicone implants cause breast carcinoma, and there is
> inadequate evidence that silicone implants cause other types of
> cancer.
>
> In its review of the literature current to 1999, the Institute of
> Medicine concluded that there was no increase in primary or recurrent
> breast cancer in implanted women.
>
> \[Slide.\]
>
> Similarly, the National Institutes of Health 2003 stated that the most
> recent studies, which have been considerably larger than previous
> studies, and have been able to assess long-term risks, do not support
> the notion that implants are related to breast cancer risk.
>
> The European Committee on Quality Assurance and Medical Devices in
> Plastic Surgery 2000 Consensus Declaration on Implants stated that
> medical studies have not demonstrated any association between silicone
> gel-filled breast implants and cancer or any other type of malignant
> disease.
>
> \[Slide.\]
>
> Still more independent agencies have presented information regarding
> cancer. The American Medical Association Report 8 of the Council of
> Scientific Affairs showed no evidence of increased risk of cancer
> among recipient of silicone breast implant.
>
> Like the United States, the Health Council of the Netherlands\' review
> found there were no indications of an increased risk of cancer in
> women with breast implants, nor of a delay in the detection of breast
> cancer.
>
> \[Slide.\]
>
> With regard to rheumatic or autoimmune disease, many independent
> reviews of the literature have been performed to examine the
> relationship of breast implants to rheumatic or autoimmune disease.
>
> In the United States, the Institute of Medicine found no evidence that
> silicone implants contribute to an increase in autoimmune disease.
>
> The American Medical Association stated that no studies have found
> evidence of a relationship between silicone gel implants and
> connective tissue disease, and the Federal Judiciary National Science
> Panel found no association between breast implants and any of the
> individual connective tissue diseases combined or other autoimmune or
> rheumatic conditions.
>
> \[Slide.\]
>
> A meta-analysis performed by Janowsky et al., published in the New
> England Journal of Medicine in the year 2000 found no conclusive
> evidence to suggest an abnormal immune response to silicone from
> breast implants, nor an association with established connective tissue
> disease.
>
> But most importantly, the American College of Rheumatology has weighed
> in on the controversy and found compelling evidence that silicone
> implants do not expose patients to additional risk for connective
> tissue or rheumatic disease.
>
> \[Slide.\]
>
> Other national agencies outside the United States that have
> investigated the relationship between silicone breast implants and
> autoimmune disease have come to similar conclusions. For example, the
> Health Council of the Netherlands found that there is unlikely to be a
> connection between silicone breast implants and autoimmune disease.
>
> A United Kingdom independent review group found no conclusive evidence
> for an abnormal immune response to silicone from breast implants and
> no epidemiologic link between silicone gel implants and any
> established connective tissue disease.
>
> \[Slide.\]
>
> The European Committee on Quality Assurance and Medical Devices in the
> Plastic Surgery 2000 Consensus Declaration on Implants concluded that
> medical studies have not demonstrated any association between silicone
> gel-filled breast implants and autoimmune or connective tissue
> diseases.
>
> Finally, Australia\'s Therapeutic Devices Evaluation Committee in 1997
> stated that several large studies have failed to establish a link
> between silicone breast implants and well-defined connective tissue
> diseases including scleroderma.
>
> \[Slide.\]
>
> The potential for silicone gel-filled breast implants to impact breast
> feeding or affect child health has also been considered by a number of
> government-funded agencies.
>
> The Institute of Medicine Report found that the evidence for an
> association of maternal silicone breast implants and children\'s
> health effects is insufficient or flawed and that there was no data to
> support the suspected transmission of silicone to infants in breast
> milk of mothers with implants.
>
> In the United Kingdom, an independent Review Group on Silicone Breast
> Implants found that published literature to date does not substantiate
> the claims that there are significant clinically apparent
> second-generation effects in children born to silicone breast implant
> patients.
>
> \[Slide.\]
>
> Among the medical associations that have considered the issue, the
> American Academy of Pediatrics stated that evidence currently does not
> justify classifying silicone implants as a contraindication to
> breastfeeding, and the American College of Obstetricians and
> Gynecologists feels that women who have had breast implants may still
> be able to breastfeed.
>
> \[Slide.\]
>
> As shown in the previous slides, many agencies in the scientific
> community have reviewed information regarding silicone gel-filled
> breast implants. These respective agencies include the Institute of
> Medicine, the National Institutes of Health, the American Medical
> Association, and other associations within the United States.
>
> In addition to those prestigious authorities, other agencies outside
> the United States have presented reviews including the European
> Committee on Quality Assurance, International Agency on Cancer
> Research, and the Health Council of the Netherlands.
>
> Each of their reviews supports our key finding that there is no causal
> relationship between silicone gel-filled breast implants and breast
> cancer, children\'s health, or rheumatic or autoimmune disease.
>
> \[Slide.\]
>
> In summary, the vast body of published literature, as well as numerous
> scientific agencies, found no increased risk of breast cancer, no
> increased risk of rheumatic or autoimmune disease, and no negative
> effects of breast implants and breastfeeding on children\'s health.
>
> \[Slide.\]
>
> This concludes the clinical portion of our presentation. In summary,
> we believe that Inamed\'s preclinical and clinical data support the
> safety and efficacy of McGhan silicone gel-filled breast implants.
>
> We found that 89 to 96 percent of all the patients in the core
> clinical trial were satisfied with their breast implant results at two
> years post-implantation.
>
> Furthermore, we see that the complication rates for Inamed\'s silicone
> gel-filled breast implants were in most cases lower than the
> complication rates for Inamed\'s FDA-approved saline-filled breast
> implants.
>
> Lastly, exhaustive studies conducted by numerous prestigious
> institutions have found no causal relationship between silicone
> gel-filled breast implants and systemic diseases, such as breast
> cancer, connective tissue disease, or other autoimmune diseases.
>
> At this time, on behalf of Inamed, I would like to express our
> appreciation for the opportunity to present our scientific data in
> support of this PMA application seeking FDA approval of McGhan
> silicone gel-filled breast implants.
>
> The efforts of everyone at FDA, or our clinical investigators, our
> technical experts, and many, many other support personnel are greatly
> appreciated.
>
> Thank you.
>
> DR. WHALEN: Ms. Inamed, I will start off with the questions.
>
> Much of the data you presented to us is looking at two- to three-year
> data and as you rightly pointed out, that is fulfilling FDA\'s
> requirements in terms of what you needed to look at. Whether or not
> that will serve to judge safety and efficacy will obviously be the
> crux of what the panel grapples with over the next 24 hours or so, and
> it may be a continuous 24 hours the way we are going.
>
> Be that as it may, why, in looking at a long-term study that you
> described earlier in your presentation, in view of what seems to be at
> least a plethora of anecdotes, and I would submit a reasonable amount
> of data of problems beyond the first decade, would you consider
> sufficient long-term data to be restricted to a 10-year point?
>
> MS. KUHNE: To be restricted to 10 years? I am sorry.
>
> DR. WHALEN: Well, as I understood your long-term data design, you had
> two phases. One is year 1 to 5 post-implant, and the second is year 6
> to 10. That, to me, means that 10 years, you have judged that you have
> long-term data. That, to me, makes no sense.
>
> MS. KUHNE: Well, currently, that is the way the protocol is designed.
>
> DR. WHALEN: I guess that\'s my question, then, why would you design it
> that way when it doesn\'t seem to judge what long-term data should be
> for this particular device.
>
> MS. KUHNE: Well, we believe that the data shows that it is safe and
> effective in combination with all of the other data and literature
> that has been published on breast implants in the past decade.
>
> Perhaps Dr. Spear, who is our clinical investigator, and Chief of
> Plastic Surgery at Georgetown University, could speak about his
> long-term experience with silicone gel implant.
>
> DR. WHALEN: If it is going to be presenting data other than what is in
> your application, then, we are not going to be entertaining it. This
> is really more of a strategic design question in view of what is a
> overwhelming public concern about the long-term safety of this device.
>
> If you want to editorially comment upon that, then, we will listen to
> it.
>
> DR. SPEAR: My name is Scott Spear. I am a paid consultant to Inamed
> and the medical monitor of the clinical research.
>
> Actually, I think that is a very interesting question. I think when
> these studies were designed, a 10-year milepost seemed like a good
> place to start. I don\'t think anybody would tell you the follow-up of
> patients should stop at 10 years. I think that is something that the
> FDA will have to sort out with the manufacturer as to whether or not
> they want to continue to track patients longer.
>
> I think realistically, in all likelihood between now and 10 years from
> now, we may see other devices come forward which will be new and
> improved over these devices and it becomes kind of an infinite issue,
> you know, how long do you track something before you come up with
> something that is even better still.
>
> I don\'t think anybody would argue against tracking patients longer. I
> think that that is a perfectly reasonable thing to bring up.
>
> DR. WHALEN: The second question is easier. When you presented the
> comments of the plastic surgeons who removed these devices upon gel
> extrusion, I assume what you are relying upon is simple gross
> inspection of the surgeon at the time of the operation and nothing
> more rigorous.
>
> MS. KUHNE: Yes.
>
> PROF. DUBLER: I want to come back to the two- and three-year issue
> because it puzzles me. I am assuming that the company had some
> long-term plan to bring these back on the market, and why limit your
> date to two to three years when it seems as if the five-year mark is
> really an interesting one, and when the continued rate of failure
> grows over those years, so why did you limit your data collection to
> two and three years?
>
> DR. SPEAR: I can speak to the fact that I don\'t think it has been
> limited to two or three years. I think you are seeing a snapshot of
> the data at three years, which has been arranged with the FDA as a
> reasonable time to look at the data.
>
> I think there is precedent in terms of other devices in terms of doing
> that, but I don\'t think is anybody\'s intention to stop collecting
> data. I think it will be collected again at five years and the MRI
> studies are designed to go out until nine years.
>
> PROF. DUBLER: I understand that going forward, but these conversations
> began with the FDA over a decade ago, and they have been implanted
> over all this time in protocols.
>
> Where are the data that give us the experience of the company with
> those implanted devices over the last decade?
>
> DR. SPEAR: Well, the saline studies are at five years, we have
> five-year data for that, and I don\'t think the process between the
> FDA and the manufacturers has been all that simple in terms of even
> putting together the studies.
>
> I mean this study was not started until three years ago, McGhan or
> Inamed didn\'t start its adjunct study until 1998. I think it is a
> very reasonable question to ask why didn\'t that happen in 1992. You
> would have to ask the FDA why it took from 1992 to 1998 to get that
> study rolling.
>
> I think there was a lot of issues in front of the FDA at that time,
> but we do have the saline data five years. You have these devices in
> Europe, in many countries, the whole time, and there is data available
> from that, and that is what is quoted in some of this epidemiological
> information.
>
> Frankly, I don\'t think anybody would mind seeing longer term data,
> but I am not sure many of these things are going to change long term.
> I think the rupture rate is one thing that you would want to know
> about and certainly people suspect it will increase like everything
> else with time, but many of the other things are not probably
> time-dependent, such things as rippling as paresthesia, and things
> like that.
>
> DR. NEWBURGER: I have a question which is of the explanted prostheses,
> has the capsule in the area from which they have been explanted been
> removed, have biopsies been done, has the histologic reaction been
> characterized, have they been analyzed for presence of silicone?
>
> Then, I have, after you answer that, one other question, please.
>
> DR. SPEAR: I don\'t think that was part of the Inamed PMA
> presentation. That has certainly been done experimentally in other
> research, and depending upon what device and what the circumstances
> were, you can sometimes find silicone in the capsule.
>
> I think the literature is pretty consistent that if there is silicone
> in the capsule, it is usually confined to the capsule, and once you
> get further away, it very rapidly drops off to a normal baseline.
>
> DR. NEWBURGER: I am interested in what is the mechanism whereby some
> people would form very painful capsule reactions which would require
> reoperation and others are just able to live with it.
>
> DR. SPEAR: Well, there are different theories as to what causes the
> capsular contracture or capsule reactions. What is good in terms of
> these devices is that the incidence that is reported in the study is
> much lower than with earlier generation devices before the last FDA
> hearings in 1991 and 1992.
>
> Probably the most widely accepted theory is that there is a low level
> of bacterial contamination that surrounds some implants, that causes a
> capsular response, but I am not sure that is the only cause. It is
> probably multifactorial. It can be related to hematoma, it can be
> related to multiple surgeries, and sometimes you just can\'t figure
> out what it is, but in the data for this study, in the augmentation
> group, it runs at 8 percent at three years, which is significantly
> lower than what you see in historical literature.
>
> DR. NEWBURGER: And the second question I think Dr. Spear might be the
> best to address it, could you explain to those of us on the panel who
> do not routinely implant breast prostheses what would be a difference
> in implantation technique for silicone versus saline that might in
> some way account for some of the differences in the reactions that you
> see down the line?
>
> DR. SPEAR: Well, I don\'t think it is very much technique-dependent.
> About the only thing I can imagine that is different in the technique
> is the size of the incision. A saline implant is typically put in
> uninflated and then it is filled, so it is a smaller incision, which
> would explain perhaps one of the complications which is a scarring,
> which is more with silicone.
>
> In terms of the other complications, I think it is more the behavior
> of the device than the methodology of putting it in. Saline implants
> do behave somewhat differently than silicone implants.
>
> DR. NEWBURGER: Thank you.
>
> DR. ANDERSON: In the public sessions this morning, there was a lot of
> discussion about rupture. I note that you at no point in your data
> analysis did you break out the few patients that had ruptured to talk
> about their experience to see if, in fact, they really were similar to
> the other group.
>
> Why is the rupture data not shown to us here?
>
> DR. SPEAR: You mean in terms of the sort of history of those patients,
> what kind of situation they had?
>
> DR. ANDERSON: Your argument, the argument that is being presented is
> that this is a safe and effective device and that it is equivalent or
> better than saline, but the concern about rupture between saline and
> silicone is at least theoretically different because of the
> persistence of gel.
>
> But you didn\'t show us any data about your rupture patients, what
> happened to them, and I think that that would be helpful if we knew
> more about those patients.
>
> DR. SPEAR: I think the data, at least some of that data is in the
> presentation. I think the most significant piece of data is that there
> was no extracapsular silicone in any of the rupture patients.
>
> I think there were some 26 implants that were ruptured as of three
> years, and of those 26, there was no extracapsular silicone. From a
> surgical point of view, it means that when the implant is removed, it
> is relatively easy to remove at least all the gross silicone.
>
> Beyond that, if you are asking for sort of endpoints in those
> patients, did they all have reimplantation, I would have to go back
> and look through the data, but I think the vast majority did, because
> very few patients in the study had implants removed and left out, so
> almost all the replacement/removals ultimately had replacements with
> another device.
>
> So, there were very few patients who dropped out and had their
> implants left out, and there was no extracapsular silicone in any of
> the patients, so it would leave me to believe at least that nobody
> suffered any harm from the silicone that got outside of the implant,
> at least that we could see.
>
> DR. LI: I think it was asked once before, but could you review how you
> looked for extracapsular silicone? Was it you just looked and see if
> it was there or not?
>
> DR. SPEAR: I suppose each surgeon has his own way of looking for
> extracapsular silicone, but usually, each surgeon was asked, when he
> dealt with a implant rupture, to answer the question was there
> extracapsular silicone. It usually presents itself as a lump outside
> the capsule.
>
> So, if you have extracapsular silicone, it\'s a palpability issue, you
> can feel it or see it because the tissues will look like they have
> silicone in them.
>
> DR. LI: So, it doesn\'t rule out, for instance, diffusion of low
> molecular weight materials or if it doesn\'t clump, in other words,
> there could be several grams of liquid silicone, if you will, or of
> different molecular weights around the extracapsular area and you
> would never see it, is that correct?
>
> DR. SPEAR: I am not sure I would agree with the \"is that correct\"
> question, but is it possible that there were small amounts of silicone
> which were not grossly detectable in the capsular soft tissues around
> an implant, I think that is possible. It was not grossly detectable.
> Whether there is microscopic or other methodologies for picking up
> very small amounts, I think that is a possibility.
>
> DR. LI: I guess I was asking this in conjunction I think with what Mr.
> Powell said, in your retrieval collection, you did not see any
> retrieved components that lost more than 5 grams of material. Well, 5
> grams is actually a lot of material.
>
> In orthopedics, a half a gram would cause osteolysis in the same time
> period, so 5 grams is actually a whopping amount of material. So, if
> you had 5 grams distributed kind of uniformly rather than in a lump,
> that possibly could be missed, is that correct?
>
> MR. POWELL: Let me just correct that. What I mentioned was the fact
> that upon returned devices\' evaluations, the weights are always
> within the specified weight for that particular implant.
>
> I think in our preclinical study where we injected unsupported gel
> into the subcutaneous portion of the rat, where actually only I think
> 0.06 percent of the total mass of the silicone was not at that site of
> administration of the gel, showed that the gel really doesn\'t move
> around in the body.
>
> DR. LI: I don\'t want to jump ahead too much in the detail, but in
> your retrieval collection, I think you had something like 339
> retrievals and 133 of them were evaluated as having rupture, so even
> in those retrieved devices that had rupture, there was no apparent
> weight loss?
>
> MR. POWELL: No, I didn\'t mean to infer that. Where they could weigh
> it, and they were able to weigh the intact devices, there was no gel
> apparently missing from the devices.
>
> DR. LI: So, for those devices that were retrieved, and appeared to
> have an opening, substantial or significant amounts of silicone could
> have been lost?
>
> MR. POWELL: I am not aware of the complete data in that regard, but I
> don\'t believe\--I would have to find the data out on that.
>
> DR. LI: It is somewhat hard to believe that you could have a
> significant rupture or opening and have no loss of silicone, because
> if that was the case, we wouldn\'t really worry about ruptures, right?
>
> MR. POWELL: Right.
>
> DR. LEITCH: Perhaps you have some imaging data about the patients who
> had rupture that, you know, you had MRI documentation of some of those
> ruptures which should tell you whether or not there was extracapsular
> extravasation, and I expect some of those patients had mammograms, as
> well.
>
> DR. CROTTEAU: Back to the question that was asked about the explanted
> devices. My name is Patrick Crotteau, I am Vice President of Quality
> Systems for Inamed Corporation. I do have a financial interest.
>
> In our explant analysis, when a device has ruptured, we have found
> returned devices that are fully intact, partially intact, or just
> pieces of shells depending on what has occurred during the explant
> surgery, and based on our analysis, you can\'t make a determination
> where that silicone was lost.
>
> What we did determine is on returned explanted intact devices, that
> there was no apparent loss of silicone based on our specifications for
> filling those devices during manufacturing.
>
> DR. LI: Just to clarify, so on those devices that came back, say, the
> ones you classified as being broken or having a very large opening,
> did the surgeon at that time report any extracapsular silicone?
>
> DR. CROTTEAU: We would have to look at the actual clinical
> investigation forms. Typically, we don\'t get that information with
> the returned device, so we would have to go back to the clinical
> information to determine what those comments were from the physician.
>
> DR. LI: Well, you see what I am driving at, that perhaps the operative
> report that says whether or not you see extracapsular silicone may or
> may not be a good indication that the silicone actually leaked into
> that extracapsular area.
>
> DR. SPEAR: Maybe to wrap this up, at least in clinical practice, I
> mean there is an entity of extracapsular silicone that very
> experienced surgeons have seen, and it is an entity that happens.
>
> All I can tell you is that in the study population by multiple
> surgeons, I guess there were 60-some sites, none of these 26 ruptured
> implants had any detectable extracapsular silicone. That doesn\'t mean
> there couldn\'t be microscopic amounts of silicone, but then the
> question becomes what is the significance of a microscopic amount of
> silicone in that capsule. That is where the epidemiological studies
> begin to come into play - I mean what is the significance of that, if
> any.
>
> Regarding the MRI question, as I know it, the MRIs did not reveal any
> extracapsular silicone either, and there were some 300 MRIs done, and
> there was no extracapsular silicone including I think it was 18 or so
> implants that were diagnosed as ruptured on MRI. So, the MRI didn\'t
> show any extracapsular silicone either.
>
> DR. LI: My normal background is in the area of orthopedics, but in
> orthopedics and joint replacements, the most biologically active
> particles that we are worried about are ones that cannot be seen by
> eye. So, the fact that they are small doesn\'t necessarily mean they
> are benign.
>
> DR. BOULWARE: As a rheumatologist on the panel, I would like you to
> clarify the slide 83, the American College of Rheumatology. In the
> spirit of disclosure, I am a member of that organization, currently
> sit as a board of director.
>
> Could you tell the independent peer-reviewed research done by them, or
> was this just a simple statement in mid-nineties that said there
> isn\'t existing data at this point to draw a conclusion, because I
> have asked the ACR if they have a position statement which I needed to
> disclose, and they did not have an official position statement or a
> policy on it.
>
> DR. SMITH: Would you repeat that question, please.
>
> DR. BOULWARE: Slide 83 indicates that the American College of
> Rheumatology\--and the title says Significant Results: Independent
> Peer-Reviewed Research\-- the ACR, implants do not cause additional
> risk for connective tissue or rheumatic disease.
>
> Is that really an independent peer-reviewed research that was done or
> simply the statement that was issued in the mid-nineties that said
> there is insufficient data at that time to draw a conclusion, and
> really not a research study?
>
> DR. McLAUGHLIN: My name is Dr. Joseph McLaughlin from the
> International Epidemiology Institute. It wasn\'t their own research,
> it was a pronouncement by the College.
>
> DR. BOULWARE: Actually, I would be very interested in that because I
> am not only finishing my third year on the board, but served three
> years on the committee, so I have attended six years of meetings and
> asked them specifically if we have done this or sent it to committee,
> and have not. I was told we do not have that.
>
> Now, that is just one of many things that you have cited, but I do
> want that to be clear in the record.
>
> DR. SMITH: Hi, I am Howard Smith. I am a rheumatologist. I am Director
> of Research at the Cleveland Clinic Health Systems.
>
> The ACR, about four or five years ago, sent out a fax to all the
> members giving this position. It was an official policy of the ACR.
>
> DR. BOULWARE: Would you submit that for record then for us in terms of
> I think that is probably one of the faxes that are sent out to
> interpret\--
>
> DR. SMITH: But it was a position statement.
>
> DR. BOULWARE: No, I don\'t think it is. I think if you asked the ACR,
> they would say it is not a position statement, because they are very,
> very rigid about that. I am a rheumatologist, like you, and we spend
> all our time doing nothing but criteria\--
>
> DR. WHALEN: Obviously, it is a significant point, but the right wing
> is getting antsy, so I have to get to some questions over here. If you
> could indeed produce that in writing for us, since we are indeed going
> to be here again tomorrow, that would be appreciated, or if you
> can\'t, please inform us of that.
>
> DR. EHMSEN: Mr. Chairman, just a couple of comments, please.
>
> First, with regard to the extracapsular or intracapsular gel, I
> believe that the safety data that we presented demonstrates that
> regardless of where the gel is located, it does not create any health
> concerns. So, that is one point that needs to be made.
>
> Also, I would appreciate it if you would give Professor Brook an
> opportunity to clarify a point that he raised earlier in response to
> the question regarding the relationship between the preclinical and
> the clinical data, if you might just give him a moment, please.
>
> DR. BROOK: I think I misunderstood Dr. Miller\'s question, which was
> the relevance of preclinical data to clinical data. There shouldn\'t
> be a disconnection between these two, of course, but preclinical means
> just that, and the idea is you put incredibly difficult constraints on
> these materials.
>
> I mean in the case of the fatigue testing, you take two plates and you
> put the implant between them and six a half million times you apply at
> least 30 pounds of pressure to see whether or not there is going to be
> rupture, and all of them survived at least 30 pounds.
>
> Of course, there is a relevance because you expose these materials to
> something they would never be expected to see in the clinical
> situations. You go far beyond what you anticipate is going to be the
> real exposure. So, in that sense, there has to be a relevance between
> the preclinical and the clinical data. You are trying to make sure
> that a material that is going to go into the clinic, every expectation
> is it is going to pass all of the requirements once it gets into the
> clinic.
>
> DR. CHOTI: Three quick questions. First of all, regarding that, if
> that is the case, then, why is there still a reasonably high rupture
> rate even at two and three years, if it is put through these rigorous
> tests, what are these women doing within three years that there is
> still rupture rate, and the rupture rate keeps going up? I mean if it
> is so rigorously tested in vitro.
>
> DR. BROOK: I think I am probably the wrong person to answer that
> because I can talk about fatigue testing outside of the body.
>
> DR. CONANT: May I comment on that? Again, I am a breast imager, but
> what I hear from women is that there is a shearing, there is a motion,
> their arm raised, that is retropectoral, there is a shearing of the
> implants that is not reproduced well in the laboratory by direct
> compression.
>
> There is a twisting of the implants, possibly wrinkles, as they have
> described, weakening at wrinkles. I would love to hear a comment on
> that, but it is a very different in vivo situation, the stresses that
> an implant undergoes.
>
> DR. SPEAR: I think there are two answers to that question. One is the
> retrieval data on broken implants or ruptured implants, and one is
> just clinical experience. Clinical experience is that some implants
> unfortunately are probably damaged in the process of insertion. What
> percentage of this couple of percent of the ruptures that we see at
> three years, I don\'t know, but some are, and they will show up
> apparently as smooth, sharp openings on retrieval.
>
> I think you are referring to the issue of folding, that the testing
> done in preclinicals is a pummeling test, it is not a tumbling test or
> a folding test, and it is possible that some of these devices will
> fail because of repetitive folding and creating a fold crease.
>
> I think that is the reason why despite the fact that they do so well
> in these preclinical lab tests, a combination of the surgical trauma
> and then the real life trauma, which is not just pummeling, is I think
> the explanation about why you see failure anyway.
>
> DR. CHOTI: But if that is going up over time, it doesn\'t suggest that
> it\'s an acute process. It suggests there is some weakening or some
> process over time, not just from the mechanism of putting it in.
>
> The second question is just is there any change, any improvements in
> the product, in this product, compared to the one that was looked at
> in 1992, or is it the same product?
>
> MS. KUHNE: It is basically the same product as it was 10 years ago. I
> mean there has been some minor manufacturing efficiencies, the gel
> crosslinked a little bit more, but basically, it is essentially the
> same product.
>
> DR. CHOTI: So, the problems that were addressed over a decade ago,
> there was no modification on the device at all from over a decade ago
> to this product?
>
> DR. SPEAR: Let me answer that. This is not a preplanned answer to that
> question, but back in 1991, these devices were not turned down maybe
> because there was data they were not safe, the problem was that there
> wasn\'t enough data for these devices. They were being looked at in
> the context of two or three generations of devices which had never
> gone through a PMA process because they were pre-1976 devices.
>
> So, I don\'t think that these devices that were presented in \'91,
> \'92 FDA hearings were ever characterized as being unsafe. It is just
> that the FDA said we need data for these devices. They are an
> improvement over the historical devices, which a lot of the ill will
> associated with breast implants is from, going back into the seventies
> and eighties.
>
> So, this is a different device than was used in the seventies and
> eighties, but it is not a device that is much different than presented
> in the PMA of 1991 and 1992.
>
> Did you want to say something, Joe?
>
> DR. McLAUGHLIN: This is Dr. McLaughlin again from the International
> Epidemiology Institute.
>
> We published the first incidence rupture study of breast implants ever
> done in the July issue of The Archives of Surgery, and we followed the
> women for two years, and the rupture rate for the type of implant that
> is now being used, the so-called third generation, is approximately 1
> percent per year. It parallels the rupture rate of the Inamed product.
>
> Up until that study, in the literature when you read about rupture
> rates, they were all basically cross-sectional prevalence studies or
> explantation studies. So, the rupture rates are not as high as people
> have been led to believe.
>
> DR. CHOTI: I just wanted to clarify that the product is really the
> same in a decade. This isn\'t a fourth generation, it\'s the same.
>
> The last thing is just I am a little bit troubled by this long term.
> You know, everybody made an emphasis that women are informed that this
> does not last a lifetime, and yet there hasn\'t been really clear
> guidelines as to is there a time that you recommend\--this may be
> beyond the clinical study\--but are you recommending replacement at 10
> years, at 12 years, and if so, based on what?
>
> DR. McLAUGHLIN: Again, in our incidence study, we found that at five
> years, 98 percent of the implants were still intact, and at 10 years,
> 85 percent were still intact.
>
> So, then again, the amount of rupture is a lot lyre than people
> imagine.
>
> DR. CHOTI: Do, just to clarify guidelines, leave it in until it
> ruptures, replace it at a certain time point, what are you
> recommending as you get beyond 10 years?
>
> DR. SPEAR: It is interesting, this came up in 1991 and \'92, when the
> FDA decided to limit the availability of the devices, and the question
> was what do you tell women who currently have implants.
>
> The question, the answer really hasn\'t changed very much in my
> opinion. I think the advice to women, whether they have an implant for
> reconstruction or for augmentation, is that they should be seen
> periodically by their surgeon every\--I think one year is too short,
> five years is too long\--every two to three years to be monitored for
> evidence of problems, and the most likely problem would be a silent
> rupture.
>
> The good news is that the term \"silent rupture\" tells you that these
> are usually asymptomatic, in other words, they don\'t cause symptoms,
> they don\'t make people sick, they don\'t cause physical problems in
> the vast majority of patients.
>
> But on the other hand, I think, as has been pointed out, we don\'t
> want to see silicone outside of the capsule, and I think if it\'s
> outside the implant, there is probably a greater likelihood it will
> get outside the capsule with trauma, that they should be replaced once
> there is a diagnosed rupture.
>
> So, I think the advice would be not that every implant that is 10
> years old should be removed, but that every patient with an implant
> should be seen periodically because at least most surgeon\'s clinical
> experience, if the patient doesn\'t have a capsular contracture, you
> can diagnose a ruptured implant just by physical examination. You
> don\'t need a \$1,000 MRI to do it.
>
> DR. CHOTI: So, you are suggesting guidelines leave it in until it
> ruptures. That is basically what you are saying?
>
> DR. SPEAR: Well, I can tell you from clinical practice if someone
> comes in to see me and they have concern, and they have had an implant
> in, let\'s say, 15 years or 20 years, and they say I am worried, I
> have had an implant for 15 or 20 years, what should I do, and I tell
> them if you are worried, the fact is that your risk of rupture is
> time-dependent, maybe you should go ahead and replace it and reduce
> your worry.
>
> If they are not worried, frankly, and they have no clinical symptoms
> or signs of a problem, I would tell them just leave it in, be seen
> every two or three years. You can usually diagnose a problem just on
> physical examination.
>
> DR. WHALEN: Brent, do you have a question?
>
> DR. BLUMENSTEIN: I have a number of questions about the methodology.
> On slide 43, you mention that what is represented, I assume on the
> subsequent slides are Kaplan-Meier estimates of three-year event
> rates, and I just wanted to confirm that that is the case.
>
> DR. BECKSTRAND: That\'s true.
>
> DR. BLUMENSTEIN: Then, these estimates do not include censoring for
> prior complications as specified in the guidelines?
>
> DR. BECKSTRAND: That is true.
>
> DR. BLUMENSTEIN: Then, subsequently, on slide 72 and some other
> slides, you present comparison of the Kaplan-Meier estimates from the
> silicone-filled implants to the saline-filled implants. Are the
> estimates for the saline-filled implants, Kaplan-Meier estimates
> without censoring?
>
> DR. BECKSTRAND: That is true, exactly the same analysis.
>
> DR. BLUMENSTEIN: You recomputed them, because a few years ago, when
> you were presenting the saline-filled estimates, you were censoring
> for prior events.
>
> DR. WHALEN: Excuse me, can you just identify yourself, so that we know
> who you are.
>
> DR. BECKSTRAND: Maggie Beckstrand, Inamed Corporation. I have a
> financial interest.
>
> DR. WHALEN: And your capacity with them?
>
> DR. BECKSTRAND: I am sorry?
>
> DR. WHALEN: You are their statistician?
>
> DR. BECKSTRAND: Senior biostatistician.
>
> DR. WHALEN: Thank you.
>
> DR. BECKSTRAND: Actually, when we presented the saline data, that was
> a misinterpretation, and we were not censoring for previous
> complications.
>
> DR. BLUMENSTEIN: So, your estimates then are in compliance with the
> guidelines that the FDA put out in February.
>
> DR. BECKSTRAND: That is true.
>
> DR. BLUMENSTEIN: You present a lot of different complications and a
> lot of different Kaplan-Meier estimates of risk at three years.
>
> Why are you choosing not to pull all this together in one composite
> risk of, say, something to bad thing, as a composite of women who
> experience something bad as opposed to women who do not?
>
> DR. SPEAR: I think much of how the data is presented was by the
> discussion with the FDA about how the data be presented. I don\'t
> think anybody would have a problem saying what percent of patients had
> any complication as a total, but many of these complications are
> misleading in the sense that one person could have had four things, so
> the total number could be more than 100 percent if you did it that
> way, but if you wanted to look at how many patients had some problem
> or other, I think there would be no problem doing that. It just
> wasn\'t the way the data was presented, I think more or less by
> agreement.
>
> DR. BLUMENSTEIN: To me, it doesn\'t really show the single thing that
> I would think that most women would want to see, and that is what is
> my risk of having something bad happen.
>
> DR. BECKSTRAND: We did actually break it down into three different
> types of bad things, which would be the general breast surgery risks,
> breast-related cosmetic risks, and breast-related non-cosmetic risks.
>
> We have those numbers. For example, you will see the slide, it\'s
> general breast surgery complications, and lists all of the
> complications included in that Kaplan-Meier, three years\'
> augmentation, 43 percent of the patients experienced a complication
> general breast surgery, and then we have another slide for the
> cosmetic complications, 9 percent, other than non-cosmetic
> complications 13.
>
> So, we did not choose to lump it all into one big, any type of
> complications.
>
> DR. BLUMENSTEIN: So, you don\'t have a back-up slide with such an
> estimate on it?
>
> DR. BECKSTRAND: Where it brings together all three? No, in advisement
> with Dr. Spear, we chose not to, because we thought it was very
> important to break out the general breast surgery complications that
> occur.
>
> DR. BLUMENSTEIN: I can see the sense in breaking it out, but it would
> also seem useful to have one composite bad thing, risk of a bad thing.
>
> It really brings me to another issue. I see that you are choosing to
> present the three-year Kaplan-Meier estimates. I don\'t see any graphs
> of risk either as 1 minus Kaplan-Meier or whatever, however you choose
> to do it.
>
> It seems to me that this becomes extremely important when you talk
> about things like reoperations because the timing of the reoperations
> would seem to be a big factor in looking at the data as a whole as
> opposed to looking at the cumulative risk of pre-operations at a
> single point in time, say, three years.
>
> DR. BECKSTRAND: We have got some graphs.
>
> \[Slide.\]
>
> This would be our risk at 1, 2, and 3 years Kaplan-Meier. It is not
> the survival curve, but it\'s at those three time points, this is the
> risk.
>
> DR. BLUMENSTEIN: I personally would prefer to see a more conventional
> Kaplan-Meier presentation.
>
> On slide 60, this has to do with reproductive effects and lactation
> effects, and I was just curious about what the denominator was for the
> computation of those risks and the appropriateness. Apparently, you
> used the denominator of the whole cohort of patients studied, and I am
> curious as to what your rationale for that is.
>
> DR. BECKSTRAND: Right, we did use the denominator for those, but we
> also looked at it from the standpoint of how many patients, in terms
> of lactation, how many patients attempted to breastfeed, and that
> denominator was 32. There were 5 lactation problems out of 32 patients
> who attempted to breastfeed, which was 15.6 percent risk, which was
> the same as\--there is a 15 percent problem with lactation
> pre-implantation in the augmentation group, as well.
>
> We originally looked at it with the whole cohort, and FDA asked us to
> look at it from the other perspective.
>
> DR. BLUMENSTEIN: Second to last question. In the slides 79 through 89,
> this is just like fingernails on a chalkboard to me, but on the slides
> you say there is, well, like the one that we were discussing a few
> minutes ago with the American College of Radiology, it says,
> \"Implants do not cause additional risk of connective tissue or
> rheumatic disease.\"
>
> Other slides, you say, \"There is no evidence of an immune\"\--like
> just above that you say\--this is on slide 83\--you say, \"No evidence
> of an abnormal immune response.\"
>
> The issue here is that these are studies that looked for something and
> failed to find it, and the conclusion of no cause or no relationship,
> and so forth, is not a correct conclusion. If you look for a needle in
> a haystack and you fail to find it, you can\'t say that there is no
> needle in the haystack. You have to say you failed to find it, and
> then you have to characterize how hard you looked, with a sensitive
> metal detector or just rummaging around.
>
> So, the language that was used to describe this often did indicate
> that there was no evidence or something like that, but your slides
> actually state these as definitive conclusions.
>
> The other question I had was do you folks market a silicone breast
> implant in Europe?
>
> MS. KUHNE: Yes, we have been marketing it there for over 25 years.
>
> DR. BLUMENSTEIN: Do you have data from studies in Europe?
>
> MS. KUHNE: Not data that would satisfy FDA\'s requirement for clinical
> endpoints. There has been no controlled clinical trials in Europe on
> Inamed\'s breast implants.
>
> DR. WHALEN: Dr. McGrath.
>
> DR. McGRATH: I have a couple of sort of clinical questions. One, I am
> a plastic surgeon and user, and I appreciate seeing the percentages on
> the silent ruptures and the rupture rate, but I want to know why they
> ruptured.
>
> Now, we have danced around this question before and no one answered
> it, and what I want to hear from you is do you know why these implants
> break down over time? What happens to them?
>
> DR. SPEAR: Dr. McGrath, I think the answer I gave you is going to be
> the answer, that some are ruptured because of trauma at the time of
> insertion, not all of them obviously, and over time some rupture or
> fail I think because of the fold flaw method. I think the fold flaw is
> probably the most likely suspect over time. It is the thing that they
> are most vulnerable to.
>
> They are very strong in some ways, but they don\'t handle\--
>
> DR. McGRATH: These are your assumptions, Dr. Spear. Is there any data
> on this question? I think we need to understand whether the polymer is
> thinning or the seal is coming off or what is happening to these
> things that they fail.
>
> DR. CROTTEAU: In our retrieval study, the primary purpose of the
> study\--and this is a study that is conducted both for saline and
> silicone breast implants\--we are trying to determine modes of failure
> for each type of device. On both studies, they are ongoing studies of
> looking at returned devices, we do not see any changes in the shell
> physical characteristics when we can measure it.
>
> As far as the elongation, the strength of the devices, on explanted
> devices, we do not see any change in thickness or thinning of the
> shell. We do not see any weakness in our patch-adhered joint.
>
> What we do see is in the case of the silicone devices, 18 percent of
> devices have manifestations of surgical damage, so when we get
> devices, we go back and we evaluate the devices both macroscopically
> and microscopically to determine if we can tell how the device failed.
>
> We have studied typical surgical damage and have a set of standards
> that our technicians compare device damage to based on forceps,
> sutures, scalpels, and characterize those type of failures.
>
> We also have an ongoing study that shows or tries to determine why we
> have both smooth-edged openings and sharp-edged openings in devices.
> When we have a smooth-edged opening that is typically and has been
> demonstrated to be caused by a fold and actual abrasion of the
> devices, this is not a typical mode of failure for silicone devices,
> it is a more predominant mode of failure on saline devices.
>
> For sharp-edged openings, beyond surgical damage, we have an ongoing
> study to determine why those are occurring, but we have not determined
> statistically any modes of failure that determine why we have a
> sharp-edged opening in the device.
>
> This is part of an ongoing program, part of our conditions of approval
> for saline, and again part of an ongoing program on silicone gel.
>
> DR. LI: Could I follow up on that? In looking over your retrieval
> data, I was a little confused over the smooth edge/sharp edge
> description because those aren\'t normally materials terms that
> describe rupture.
>
> But I was a little confused over this issue about what you call smooth
> edge openings occurring at a fold. Now, in the breast implants
> retrieved that I have got, many of them are quite supple and there are
> no permanent folds or deformations in the device.
>
> So, are you saying that some of the retrieved devices come back with a
> permanent crease in it?
>
> DR. CROTTEAU: You can actually see physically a crease in the shell,
> and at the apex of the crease, you see a thinning and then a wearing
> through of the shell. This is much more evident in saline devices, but
> we can determine, you actually see a crease in the shell.
>
> DR. LI: So, this is a permanent deformation of the shell?
>
> DR. CROTTEAU: Well, it is either a permanent deformation or is a
> shadow left in the shell. Again, it is a manifestation where you can
> see where the device was creased and then again it shows that
> typically at the apex, that crease, thinning of the shell.
>
> DR. LI: For what you call your sharp edge openings that you said
> didn\'t appear to follow a crease line, is it possible that there was
> a fold while it was in the patient, that when you took it out, it was
> still soft enough to where the fold disappeared?
>
> DR. CROTTEAU: That\'s possible. Again, we cannot determine what is
> causing the majority of the sharp edge openings at this point in time,
> but we do not see any changes in mechanical properties or physical
> properties of devices that are explanted.
>
> DR. LI: Did you do any microscopy? Oftentimes you could see, for
> instance, if it\'s a scalpel mark, if the fracture is outside-in, or
> inside-out.
>
> DR. CROTTEAU: Yes, and we actually do photomicrographic analysis when
> we need to. We have photomicrographs of typical surgical damage that
> the technicians use when they compare the devices.
>
> DR. LI: So, for the ruptured devices that you believe were surgically
> induced, those were all outside-in ruptures?
>
> DR. CROTTEAU: Well again, if it is in the case of a suture, you will
> see an entry and an exit, so you can\'t say they are all outside-in,
> you can depending on the type of damage. It it\'s a forceps damage,
> you may see that it has been damaged actually on the inside of the
> device and then propagated to the outside.
>
> DR. LI: One more detailed question on the surgically-induced ruptures.
> First of all, these shells are relatively thin, they are three-tenths
> to 0.45 millimeters thick. So, you are saying that it is possible
> essentially if you nick the wall with a scalpel, that you have nicked
> it enough, so the surgeon wouldn\'t detect it as a leak, but you have
> only gone through 0.1 mm instead of 0.13 or 0.3 mm, so wouldn\'t you
> expect those ruptures to happen earlier?
>
> So, is there a correlation between those types of ruptures and the
> length of implantation?
>
> DR. CROTTEAU: Again, when we receive the devices back, they have
> failed, so we can\'t determine whether it was a nick that then
> propagated into a failure or it was a cut through. Now, typically,
> when you look at them, you can tell what the initial contact was, but
> you can\'t tell when that propagated to a point of failure.
>
> DR. LI: Just one last question for the moment. Of the 339 retrieved
> devices that you reported on, were all these 339 from the three
> cohorts, or were they from the 79,000 implants that you have put in?
>
> DR. CROTTEAU: No, those 339 are from these three cohorts.
>
> DR. LI: Are exclusively from these three cohorts.
>
> DR. CROTTEAU: Again, we have ongoing analysis of other devices, but
> the data that was presented represents the clinical study.
>
> DR. LI: Because it\'s a little misleading because in some of your
> tables, you used as the numerator 79,000 devices and reported
> percentage, so that is a little misleading.
>
> DR. CROTTEAU: That is I think in our postmarket information, not in
> our explant or retrieval.
>
> DR. WHALEN: Dr. Conant, did you have a question?
>
> DR. CONANT: Again, I am a breast imager, but I have got a couple of
> questions about the patient satisfaction side of it. I find it a
> little contradictory that when questioned about how satisfied they are
> with their implants, 89 to 96 percent of the women were very
> satisfied, but at the same time, at two years, the reoperation rate
> was so high, 20 percent, 45.9, 33 percent.
>
> I am questioning how patients were queried on satisfaction, and if I
> take the lowest level of that group, at 89 percent, still more than
> that number had reoperations. I can\'t imagine being satisfied if you
> have to go back to the OR in the same period of time.
>
> Could you clarify that?
>
> MS. KUHNE: For the general overall satisfaction rate, it was just a
> question asked at different points in time postoperatively how
> satisfied are you with your breast implants on a 5-point scale.
>
> Indeed, as you indicate, I mean many of these patients had
> complications, but that didn\'t cause them to be unsatisfied with
> their breast implant surgery in general.
>
> DR. CONANT: So, they were questioned at multiple times during their
> three years.
>
> MS. KUHNE: Right.
>
> DR. CONANT: Were they pooled responses?
>
> MS. KUHNE: Right. The satisfaction question that you are referring to
> was not a pre- and post-satisfaction, it was just post-implantation
> annually, and they are asked that question how satisfied are you with
> your breast implant.
>
> DR. CONANT: Did you look at this relative to whether they had been
> back to the operating room, whether that group was less satisfied,
> whether that impacted on their satisfaction?
>
> MS. KUHNE: We didn\'t look at each patient in terms of, you know,
> specific for unsatisfaction, but we did look, for instance, at
> instances for, you know, capsular contracture is a very common
> complication, but only like 18 percent of those patients indicated
> that they were not satisfied.
>
> DR. CONANT: My next question is since we only have two years I think
> for reoperation data, I am wondering if you all were able to
> extrapolate. You showed when he asked, I am not a statistician, he
> asked for the Kaplan-Meier and showed three different curves slightly
> increasing over time, not a straight line, if you extrapolated to five
> and 10 years in terms of reoperation, because as you said, quite a few
> of these reoperations were capsular procedures which were in many
> cases I think repetitive procedures, whether you could comment on what
> the expected reoperation would be at later years like five and 10.
>
> MS. KUHNE: I don\'t think we can really extrapolate from the
> information. I don\'t think there is a mathematical way to do that. I
> don\'t know if Dr. Spear has a comment on what he would expect from
> the clinical standpoint.
>
> DR. SPEAR: Well, I think most of us have learned that things
> deteriorate with time, it doesn\'t matter what you are talking about,
> and I think as patients have implants longer and longer, the number of
> patients who have a reoperation is going to come up for whatever
> reason.
>
> I am not sure it will all be for capsular contraction. I think what
> that data shows me, interestingly, is that even though the numbers are
> there, that from the patient\'s perspective, the numbers of this and
> that don\'t change the fact that 90 percent plus, particularly of the
> augmentation and revision patients, are happy with their device
> despite the fact that 20 percent have a reoperation, despite the fact
> that 8 percent have a capsular contracture, they are still overall
> happy with their device.
>
> A few patients have removed their device because they weren\'t happy,
> but when you look at the totality of the thousands of patients in the
> study, 90 percent are still happy despite the fact that we have listed
> very definitely everything that one could think of that someone could
> have a problem with, from bruising to itching to paresthesia, I mean a
> pretty definitive list of things that people could answer yes to, but
> with all those things in there, still 90 percent plus were satisfied.
>
> DR. CONANT: Three years.
>
> DR. SPEAR: Yes, and I expect that with time, it might change. You
> know, things do change, but it didn\'t change much from one year to
> two years, it changed a very small amount.
>
> DR. CONANT: I have just a couple short comments and questions.
>
> You compared the saline versus the silicone in terms of rupture, and
> the saline had a much higher instance of rupture, still not very high,
> I think around 5.6, something like that.
>
> I think that is a very difficult group to compare, because we know
> that when saline implants rupture, they deflate, and one knows that,
> patients are aware of that, versus dealing with this silent rupture.
>
> I just think that that has to be said to the audience because it\'s a
> very different clinical situation.
>
> DR. SPEAR: Can I respond to that?
>
> DR. CONANT: Sure.
>
> DR. SPEAR: I think that is a very valid point, the fact that one is
> not silent and one is silent, but I think that is why the MRI study
> was included in the study, and the MRI study still gives you a lower
> number of silent ruptures than you would have of the saline ruptures.
>
> DR. CONANT: Which takes me to the next point, which is the MRI study.
>
> DR. WHALEN: Can I just interject before you get to that point? I want
> to again echo that I strongly encourage any and all questions. We are
> going to hopefully get to a point where the panel is going to be
> making comments, so please ask your questions at this point, reserve
> your comments until a point this evening when we get to that.
>
> DR. CONANT: Question. How did you decide the sample size for the MRI
> study? I notice the compliance dropped off considerably at year 2. I
> am wondering how you recruited the patients, what that plan was?
>
> MS. KUHNE: The sample size was determined based on the specific
> precision that was required actually per the FDA guidance document. It
> was about 34 percent of the overall patient population is what it ends
> up to be.
>
> In terms of compliance, we are attempting to get these patients back
> in to get their MRIs.
>
> PROF. DUBLER: Dr. Whalen, I had a follow-up question.
>
> DR. WHALEN: We will get to you in just one second, Dr. Dubler.
>
> DR. LIEBERMAN: I wanted to follow up a little bit on the satisfaction
> data and ask how you can square again this very high satisfaction rate
> with the decrease in so many measures of well being. You put up that
> they were above average even at the two- or three-year mark, but most
> of them had decreased and many of them had significantly decreased.
>
> MS. KUHNE: I think again a lot of that has to do with the fact that
> they started so high to begin with and there wasn\'t much room for
> them to go but down in some instances.
>
> DR. LIEBERMAN: It\'s a pretty consistent pattern.
>
> DR. SPEAR: Can I respond to that, too? I think that is a very
> interesting question. It has troubled I think some of us, as well as
> you, but I want to emphasize that the decision to have elective
> surgery is a courageous decision regardless of what it is, and I think
> that you get these people at a point when they are feeling very good
> about things in general.
>
> The fact that even though there is a decline in some of these
> measures, and even though it is a statistically significant decline, I
> am not sure it\'s a clinically significant decline because it is a
> very small measure, too. They are still very, very high on the scale.
>
> But I think the point that they start at the top, there really isn\'t
> much room for them to move except down. I mean if you get 100 on the
> exam, you can\'t get 101, so the fact is sort of it\'s just a
> peculiarity of the measure that they couldn\'t do better, they could
> only do the same or worse, because of the fact that they scored
> perfectly, many of them, at the initial assessment.
>
> But I think the fact is even though it is a statistically significant
> change, I am at a loss to give it any clinical significance.
>
> DR. LIEBERMAN: We mostly have yes\'s or no\'s in significance.
>
> The other question I had you talked about cancers and you talked about
> breast cancer, and you talked about rheumatologic disease. There are
> some studies that have suggested increases in lung cancer and brain
> cancer specifically glioblastoma, and you didn\'t address that point,
> so I would like to hear what you think about that.
>
> MS. KUHNE: We didn\'t address that point because that wasn\'t an
> endpoint in the study, and we didn\'t specifically collect that
> information, although we did look at, in terms of the numbers of lung
> cancers and brain cancers that we had on some of the patients who had
> report of complication of cancer postoperatively, and if you give me
> one moment, I can find that information for you.
>
> DR. LIEBERMAN: I think your numbers, I mean given the size of your
> cohort, the numbers are probably pretty small, so I think part of it
> has to be based on the literature, as well as what is found in the
> study.
>
> DR. SPEAR: Let me just say that in terms of the literature, what is
> interesting is that the overall mortality of the patients who had
> breast implants or breast augmentation is lower than the general
> population.
>
> There are some markers that are higher, there are some that are lower,
> and I think it is my opinion anyway that I would not give breast
> implants a protective effect for preventing certain cancers, and I
> don\'t think there is any evidence that there has a causative effect
> for causing certain cancers.
>
> I think that there is some that it is better in and some that it is
> worse in. It is probably much more a reflection of the underlying
> population who got the implants rather than the effects of the
> implants.
>
> DR. WHALEN: If you about to present information, this is information
> in the PMA, but not today presented, or information that was not in
> the PMA?
>
> MS. KUHNE: It\'s in the PMA. It\'s we didn\'t collect those as
> specific endpoints, we didn\'t solicit that type of information.
>
> DR. WHALEN: Then, go ahead, please.
>
> \[Slide.\]
>
> MS. KUHNE: These are patients in the reconstruction group of the core
> study, and there was one patient who had brain cancer. In the revision
> group of the core study, I am sorry, there was no patients in the
> revision group. In the reconstruction portion of the adjunct study,
> there were two patients who had lung cancer and two patients who had
> brain cancer, and, of course, these patients were all ones who first
> presented with breast cancer.
>
> DR. WHALEN: Dr. Dubler.
>
> PROF. DUBLER: Thank you so much. I had a follow-up question to Dr. Li
> that I didn\'t want to lose. We are very interested, obviously, in
> what makes these things rupture. Since surgical technique has been
> noted by a number of people as a likely reason for some ruptures, what
> would be your solution to that problem?
>
> DR. SPEAR: Well, I think it\'s the reality that you can\'t control
> every surgeon. I think the company has the intention of having an
> educational program to try to educate surgeons how to best use these
> devices if they are approved, but I mean as long as there is humans,
> there is going to be human variability and there will be some surgeons
> who do better than others, there will probably be some surgical error.
>
> A lot of times it sounds like these errors are not things you can even
> detect in the operating room. They may be subclinical trauma to the
> implant, not enough to actually rupture it putting it in, but enough
> to stress it or to create a point of propagation so that later on it
> would rupture there.
>
> So, short of making a very large incision, which plastic surgeons are
> loathe to do, there is going to be some mechanical trauma with
> insertion by some surgeons.
>
> PROF. DUBLER: Do you have any data that would show that
> board-certified plastic surgeons have a lower rupture rate than
> others? How do we bend our minds around this data?
>
> DR. SPEAR: I wish I had that data, but I don\'t have that data.
>
> DR. MILLER: I just have a couple of questions briefly. It was my
> understanding that in the last five, six years, that significant
> changes had been made in the manufacture of the devices, but that is
> not true? When was the last time that you made a major change in the
> manufacture of the devices in regard of the envelope and limiting the
> gel bleed and that sort of thing?
>
> MS. KUHNE: I can\'t answer right now when we made the last change,
> maybe Pat can answer that, but it is the same device that was used 10
> years ago, we have not made any major changes since that time.
>
> DR. CROTTEAU: But to the manufacturing method, again, the design of
> the device hasn\'t changed, but we have made significant changes to
> the manufacturing method to enhance the reliability of the
> manufacturing method.
>
> In devices that were made previously, the manufacturing methods tended
> to be uncontrolled, unvalidated manufacturing methods. In the last few
> years, the manufacturing methods have all been validated to
> demonstrate that they can repeatedly produce the desired device.
>
> So, those type of controls in the manufacturing method have been
> enhancements made to the manufacturing method surrounding the same
> specifications to the end device, so that the variability in the
> product coming out of our production line is much less variable than
> it was, say, 10 years ago.
>
> DR. MILLER: Thank you. I had another question. Because you didn\'t see
> in the animal studies or didn\'t observe in the core study any
> presence of silicone gel outside of the capsule, are you suggesting
> that this never occurs or does not occur?
>
> DR. SPEAR: I am not suggesting that. In fact, I think one of the
> things that has changed over the last decade is surgical practices, as
> well as the design of the devices. There was a time surgical practices
> included something called closed capsulotomy, where if you are dealing
> with a patient with capsular contracture, the treatment was to squeeze
> the implant with as much force as you can humanly muster and fracture
> your thumbs and break up the capsule.
>
> Undoubtedly, that was the cause of a great many patients who did wind
> up with extracapsular silicone because you could rupture the device,
> rupture the capsule, and send silicone into the soft tissues all in
> one moment.
>
> I think it is pretty clearly known by board-certified plastic surgeons
> that this is not a good idea to do, it is discouraged by the
> manufacturers in the package insert, and I think a change in culture
> is part of the reason why I think extracapsular silicone is a much
> rarer event today than it was 15 years ago because the devices are
> made to higher specifications and I think because surgical practices
> have changed.
>
> It can still happen, it can still be microscopic amounts. I think if
> someone is in an automobile accident and hits the steering wheel, they
> could break a device and send silicone into the soft tissues, but
> those are very unusual events, they are not common events.
>
> DR. WHALEN: So, the capsulotomies now are only done during
> mammography, I guess, right?
>
> DR. SPEAR: Well, if you heard the pressures, you know, I am not the
> radiologist in the group, but pressure exerted with a mammogram is
> substantially less than with a closed capsulotomy. I think it\'s 30
> pounds per square inch or less on average. Closed capsulotomies were
> much more forceful. So, I think it is unusual to have an implant
> rupture with a mammogram also.
>
> DR. McLAUGHLIN: I would like to get back to a question from Dr.
> Boulware. I have in my possession now the position statement.
>
> DR. WHALEN: Good. That is something that we have asked that copies be
> provided to us. We don\'t further comment at this particular juncture.
>
> Dr. Olding.
>
> DR. OLDING: I still have a problem with detection of rupture. To me,
> if you accept the possibility or the probability, whatever, that, in
> fact, distant disease is not a problem here, take that whether you
> believe it or not for a moment think that, so then it becomes local
> complications.
>
> If it is a local complication, if it is going to rupture, my patients
> are going to want to know. It is called silent rupture presumably
> because you can\'t detect it in any manner except perhaps for an MRI.
>
> Why would I not advocate an MRI for my patient on a yearly basis, you
> pick the time interval?
>
> DR. SPEAR: I think the term silent rupture really refers to whether
> the patient is aware of the rupture. I don\'t think it would be
> appropriate to say that it refers to the fact that it can\'t be
> diagnosed. I think it just means that a patient is not aware, it does
> not have any symptoms.
>
> When I see a patient in clinical practice who either thinks they have
> a rupture or who has had an MRI for whatever reason, then, comes to
> see me, I think the definitive test is actually the physical
> examination.
>
> I have often, I mean I have removed implants when the MRI suspects
> rupture, and the implant is intact, and I have had patients who come
> to me with an MRI suspicion of a rupture and, in fact, on clinical
> examination, I am absolutely positive the implant is intact.
>
> So, I think the term \"silent\" does not mean that a physician cannot
> detect a broken implant in the absence of capsular contracture. If you
> have a capsular contracture, all bets are off because you can\'t
> really examine the implant.
>
> But then the other issue is what is the danger of a silent rupture,
> and although I don\'t think it is desirable to have a broken implant
> in a patient without addressing it, the fact is that the risk of a
> broken implant that is not symptomatic is very low.
>
> DR. OLDING: Presumably, that is a step that precedes extracapsular
> rupture. So, if you can predict in advance of an extracapsular rupture
> by some method, and I believe MRI is something like 96 or 98 percent
> specific and sensitive, somewhere near that, although there are going
> to be some that it misses, the vast majority it should pick up.
>
> So, again, I have had patients who I have explanted that I did not
> think were ruptured, and were ruptured, and vice versa. Would you not
> want to recommend an MRI?
>
> DR. SPEAR: I personally don\'t recommend MRIs to my patients as a
> routine. I think it\'s a very expensive test for very little yield
> personally. Now, there is nothing to stop a surgeon from recommending
> an MRI if the patient wants one or if they think it is appropriate. I
> don\'t think it\'s the standard of practice at the moment to get MRIs
> because of the length of time a device has been in place.
>
> It is going to be part of the ongoing study here. There is an MRI
> study in place for a total of nine years. The incidence you just gave
> me the numbers again, the silent rupture incidence at three years was
> 2.7 percent in this particular study.
>
> I just don\'t think it\'s a necessary test because although there is a
> natural progression from intracapsular silicone to the greater risk of
> it being extracapsular, again, none of the patients in this study had
> extracapsular silicone at least that was grossly discernible.
>
> I think the chances are for a non-traumatic rupture, in other words,
> one that doesn\'t happen from a closed capsulotomy, the chances of
> silicone getting outside the capsule are still very low.
>
> DR. OLDING: I would agree with that, but I still know that my patients
> are going to want to know if they have ruptured implants because that
> is going to be the decisionmaker for them or most of them.
>
> MS. KUHNE: I just wanted to clarify something. We did calculate silent
> ruptures separately, but those silent ruptures are included in our
> overall rupture rate.
>
> The rupture rates that are reported for the different cohorts be it
> the 1.2 percent for augmentation, and 6.3 percent for reconstruction,
> 3.6 percent for revision includes ruptures that are both asymptomatic
> and symptomatic, confirmed and nonconfirmed, so I just wanted to
> clarify that silent ruptures is included in that overall rupture rate,
> so patients would know.
>
> DR. BRENNER: My name is Jim Brenner. I am a radiologist and a paid
> consultant to Inamed.
>
> A couple of points. First of all, perhaps not every plastic surgeon is
> as adept as Dr. Spear at examining patients, and perhaps not every
> radiologist is as adept at identifying true intracapsular ruptures
> from folds, so that the discussions Dr. Spear had may represent, in
> part, variability both in interpretation of the MRI scans, which are
> not necessarily a reproducible automated test, and the variability of
> the examiner.
>
> In the first place, in this study, there was on-site reading by the
> radiologist and there was a secondary reading by a central reviewer to
> ensure as high an accuracy of identifying intracapsular rupture,
> indeed, implant failure.
>
> I think of at least one occasion where I was called by the plastic
> surgeon that his or her radiologist did not believe there was a
> rupture, I had read a rupture, and he was kind enough to call me back
> and inform me that, indeed, there had been a rupture, so there was an
> attempt during the study to maximize the sensitivity of rupture, and
> not underestimate its presence.
>
> In fact, as you will note from JoAnn\'s presentation, the two
> indeterminate readings were also included as probable ruptures, so
> that when an intracapsular rupture is identified, it\'s a notable
> clinical finding.
>
> Now, how you conclude with respect to the possibility of silicone
> getting beyond the capsule is a matter of discussion for this panel. A
> great deal of evidence has been submitted that the biocompatibility of
> that silicone with respect to the potential pathologic effects
> doesn\'t seem to be supported by the literature or to a limited extent
> in this study.
>
> So, all I can report is what we found during the study. I should note,
> because the difficulty in reconciling why implants rupture over time
> was raised by Dr. McGrath and others, is still not easily reconciled.
>
> If, in fact, the theory, as Dr. Spear suggested, is that folds may be
> a weak point, I can tell you that in virtually, well, certainly over
> 90 percent of the implant studies I reviewed in this cohort, as well
> as those which I have reviewed over the last 10 years, I do see folds.
> So, folds are almost an ubiquitous finding when you look at implants
> intact, and whether or not they are the source of potential failure is
> extraordinarily difficult to identify.
>
> Most of the implant failures that I observed in this study, and I have
> observed elsewhere, do not represent complete collapses of the
> envelope itself, but rather more focal collapses, so-called inverted
> loops or subcapsular signs, that may lend credence to Dr. Conant\'s
> observation that shearing forces may play a small part if there is a
> slight adhesion because of oil migration through the implant.
>
> DR. WHALEN: If I am reading the panel correctly, Dr. Manno\'s question
> may be the last for sponsor. So, everybody knows where we are going, I
> plan on getting through FDA\'s presentation before we break for
> dinner.
>
> I also have strong hopes that we can get through all panel discussions
> and FDA\'s questions before we adjourn for tonight or tomorrow
> morning, whenever that may be. So, that is where we are headed for
> tonight.
>
> Dr. Manno, the last question for sponsor.
>
> DR. MANNO: I guess because of the time, I will limit myself to one
> question.
>
> On slide 34, it was the core post-approval proposal Phase II, where
> you say you had mailed surveys. You said you have a mechanism for
> being sure that nobody is missed. Could you tell me again how you are
> going to do that?
>
> MS. KUHNE: To ensure compliance. I didn\'t mean to allude to the fact
> that we would have 100 percent compliance for those surveys. What it
> meant was that we would follow up carefully with those patients, they
> are direct mailed surveys, at least that is what the proposal is, and
> we have done this before, direct mail surveys, and we send out
> reminders to the patients that the survey is coming up, we send out
> the survey, and then we send out other reminders and follow-up phone
> calls to encourage the patients to complete the questionnaires and
> return them to the company.
>
> DR. MANNO: Is there any difference in response or any trend that you
> might see developing when you have to go through, say, the phone calls
> at the end, because I think it may be documented, and I can\'t tell
> you where, at any rate, that a response can change not to your benefit
> when the people don\'t respond on the first, second, or third try, and
> you go to a personal contact, they get belligerent maybe.
>
> I am just asking if there has been any notice in any of these that you
> have had. I think that might make an impact.
>
> MS. KUHNE: Right.
>
> DR. MANNO: Along the same line with the mailed, it seems to me\--well,
> that is a comment, I will hold it for later.
>
> DR. WHALEN: I would like to thank Inamed and I would ask Commander
> Allen to begin the FDA\'s presentation.
>
> **FDA Presentation**
>
> **ODE and Office of Surveillance and Biometrics**
>
> **Introduction and Mechanical Testing**
>
> CDR ALLEN: I am Samie Allen, the lead reviewer for this PMA.
>
> For your convenience, we have provided you a hardcopy of the slides.
> Please refer to this handout because there are changes to the clinical
> slides from that posted last Friday.
>
> \[Slide.\]
>
> FDA\'s review team was comprised of may reviewers from across the
> Center for Devices and Radiological Health, as well the Center for
> Drug Evaluation and Research. However, this slide shows those FDA
> reviewers who are presenting today.
>
> \[Slide.\]
>
> I will now present an overview of the mechanical testing, device
> description, retrieval study, and shelf life information.
>
> \[Slide.\]
>
> There are seven styles under PMA review for the indications of primary
> augmentation, primary reconstruction, and revision. As a note, not all
> seven styles were included in each of the clinical styles to be
> discussed later by Dr. Dawisha.
>
> The styles are available in different combinations of shapes,
> profiles, surfaces, and volumes.
>
> All styles are single lumen but Style 153. Style 153 is a double lumen
> device with inner and outer lumens filled with silicone gel. The inner
> lumen is located at the lower pole of the implant and its function is
> to maintain the curved profile.
>
> All styles are comprised of the same basic components a 3-layer shell,
> a 2-layer patch, silicone gel filler, ,and a silicone adhesive to seal
> the hole. The material specifics will be provided by Dr. Arepalli as
> part of the chemistry overview.
>
> \[Slide.\]
>
> As per FDA\'s breast implant guidance, these are the 3 mechanical
> tests performed to support a silicone gel-filled breast implant.
>
> \[Slide.\]
>
> Gel cohesion, as a whole, is addressed by both gel cohesion testing as
> per ASTM F703, as well as penetrometer testing. These tests assess the
> cohesive and cure characteristics of the gel. All testing met the
> acceptance criteria.
>
> \[Slide.\]
>
> Gel bleed testing was performed a per ASTM F703. The average weight
> gain for smooth Style 40 and textured Style 110 at 8 weeks are shown
> here.
>
> ASTM F703 does not include an acceptance criterion for this testing.
> The ASTM F703 test methodology was not established to mimic
> physiological conditions, but instead to accelerate the bleed
> diffusion process to compare various smooth implant designs.
>
> \[Slide.\]
>
> Fatigue testing was performed on smooth Style 40 and textured Style
> 110, both of which were considered representative of the styles under
> PMA review. Final, sterilized devices with the thinnest shells were
> used.
>
> Inamed performed the fatigue testing as per the recommended test
> method described in FDA\'s breast implant guidance.
>
> The resulting endurance load levels at 6.5 million cycles runout were
> 55 pounds for Style 40 and 30 pounds for Style 110. Based on an
> expected in-vivo load of 3.7 pounds, this equates to safety factors of
> 11 and 6, respectively.
>
> Fatigue testing also included determination of the ultimate static
> load, or force to failure due to a single compression of the implant.
> The results were far greater than the 55 pounds expected during
> mammography.
>
> \[Slide.\]
>
> The sponsor conducted retrieval studies to better understand the
> possible modes of gel-filled breast implant failure in vivo, which
> could lead to improvements in manufacturing, device design, surgical
> technique, and/or labeling.
>
> The study included 339 implants retrieved in just over a 2-year
> period. All 339 implants were those styles under PMA review.
> Forty-five percent of these were from the core or adjunct study. The
> remaining 55 percent were implanted prior to the 1992 call for PMAs,
> were returned unused due to an intraoperative observation, or for
> which a specific link to a study could not be made, such as an unknown
> serial number.
>
> Physician observation, such as rupture or non-rupture, were made at
> the time of explantation.
>
> Laboratory observations were made by Inamed to categorize each explant
> with a primary device characteristic, such a sharp-edge or smooth-edge
> openings.
>
> Mechanical testing was performed, but this testing was inconclusive in
> assessing the mode of failure.
>
> Analyses of sharp-edge openings were performed to characterize those
> created by surgical damage.
>
> \[Slide.\]
>
> This table summarizes the cause or mode of failure for each of the
> device characteristics based on all analyses performed.
>
> Smooth-edge mode of failure is fold flaw. Only 18 percent of the
> sharp-edge openings could be linked to surgical damage. The mode of
> failure for the remaining 82 percent is unknown.
>
> For broken devices, for example, those devices with the shell torn
> into pieces, possible causes include explantation surgical technique
> or propagation of a smooth-edge or sharp-edge opening.
>
> For device surface observations, for example, scalloping at the radius
> or dimpling, one possible cause is excess stress caused by the
> implantation technique or capsular contracture.
>
> For gel-related observations, for example, particles or bubbles in the
> gel, Inamed offers one possible cause for the bubbles as excess stress
> prior to implantation or during explantation that led to air
> permeating through the shell.
>
> For functional devices, there was no opening or surface or gel
> observation. Therefore, there is no mode of failure to assess.
> However, these devices included those removed for complaints, such as
> capsular contracture.
>
> Inamed considers these retrieval study findings to be inconclusive to
> determine any specific steps to take with regard to improvements in
> device manufacturing, device design, surgical technique, or labeling.
>
> \[Slide.\]
>
> With regard to shelf life, device and package testing were performed.
>
> Inamed provided a combination of real-time and accelerated testing on
> their subject device, as well as on their approved saline-filled
> breast implants, to support a 2.5 year shelf life on their package
> label.
>
> Inamed continues to collect data with a goal of supporting a 5-year
> shelf life.
>
> \[Slide.\]
>
> In conclusion, FDA considers the gel cohesion testing, gel bleed
> testing, fatigue testing, retrieval study, and shelf life information
> to be adequate. However, the correlation between these tests and the
> long-term clinical performance of the implant is not well understood.
>
> The panel should consider these results in your safety assessment of
> this breast implant.
>
> Thank you.
>
> Dr. Arepalli will now present FDA\'s review of the chemistry data.
>
> **Chemical Testing**
>
> DR. AREPALLI: Thank you, Samie.
>
> Good afternoon. My name is Sam Arepalli. I am the chemistry and
> materials reviewer for this PMA.
>
> The next few minutes I will be giving a brief overview of the
> chemistry/material aspects of this device. Please bear with my, my
> presentation will contain some highly technical words.
>
> \[Slide.\]
>
> As Commander Allen stated earlier, the device components are the
> silicone shell, silicone patch, silicone gel filler, and silicone
> adhesive.
>
> The shell is manufactured from two elastomers. They are a mixture of
> high molecular weight vinyl containing siloxane polymer, a low
> molecular weight methylhydrogen containing siloxane crosslinker.
>
> A platinum-silicone complex is used as catalyst and the elastomer is
> reinforced with a treated amorphous silica to enhance toughness. The
> shell consists of inner and outer layers, which are also called base
> layers, and are sandwiched around a \"barrier layer\" designed to
> impede the diffusion of components of the gel through the shell.
>
> All layers of the shell are produced using a copolymer of
> poly(dimethyldiphenyl)siloxane. The barrier layer differs from the
> base layer in that it contains a higher percentage of diphenylsiloxane
> in the copolymer.
>
> The patch is manufactured from two types of silicone elastomer. The
> inner layer of the patch is a two-part platinum cure elastomer similar
> to the shell material, except the polymer is
> poly(dimethyl-methyltrifluoropropyl) siloxane copolymer. The outer
> layer of the patch is a peroxide cure dimethyl silicone elastomer.
>
> The gel is manufactured from a formulation that is approximately 15
> percent by weight of a silicone polymer with chemically reactive
> molecules along the polymer chain that forms a 3-dimensional network.
> The gel also contains approximately 85 percent of liquid silicone
> polymer which is also called silicone oil.
>
> The RTV adhesive used to seal the fill hole in the patch is an
> oxime-cured silicone with an organotin catalyst.
>
> \[Slide.\]
>
> The chemical analyses were conducted in accordance with the FDA Breast
> Implant Guidance Document. Both the shell and the gel were subjected
> to the analyses separately.
>
> The first analysis carried out was degree of crosslinking. The degree
> of crosslinking in the shell was measured by the Sal Fraction method
> and was found to be 3.4 crosslinked unit/molecule. Physical
> characteristics like break force and elongation were measured for
> different lots to ensure uniformity of the crosslinking.
>
> To ensure degree of crosslinking uniformity for the filler material,
> penetrometer studies were conducted on different lots of the gel and
> were found to be 3.5 to 7.5 mm which meets the sponsor\'s specs.
>
> \[Slide.\]
>
> Volatiles. The device was tested for volatile compounds. The volatile
> compounds were analyzed for the shell component and were found to
> contain 279 micrograms of 1,1,1-trichloroethane and 251 micrograms of
> isopropyl alcohol. The gel was not tested for volatiles as it does not
> contain any volatile solvents.
>
> \[Slide.\]
>
> Extractables. This slide talks about the analysis methods for the
> extractables. The shell and the patch were separated from the gel
> filler. In addition to the shell/patch and the gel of the finished
> device, virgin shell/patch that is not exposed to gel filler is also
> used for analyses of extractables.
>
> The shell and the patch together, and the gel filler were separately
> subjected to exhaustive extraction with n-hexane at 35 degrees C. The
> residue obtained was concentrated and was subjected to gravimetric
> analysis, gel permeable chromatography, infrared spectroscopic
> analysis. The results were consistent with those of typical silicone
> polymers.
>
> \[Slide.\]
>
> GC-MS Analysis. The extracted residue was subjected to qualitative and
> quantitative analyses using gas liquid chromatography coupled with
> mass spectrometer. The results were provided in FDA\'s summary panel
> memo.
>
> The low molecular weight cyclicoligosiloxanes up to D~10~ are not
> detectable at the sensitivity level of the instrument used. Higher
> cyclic and linear oligosiloxane concentrations of the subject device
> are comparable to those present in the FDA-approved saline-filled
> breast implant devices as far as ppm of the implant are concerned.
>
> \[Slide.\]
>
> Metal Analysis. Analyses for heavy metals were carried out on shell,
> patch, and gel filler separately. The metal analyses showed they are
> present in trace amounts as shown in Table 2 and Table 3 of the panel
> pack.
>
> While saline-filled breast implants contain tin only, the gel-filled
> breast implants contain platinum, as well as tin, are used in the
> manufacture of the device.
>
> This slide provides the tin and platinum concentrations in the shell,
> patch, and gel filler separately.
>
> \[Slide.\]
>
> Analysis for Silica. Spectroscopic studies were conducted to show that
> there was no free silica present in the device. X-ray diffraction
> studies indicated that the bound silica is present in the amorphous
> form, not in the crystalline form.
>
> \[Slide.\]
>
> Finally, in conclusion, the envelope shell and the gel materials were
> separated and chemical analyses were conducted in accordance with the
> FDA Breast Implant Guidance Document.
>
> The shell and the gel were tested for degree of crosslinking and
> volatiles. Each component was hexane-extracted in a soxhlet and the
> residue obtained was subjected to gravimetric, gel permeable
> chromatography, FTIR, and qualitative and quantitative analyses by
> GC/MS.
>
> The shell and gel were analyzed for heavy metals.
>
> The elastomer shell was analyzed for the presence of free silica and
> the bound silica was proved to be in amorphous form, not in the
> crystalline form.
>
> Inamed has performed extensive chemical analyses of their breast
> implant device. FDA notes no deficiencies in the information they have
> provided. This is important information for toxicology testing that
> will be addressed next. Also, FDA recommends that the panel consider
> these chemistry data in their deliberation on the long-term safety of
> the implant.
>
> Thank you very much.
>
> Dr. Berkowitz will present the FDA\'s review of the toxicology
> information.
>
> Dr. Berkowitz.
>
> **Toxicology Overview**
>
> DR. BERKOWITZ: I am David Berkowitz, the toxicology reviewer for this
> PMA.
>
> The objective of the toxicology studies is to provide an assessment of
> the toxicological risks likely to be associated with the device.
>
> The gel-filled prosthesis differs from the saline implant in two ways.
> First, the potential exposure to the implant materials is about 40
> times higher than the exposure to saline implants. A woman exposed to
> two, 800 ml prostheses would be potentially exposed to 1,600 grams of
> silicone gel and about 40 grams of silicone elastomer.
>
> The exposure to the saline-filled prosthesis is only to the elastomers
> in the two shells. Secondly, the shell of this prosthesis contains a
> diphenyl-substituted polydimethylsiloxane which is not present in the
> approved saline implants.
>
> \[Slide.\]
>
> The gel-filled breast implant toxicological investigations can be
> considered under the six categories shown on the screen:
> pharmacokinetics, biocompatibility testing, subchronic toxicity
> testing, which is implantation testing, reproductive and
> teratogenicity testing, immunotoxicology, genotoxicology, and
> carcinogenesis testing. I will present a brief summary of the
> conclusions drawn from these studies.
>
> \[Slide.\]
>
> Pharmacokinetics. By weight, the overwhelming component of the
> elastomer and the silicone gel are the long chain polydimethyl
> siloxanes as we have heard. Inamed tested the fate of these compounds
> in rats by using subcutaneous implants of a gel made from radiolabeled
> polydimethyl siloxanes incorporated into the same mixture used to make
> the Inamed gel.
>
> The radioactivity in the blood peaked at 21 days after implantation.
> After 30 days, only 0.06 percent of the radioactivity was released
> from the gel, even though the gel was not encapsulated in a shell. So,
> these high molecular-weight materials are stable and don\'t migrate to
> an appreciable extent in this time frame.
>
> The important toxicology issues are likely to be related to the lower
> molecular weight cyclic siloxanes, mainly D4 and D5. The
> pharmacokinetics of these compounds have been studied by the Meeks
> group at Dow Corning and by Hoan-My Do Luu and Joe Hutter at FDA.
>
> These materials diffuse out of the implants, but at slow rates. The
> toxicology studies were designed to detect any potential toxicological
> effects, including those of the cyclic siloxanes or any other low
> molecular weight compounds that emerge from the prosthesis.
>
> \[Slide.\]
>
> Biocompatibility testing is listed on the slide: cytotoxicity,
> irritation and sensitization, acute systemic toxicity, implantation
> testing, subchronic toxicity, hemolysis, and pyrogenicity. The results
> of these tests were all negative.
>
> \[Slide.\]
>
> Because many of the breast implant recipients are likely to be of
> childbearing age, the reproductive safety of the gel implants is an
> important consideration. In addition, the shell contains a
> diphenyl-substituted siloxane.
>
> This was of some concern because compounds such as
> cis-2,6-diphenylhexamethylcyclotetrasiloxane have estrogenic activity.
> This compound is a D4 in which two phenyl groups replace two methyl
> groups. Although diphenyl-substituted cyclic siloxanes were not
> detected in the chemical analyses, we considered the reproductive
> toxicity testing to be another check on this potential hazard.
>
> The shell was extensively tested in rat experiments, in a 1-generation
> study, and in a 2-generation study, which included histological
> observations of the ovaries and uterus of the F1 generation.
>
> In the 1-generation study, the numbers of anomalies in the sham and
> treated control groups were not significantly different. There were
> 418 pups produced by the sham group and 448 by the treated group.
> There was no evidence of reproductive or teratogenic effects of the
> shell in the study.
>
> The shell was also tested in a 2-generation study. Both the F1, as
> well as the F0 animals, used for mating were also implanted with
> pulverized shell material 5 weeks prior to mating, so two successive
> generations were exposed to the shell materials.
>
> As shown on the slide, the mating indices and the fertility indices
> were the same in both the F0 and F1 generations. There were no
> significant differences between the sham and treated groups. There
> were no significant teratogenic effects. The gel was tested in a
> similar protocol and the results were also negative.
>
> Comprehensive reproductive and teratogenicity testing revealed no
> reproductive or teratogenic effects.
>
> \[Slide.\]
>
> Immunotoxicology Testing. The immunotoxicology testing was conducted
> in mice. The reporting included spleen and thymus weights, thymus
> histopathology, hematology, including differential counts and natural
> killer cell activity. The measurement of splenic antibody forming
> cells and the mixed leucocyte reaction were used to assess complex
> immune functions requiring more than one component of the immune
> system.
>
> Some results of the testing of the gel are shown on the screen. The
> sham control mice received 1 ml of saline and the test mice were
> implanted with 1, 2, or 3 ml of gel. As shown on the slide, the
> results in the presence of cyclophosphamide, the positive control,
> were all significantly different from the sham control. The only
> significant finding in the highest gel exposure, that is the 3 ml
> implant, was the higher spleen weight. This was shown to be an
> artifact in subsequent testing.
>
> We conclude that there was no evidence of significant immunotoxicity.
> Similar testing was performed on the shell and the results were also
> negative.
>
> \[Slide.\]
>
> Genotoxicity was tested using bacterial mutagenesis, mammalian cell
> forward mutation assay, chromosome aberration assay, and a mammalian
> cell transformation assay.
>
> The results of the in vitro genotoxicity testing were all negative.
>
> \[Slide.\]
>
> For carcinogenicity testing, approximately 120 rats per group were
> implanted with Inamed prosthesis materials and a low density
> polyethylene control, and the animals were followed for two years.
>
> The animals were examined for tumors and for other toxicological
> effects. Hematology, blood chemistry, gross pathology, and
> histological pathology were all reported. The major pathology seen was
> foreign body or solid state carcinogenesis. This is regularly seen in
> rodents.
>
> The results with the gel were that the treated animals had a longer
> time to tumor and a longer survival time than the polyethylene control
> animals. There were twice as many tumors in the polyethylene control
> than in the gel animals. In the implantation study mentioned
> previously, fibrous tissue developed between the particles of material
> put in, but the gel was only surrounded by fibrous tissue on the
> external surface. This may be why fewer foreign body tumors were seen
> at the gel implantation sites.
>
> The phenyl/phenyl shell and low density polyethylene control were
> pulverized and delivered in gelatin capsules. In this testing, the
> overall survival of the shell-treated animals was shorter than the
> survival of the polyethylene control animals, which was shorter than
> the survival of the sham control animals.
>
> The difference between the shell and the polyethylene control and sham
> were not significant when the implantation site tumors were removed
> from the analysis. The implant site tumors were of mesenchymal origin,
> as is expected in foreign body tumors and rodents. The data do not
> demonstrate a carcinogenic effect with any of the implant materials.
>
> Studies currently in progress at Dow Corning indicate that D5, which
> may be present at very low levels, if at all, in the gel, causes
> uterine adenocarcinoma in rats. A risk assessment indicates that the
> risk is negligible, but we will continue to follow this until the
> study is completed.
>
> The application contains extensive and comprehensive toxicology
> testing on breast implants. My review of these data indicate that the
> toxicological effects were not significantly different than the
> effects of the control materials.
>
> Dr. Sahar Dawisha will now present the results of the clinical
> investigations.
>
> **Clinical Data Overview**
>
> DR. DAWISHA: I was going to say good afternoon, but I guess good
> evening is in order here. I am Dr. Dawisha.
>
> \[Slide.\]
>
> I reviewed the prospective clinical data contained in the PMA. I am
> going to be providing an overview of the data. This data constitutes
> the majority of the clinical safety and effectiveness information.
>
> I also will be pointing out important clinical issues that I would
> like you to address as stated in the panel questions.
>
> \[Slide.\]
>
> This slide shows the prospective studies conducted by the sponsor
> which are included in the PMA, all of which are open label,
> multi-center, and which collected local complications.
>
> I should point out that these studies did not address long term and
> general health effects thought to be related to breast implants, such
> as the risk of cancer, connective tissue disease,
> reproductive/teratogenic effects, and later effects on offspring. For
> these issues, the sponsor is utilizing the published literature and
> animal data.
>
> At the conclusion of FDA\'s presentation, you will be asked to address
> the adequacy of this information in the assessment of safety of the
> sponsor\'s product.
>
> \[Slide.\]
>
> Of the three studies, the core study constitutes the majority of the
> clinical safety and effectiveness prospective data, and my
> presentation will focus on this study.
>
> Patients with all three indications were enrolled, and the study is
> intended for 10 years of follow-up.
>
> It is the only study which included prospective screening for
> asymptomatic rupture via MRI in a subset of patients at years 1, 3, 5,
> 7, and 9 after implantation.
>
> It is the only study that also collected quality of life information
> and a variety of connective tissue disease signs and symptoms.
>
> The quality of life information was collected to supplement the
> patient satisfaction information, and the CTD signs and symptoms were
> collected in an effort to determine whether a referral to a
> rheumatologist was needed.
>
> \[Slide.\]
>
> The adjunct study was intended to make the implants available for
> patients with public health needs of primary breast reconstruction or
> revision of an existing implant due to medical or surgical reasons.
>
> Local complications are to be prospectively collected at years 1, 3,
> and 5 post-op, and the 1 and the 3-year data are available from this
> study.
>
> \[Slide.\]
>
> The 1990 study originated in response to FDA\'s pending call for
> gel-filled breast PMAs. Follow-up was yearly for local complications
> up to five years after implantation.
>
> Because the majority of the patients enrolled in this study were
> augmentation, I will be referring only to the augmentation cohort and
> only to the 4 of 11 styles for which the sponsor is seeking approval.
>
> \[Slide.\]
>
> Now that I have provided a brief overview of the three prospective
> studies conducted by the sponsor, I will discuss the results of each
> study individually beginning with the core study.
>
> \[Slide.\]
>
> Before I begin with each indication separately for the core study, I
> would like to point out the median ages of the three cohorts in the
> core study: 34 years for augmentation, 50 years for reconstruction,
> and 44 years for revision.
>
> These ages are consistent with those reported by plastic surgeons for
> U.S. women seeking breast implants, and as you can see, the median age
> for the augmentation patients is considerably younger, and is within
> childbearing years. This needs to be considered in the determination
> of safety for each indication as stated in the panel questions.
>
> \[Slide.\]
>
> I will now discuss the results for the core augmentation group.
>
> \[Slide.\]
>
> This slide summarizes the patient disposition for the core
> augmentation cohort.
>
> There were 495 patients implanted, with one patient excluded due to an
> age protocol violation, and data are reported for 494 patients.
>
> At two years, 90 percent of the expected patients he a follow-up
> visit. At the time of database closure, 83 percent of the augmentation
> patients were available for a three-year visit and follow-up at three
> years was obtained for 81 percent of these patients.
>
> There was no information available for the cause of death of the one
> death reported in this cohort.
>
> For the 13 patients who were discontinued through three years due to
> removal without replacement of their study implants, most had changed
> to saline-filled implants or to gel-filled implants from other
> manufacturers.
>
> Ten of these patients reported at least one complication, which is
> reported in the Kaplan-Meier risk rates on the next slide.
>
> \[Slide.\]
>
> This slide summarizes the cumulative Kaplan-Meier risk rates of first
> occurrence of selected complications through three years, on a
> by-patient basis, with the 95 percent confidence intervals shown in
> parentheses.
>
> The complication with the highest rate reported was all severity
> levels of swelling, at 23.3 percent, which is not shown here because
> the time to resolution was within a week. Reoperation, at 20.6
> percent, was reported at the second highest rate, and capsular
> contracture, Baker Grade III or IV is the next highest rate, at 8.3
> percent.
>
> Note that the breast pain and nipple sensation change shown here only
> includes reports of moderate or greater severity, and scarring
> includes all severity levels.
>
> I will next discuss reoperation and implant removal, followed by
> rupture.
>
> \[Slide.\]
>
> With respect to reoperations in the augmentation group, there were 248
> additional procedures performed in 19 percent of the patients.
>
> The two most commonly performed procedures were capsule related, which
> is due to capsular contracture, and implant removal with replacement,
> which I will discuss next.
>
> \[Slide.\]
>
> This slide summarizes the primary reasons for implant removal. If more
> than one reason was reported, the following hierarchy was used to
> determine a primary reason: rupture, infection, capsular contracture,
> extrusion, necrosis, healing related, pain, unsatisfactory cosmetic
> outcome, and lastly, patient request.
>
> There were a total of 60 implants removed through three years in 32
> patients; 51 of these were replaced and 9 implants were removed
> without replacement.
>
> Of the 60 implants removed, the majority, or 70 percent, were removed
> to treat a complication or to correct an unsatisfactory cosmetic
> outcome.
>
> Thirty percent of the implants were removed or replaced due to patient
> choice.
>
> Of these 18 implant removals for patient choice, 13 were for a size or
> shape change and 5 were due to patient concern, which the sponsor
> refers to in their application as media anxiety.
>
> The specific complications which necessitated implant removal in these
> patients are shown with the white background. Of the 60 implants
> removed, the most common reason was capsular contracture, 45 percent
> of the primary reasons for implant removal.
>
> \[Slide.\]
>
> The next two slides summarize the implant rupture information for the
> core augmentation cohort through three years.
>
> For simplicity, this information is based on the date of database
> closure in order to be consistent with the Kaplan-Meier values
> reported in the application, and does not include rupture status which
> has been confirmed since that date.
>
> 166 patients, or 331 implants, were enrolled in the serial MRI
> screening cohort. At the first screening of approximately one year
> after implantation, 139 of the expected patients, or 87 percent,
> underwent MRI screening for asymptomatic rupture.
>
> At the second serial MRI screening at approximately three years after
> implantation, only 83 of the expected patients, or 64 percent,
> underwent MRI screening for asymptomatic rupture.
>
> There were a total of 145 patients, or 289 implants, who had at least
> one serial MRI screening, which constitutes about 29 percent of the
> total core augmentation implants.
>
> Of these 289 implants screened with MRI at least once, there were 3
> implants reported with asymptomatic or silent rupture.
>
> The sponsor reports a silent rupture rate of 1.2 percent through three
> years on a by-implant basis based on this MRI screening.
>
> \[Slide.\]
>
> The previous slide summarized asymptomatic ruptures. This slide
> discusses the symptomatic ruptures and the overall rupture rate
> reported by the sponsor.
>
> For those patients who were not included in the MRI screening
> subset\--that is the \"No MRI\" screening group\--there were 2 implant
> ruptures which were symptomatic, one due to pain in axillary nodules,
> and one due to capsular contracture.
>
> Note that there were two additional potential symptomatic ruptures
> which the sponsor excluded from the rupture rate, which were shown in
> figure 1 and discussed in my review memorandum: one symptomatic
> rupture determined intact with mammography but not with MRI or
> explant, and one explant reported intact by the physician, but found
> to have a sharp-edge opening on microscopic evaluation.
>
> For the overall by-implant rupture rate of 0.6 percent, the sponsor
> combined the 3 silent ruptured or asymptomatic ruptured implants from
> the previous slide with the 2 symptomatic ruptures shown here using
> the entire cohort for the denominator, for a total of 5 ruptures in 5
> patients.
>
> The overall rupture rate excludes potential silent ruptures in the
> \"No MRI\" group, which is about 71 percent of the core total
> implants.
>
> Most of the ruptures identified in this cohort were asymptomatic.
>
> \[Slide.\]
>
> In addition to local complications associated with the implants, the
> sponsor also collected other safety information, such as self-reported
> reproductive problems, lactation problems, breast disease, breast
> malignancy, abnormal mammogram reports, connective tissue disease
> diagnoses, and connective tissue disease signs and symptoms.
>
> Through three years, there was no increase in reports of reproductive
> and lactation problems. There were 32 new patient reports of breast
> disease and 12 reports of abnormal mammograms, the results of which
> were mostly benign.
>
> There was one new report of a breast malignancy, which occurred 27
> months after breast implantation in a 39-year-old women who was
> diagnosed with invasive intraductal adenocarcinoma in situ.
>
> Note that there is no comparison group of patients with similar
> characteristics followed for the same duration, so conclusions cannot
> be made from these data.
>
> There was also one patient, a 46-year-old, reported as having
> rheumatoid arthritis 11 months after breast implantation. Review of
> the diagnosing physician\'s notes indicates no mention of joint pain
> or swelling, a negative rheumatoid factor, and treatment with a
> non-steroidal anti-inflammatory agent, indicating that the patient
> does not likely have RA.
>
> \[Slide.\]
>
> Recall that the sponsor collected a variety of signs and symptoms,
> some of which could be related to connective tissue disease, in order
> to assist in referring patients to a rheumatologist if needed.
>
> This table summarizes selected reports of before and through two years
> after breast implantation.
>
> The starred entries contain general categories which encompass a
> variety of signs and symptoms, and the unstarred entries show specific
> signs and symptoms of interest.
>
> As you can see, all signs and symptoms increased in frequency over
> time for the core augmentation group.
>
> Without a comparison group of women with similar demographic
> characteristics and without implants followed for the same duration,
> it cannot be concluded that this increase is attributable to having
> breast implants.
>
> \[Slide.\]
>
> With respect to effectiveness, while the majority of patients who
> completed two years of follow-up and who responded to satisfaction
> questionnaires reported being satisfied with their implants, there
> were small declines in mean satisfaction over time for both general
> satisfaction questions and for satisfaction compared to pre-operative
> expectation of satisfaction.
>
> With respect to general quality of life measures, such as the SF-36
> and the MOS-20, there were small declines in mean values of all scales
> at two years compared to pre-op, however, the two-year values were
> still higher than normative values compared to age and gender-matched
> normal controls.
>
> With respect to specific quality of live measures, mean values of some
> measures improved over time, while others declined, as shown on this
> slide.
>
> \[Slide.\]
>
> Now, a summary of the core reconstruction patients.
>
> \[Slide.\]
>
> Enrollment for the core reconstruction group began later than for core
> augmentation, such that only about 58 percent of the patients were
> eligible for a three-year visit at the time of database closure.
>
> At both two and three years following breast implant reconstruction,
> over 90 percent of the expected patients had a follow-up visit.
>
> The 7 patient deaths through three years were due to breast cancer
> recurrence or were accidental.
>
> Of the 16 patients who discontinued due to removal of their implants,
> most had replacement with saline-filled implants or with gel-filled
> implants from other manufacturers.
>
> All of the discontinued patients due to implant removal had at least
> one, and in most cases several complications, which is captured in the
> Kaplan-Meier risk rates shown on the next slide.
>
> \[Slide.\]
>
> The by-patient cumulative Kaplan-Meier risk rates of first occurrence
> are shown here through 3 years. The complication with the highest risk
> rate is reoperation, at 45.9 percent, followed by implant removal or
> replacement, at 25.3 percent.
>
> \[Slide.\]
>
> With respect to reoperations, there were 242 additional surgical
> procedures performed in 42 percent of the patients. The two most
> commonly performed reoperation procedures were capsule related, which
> is due to capsular contracture, and implant removal with replacement,
> which I will discuss on the next slide.
>
> Note that scar revisions, wound repair, as well as pocket revisions
> were also common in this population.
>
> \[Slide.\]
>
> The primary reason for implant removal is shown here using the
> hierarchy previously discussed. Of the 56 implants removed through 3
> years, 51 implants were replaced and 5 implants were not replaced.
>
> Most implants were removed to treat a complication or to correct an
> unsatisfactory cosmetic outcome\--that\'s 92.9 percent\--as opposed to
> patient choice for size or shape change, which was 7.1 percent.
>
> Of the specific complications which necessitated implant removal,
> cosmetic problems, such as asymmetry, malposition, contour deformity,
> and wrinkling were the most common, at 46.4 percent, followed by
> capsular contracture, at 21.4 percent.
>
> \[Slide.\]
>
> With respect to ruptures for the core reconstruction group, 108
> patients, or 184 implants, were enrolled in the serial MRI screening,
> and there is data for 170 implants at around 1 year after
> implantation. This constitutes about 47 percent of the total core
> reconstruction implants.
>
> Of these 170 implants screened at least once, there were 8 implants
> reported as ruptured. The by-implant silent rupture rate reported by
> the sponsor is 4.7 percent based on these 8 ruptures.
>
> Although this is reported as through 3 years, only 2 implants in 2
> patients had reached their second MRI screening at 3 years, therefore,
> almost all of the data is based on the first screening at 1 year.
>
> \[Slide.\]
>
> With respect to symptomatic and overall ruptures, the sponsor reported
> 5 symptomatic ruptures in the patients who did not undergo MRI
> screening. Three of these were actually asymptomatic and discovered
> through MRI, but were not included in the silent rupture rate. One was
> due to asymmetry and one was due to flattening of the implant.
>
> For the overall by-implant rupture rate of 4.2 percent, the sponsor
> combined the 8 silent ruptured implants, shown on the previous slide,
> with the 5 ruptures shown here, for a total of 13 ruptures in 12
> patients.
>
> This overall rate excludes potential asymptomatic ruptures in the \"No
> MRI Screening\" group, which is about 53 percent of the core
> reconstruction implants. Most of the ruptures in this cohort were
> asymptomatic and identified through MRI.
>
> \[Slide.\]
>
> With respect to other complications through 3 years, there were no
> increased reports of reproductive or lactation problems. With respect
> to breast disease, there were 5 new reports of breast malignancy, all
> of which were either recurrence or metastases of the original tumor.
>
> There was 1 new report of a connective tissue disease, a 42-year-old
> patient was reported as having scleroderma four months following
> breast implantation. The physician notes, however, associated with
> this diagnosis indicate that the patient has undifferentiated
> connective tissue disease.
>
> Without a comparable group of patients, conclusions regarding the
> association of these reports with the implants is not possible.
>
> \[Slide.\]
>
> This table summarizes the results of selected self-reported connective
> tissue disease signs and symptoms, again with the starred entries
> representing general categories encompassing a variety of signs and
> symptoms.
>
> As you can see, reports all increased from before to through 2 years
> after implantation.
>
> Without a comparison group of patients with similar demographic and
> co-morbidities and without implants followed for the same duration, it
> cannot be concluded that this increase is due to the breast implants.
>
> \[Slide.\]
>
> With respect to effectiveness, most patients completing 2 years
> reported being satisfied, however, there were declines in overall
> patient satisfaction and in satisfaction compared to pre-operative
> expectation.
>
> Mean values of general quality of life measures improved for this
> cohort, and the mean values of specific quality of life measures, some
> of which improved and some worsened over time.
>
> \[Slide.\]
>
> Now, for a summary of the core revision patients.
>
> \[Slide.\]
>
> At the time of data cutoff, about 91 percent of the core revision
> patients were eligible for a 3-year visit.
>
> The follow-up rate is comparable to that of the core augmentation
> group.
>
> Of the 10 patients having removal of their implant, most changed to
> saline implants or to implants from other manufacturers. Five of these
> patients reported at least one complication, which is included in the
> Kaplan-Meier rates on the next slide.
>
> \[Slide.\]
>
> Like the core augmentation and core reconstruction groups, reoperation
> is the most frequently reported complication, at 33.4 percent, which
> is followed by implant removal or replacement, at 13.4 percent, and
> capsular contracture, Baker Grade 3 or 4, which is 9.8 percent.
>
> \[Slide.\]
>
> With respect to reoperation, there were 190 additional surgical
> procedures performed in 31 percent of the patients through 3 years.
>
> Like the core augmentation and core reconstruction patients, the two
> most common reoperations were capsule related followed by implant
> removal with replacement.
>
> \[Slide.\]
>
> The primary reason for implant removal is shown here using the
> hierarchy discussed previously.
>
> Of the 46 implants removed through 3 years, about two-thirds were
> removed to treat a complication, including unsatisfactory cosmetic
> results, and about a third were removed due to patient choice.
>
> Of the specific complications necessitating implant removal, cosmetic
> problems, such as asymmetry, malposition, or ptosis constituted the
> most common primary reason, at 32.6 percent, followed by capsular
> contracture, at 15.2 percent, and followed by implant rupture, at 13
> percent.
>
> \[Slide.\]
>
> With respect to MRI screening, there were 77 patients, or 148
> implants, who were enrolled in the serial MRI screening cohort.
>
> There is data for 138 implants with at least one MRI, which is 94
> percent of the expected implants, and which constitutes about 38
> percent of the total core revision implants.
>
> Of these 138 implants screened at least once, there were 4 implants
> reported as ruptured.
>
> The by-implant silent rupture rate of 2.9 percent reported by the
> sponsor through 3 years is based on these 4 ruptures.
>
> Again, although this is reported as \"through 3 years,\" most of the
> data is based on the first screening at 1 year, with only 2 implants
> in 1 patient having reached their second screening at 3 years.
>
> \[Slide.\]
>
> This slide summarizes the symptomatic ruptures and the overall rupture
> rate.
>
> For those patients not included in the MRI screening subset, there
> were 4 implant ruptures which were symptomatic, 2 implants that were
> reported with nodules or bulges noted in the same patient, 1 due to a
> motor vehicle accident, and 1 due to softening of the implant.
>
> For the overall by-implant rupture rate of 2.2 percent, the sponsor
> combined the 4 asymptomatic ruptures shown in the previous slide with
> the 4 symptomatic ruptures shown here, and used the entire cohort for
> the denominator, for a total of 8 implant ruptures in 7 patients.
>
> This overall rupture rate excludes potential asymptomatic ruptures in
> the \"No MRI\" group, which constitutes about 68 percent of the core
> revision implants.
>
> Half of the ruptures in this cohort were asymptomatic and identified
> only through MRI screening.
>
> \[Slide.\]
>
> Through 3 years, there were no increased reports of reproductive or
> lactation problems. There were 13 new reports of breast disease, all
> of which were benign.
>
> There was 1 new report of a connective tissue disease, a 50-year-old
> patient was diagnosed with fibromyalgia 11 months after implantation.
> Review of the diagnosing physician\'s notes confirms this diagnosis.
>
> \[Slide.\]
>
> This table summarizes selected self-reported CTD signs and symptoms
> results.
>
> All entries in this table represent general categories encompassing a
> variety of specific signs and symptoms. As you can see, all reports
> through 2 years compared to before were increased.
>
> \[Slide.\]
>
> With respect to effectiveness, of the patients who completed 2 years
> of follow-up, most patients reported being satisfied with their
> implants, however, mean satisfaction levels declined over time for
> both general satisfaction and for satisfaction compared to
> pre-operative expectation.
>
> Mean values of general quality of life measures, such as the SF-36 and
> the MOS-20, declined over time, as well. However, the 2-year values
> were still higher than those reported for normative age and gender
> matched populations.
>
> Of the specific quality of life measures, only the Body Esteem and
> Sexual Attractiveness subscale improved over time, while all other
> worsened.
>
> \[Slide.\]
>
> I would like to point out the limitations in comparing the data from
> the sponsor\'s gel-filled implants to their saline-filled implants.
>
> First, the rupture rates cannot be compared because rupture of a
> saline-filled implant is immediately evident, while, as you can see
> from the data, most gel-filled implant ruptures are asymptomatic and
> not immediately evident.
>
> The saline-filled breast implant data is a historical control group,
> with inherent differences in baseline demographics, in surgical
> characteristics, and in surgical practices, which is not addressed in
> the sponsor\'s comparison.
>
> Finally, the sponsor did not provide confidence intervals for their
> comparison.
>
> For the complications of reoperation, removal, and capsular
> contracture, which are less subject to interpretation than implant
> wrinkling, palpability, or breast pain, for example, the confidence
> intervals are overlapping for the saline-filled implants compared to
> the gel-filled implants, suggesting no significant differences.
>
> \[Slide.\]
>
> The adjunct study and 1990 studies are summarized in this slide.
>
> The follow-up rate is poor in the adjunct study.
>
> The complication rates reported in these studies are comparable to
> those in the core study.
>
> However, the implant rupture rates cannot be compared because
> asymptomatic screening for silent rupture was not performed in these
> studies.
>
> \[Slide.\]
>
> In summary, reoperation, followed by implant removal or replacement,
> is the most frequently reported complication.
>
> Capsular contracture reoperation procedures constituted the majority
> of these reoperations.
>
> For implant removal, most implants were removed to treat a
> complication, including unsatisfactory cosmetic outcomes.
>
> The frequencies of signs and symptoms related to connective tissue
> disease increased over time.
>
> With respect to effectiveness, while patient satisfaction is high, it
> declines over time.
>
> General quality of life measures improved only for the reconstruction
> cohort.
>
> Of the specific quality of life measures, only the Body Esteem Scale,
> and specifically only the Sexual Attractiveness subscale consistently
> improved.
>
> \[Slide.\]
>
> Implant rupture, in particular asymptomatic rupture, is a key clinical
> issue regarding focal complications.
>
> The overall rupture rate reported by the sponsor is under-ascertained
> because MRI screening for asymptomatic rupture was performed in only a
> subset of the patients and only in the core study, and most implant
> ruptures were asymptomatic.
>
> As you can see, of the total 26 implants reported as ruptured in the
> core study, 15 implant ruptures, or 57.7 percent, were asymptomatic.
>
> These asymptomatic ruptures are based on a third of the total core
> study implants enrolled and essentially includes only the first MRI
> screening at 1 year.
>
> Because of the critical nature of implant rupture in the determination
> of safety, you will be asked to address the adequacy of the rupture
> rate information in the determination of safety of this PMA.
>
> A final and important note is that almost all of the asymptomatic
> ruptures detected via MRI were intracapsular, that is, within the
> fibrous capsule.
>
> \[Slide.\]
>
> There is currently no method of determining whether and/or when an
> intracapsular rupture will become extracapsular, however, it is known
> that extracapsular silicone is associated with local and potentially
> systemic effects (to be discussed) and is difficult to remove,
> prolonging explant surgery time and complexity.
>
> Because there are no current standardized guidelines for the frequency
> (or for the method) of screening for asymptomatic rupture, you will be
> asked to address screening methods and frequency for screening for
> asymptomatic rupture if you recommend approval.
>
> You will also be asked to provide a recommendation for the necessity
> of removal of asymptomatic ruptured implants.
>
> Thank you. This concludes my presentation.
>
> Dr. Irony will discuss the statistics.
>
> **Statistical Review**
>
> DR. IRONY: Good evening. I am Telba Irony, the statistical reviewer
> for the Inamed silicone-filled breast implant study.
>
> In this presentation, I will comment on the statistical techniques
> that were used in the design and analyses of the study presented by
> the sponsor. I will also point out to possible biases that should be
> taken into account when the results of the study are analyzed.
>
> \[Slide.\]
>
> The safety and effectiveness of the Inamed breast implants were
> evaluated through four clinical studies. My statistical comments refer
> only to the core study, a prospective, multi-center, 10-year study
> initiated in 1999. It is the primary study to support this pre-market
> approval submission.
>
> The reported follow-up times were 4 weeks, 6 months, 1, 2, and 3
> years.
>
> The results through 2 years post-implant are complete and the data
> reporting through 3 years has not been completed yet.
>
> Safety data will continue to be collected at scheduled follow-up times
> through 10 years.
>
> \[Slide.\]
>
> The Core Study. The core study was composed of three cohorts:
>
> The augmentation group started with 494 patients and 83 percent of
> those patients had traversed the 3-year visit. Excluding the patients
> that did not reach 3 years after implantation, the patients that had
> their implants removed, and the dead, 398 patients were expected at 3
> years. 322 provided 3-year results, translating into 19 percent lost
> to follow-up.
>
> The reconstruction group had initially 221 patients and 58 percent had
> traversed the 3-year visit. By excluding the patients that did not
> reach the 3-year visit, the patients that had the implants removed,
> and the deaths, 116 were expected at 3 years. Since 105 presented
> 3-year results, 9 percent were lost to follow-up.
>
> Finally, the revision group started with 225 patients and 91 percent
> traversed the 3-year visit. 192 patients were expected at 3 years.
> Since 160 patients had 3-year data, 17 percent were lost to follow-up.
>
> \[Slide.\]
>
> It is important to point out the descriptive nature of the study.
>
> There were no claims, targets, or control groups. No hypothesis tests
> were performed. As a result, the safety and effectiveness endpoints
> for this product are summarized by the use of point estimates and
> confidence intervals.
>
> Consequently, the adequacy of the sample size should be evaluated
> based on the width of the confidence intervals, that is, the
> precision, for the rates of the adverse events.
>
> The acceptability of the resulting rates and their precision must be
> evaluated from a clinical perspective, keeping in mind the limitations
> of the study and the possible biases that could have influenced the
> results.
>
> The resulting rates should help the decisionmakers to form an opinion
> about the safety and effectiveness of the implants and weigh their
> risks and benefits.
>
> \[Slide.\]
>
> Safety was addressed by estimating rates of complications and rates of
> secondary surgeries.
>
> The following statistical techniques were employed: Kaplan-Meier
> analyses, \"prevalence\", and \"incidence.\" The quotes mean that in
> this case, prevalence and incidence have a slightly different meaning
> than the usual prevalence and incidence.
>
> I will address these three techniques and discuss their merits and
> flaws.
>
> \[Slide.\]
>
> Kaplan-Meier Analyses. For each adverse event, including implant
> rupture, reoperation, implant replacement, and removal, a Kaplan-Meier
> analysis was conducted on the time to first occurrence of that event.
>
> The result of such analysis, at each considered time point, is the
> estimated probability that a patient will experience that adverse
> event from the time of implant up to the considered time point.
>
> The advantage of this technique is that it allows women who were not
> followed for the entire duration of the study to contribute
> information to the analysis for the time they were in the study.
>
> However, it is very important to recall that this technique is based
> on the assumption that the censoring mechanism is independent of the
> occurrence of the adverse event. In other words, it assumes that the
> reason for the patient not returning for the follow-up visit is not
> associated with the fact that she has or has not experienced the
> complication.
>
> Panel members should evaluate how reasonable this assumption is in our
> context. If patients are lost to follow-up because they experienced
> adverse events, then the actual rates should be larger than the
> estimated rates.
>
> \[Slide.\]
>
> Despite the fact that the follow-up times were in weeks, months, and
> years, the Kaplan-Meier rates were computed by considering days as
> units of time.
>
> This makes the estimated rates much more accurate, alleviating the
> problem of interval censoring, since there is not a large time
> interval between the occurrence of the event and the recording of that
> event. This procedure assumes that reporting the occurrence of the
> event is accurate to the day, which may not be possible for all
> events.
>
> Correlations among adverse events were not investigated. If adverse
> events are positively correlated, fewer patients will be affected
> although the ones affected will tend to experience more adverse
> events.
>
> Whenever Kaplan-Meier curves are constructed for several adverse
> events, that may or may not be correlated, the problem of competing
> risks arises. If a patient that experiences the first complication is
> removed from the pool of patients, that patient is not a candidate to
> experience another complication.
>
> In this case, this did not happen because the patient that experienced
> an event was returned to the pool of candidates to experience another
> event. The only exception was when the patient experienced implant
> removal with or without replacement.
>
> \[Slide.\]
>
> In this slide, the Kaplan-Meier rates for reoperation are displayed to
> exemplify the results of the procedure.
>
> The intervals in the table are 95 percent confidence intervals for the
> chance that a patient will experience reoperation by 4 weeks, 6
> months, 1, 2, and 3 years for each cohort, augmentation,
> reconstruction, and revision.
>
> Since we are dealing with an estimation procedure, it is very
> important to take into account the whole confidence interval, and not
> only the midpoint.
>
> So, how should we read this table? For instance, read the contents of
> the last cell on the first row as follows: For an augmentation
> patient, the 95 percent confidence interval for the chance of
> reoperation by 3 years goes from 16.8 percent to 24.4 percent. The
> mean point is 20.6 percent.
>
> The 3-year data collection is not complete yet. A correction for the
> incomplete data was performed for the reconstruction cohort\--see the
> red star on that table\--because for that cohort, a large fraction of
> patients did not reach the 3-year window. Note that for that case, the
> interval is wider. For the other cohorts, the correction was not
> necessary.
>
> \[Slide.\]
>
> In addition to the Kaplan-Meier rates, the sponsor estimated the
> prevalence and the incidence of adverse events at each follow-up time
> point.
>
> Here, the prevalence is the percentage of patients seen at a given
> follow-up visit who are experiencing a specific adverse event. The
> incidence is the percentage of patients seen at a given follow-up
> visit who are experiencing a specific adverse event, not experienced
> at earlier visits.
>
> What distinguishes the prevalence and incidence in this case from the
> usual prevalence and incidence is that the percentages are conditioned
> on the fact that the patients return to the follow-up visit.
>
> These measures are extremely sensitive to biases generated by losses
> to follow-up. Perhaps the patient did not come back to the follow-up
> visit because she has had a complication. On the other hand, she may
> not have returned because she was doing fine and saw no reason to come
> back to the follow-up visit.
>
> \[Slide.\]
>
> As additional safety information, data on connective tissue disease
> signs and symptoms were collected and analyzed.
>
> Patients completed an activity and lifestyle questionnaire prior to
> receiving their breast implants and 2 years after implantation.
>
> The frequencies of patients reporting 8 categories of signs and
> symptoms of connective tissue disease before implantation was compared
> to the frequencies 2 years after implantation.
>
> For all 3 cohorts, all 8 frequencies increased after implantation. The
> only exception was the urinary symptom in the reconstruction group.
> Its frequency remained the same before and after implantation.
>
> It is very unlikely that all these increases happened by chance.
>
> \[Slide.\]
>
> In order to assess the statistical significance of the increases in
> the frequencies, the sponsor performed a Bonferroni correction that
> was too conservative for this case, especially if there are
> correlations among the signs and symptoms, which cannot be ruled out.
>
> As a consequence, it was difficult to detect statistical significance
> with the study sample size.
>
> \[Slide.\]
>
> Despite the conservative statistical analysis, the increase in the
> frequency of some signs and symptoms was still statistically
> significant.
>
> However, because there was no control group to be compared to the
> breast implant patients, the clinical interpretation of these results
> is problematic.
>
> These were the main statistical issues in this submission and at this
> point I conclude my presentation.
>
> Dr. Lori Brown will now present FDA\'s review of the surveillance data
> and literature.
>
> Thank you for your attention.
>
> **Medical Device Surveillance and Literature Review**
>
> DR. BROWN: Good evening. I am Lori Brown and I will review medical
> device surveillance and published literature on breast implants.
>
> Because silicone gel breast implants have been available for nearly 40
> years and there is extensive medical literature on them, Inamed was
> asked to review and summarize the literature on this product as part
> of the PMA.
>
> \[Slide.\]
>
> Device manufacturers are required to report adverse events to CDRH.
> This includes deaths, serious injury, or malfunction (that is a
> failure of the device to meet its performance specifications or
> otherwise perform as intended.
>
> We also receive voluntary reports from medical providers, consumers,
> and others through the MedWatch program.
>
> \[Slide.\]
>
> There are three basic surveillance databases used at CDRH.
>
> Currently, MDR and MedWatch reports are entered into MAUDE database.
>
> Some reports from manufacturers are reported through the Alternative
> Summary Reporting system. This system is for reporting events that are
> well known and numerous, such as rupture or capsular contracture for
> breast implants.
>
> Instead of sending us 100 individual reports that say there was a
> breast implant rupture, the manufacturer sends one quarterly report
> saying there were 100 breast implant ruptures reported to them.
>
> The third database, Device Experience Network was used prior to the
> development of MAUDE so has historical data.
>
> I will show you overall reports for silicone gel breast implants but
> then restrict my remarks to reports from MAUDE.
>
> \[Slide.\]
>
> Just some precautions about surveillance systems in general.
> Surveillance is not the equivalent of a clinical study. Because of
> under-reporting, rates cannot be calculated. Also, the number of
> individuals at risk may not be known. The number of devices ever sold
> cannot be used as the denominator.
>
> \[Slide.\]
>
> The FDA does not check for the accuracy and completeness of reports
> and these reports do not establish a causal link between the device
> and the reported event.
>
> \[Slide.\]
>
> These reports are useful for providing a signal to regulators of
> potentially important adverse events and for providing an important
> signal to manufacturers to guide them in improving the design and
> manufacture of their product.
>
> \[Slide.\]
>
> This slide shows reports for silicone gel breast implants overall and
> for Inamed silicone gel implants. A total of 134,000 reports were sent
> to the FDA between 1984 and mid-2003. Shown in the righthand column
> are adverse event reports for Inamed, previously McGhan Medical. By
> mid-2003, there were 14,414 reports for Inamed silicone gel breast
> implants.
>
> \[Slide.\]
>
> Medical device reports in the MAUDE database are coded with device
> problems and patient problems. This slide shows the three most
> commonly reported device problems for Inamed implants. Each report can
> have multiple adverse events coded.
>
> The most common problem reported was explantation, a close second was
> implant rupture, and the third most commonly reported problem was
> migration. Some of these reports were for implant migration and others
> were for gel migration. Data from the DEN database and summary
> reporting databases are similar in that implant rupture and
> explantation are the most frequently reported adverse events.
>
> \[Slide.\]
>
> This slide shows the most commonly reported patient problems for
> Inamed breast implants. Reports from the other two CDRH databases are
> generally consistent with this.
>
> \[Slide.\]
>
> In addition to reviewing MAUDE reports overall, we perform analyses to
> examine issues of interest in greater depth. These next two slides
> show the results of such analyses.
>
> The first MAUDE analysis is on breast implant rupture during
> mammography. We performed this analysis in response to a patient
> complaint in November 2002. After identifying 17 reported cases of
> breast implant rupture during mammography from the literature, we
> searched the MAUDE database for reports of such incidents.
>
> This analysis includes silicone gel and saline breast implants and is
> not specific to Inamed. Between 1992 and 2002, FDA received 33 reports
> describing breast implant rupture during mammography.
>
> In these 33 reports, 19 were for silicone gel implants, 11 for saline,
> and in three reports, implant type was not stated. There were 8
> additional reports that implied but did not explicitly state that the
> rupture was due to mammography. All 8 of these implants were gel.
>
> \[Slide.\]
>
> We also did an analysis of MAUDE data on breast implants and
> reproductive issues. We performed this analysis because there is only
> limited information on this issue in the published literature.
>
> Again, this analysis includes silicone gel and saline implants and is
> not specific to Inamed products. Overall, we found 130 reports that
> reported injury or illness in mothers or their children that were
> attributed by the reporter to breast implants.
>
> The majority of these reports simply stated that the children were
> ill, but provided no details. In 23 reports, some detail was provided
> about the child\'s health problem and these included gastrointestinal
> problems, allergies, pulmonary respiratory problems, connective tissue
> disease, and a variety of other problems.
>
> There were also 5 reports in which the reporter attributed a child\'s
> birth defect to mother\'s implants and 9 reports describing difficulty
> nursing because of breast implants.
>
> \[Slide.\]
>
> Inamed performed a review of the literature on breast implants as part
> of this PMA. We reviewed and supplemented their review. Please note
> that the literature does not refer specifically to the Inamed products
> under review and in some cases includes both silicone gel and saline
> breast implants.
>
> Also, note that there are numerous published papers that have not been
> reviewed here. Obviously, for the purposes of this presentation,
> positive findings will be highlighted. This presentation does not
> include a critique of methods from individual studies or a listing of
> their strengths and weaknesses or we would be here all night.
>
> \[Slide.\]
>
> There are case reports describing children of women with implants with
> scleroderma-like esophageal disease and children with autoantibodies
> and clinical rheumatic complaints. A Swedish cohort study of 5,874
> children of women with breast implants indicates that these children
> were not at an excess risk for esophageal disorder, rheumatic disease,
> cancer, congenital malformation overall, or perinatal death compared
> to 13,999 children of women with breast reduction surgery.
>
> The results were similar for offspring of Danish women with breast
> implants compared to breast reduction and plastic surgery controls.
> However, in the Danish study, there was a twofold increase in risk for
> esophageal disorders and for malformations involving digestive organs
> in children born after maternal implant surgery.
>
> There were similar increases in children of women in the comparison
> group undergoing other plastic surgery or breast reduction surgery
> leading the authors to conclude that the association is with some
> aspect of the surgery rather than with breast implants.
>
> There are two issues in breast feeding - first, whether breast milk is
> safe, and second, whether women are able to nurse after implantation.
> A single study indicated that there are not increased levels of
> silicon in breast milk from women with implants compared to control
> women, and that infant formula and cow\'s milk had higher levels of
> silicon, not silicone. Other studies indicate that women with breast
> implants are less likely to attempt nursing an infant and that women
> with breast implants or other types of breast surgeries are less
> likely to successfully breast feed.
>
> \[Slide.\]
>
> Numerous studies have evaluated whether connective tissue disease is
> more likely to occur in women with breast implants. Using a
> statistical technique to combine the results of these studies,
> Janowski et al. found that while the adjusted relative risk of all
> connective tissue disease combined from 14 studies was slightly
> elevated in women with implants, that analysis for individual specific
> connective tissue disease, including arthritis, lupus, scleroderma,
> dermatomyositis, and polymyositis were not increased significantly.
>
> There was a slight increase in the summary adjusted relative risk for
> Sjogren\'s syndrome. When they excluded the results from one large
> study that relied on self-reported connective tissue disease, the
> results were no longer statistically significant.
>
> Likewise, based on their analysis of the literature, the Institute of
> Medicine concluded that there was not evidence to support an elevated
> risk for these diseases in women with breast implants.
>
> \[Slide.\]
>
> While numerous studies have consistently not found an increase in
> connective tissue disease, there has been concern over an atypical
> disease syndrome. The Institute of Medicine forcefully refuted
> conjecture over a new atypical syndrome associated with silicone
> breast implants. Some fibromyalgia experts have proposed that atypical
> syndrome reported in women with implants may be fibromyalgia.
>
> However, studies evaluating fibromyalgia in women with implants have
> had mixed results. This slide shows three studies in which
> fibromyalgia was not statistically increased in women with implants,
> albeit in two of these studies, fibromyalgia was increased but not
> statistically significant.
>
> \[Slide.\]
>
> The study by Kjoller, et al. from Denmark actually reports on two
> cohorts of women with implants, one a public hospital cohort and the
> other a private clinic cohort. In each of these cohorts, unspecified
> rheumatism including fibromyalgia were significantly increased
> compared to sex specific national hospital discharge rates.
>
> The study comparison group, women undergoing breast reduction or other
> plastic surgery, also had a significantly increased risk for
> fibromyalgia leading the authors to conclude that it was the plastic
> surgery rather than the breast implants associated with fibromyalgia.
>
> The second study on this slide is one that I performed here at FDA and
> shows the relative risk for fibromyalgia in women with extracapsular
> silicone detected by MRI compared to other women with silicone gel
> breast implants. There is a near three-fold elevation in self-reported
> fibromyalgia in women with extracapsular gel.
>
> \[Slide.\]
>
> Breast cancer risk for women with breast implants has been examined in
> numerous studies and these studies do not support an association. This
> slide shows several studies on cancer other than breast.
>
> Highlighted in red are cancer sites for which there was a
> statistically significant increase in more than one study. Blue
> numbers are for sites statistically significant in one study. NS is
> evaluated but not statistically significant and empty boxes indicate
> that this was not evaluated in the study. Sites which were elevated in
> any analysis in more than two studies are lung, vulva, and all sites
> combined.
>
> \[Slide.\]
>
> As already discussed, adverse event reported to the FDA and case
> reports from the literature indicate that breast implants may be
> ruptured by compression during mammography. Although breast implants
> are tested to withstand the compressive force of mammography, there
> are changes to the implant in vivo which may contribute to
> vulnerability to rupture. It is not known how often implant rupture
> during mammography occurs since there are only case reports.
>
> Silicone gel is radiodense and obscures part of the breast during
> mammography. Implants also decrease the compressibility of the breast.
> Special techniques are required to image breast tissues when implants
> are present and these techniques require additional views, so increase
> exposure to radiation, time required for examination, and cost. In
> some women, capsular contracture may preclude the use of mammography
> and adjunct methods of cancer detection are necessary.
>
> Several studies have reported delay in breast cancer detection in
> women with implants. One study reported that although there was a
> delay in detection, breast cancer mortality was not increased in women
> with implants.
>
> Another study found no difference in tumor size, axillary lymph node
> involvement, or histopathology in women with implants, but this study
> also reported that treatment options for women with implants did
> differ with mastectomy being preferred over breast preserving
> treatments.
>
> \[Slide.\]
>
> Two cohort studies have found a slight elevation in risk for
> neurologic disease in general among women with cosmetic breast
> implants. In these studies, there were similar findings of increased
> risk for neurologic disease overall in their comparison group of women
> undergoing breast reduction surgery.
>
> They concluded that neurologic disease is unlikely to be causally
> related to the implants, but rather appears to be associated with
> characteristics of women undergoing aesthetic breast surgery. They did
> not delineate these characteristics.
>
> \[Slide.\]
>
> Three studies evaluated mortality from various causes in women with
> cosmetic breast augmentation. This slide shows the standardized
> mortality ratios and 95 percent confidence limits of the implant
> population versus the comparison population.
>
> In the first study shown here, death from all causes was significantly
> reduced in women with breast implants compared to the general U.S.
> population. This reduction was attributed to the generally healthier
> status of patients seeking plastic surgery.
>
> However, there was a significantly increased mortality rate for both
> suicide and brain malignancy in women with implants. Similar studies
> performed in Sweden and Finland found either slightly increased risk
> for mortality from all causes or no difference.
>
> However, both studies also found an increase in death by suicide in
> women with implants. The reason for this increased mortality is not
> clear. Pukkala, et al. have suggested that this may be due to
> underlying psychopathology in women seeking cosmetic augmentation.
>
> Studies seeking to characterize women desiring cosmetic augmentation
> or after cosmetic augmentation have been limited and seriously flawed
> leaving room for conjecture on this point.
>
> \[Slide.\]
>
> In 1999, prior to the submission of this PMA, based on their review of
> the literature, the Institute of Medicine concluded that reoperations
> and local and perioperatve complications are frequent enough to be a
> cause for concern and to justify the conclusion that they are the
> primary safety issue with breast implants. In several reports, the
> rate for reoperations is around 33 percent. This is likely an
> underestimate based on study methodology.
>
> Also, I made a mistake by putting Gutowski, et al., under here. This
> is saline breast implants.
>
> \[Slide.\]
>
> The Institute of Medicine reported that these risks for reoperation
> and local complications continue to accumulate over the lifetime of
> the implant and that quantitative data on this point are lacking for
> modern implants and deficient historically.
>
> The IOM also said that information concerning the relatively high
> frequency of local complications and reoperations is an essential
> element of adequate informed consent for women undergoing breast
> implantation.
>
> \[Slide.\]
>
> Numerous studies have reported high rupture rates based on implant
> status at explantation. These studies were thought to be biased
> because they represent women who were having implants removed because
> of problems. A meta-analysis of 35 of these studies by Marotta et al.
> indicated that the failure rate was 30 percent at 5 years, 50 percent
> at 10 years, and 70 percent at 17 years.
>
> Two studies of breast implant rupture as assessed by MRI imaging are
> shown on this slide. The first bullet shows results of a study which I
> conducted here at FDA. In this study, the median age of implants was
> 16.7 years. Fifty-five percent of implants were evaluated as ruptured
> and 22 percent of ruptures were extracapsular.
>
> In a similar study performed in Denmark, the median age of implants
> was 10 years. Twenty-six percent of implants were ruptured in this
> study. The differences in the two studies may be due to implant age,
> differences in rupture rate for different manufacturers, which would
> have differed between these two studies, and problems with the MR
> imaging at one of the facilities in the Danish study that imaged over
> one third of the women.
>
> \[Slide.\]
>
> When breast implants rupture, silicone gel may migrate out of the scar
> capsule and through tissues. Across a series of studies, gel migration
> was observed for 11 to 23 percent of ruptured implants. There have
> also been cases of gel migration from intact implants.
>
> These may be cases of silicone oil migration from intact implants or
> possibly gel migration from minimally ruptured implants. The frequency
> and severity of distant gel migration are unknown.
>
> Migration may result in gel or oil being found in lymph nodes,
> intraductal extensions of gel in the breast, granuloma formation,
> transcutaneous leakage of gel, ulceration, tissue destruction, and
> scarring. Silicone in the tissues for these studies are typically
> confirmed by microscopic examination of tissues, granulomatous
> response, or by imaging.
>
> In summary, there is extensive literature on breast implants. Not all
> of this information is specific to silicone gel implants or to Inamed
> products, and there are conflicting results from some studies. The
> literature offers a rich source of information on breast implants in
> general and should be considered.
>
> Commander Allen will now discuss the proposed post-approval study plan
> and labeling.
>
> Thank you.
>
> **Proposed Post-Approval Study and Labeling Overview**
>
> \[Slide.\]
>
> CDR ALLEN: I will now present an overview of the proposed
> post-approval study plan and labeling. We have panel questions
> regarding these two topics.
>
> This information and the panel questions should be viewed in the
> context that FDA has not made a decision on the approvability of the
> device at this time.
>
> \[Slide.\]
>
> The core study protocol, as well as informed consent, currently
> requires yearly follow-up with a physician through 10 years, including
> MRI screening for silent rupture at 1, 3, 5, 7, and 9 years. If their
> device is approved, Inamed is proposing a two-phase post-approval
> study.
>
> Phase I involves patients in the core study continuing with their
> evaluations as per the current protocol through their 5-year
> evaluation timepoint.
>
> Phase II involves a mail-in survey completed by the patient each year
> from the 6 through 10-year timepoint. This survey focuses on the
> safety outcomes of breast pain, capsular contracture, implant rupture,
> and reoperation, as well as patient satisfaction. No other endpoints,
> including MRI assessments, would be captured.
>
> As I mentioned, FDA has a question for you regarding the proposed
> post-approval plan.
>
> \[Slide.\]
>
> With regard to labeling, the Directions for Use would be packaged with
> the device and be posted on Inamed\'s web site.
>
> The Patient Brochure would not be distributed as part of the packaged
> device. Instead, it would be distributed to surgeons who could then
> provide it directly to their patients during their consultation
> visits. It would also be posted on Inamed\'s and FDA\'s web site.
>
> Inamed is also proposing to conduct a focus group study of the Patient
> Brochure to improve its quality.
>
> \[Slide.\]
>
> This concludes FDA\'s presentation. Thank you for your attention. I
> will now turn it over to the panel.
>
> DR. WHALEN: If the FDA review team could assemble at the table of
> inquisition here to entertain panel questions, please.
>
> Who would like to begin?
>
> DR. ANDERSON: We have heard a mixture of testimony. This morning we
> heard anecdotal cases from individuals that said they had problems
> related to connective tissue disorders, and they attributed them in
> their anecdotal cases to rupture.
>
> Then, we heard testimony from the company that provided us data about
> the overall group of people who have had implants, but did not give us
> specific data about the outcome of the patients that had rupture.
>
> What I am hearing, and I would like confirmation or tell me if I am
> missing this, what I am hearing from your review, in your review of
> their data, in slide 99, Dr. Brown, your study suggests that\--I am
> sorry, this is literature data\--that, in fact, there could be
> heightened rates of fibromyalgia among ruptured patients.
>
> I also heard, in a slide earlier, that there were eight factors that
> people self-reported in terms of connective tissue disease/disorder
> symptoms, and actually, all eight were higher post-implant than
> pre-implant, and that that seemed unlikely to be related to chance
> alone.
>
> So, is it true, then, that we do not have resolution about what
> happens to these ruptured patients in terms of the connective tissue
> disorders?
>
> DR. BROWN: As I pointed out, the studies about fibromyalgia and breast
> implants have had mixed results. In the study that I performed at FDA,
> it was not women with ruptured breast implants who were more likely to
> report fibromyalgia, but rather women who had extracapsular silicone
> gel as determined by MRI.
>
> As far as signs and symptoms, I will let Dr. Dawisha comment on that.
>
> DR. DAWISHA: I guess the answer is yes, that this issue is not
> resolved at this time.
>
> DR. LI: I have a couple of questions for Ms. Allen. The first question
> I have is on the retrieval study, they listed 158 of the 339 retrieved
> devices as being functional. As I go back and read the fine print,
> they said that 17 percent of all the devices that reported ruptured,
> were also classified as functional, and 23 percent of all the devices
> that reported non-ruptured were rated nonfunctional.
>
> So, given that, what does functional mean, because I would think that
> a ruptured implant, regardless of anything else, is really a
> nonfunctional implant.
>
> CDR ALLEN: I will give it my best shot. Maybe Inamed will have to fill
> in, but my understanding is that the ruptured designation was made by
> the physician at the time of explantation, and what could have
> happened was that for the example of a physician noting it as
> ruptured, it goes back, and it is deemed functional, is that possibly
> they removed it and it was nicked after the fact and they
> found\--excuse me, I said that wrong. It was deemed ruptured by the
> physician, but the laboratory found no opening, so actually I can\'t
> remember Inamed actually addressing that.
>
> The opposite way is that they believe that during the explantation
> approach, that there might have been an opening made at that time.
>
> DR. LI: I was just a bit confused over this, I am not quite exactly
> sure, maybe Dr. Spear can answer why you would have a situation where
> the surgeon would report an implant ruptured at explantation, yet,
> when it goes back to the company, the company finds it not ruptured,
> and conversely, how were implants turned in as being labeled as
> non-ruptured, and yet the company will find 23 percent of them as
> being ruptured.
>
> CDR ALLEN: I would let Inamed speak.
>
> DR. WHALEN: From the point of view of process, if you feel that
> really, Inamed has to clarify something very specifically right now,
> we will entertain it, otherwise, they have a summation period tomorrow
> morning where they can comment.
>
> DR. LI: Maybe my question to Ms. Allen is are you satisfied with their
> analysis and discussion of things that are ruptured and things that
> aren\'t, and then their classification is functional?
>
> CDR ALLEN: That\'s a good question. Inamed performed the study as per
> the protocol, and the protocol is something we have looked at and we
> accepted. I would say that it\'s discouraging, though, that the goal
> of the retrieval study, which was to determine the mode of failure, to
> assess what is going on, we didn\'t really get there, so I don\'t know
> if that is a fault of the design of the study itself, and I don\'t
> know where to take that from there.
>
> At this point, we don\'t have any questions posed specific to the
> retrieval study they have. I think it\'s a bigger question for us to
> look at.
>
> DR. LI: This question has been bothering me all day. This has to do
> with the crosslink density of the implant and for surgical colleagues,
> why I think the crosslink density is important besides determining the
> physical properties of the implant, it would also control things like
> the ability for molecular species to flow through it, its diffusion
> characteristics.
>
> It will also, the crosslink density will also be related to the amount
> and type of things you can extract out of it, but I am a little
> concerned that the only test for the crosslink density appears to be
> assessing the physical properties of the implant, which don\'t address
> the crosslink density.
>
> In particular, the thing that confuses me is that I believe it\'s a
> three-layer structure, and if I did my reading right, the middle layer
> is supposed to be a barrier layer presumably to reduce diffusion of
> low molecular weight materials, and it is supposed to have been more
> highly crosslinked.
>
> Yet, the penetrometer data and the mechanical testing data show that
> the mechanical properties of the middle layer is exactly the same as
> the base layers, so on one hand, you are telling me the middle layer
> has a crosslink density and you are going to assess the crosslink
> density by mechanical properties, but yet your mechanical property
> test shows that between two layers, you should have different
> crosslink densities, they are the same.
>
> DR. AREPALLI: As a matter of fact, I don\'t think even you have the
> barrier layer, you can completely eliminate the diffusion. So,
> regardless what kind of barrier layer you put in, there will be some
> diffusion.
>
> I don\'t have the details here, but as far as I remember, penetrometer
> is used for the gel, the crosslinking was used for the shell.
>
> DR. LI: Excuse me. My question is are you comfortable with the use of
> mechanical properties alone to assess crosslink density?
>
> DR. AREPALLI: They use the mechanical properties to make sure that the
> degree of crosslinking is uniform across the lots, like elongation and
> break force, if I remember correctly.
>
> DR. LI: I understand that\'s the goal, but I personally don\'t think
> that is a good connection between mechanical properties and crosslink
> density. So, maybe my follow-up question is, what correlation or
> association can you show me that penetrometer data and/or mechanical
> property data is actually linked to crosslink density?
>
> DR. AREPALLI: All I can say is the mechanical properties, because they
> are the same across the lot, I would say that the degree of
> crosslinking is uniform across the lots, but if you ask me the proof
> for it, I don\'t have any evidence for that.
>
> DR. WHALEN: Dr. Witten.
>
> DR. WITTEN: I just wanted to say that some of these questions may
> really be questions for the sponsor, like whether or not the
> assessment, there should be another assessment of middle layer, that
> kind of thing. We are probably best answering questions about our
> presentation, what is the presentations.
>
> DR. WHALEN: To follow that up, are you postulating that we are going
> to work into the schedule, another question session with the sponsor
> since we already did that?
>
> DR. WITTEN: That is up to the panel during the panel discussion, if
> you have some questions that you need addressed.
>
> DR. EHMSEN: Mr. Chairman, we certainly would appreciate an opportunity
> to comment on some of the comments that were made by the FDA.
>
> DR. WHALEN: Beyond your summation tomorrow that is already in the
> schedule?
>
> DR. EHMSEN: Okay.
>
> DR. WHALEN: No, I am asking. You need some time beyond your summation
> period?
>
> DR. EHMSEN: Yes, please.
>
> DR. WHALEN: We will take that under advisement and we will continue
> with as many questions as we can through to FDA since we are probably
> going to be going until midnight the way it is with the schedule as it
> is written, if we want to try to get through tomorrow before people
> have their travel commitments, but we will take that under advisement
> and deal with it during a break period.
>
> Dr. Miller.
>
> DR. MILLER: I wonder if the FDA could help us interpret these
> increased frequencies of these collagen and vascular disorder symptoms
> because I mean I have, after sitting here today, an increased
> frequency of all these symptoms.
>
> \[Laughter.\]
>
> DR. MILLER: So, it is hard for me to know how to interpret this piece
> of data, especially in light of all the other data that has been
> presented today which sort of doesn\'t leave the question wide open as
> I think was just said.
>
> DR. DAWISHA: I think we would all agree that without a control group,
> we are all left with that question of how do you interpret this data.
> The data are the data.
>
> DR. WHALEN: Dr. McGrath.
>
> DR. McGRATH: I have a question for Dr. Brown first.
>
> Under MAUDE analysis where you are looking at the breast implant
> rupture during mammography, do you know how old those implants were
> that you were picking up during the last decade, that ruptured during
> mammograms, do you have any idea of what their age was at the time
> they ruptured?
>
> The second question is do you have any MAUDE reports of rupture
> following blunt trauma?
>
> DR. BROWN: In response to the first question about the age, I don\'t
> recall the exact age of these, and it is not always provided in the
> report, but as I recall, it\'s around 16 years.
>
> DR. McGRATH: So, they are quite old.
>
> DR. BROWN: Yes, and that is not on all of the implants that were in
> there, that is only given the ones where they did provide an age.
>
> As far as blunt trauma, yes, there are reports of blunt trauma, as
> well as there are reports of blunt trauma in the literature as a
> source of rupture, as well.
>
> DR. McGRATH: Coming into your MAUDE analysis, you are getting
> something.
>
> DR. BROWN: I have seen them over the years, yes.
>
> DR. McGRATH: But not numerous.
>
> DR. BROWN: I have never enumerated them, so I don\'t know how many
> there are, but I have seen them.
>
> DR. WHALEN: Other questions? Brent.
>
> DR. BLUMENSTEIN: I am particularly struck by slide 45 using the FDA
> presentation. The CTD, I forget what that stands for, connective
> tissue disease, so what we have here is showing that pre-implant to
> post-implant, at 2 years, for 386 patients, these are the same
> patients? In other words, this is a paired analysis?
>
> DR. DAWISHA: Yes.
>
> DR. BLUMENSTEIN: In every one of those, if I have scanned it
> correctly, there is an increase.
>
> DR. DAWISHA: That\'s right.
>
> DR. BLUMENSTEIN: This seems rather alarming to me, I mean because you
> are not censoring, you don\'t have a criterion set up, there is no
> regression to the mean issues going on here. This is just simply at
> two points in time, you have assessed these two sets of features.
>
> DR. DAWISHA: That\'s right.
>
> DR. BLUMENSTEIN: Has there been any attempt to make a composite
> outcome or some other conclusion like that, I mean some other endpoint
> point like to test the significance of this?
>
> DR. DAWISHA: What do you mean a composite outcome?
>
> DR. BLUMENSTEIN: Maybe a multivariate outcome, maybe a score that
> combines outcomes.
>
> DR. DAWISHA: You mean to combine all the data?
>
> DR. BLUMENSTEIN: I am interested if we have a statistical null
> hypothesis is there is no change, I am interested in what the
> statistical significance of that hypothesis is.
>
> DR. IRONY: As I pointed out in my slide, some of these changes were
> statistically significant. There was a Bonferroni correction and, you
> know, the requirements to detect statistical significance were very
> conservative in my opinion. However, there was no control group to
> compare those, so one might say that the same increase in frequencies
> will happen in the general population after two years.
>
> That is why we have some problems in interpreting the changes
> clinically.
>
> DR. WITTEN: Excuse me.
>
> DR. WHALEN: Dr. Witten. Go ahead, please.
>
> DR. WITTEN: I just want to mention that as Dr. Dawisha had said in her
> discussion, that the purpose of this wasn\'t actually as a study per
> se to examine a specific hypothesis about connective tissue disease.
> It was to collect the signs and symptoms to assist the physician in
> referring a patient to a rheumatologist if needed.
>
> So, that may explain the limited amount of analysis that was done on
> this, or correct me if I am wrong, Dr. Dawisha.
>
> DR. DAWISHA: No, that\'s right.
>
> DR. BOULWARE: Dr. Dawisha, can you clarify for me what the first row
> muscle is versus the fourth one, muscle pain and joint versus joint
> pain?
>
> DR. DAWISHA: The muscle is a general category that incorporates a
> variety of signs and symptoms. This is the way the sponsor had
> provided the data. Joint pain is one specific question of joint pain,
> and muscle pain is one of the questions of muscle pain. Muscle pain
> came from the muscle category and joint pain came from the joint
> category.
>
> DR. WHALEN: For everybody using mikes, I am pretty sure these are
> directional mikes, and if you come from the side, it really doesn\'t
> work very well, so try to help out the people who are trying to know
> what we are saying.
>
> DR. LEITCH: Dr. Brown, your study about the extracapsular silicone, I
> was wondering how those patients were identified as having
> extracapsular silicone, at what time frame in which they were, you
> know, years were they diagnosed, and it is self-report of fibromyalgia
> diagnosis, it wasn\'t evaluated any other way?
>
> DR. BROWN: Right. This was a study of breast implant rupture that was
> based on a cohort that was put together by the National Cancer
> Institute, and we used one of the sites at that study and had MRI
> performed on women who remained in that area, and there were 344 women
> who had MRI examination.
>
> So, the extracapsular silicone was based on the evaluation by three
> radiologists who then voted as to whether the implant was ruptured,
> indeterminate, or intact, and they also voted on whether or not there
> was extracapsular silicone.
>
> Before they had the MRI examination, we did a survey with these women
> during which they were invited to the MR examination. At that time,
> they were asked whether or not a doctor had ever diagnosed them with
> fibromyalgia, so this is a self-report of doctor-diagnosed
> fibromyalgia.
>
> DR. LEITCH: And no other documentation?
>
> DR. BROWN: No, that is the extent of the documentation, it is a
> self-report, but we did ask them whether a physician had diagnosed
> them with fibromyalgia.
>
> DR. CHOTI: I was intrigued by the way you presented the data of the
> increased rupture rate in the reconstruction compared to the
> augmentation, something like 4 times the rate, I think, if I am not
> mistaken.
>
> In addition, the silent rupture was significantly higher, and it was
> clearly underestimated given that most MRIs were done only at one
> year. So, it is a little bit of concern what a high potential silent
> rupture rate is present in the reconstruction.
>
> First of all, perhaps a little speculation as to why the rupture rate
> is higher in the reconstruction. We heard from the sponsor perhaps
> it\'s surgical manipulation folds. It is not something, at least to
> me, why it would be so much higher in the reconstruction compared to
> the augmentation.
>
> Another question of the group, perhaps to comment on, is there any
> reason to suspect that the extracapsular spread be any different in
> the reconstruction compared to the augmentation. They both, I am sure,
> have capsule formation.
>
> Dr. Brown, perhaps in your study, did you look at reconstruction
> versus augmentation?
>
> DR. BROWN: The cohort that we used was purely an augmentation cohort
> because one of the outcomes for this study at the National Cancer
> Institute was breast cancer, so therefore, they only were enrolling
> women in the study who had augmentation mammoplasty.
>
> As far as there being a difference between extracapsular in
> reconstruction versus augmentation, I don\'t know the answer to that.
> I don\'t think that I have ever seen it broken down that way.
>
> DR. CHOTI: But I am concerned about such a potential high leak rate in
> the reconstruction group.
>
> One other question, Dr. Brown, regarding your review of mammography.
> We talked about potential risks, missing a cancer, but one issue that
> came up is did you find any evidence in the literature to suggest that
> women with implants for augmentation are less compliant with
> mammography in a fear, whether it is valid or not, women\'s fear that
> they may rupture their implants during mammography and, thus, not
> comply with cancer screening?
>
> DR. BROWN: I have not seen such a study in the literature, however, in
> our analysis of the MAUDE data, there were several reports of women
> who feared rupture during mammography, and they also feared the pain
> during mammography based on capsular contracture or breast pain,
> which, of course, women without breast implants may fear also.
>
> They also feared\--we are talking now about fear, so they are
> reporting fear\--some women also feared having breast cancer missed
> because of their breast implants. So, the answer is yes, in the MAUDE
> reports, we did see fear of getting mammography, fear of pain during
> mammography, and fear of not being diagnosed with cancer in a timely
> fashion.
>
> DR. CHOTI: But if they are afraid of increased cancer rate, then,
> perhaps their compliance may be greater.
>
> DR. BROWN: I do not know. Again, as I pointed out, MAUDE and data from
> surveillance system are not the same as a study, a clinical study.
> There is no denominator, so I do not know whether that is actually
> going on in this population.
>
> DR. WHALEN: Dr. Conant.
>
> DR. CONANT: Back to the rupture issue, I am interested in what you
> feel about this underestimation of rupture potentially because of the
> small population screened with MR for silent ruptures.
>
> I did some quick math. I think the reconstruction cohort was
> particularly interesting because 50 percent of it was actually
> screened with MR, which may reflect the higher number of ruptures
> detected.
>
> But I am wondering, you know, when we look at that rate of rupture,
> how do you think that compares to your literature search if you take
> into the fact that many of them are actually screened?
>
> DR. BROWN: Well, as Dr. Dawisha pointed out in each of the slides
> where she showed you the MR, the results of the MR study, there were
> up to two-thirds of the women from each cohort who had not been
> imaged, so you can do a rough calculation to guesstimate what may have
> happened if those women had, in fact, been imaged.
>
> DR. CONANT: It is sort of interesting to look at those numbers and
> compare the rupture rate or estimated rupture rate. I also believe
> that there is documentation here about the group of age for
> mammography that showed a fairly low compliance with this in the study
> cohort.
>
> I am wondering if someone had a comment on that.
>
> DR. WHALEN: Apparently not.
>
> Other questions?
>
> DR. MANNO: I would just like to comment that on the control that was
> mentioned or the lack thereof, I think just calling it \"control\" is
> a problem. I think they are going to have to be age matched especially
> if you are going to go with all three groups or at least the
> augmentation to the cancer group that had the implants. I think it
> should be implied.
>
> DR. WHALEN: Other questions of the FDA? Yes.
>
> MS. GILBERT: With respect to the connective tissue disease summary on
> the core augmentation, I wanted to come to a question of if a patient
> reported muscle pain, would they also be reporting that they had a
> problem in the muscle and maybe morning stiffness, so would those get
> captured in the same complaint where they get captured two or three
> places?
>
> DR. DAWISHA: Yes, that\'s true. I mean there were several questions,
> about 50 specific signs and symptoms that were asked, so there could
> be multiple reporting.
>
> MS. GILBERT: So, when there is concern that seven indicators are going
> in the same direction, it may not be seven independent things going in
> the same direction, is that correct?
>
> DR. DAWISHA: That is true although the categories are exclusive of
> each other. So, each of these major categories have independent
> questions that are exclusive of the other categories, but some of the
> symptoms could be related.
>
> MS. GILBERT: It is more that I am asking if I had muscle pain, for
> example, would I answer the question, do you have muscle pain as yes,
> then, muscle, yes, and then morning stiffness, yes.
>
> DR. DAWISHA: You might.
>
> MS. GILBERT: Okay. Thank you.
>
> DR. WHALEN: Dr. McGrath.
>
> DR. McGRATH: One other thing, breast pain. This has bothered me all
> day that we don\'t talk about this. I realize we don\'t have control
> groups, and so forth, but as you looked at this, was there any prior
> question ever about whether patients had breast pain before the
> implants were put there, and then also did you notice any changes in
> the number of people reporting breast pain over time?
>
> DR. DAWISHA: Breast pain, you are talking about the breast pain in the
> Kaplan-Meier risk grades after? Those complications were only assessed
> after implantation.
>
> What I did look at was the sponsor asserts or included breast pain in
> a general surgical category of complications. What we were able to get
> was the median duration of the breast pain, which was about a month,
> but all those questions that are in the Kaplan-Meier results were only
> asked after implantation.
>
> DR. WHALEN: Dr. Li.
>
> DR. LI: Can you help the non-radiologist here? For using an MRI to
> detect silent rupture, is there any data that shows how accurate that
> test is, you know, the percentage of false positives, false negatives,
> or how big the rupture has to be before you can see it?
>
> DR. DAWISHA: In this study, the ruptures that were identified via MRI
> were considered the classic signs of rupture, like the Linguini sign
> or air within the implant, there are specific signs that you look for
> on MRI which indicate a rupture.
>
> I believe the sensitivity and specificity of MRI is pretty high, 98,
> 96 percent.
>
> DR. LI: Thank you.
>
> DR. WHALEN: I would say that linguini is an effective segue to our
> delayed dinner hour. We will break for 45 minutes and reconvene with
> open panel discussion at 8:20 p.m.
>
> \[Whereupon, at 7:40 p.m., the proceedings were recessed, to be
> resumed at 8:20 p.m.\]
>
> [E V E N I N G P R O C E E D I N G S]{.underline}
>
> \[9:00 p.m.\]
>
> **Open Panel Discussion**
>
> DR. WHALEN: We are about to engage the open panel discussion of the
> PMA. Prior to doing that, Dr. Witten would like to make a brief
> comment upon the definitions of safety and effectiveness.
>
> DR. WITTEN: Yes, I just passed out to the panel, I think someone is
> going to put up an overhead, that gives you the formal definition in
> our CFR of safety and effectiveness.
>
> I will read it off while it is being projected. I just provided these
> to the panel, like I said.
>
> \[Slide.\]
>
> The definition of safety is: \"There is a reasonable assurance that a
> device is safe when it can be determined, based on valid scientific
> evidence, that the probable benefits to health from use of the device
> for its intended uses and conditions of use, when accompanied by
> adequate directions and warnings against unsafe use, outweigh any
> probable risks.
>
> \"The valid scientific evidence used to determine the safety of a
> device shall adequately demonstrate the absence of unreasonable risk
> of illness or injury associated with the use of the device for its
> intended uses and conditions of use.\"
>
> \[Slide.\]
>
> The definition of effectiveness says: \"There is a reasonable
> assurance that a device is effective when it can be determined, based
> upon valid scientific evidence, that in a significant portion of the
> target population, the use of the device for its intended uses and
> conditions of use, when accompanied by adequate directions for use and
> warnings against unsafe use, will provide clinically significant
> results.\"
>
> It is these definitions that we want the panel to keep in mind when
> you are answering our questions about safety and effectiveness.
>
> DR. WHALEN: Thank you, Dr. Witten.
>
> We will be, as may be obvious, doing this last session without further
> break. We can potentially anticipate, so the audience is aware, going
> as late as until midnight, and that will be pretty much our absolute
> cutoff for tonight.
>
> Before I forget to announce it to the panel members, please be aware,
> when we adjourn tonight, that this room will be totally cleaned out,
> so all materials should be taken with you and returned tomorrow
> morning.
>
> As far as the question that arose before the prolonged dinner break as
> to sponsor having another session, the way that that will be handled
> is that if there are specific questions that any of the panel members
> feel need to be addressed, they will bring that up for either sponsor
> or FDA, and we would ask that if those specific questions are asked,
> that one, and only one, individual from either of the two
> organizations go, not to the table, but to the podium and to, as
> concisely as possible, address the question that has been raised.
>
> By random selection, but because I like to hear her talk, I have
> decided we will start this open panel session with Dr. Nancy Dubler.
> We will then progress around the table towards me going back over to
> the end of the table.
>
> Dr. Dubler.
>
> PROF. DUBLER: Thank you, Dr. Whalen.
>
> I thought I would begin by sketching out the difference between an
> ethical dilemma and the tensions that ethical situations sometimes
> present, and then, very briefly, list the seven component tensions
> that I see in the panel deliberation. So, first, just a paragraph to
> set it up.
>
> An ethical dilemma is a clash between two goods, that is, between two
> obligations of equal weight that are accepted as appropriate behavior
> for a moral individual or a moral society.
>
> An ethical dilemma presents a situation in which competing obligations
> cannot both be satisfied at the same time. Whatever choice an
> individual or society makes leads to an action that is bad or wrong.
>
> The classic example is the tension between the unresolvable tension
> between a physician\'s obligation to preserve life and a physician\'s
> equally strong obligation to support patient autonomy, which plays out
> as an unresolvable conflict in physician assisted suicide.
>
> This panel is, in contrast, faced not with an ethical dilemma, but
> rather with a set of ethical problems or tensions. In contrast to
> dilemmas, most tensions can be solved and resolved with a completely
> satisfactory solution by people of good will, creativity, and
> flexibility.
>
> Seven tensions that emerge from the discussions today: The first is
> society\'s obligation to protect its citizens, and that is what the
> FDA does in asking this panel to suggest to it, and in its decision,
> that silicone breast implants are safe and effective.
>
> It acts because it would be unreasonable for us to assume that
> citizens, individuals, would have the medical expertise and the
> epidemiological sophistication and the scientific background to make
> the kind of judgments that will be made by the panel and the FDA.
>
> The second component in the tension is the right of individuals to
> make autonomous choices and, in fact, to decide what risks they are
> willing to court and those that they are not willing to assume, and
> that is, to balance the risks and benefits of the actions that they
> take.
>
> Three. The process that they use in doing that, in executing the
> personal idiosyncratic calculus that underlies individual choice is
> what we have labeled the process of informed consent.
>
> So, choice can only be as good as the data that are presented, the
> choices that are made by the FDA, and the material that is
> communicated in comprehensible form to the person who will choose.
>
> Four. The notion of safe and effective, as I understand it, does not
> mean that an action is without possible medical consequence or risk.
> Indeed, most medical interventions promise some benefit and propose
> some risk, so, in fact, safe and effective might in certain
> circumstances require someone to balance the possible negative
> consequences against those benefits that the person will see.
>
> Five. This is peculiar to the issue we are now talking about. That is
> the role of medicine in the developing field of enhancement surgery.
> This is a difficult matter. Physicians are always assumed to be
> controlled by, and loyal to, the ethic of do no harm, and it was
> assumed that patients came to them with a problem which they could
> solve.
>
> The problem with augmentation surgery in the context of enhancement
> surgery is that many physicians see their role as creating a market
> for what they have to sell, and the ethic of the market is buyer
> beware, not do no harm. That is a tension that we have to think about
> as we go forward.
>
> Two final tensions. One, real autonomy encompasses the right to make
> foolish decisions and, indeed, I may think it is a foolish decision
> for a woman to have augmentation surgery.
>
> On the other hand, the set of values which undergird a woman\'s
> decision to seek that surgery is not available to my particular set of
> values, and whether I think it is right or foolish, if it is within
> what society says a woman can choose, that it supports her right.
>
> Finally, the final issue is I have been rather startled today by what
> I see as the lack of obligation that the sponsor felt to pursue a
> better product over the decade that I have been engaged in these
> discussions.
>
> I find it strange that this obligation of wise stewardship of the
> product that they are producing didn\'t leave any room for at least
> attempts to improve it in the last decade.
>
> Thank you.
>
> DR. WHALEN: Dr. Dubler, if there were more lawyers who thought like
> you, the world would be a better place. Thank you.
>
> Dr. Newburger.
>
> DR. NEWBURGER: I was impressed with the excellent quality of follow up
> with the studies the sponsor presented in that such a large percentage
> of patients actually were followed through the course of the greater
> period. I am troubled by the device failure rate in terms of morbidity
> of second operations.
>
> As a dermatologist, I don\'t put in breast implants, but I certainly
> see the repercussions of some of these ruptured implants in my
> patients, specifically breast cancer patients who have had
> reconstruction where they will be in for a body exam and we will find
> hard nodules in the region of the skin around the breast that has been
> reconstructed and we have had to sample these to see whether it is
> metastatic disease. With a patient who has had reconstruction, those
> hard papules or nodules have been silicone granulomas, these having
> developed early after their implantation. Of course I don\'t know when
> the rupture was.
>
> I do see that sometimes the impact of the silicone, which has traveled
> a distance, may not become manifest for a decade or more. I also feel
> a little uncomfortable right now about the short duration of the study
> in terms of long-term safety, so I would feel real happy knowing the
> longest follow up which we have with real data on any of these
> patients.
>
> That\'s all I have completely from a clinical perspective.
>
> DR. WHALEN: Dr. Boulware.
>
> DR. BOULWARE: I will limit my comments to my specialty of
> rheumatology, primarily the issue of connective tissue diseases. Let
> me start by saying that one connective tissue disease is not the same
> as all connective tissue diseases.
>
> In the practice of rheumatology, the patients that we would typically
> see with, quote \"connective tissue\" disease can vary from strain,
> sprains, to severe rheumatoid arthritis, polymyositis.
>
> Most of us tend to categorize these into\--I will give you my own
> classification, there is very of theme. They are immune-mediated,
> inflammatory diseases with systemic or local effects, rheumatoid
> arthritis, systemic lupus erythematosus, ankylosing spondylitis, to an
> extent scleroderma, and not in our specialty, inflammatory bowel
> disease, and other types of inflammatory diseases that have these kind
> of manifestations.
>
> Then, there is another area as you continue the spectrum that it goes
> down to fibromyalgia, and this gets very uncomfortable even for
> rheumatologists in defining who does and doesn\'t have fibromyalgia.
>
> For the first list of diseases I gave you, the inflammatory ones, the
> American College of Rheumatology and a number of organizations, the
> European community have come up with a list of criteria, so that we
> can even agree what those are, and those sometimes are not always
> agreeable, but we have data on sensitivity, specificity, so we are
> fairly comfortable.
>
> When you look through the fibromyalgia literature, the criteria is
> much newer and now there are people who are being included in that who
> are in these studies we have seen today that are self-reported, may
> not have fit criteria, may not even have, they may have been very
> loosely diagnosed or not diagnosed at all, so I am very uncomfortable.
>
> As I get further down, we have included the look at symptoms in broad
> categories of muscle, which includes, as I looked at the category of
> the study done by the sponsors, neck pain, back pain, any kind of
> pain, weakness, et cetera, which I think many of us, if we filled out
> today, would have to admit that we had those.
>
> So, as we go from the very\--fairly well agreed-upon inflammatory
> diseases down to almost symptoms, I become more uncomfortable.
>
> I am very comfortable with the data thus far that has been presented,
> not necessarily by the sponsors, but somewhat by the sponsors,
> reconfirming other published literature. That first category of
> inflammatory diseases, I am fairly comfortable that that is probably a
> safe area, that there is not a very good relationship.
>
> As I get further down, I am less comfortable, but I know in my
> practice, very often\--and in rheumatology\--while what we commonly
> see, where there is smoke, there is fire, if we equate smoke with a
> symptom, it doesn\'t necessarily mean there is a musculoskeletal
> problem underlying that or a fire.
>
> Very often I will see patients who come in with complaints much like
> what was listed on here, which turn out to have very different
> diseases that are not musculoskeletal based, depression being a very
> common one, and it becomes very cloudy and difficult.
>
> So, I am not so comfortable in that area at this point, but I am
> comfortable that the relative frequency which they were reported is
> not very different from what I would think a control population would
> have for that.
>
> In fact, I was pointed out to a study done in Denmark, reported in
> 2000, comparing the patients who had cosmetic implants with plain
> cosmetic surgery without implants, showed very little difference in
> terms of their complaint level, suggesting that the implant was not
> the likely cause as much as the population in which the surgery
> occurred.
>
> DR. WHALEN: Dr. McGrath.
>
> DR. McGRATH: I am going to comment as a plastic surgeon user of these
> devices and I guess start by saying that I really came to this panel
> eager to hear the data because I have been waiting to hear these
> numbers and to hear the information, so that I could start to think
> based on the science that was going to be presented.
>
> Where I am right now is I have been some things that I don\'t think
> are issues and some things I really still have questions about. The
> thing that I do not think are issues from my own experience is I do
> believe patients benefit enormously psychologically on both sides,
> both on the cosmetic side, as well as the reconstructive side, from
> the use of breast implants and that there is a positive benefit to the
> gel product. It does give a more natural feel under the skin
> particularly in slender patients, and so forth.
>
> I absolutely support the concept of patient autonomy. I don\'t feel
> paternalistic about telling patients whether they are doing the right
> thing by choosing to have a reconstruction or to enlarge their
> breasts, but I do feel strongly that they have to have accurate
> information when they are making that decision.
>
> That then takes me to three areas that seem to be a little bit
> surprising to me from the numbers that I have heard just over the last
> 12 hours. First of all, the reoperation rates. Now, we know that they
> are running about 20 percent over three years on the core augment
> group, they are running about 45 percent over three years on the
> reconstruction group.
>
> Somehow I had been going along thinking this was\--or I had heard or
> the word was that this was because patients wanted to change their
> implants to get bigger ones or smaller ones or they didn\'t like the
> way they look. That is not what the data is saying now. What it is
> saying is that it was because of complications.
>
> In the augmentation group, 70 percent of them went back for an
> implant, a second operation because of complications, and 92 percent
> of the reconstruction patients who went back, went because of
> complications, not because of some wish to change size or the type of
> implant. I think those are high numbers.
>
> The second thing is the rupture rates. I don\'t understand why they
> rupture, and I don\'t feel like I really got a clear answer yet from
> the manufacturer. Perhaps tomorrow morning they can readdress that
> again, because I think if we don\'t know why they are rupturing, and I
> don\'t buy the argument that it is surgeon trauma because the data
> that we did have said that they could find something that suggested
> that they were sharply damaged in 18 percent of the cases either at
> the time of insertion or removal, and I know in my own case, I am much
> less careful when I am removing one than when I am inserting it
> obviously.
>
> So, I don\'t know how that holds up, but that still leaves me with
> that other 82 percent that it is very hard to account for why these
> products aren\'t more durable.
>
> Also, the question of how to detect these ruptures, to put that
> financial burden on patients of going for an MRI at frequent
> intervals, it is a very high price for them, and then if it\'s
> ruptured, whether and when to remove it. I don\'t have answers to
> these questions yet.
>
> This question of rupture has enormous implications for my patients.
> This puts a financial burden on them, particularly the ones that
> aren\'t operating under health insurance. It\'s a health risk, and I
> think it\'s a psychologic burden, too. I think as people go back and
> deal with these problems over and over, it is very emotionally
> wearing.
>
> The last thing I would bring up is I just haven\'t seen any new data
> on mammogram interpretation, and I would like to see some of that,
> too, in the core augment group.
>
> My last thoughts are that if the manufacturer goes further, I would
> sure like to see more fleshed out on the informed consent. I certainly
> think other than simply perhaps the mention of a potential focus
> group, I certainly would like to see the opportunity for something
> much more elaborate and formal in terms of patient education.
>
> Lastly, I think a registry would have to be something that the
> manufacturer is just going to have to address.
>
> DR. WHALEN: Dr. Leitch.
>
> DR. LEITCH: Well, as a cancer surgeon, I, of course, do the surgery
> that makes a woman have to think about having a breast implant, so I
> have to be concerned about what her options are for reconstruction and
> does she really have a choice.
>
> I must say in the prior climate with the silicone gel implants, even
> though breast cancer patients theoretically had a choice to have them,
> many of them didn\'t because they said, well, gosh, it they are not
> safe for augmentation, why do they think they are safe for me.
>
> So, they would select the saline implants and then be unhappy because
> they had rippling effect of the implants and the cosmetic result
> wasn\'t as nice as they had hoped for.
>
> But these concerns that are being raised today are the things our
> patients think about and have heard about, and we have to give
> attention to them.
>
> Now, the other things with respect to cancer that I would like to
> address are the issues I think that we can give our patients good
> competence about, and that is that having silicone gel breast implants
> does not increase their risk for developing a subsequent breast
> cancer, it is unlikely that it contributes to other cancer site
> development. The two sites that were listed most frequently, lung and
> vulvar cancers, have other lifestyle issues that may contribute to
> risk in that aspect, so I don\'t think that has been clearly shown to
> be associated.
>
> The other thing is mammography with breast implants, and it is clear
> that adequate mammography in these patients requires additional views,
> with the Ecklund views, and visualization can also be improved if the
> implants are placed in the subpectoral location, which is more common
> these days.
>
> A lot of the studies that were looked at in the IOM Report were
> studies where mammography, you know, looking at detection of cancer in
> late diagnosis, mammography was done prior to wide use of Ecklund
> views.
>
> So, I don\'t think that data can be stated to be exactly what the data
> is at the present time where careful Ecklund views are done in implant
> patients. The other thing is even in those studies, interestingly,
> anywhere from 8 to 20 percent of cases were DCIS or the earliest stage
> with breast cancer that can be found.
>
> So, even in that time when mammography wasn\'t ideal for implants,
> still, they were able to detect this earlier stage of cancer.
>
> These days also, women do have other imaging options if their breasts
> cannot be adequately imaged with implants in place, there are other
> options with sonography and MRI, which as is being mentioned is an
> expensive alternative, but nevertheless, it exists as an alternative
> which we use for people who have dense breasts for other reasons.
>
> I think the big thing that has come out probably for all of us is the
> issue of implant rupture, and this really I think is where a lot of
> the discussion is coming up. I think the sponsor is saying, well,
> look, you know, we got the saline implants approved and the
> complication rate in some areas is less with the silicone, it stands
> to reason that these should be approved, as well, you might think that
> would be the case.
>
> So, I think the differential that we are really looking at here is the
> issue of implant rupture and what that means to the patient. For
> example, with mammography, it makes a difference if it\'s an
> extracapsular versus an intracapsular rupture because if the silicone
> gets out of capsule into the substance of the breast tissue, then,
> that opaque material obliterates the breast tissue, so you can\'t
> examine it well. Even if you do the Ecklund views, you can\'t push
> away that extravasated silicone, so it does cause a problem in that
> regard.
>
> Extravasated material can infiltrate the muscle of the chest wall and
> be very painful for the patient, I have certainly seen that,
> generally, in patients with older implants. I must say among my breast
> cancer patients, I really have not experienced a lot of complications
> with the silicone gel implants. Most are from patients who have
> implants many years ago and then have extravasation problems.
>
> So, these are the issues. I think some of the things in terms of
> rheumatologic issues, maybe it is the case that people who have the
> extracapsular extension are the ones that become more sensitive to
> this although certainly I think all of us have seen patients who had
> actual silicone injections into their breasts and while they have a
> lot of local issues in terms of lumps and bumps, they don\'t have a
> lot of systemic symptoms.
>
> So, it may take us several factors to come together to make that
> extracapsular silicone be an issue, but that may be in the study that
> Dr. Brown cited may be an example of that although it is not a perfect
> study to look at it.
>
> That summarizes my concerns at the present time. I do think the issues
> about the follow-up study we need to go into if the product were to be
> approved. I think all of us do have concerns about the follow-up, as
> Dr. McGrath mentioned, in terms of MRI and the role it would play, so
> I think we need to address those types of issues.
>
> DR. WHALEN: Dr. Chang.
>
> DR. CHANG: I make my comments in the context of my being a practicing
> plastic surgeon. I believe that the sponsor, in presenting their data,
> have really shown due diligence in gathering the preclinical studies,
> as well as in the excellent follow-up of patients in the time period
> of one and two years, and most of the three-year data.
>
> I believe they have shown that there is efficacy and a high rate of
> patient satisfaction.
>
> Some other comments. Remaining unanswered questions, as Dr. McGrath
> said, the important question is why do ruptures occur. It is a fairly
> high rate for reconstructive patients, 6 percent, why are they caused,
> how can we improve and try to diminish these numbers.
>
> Another question I have is I am just wondering, how did the sponsor
> decide on the exact thickness to use for the implants, where they may
> range from 13 to 18,000ths of an inch, and would it have made a
> difference in pliability and rupture rate if it had gone to 20,000ths
> of an inch, so that is a question which may or may not be addressed in
> closing statements by the sponsor.
>
> The last major question I have are what the repercussions of
> extracapsular gel migration when it occurs.
>
> I was again impressed three years ago by the due diligence and
> presentation of data for one-year, three-year, and five-year follow up
> of saline implants, sponsor has related the complication rate to
> saline implants, data that were presented three years ago.
>
> I was impressed that they had physician follow-up of these patients,
> so then I ask, and my statement is I believe there is an irrational
> optimism on the part of sponsor to think that a Phase II study using
> mail-in survey is going to come anywhere near the success rate that
> sponsor has had in gathering significant data to see what happens on a
> long-term basis.
>
> So much of the public comment stressed the importance of this
> long-term data. So, I really don\'t think that a mail-in survey would
> be appropriate if one wants to achieve the success that has been shown
> in presenting data during this presentation today.
>
> Lastly, the issue, if the FDA were to approve this device, is the
> concerns about what kind of labeling and the patient education of the
> reoperation rate and local complications.
>
> Thank you.
>
> DR. WHALEN: Dr. Choti.
>
> DR. CHOTI: Perhaps to reiterate some of the points made, just as a
> clinician, to a little bit of what I have learned in my concerns, one
> is regarding the device. I am concerned about the performance of the
> device.
>
> I think we have learned that there are some issues related to it,
> particularly the reoperation rate, the local complication rate,
> particularly of concern, the pain, capsule formation, and
> particularly, as mentioned over and over, the leakage rate, which it
> is clear that it\'s a delayed effect, or it continues to go up.
>
> So, while the systemic effects are less clear, I think, and I am
> perhaps somewhat more comfortable with the fact, or at least the
> evidence is less clear that there is a strong correlation with the
> systemic effect, I think that is also still a concern and it\'s an
> open question mark, difficult to address, it\'s a complicated question
> to look at the systemic effects, but I think to say that free silicon
> from a ruptured extracapsular implant, that the presence of free
> silicon isn\'t totally inert, I think it is still difficult to say and
> still a concern.
>
> I think, though, the local effect of a rupture is a potential problem,
> and as I said, the performance of the device results in a significant
> potential for delayed rupture and leakage. So, these are some of the
> questions that I am still grappling with.
>
> I think the study was well done, I think it was as designed. I think
> the follow-up was excellent, I mean the compliance was excellent with
> follow-up. The problem is really the short-term follow-up. I think
> that a lot of the concerns we have are related to the delayed effects,
> and that is really not addressed by two- and three-year follow-up.
>
> The review of the peer-reviewed, although compelling, and certainly
> there were a lot of groups that came out and suggested that the
> concerns perhaps are not as great as one should have thought about 10
> years ago or 12 years ago, but I still think that looking at this
> evidence, it is still not clear in my mind.
>
> For example, I am concerned why we really haven\'t seen much data out
> of Europe, for example. There are really no good registries, so it is
> still not clear from large population-based studies as to the
> performance, long-term performance of these devices.
>
> I am looking forward to having some of these questions addressed
> hopefully. Those are the main points that I would like to make.
>
> Thank you.
>
> DR. WHALEN: Dr. Blumenstein.
>
> DR. BLUMENSTEIN: The form in which the data from the sponsor was
> provided to me was problematic. It was given to me as a CD-ROM,
> contained a heap of PDF files with one PDF file showing the contents
> of the CD-ROM as a list of topics along with PDF file names.
>
> Furthermore, the PDF files contained scanned images of pages rather
> than converted documents, therefore, were not searchable. A collection
> of PDF files without navigation tools and searching capabilities is
> much less than an optimal replacement for paper.
>
> It was therefore difficult and time-consuming to assess the data on
> the CD-ROM. It is surprising to me that the full capabilities of the
> PDF technology were not exploited and the sponsor would condone this
> type of barrier to easy access to the data.
>
> From a statistical viewpoint, the presentation of the PMA data is
> deficient and unimaginative. The FDA guidance document was
> inadequately implemented, and there was no effort to go beyond the
> underlying principles of the guidance document.
>
> There were no substantive efforts to employ supplemental analytic
> techniques to enhance the presentation of the data. For example,
> minimal graphs or other visual aids were included on the CD-ROM. Also,
> the use of time, as in Kaplan-Meier plots, could help by illustrating
> where there might be higher hazards or non-constant hazards of events.
>
> An example of an inadequate implantation of the FDA guidelines is the
> absence of a comparison of the characteristics of women who have
> follow-up to those who do not. Another example is the absence of
> proportional hazard regression models, that is Cox regression, using
> time-dependent covariates. Both of these are in the guidance document.
>
> There is no presentation of an overall composite failure outcome
> analysis, such as bad-thing free survival. Such an analysis would be
> the single most important characterization of device risk and
> performance.
>
> Instead, the sponsor presented three composite outcome analyses
> partitioning bad things into three classes of bad things. The analysis
> by the sponsor dilutes the overall risk and negative aspects of the
> device\'s performance.
>
> Also, the presentation of the sponsor\'s composite risk analyses is
> inadequate, for example, the sponsor\'s material has no graphic aids,
> such as the Kaplan-Meier plots.
>
> The constellation of side effects that were prospectively collected to
> potentially detect increases over two years that are notable, but
> difficult to interpret because of the absence of a control group.
>
> Specifically, the increase in frequency of the side effects over two
> years is confounded by aging. Statistical modeling using all three
> patient groups and patient age at entry as a covariate might provide a
> means of clarifying the meaning of these data.
>
> The three groups differ with respect to mean age and therefore can
> provide an estimate of the trend over age in the reporting of these
> side effects. The length of follow-up is inadequate. The amount of
> follow-up does not meet the minimal requirements in the FDA guidance
> document.
>
> In addition, it is my judgment that the minimal follow-up specified in
> the FDA guidance document is inadequate.
>
> DR. WHALEN: Brent, next time try not to sugar-coat it so much.
>
> Dr. Conant.
>
> DR. CONANT: That\'s a tough act to follow.
>
> I would like to start by speaking of my concern about the
> underestimation of rupture based on the small number of patients
> screened with MR and only for such a short interval.
>
> I am concerned about the concept of silent rupture and that since we
> are not detecting these cases unless these women are screened, we may
> need to create some prospective or some guidelines for screening of
> women who have silicone implants placed.
>
> I am concerned also about the lack of evaluation of the individual
> rupture cases. From my experience in the operating room helping take
> out ruptured implants as an imager with an ultrasound. You can\'t see
> the free silicone, so by just visually inspecting, saying there is no
> extracapsular silicone, I am not sure that is an adequate endpoint,
> and it worries me in terms of local complications.
>
> I am going to leave the connective tissue disorder discussion to my
> rheumatology colleagues.
>
> So, I am concerned that not only are we underestimating the ruptures
> because of lack of long-term follow-up and small numbers screened even
> at one-year and three-year, that we are not fully evaluating the
> extracapsular extent of silicone.
>
> I am also concerned about the possible simplification of the patient
> satisfaction measurements. There are so many other aspects of
> satisfaction than are you happy with your implant, and I would love to
> see a little bit better breakdown of that, for example, are you
> concerned about cancer screening with your implant, are you concerned
> about the need for implant screening and the cost of that.
>
> Getting to my specialty breast imaging, I would just like to make a
> few comments about that, that our additional imaging now really does
> image the breast tissue better than it used to. Our limitations are
> really those patients with severe capsule contraction.
>
> I personally have not seen extravasation cause a limitation in
> detection, because extravasation or free silicone is usually focal or
> thin sheets streaming along the pectoralis muscle or along the margin
> of the implant, but it rarely gets in the way of cancer detection, but
> when a lesion is detected with breast imaging, our options of how to
> approach the lesion with biopsy are often limited.
>
> For example, with capsular contraction, we can\'t do as many of our
> percutaneous simple stereotactic core biopsies or even
> ultrasound-guided biopsies because of the limitation of space around
> the implant and the inability to manipulate the breast, so it becomes
> a more complex situation with more risks than the normal patient.
>
> And what else - I am a little concerned also about the screening
> compliance, which we talked about earlier. I personally have seen
> patients refuse screening mammography because they have their implants
> and they are worried about that. I would hate for those women to have
> the burden of more expensive screening techniques.
>
> DR. WHALEN: Dr. Lawrence.
>
> DR. LAWRENCE: Thank you.
>
> While I agree with many of the things that have been said here this
> evening, I am going to focus on one issue, which is my particular area
> of interest, and that is the child.
>
> Therefore, we find that mothers who get implants fall into two major
> groups from that standpoint, those who are outside the childbearing
> years and therefore it becomes a decision and issue for the mother
> alone, and perhaps choice is appropriate.
>
> For the woman who is still in her childbearing years, it is a very
> important decision because we are talking about putting a foreign body
> in and some interesting chemistry into the breast.
>
> I think the data is not very robust as to the effect on the child who
> is born to a mother who has an implant, because there have been no
> controls and the follow-up has not been very extensive.
>
> One would need to look first at the exposure during pregnancy, and of
> all of the toxins and non-toxins that are in a woman\'s body, the
> exposure is far greater transplacentally than it is through the breast
> milk, so that even collecting cord bloods would be an interesting
> thing to do, and certainly to follow children born to mothers with
> implants and without implants for a much longer period of time, a
> minimum of 10 years.
>
> Then, with respect to lactation, it was also stated that it had no
> effect on lactation. Well, the only way one could confirm that would
> be if you were studying women who had lactated before the implant,
> then, had an implant and failed to lactate.
>
> One has to look at the reason for having an implant, and for some
> women, it is because their breasts are rather abnormal, not only
> small, but abnormal. The potential for that woman to be able to
> produce milk is much lower than the average woman, so the fact she has
> an implant doesn\'t necessarily explain the reason that she is unable
> to lactate when she has a baby. Therefore, that issue has to be
> discerned.
>
> Also, in the surgical procedure for placing the implant, it should not
> be done peri-areolarly. That would cut all the appropriate nerves for
> the let-down reflect, and it can be inserted otherwise, and I am not
> speaking as a surgeon now, I will quickly reassure you, but it is an
> important issue for women of that age group just how you operate on
> the breast.
>
> Then, with respect to what gets into the milk, the American Academy of
> Pediatrics did say that implants were not a problem for breast milk.
> It is interesting because to my knowledge, they have never studied it.
>
> We do know that if you give mothers two tablespoons of Maalox with
> simethicone you can raise the D2 levels in the breast milk rather
> dramatically, so silicone as an inert material most of the time, does
> that make any difference, will it be absorbed from the baby\'s stomach
> if it is in the breast milk?
>
> So, those questions have not been answered. They could be answered by
> some very simple studies.
>
> DR. WHALEN: Dr. Lieberman.
>
> DR. LIEBERMAN: Well, I think that looking at the data, I am concerned
> at the high rate of local complications, and I think that they are
> serious. I know that the saline implants have been approved with
> comparable rates of local complications, but I think the question is
> are those entirely comparable situations.
>
> I don\'t think we know if rupture is comparable to deflation and
> saline, and how serious that might be. It is not clear to me how often
> there is extracapsular silicone that is out there and then what that
> means.
>
> I think Dr. Brown\'s study, starting to look at the effect of
> extracapsular silicone versus when the silicone stays intracapsular
> raises some real questions about an association with things like
> fibromyalgia, and other studies, bigger studies that look at the
> entire group of women with breast implants wouldn\'t detect that
> because it\'s a small proportion of the women, so negative studies in
> larger populations don\'t particularly reassure me with regard to
> that.
>
> I think there is also an increase\--it kind of goes along with that
> increase in symptoms that we saw that is very hard to interpret
> because there is no control group, and as we get older, we all get
> more symptoms, but some of the rises over a two-year period look
> impressive. I am not quite sure what to do with that.
>
> I think there is clearly a need for much more data and for much longer
> term follow-up to get more data on some of these outcomes, such as
> connective tissue diseases, cancer. I would like to see the data from
> all of the studies with cancer, and not discard the ones that aren\'t
> significant, to look if the relative risk is about the same in all of
> them and the difference in significance is only because of the number
> of people in the study.
>
> The other thing I am concerned about is should this get approved, the
> issues of informed consent, of making sure that women are truly
> educated and truly able to make educated choices is very important,
> and I think the other question will become how do we monitor these
> women over time, both to learn from their experience, but also to
> assure their safety.
>
> DR. WHALEN: Dr. Manno.
>
> DR. MANNO: I will make some comments as a toxicologist, but I am also
> concerned on experimental design in some areas. I pretty much agree
> with what the physicians have said here with the concerns.
>
> I am concerned about the rupture problem, the etiology of the problem,
> what is happening to that silicone. There was a comment that it is not
> moving out of the capsule, but yet it looks like, according to the
> physicians who work with these things, they can\'t see it.
>
> There was also a comment made concerning, well, we can\'t ask the
> surgeons to look too far, you can\'t tell them what to do. That
> offends me. If you are doing any kind of a research study, you have to
> have the cooperation, you have to have the design, and the design has
> to be followed.
>
> I think if criteria were given and the principal investigators at the
> various sites were told this is what they are going to do and how they
> are going to do it, they would do it. If they didn\'t, you need to
> find some who will.
>
> One thing comes to my mind in terms of the questionnaire asked about
> the patient\'s satisfaction with the implant. I don\'t like a yes/no,
> because you only have 50-50 there. If many of the questions asked lend
> themselves to questions that they could grade them on a zero to 5,
> pain, overall, is your pain\--if you don\'t have pain, it\'s zero, but
> is it excruciating, as some of the women described today, that could
> be your 5.
>
> There are tools out there to do this. Then, you could quantitate your
> response a little bit better.
>
> In terms of the controls, no toxicology study is worth its salt
> without a set of controls, and that disturbs me a great deal. I am
> concerned in some places with the gel, studies that were in the
> package that was sent to us that they are comparing or wanting to
> compare historical data with more current data.
>
> That bothers me a little bit because your controls are there to be run
> at a time that your substancing question is being tested. Yes, it may
> be the same chemical formulation, there is still a different
> environment in which this is going on. They are possibly different
> people doing the exposure, and so on, and I think that that is a
> weakness in this area.
>
> Going back to the question that the gel is not migrating from the site
> based on the fact that it was injected in the animals and it stayed
> there, one thing that bothers me a little bit that came up from the
> discussions today, was that if I remember correctly, the injection of
> the silicone was given in the area of the back.
>
> The comment today about any changes that may occur in the stickiness
> as an implant stays in, et cetera, you are putting it in a different
> tissue milieu when you are putting it in breast tissue. You are
> putting it in lipid tissue, which will make it a different environment
> in the body, and this hasn\'t been looked at.
>
> There is also a difference\--this came to mind also in the fact of the
> rupture that came up with the comment today about the testing of the
> implant in terms of there was no test for shear effect on these
> implants in terms of rupture. It just came to my mind has there been
> any correlation to the first implant rupture in a patient as to their
> handedness. That may be one point that could be looked at, if you have
> any data like that.
>
> You are obviously, if you are right-handed, you are going to be doing
> more motion of all directions with your right hand. If it tends to be
> the rupture occurs earliest that you find it, on the right side, then,
> there may be a problem with shear or some other type of abrasive
> movement involved.
>
> I think another area that gives me a great deal of concern is in the
> reproductive studies with the two generations that were done. When the
> F1 generation was looked at for birth defects, for example, and
> anything there, was looked at a few hours to a day before the babies
> would have been born or the pups would have been born, delivered.
>
> The same is true with the F2 generation. We are concerned in terms of
> safety not only with birth defects, but we are looking at problems
> that may develop in the future like occurred with the DES where it
> didn\'t show up in the offspring until they were in their late teens,
> I believe it was, or early 20s.
>
> So, I think that we are missing that segment of information as to
> long-term effects on the offspring.
>
> I am interested also because I am in the Department of Psychiatry, go
> back to the incidence of suicide and depression that might be
> occurring in these individuals. Granted, you perhaps did not have that
> information at the beginning, but it would not be unreasonable, in my
> mind, as one of the instruments of evaluation on intake of patients
> into these things would be to have a psychiatric evaluation similar to
> what is done with organ transplant patients, that give you some idea
> of their emotional stability at that point, and if there is any
> underlying problem that can be determined professionally for having
> later instances of depression or suicide occur.
>
> I am also thinking in terms of the non-cancer reporting and the cancer
> reporting that has been in the literature in terms of genetic
> histories on these people especially in view of the more recent
> development of the marker for breast cancer. I think it would not be
> unusual to include looking at genetic histories even by questionnaire
> and then, in certain instances, decide whether or not the genetic
> testing for that particular marker be done.
>
> I think I will stop at this point.
>
> DR. WHALEN: Dr. Olding.
>
> DR. OLDING: I tend to be a lumper and an organizer into little areas,
> so for me, it is really about systemic problems and about local
> problems. I have been surprised that I have been reassured in some
> areas that I thought that I was not going to be, and I have been also
> equally surprised that I have been concerned about areas that I had
> not expected to.
>
> I respond to this as a plastic surgeon and as an advocate for my
> patients. The concerns you have heard about already, the local
> complications, not only the reoperation rate and the rupture rate, but
> also what about the long-term follow-up of those patients, what is an
> appropriate follow-up, what is the length of that follow-up, what is
> the financial burden to the patient.
>
> The things that I have been reassured about are the suicide rate,
> about the probable lack of association with breast cancer, with
> collagen vascular diseases, neurologic disorders. I had really
> expected that to be the focal point of the anxiety that we heard about
> or the tension that we heard about at the very beginning. I have much
> less tension, much less anxiety about those than I did before I
> reached this area.
>
> I believe we do need to think about education, not only for our
> patients, but for the people who operate on those patients, and the
> more educated we all are, I think the happier we will be.
>
> More importantly, I am also anxious to hear the rebuttal of our
> concerns by the company.
>
> Thank you.
>
> DR. WHALEN: Ms. Brown.
>
> MS. BROWN: As a person who has been in companies responsible for
> development projects, I have been trying to put myself in the
> company\'s shoes as to how would you conduct a study on a gel implant
> today in order to get it approved.
>
> First of all, the FDA has laid out a guidance document for testing
> silicone gel implants. It includes chemistry, toxicology, mechanical
> data, and how to conduct the clinical studies, and I think that the
> company has done a good job of following the guidance document, which
> is where everybody should start in order to develop products like
> these.
>
> The other starting point is that saline implants have already been
> approved, so they set a risk/benefit ratio that has already been
> determined to be acceptable. So, for me, the question is what is the
> additional risk, what is residual risk that might be associated with
> the gel implants.
>
> I think that with respect to effectiveness, one of the previous panel
> members commented on that maybe the effectiveness parameters weren\'t
> adequate, and I believe the guidance document pretty much laid out
> what the effectiveness were that were supposed to be collected in the
> study, and that all would have been agreed on by FDA and the company
> probably years ago in the protocol with respect to outcomes, and once
> you set those, they pretty much become something that the company and
> the FDA walk forward with together.
>
> With respect to is this device safe, it appeared to me that the
> company presented data, the complication rates between the saline
> implants, the silicone implants appeared to be similar, if not, lower
> for the gel implants with the exception perhaps of the rupture.
>
> I am interested in hearing the company\'s comment on the relationship
> between disease and extracapsular rupture, as well. To me, the
> reoperation rate is troubling, but it was always troubling even with
> the saline-filled implants, but I am like Dr. Dubler, I think a
> patient should have a right to choose with adequate informed consent
> whether or not they do this, especially cancer patients.
>
> I have a sister and a sister-in-law who both were cancer patients, and
> I know the tram procedure doesn\'t cover both breasts, so what do
> those patients do. So, I am a real advocate of the right to choose.
>
> I also think, though, that the company has an obligation to have
> extremely good informed consent, and I don\'t know it takes to get
> adequate informed consent where patients really, really hear the
> message that they really are signing up for a potential reoperation,
> but I think that whatever\--I think I saw in the materials that the
> company was going to do an evaluation of the informed consent process
> or the patient advice process, and I think that that really should be
> an important focus to make sure that patients are adequately informed.
>
> With respect to extent to follow-up, two-year follow-up, I think two-,
> three-year follow-up is extremely consistent with other devices. It is
> probably two-year follow-up is consistent with other implants that the
> agency has approved.
>
> I know that the FDA is always concerned about level playing field, and
> so I know of no other implantable device that has had more than
> two-year follow-up, and correct me if I am wrong, someone from FDA,
> but to ask for more than two-year follow-up, I think is fairly
> extraordinary for an approval process, not for\--I think the company
> has already signed up and the guidance document already specifies a
> 10-year follow-up, and that is certainly appropriate.
>
> Those are my comments.
>
> DR. WHALEN: Ms. Gilbert.
>
> MS. GILBERT: Thank you.
>
> I think the consumers simply need to have more answers, more honest
> answers to some of the concerns raised. The sobering testimony
> provided today was a contrast to the findings of the sponsor.
>
> I strongly recommend long-term studies to address failure and rupture,
> follow-up, delayed effects of gel migration, again, the follow-up
> concerns and the need for recommendations. The patient and the
> consumers deserve to have honest information, and we need to have
> facts and consistent educational information.
>
> That is all I have to say.
>
> DR. WHALEN: Going back over to Dr. Miller.
>
> DR. MILLER: Thank you.
>
> I want to say first that I listened carefully to everybody who
> testified today as best as I could track, and I appreciate everybody
> who came today to speak to us and the passion that I saw, sincerity
> that I saw in everybody who spoke.
>
> Let me say that my career as a plastic surgeon has spanned the entire
> implant controversy from the beginning, and I will match the passion
> that I saw in this room today with my own passion for the safety of my
> patients and for providing good care, and that is where I come from on
> this whole issue.
>
> I am very concerned to understand what happens with these implants and
> the impact that they have on the health of my patients.
>
> When I look at the mandate we have to look at the safety and
> effectiveness, when I think about the effectiveness, it is clear the
> implants are effective. I mean that is clear. The implants are
> designed to make the breasts larger or to create a breast where there
> was no breast before.
>
> Nobody would argue that the implants don\'t successfully do that, that
> they are very successful at doing that. The benefit of the implants,
> because it overlaps many areas beyond that very strict criteria,
> creates a lot of opportunity for controversy, because suddenly we not
> are asking the implants make the breast bigger, we are asking should
> you make a breast bigger.
>
> A lot of different opinions begin to creep in about the
> appropriateness of doing that, and this begins to shade this
> cost/benefit, this risk/benefit analysis, and that is why I think this
> problem is so difficult to resolve and so unique.
>
> I am convinced of the effectiveness of the device. As far as the
> safety goes, I think it is okay to hold the implants to a slightly
> higher bar than other devices because of some controversy possible
> over the benefit. I mean if there is a questionable benefit, then,
> there has to be maybe a higher level of safety, I am okay with that.
>
> I am satisfied with the safety that I have seen in terms of the
> long-term effects of these implants. I think there are questions that
> exist, but I think that the experience of 40 years, I think that the
> nice analysis of the data, and the published studies that were done by
> both the FDA and the sponsor summarized the literature very well.
>
> To me, it is fairly convincing that there is no evidence that these
> things harm people in the long term with systemic problems. It is hard
> to make a case for that. I am a little dismayed at the data that has
> been presented in terms of the symptomatology because that is so hard
> to interpret and all it does is cast doubt about how systemically safe
> these devices are without answering any questions, it is just another
> shadow of doubt is thrown in, and that, I didn\'t find very helpful,
> but the data is there.
>
> I am troubled by the number of people who genuinely feel harmed by
> these devices. When I listened to these stories and hear about the
> level of personal life disruption and injury, that people sincerely
> believe has been caused by these implants, I have to wonder why is
> this.
>
> I think we need to try and answer that question dispassionately to
> find a solution, because these people are suffering, there is no
> question about, and not suffering for no reason. So, what is the
> reason?
>
> I am unconvinced it\'s the breast implants. I think it does them no
> service to just endorse the idea that the breast implant is the cause,
> because if the breast implants are not the cause, then, we are not
> searching for the right cause in these people. I think we need to work
> hard to study these individuals and see why are they having these kind
> of problems.
>
> There was a very interesting paper I want to refer to the rest of the
> panel and the rest of the audience by Barsky and Boris out of Boston,
> talking about the functional somatic syndrome, and I don\'t think
> every patient who we saw today is afflicted with the functional
> somatic syndrome, but I think a large number of them can be
> categorized in this category, and I would encourage a consideration of
> that, an explanation of that.
>
> A couple of other points. The issue of reoperation as a complication,
> I mean aesthetic surgery and reconstructive surgery with the device in
> some ways it is a process, and with other procedures and other
> operations, a reoperation is a failure and a complication.
>
> It is not really fair to consider a reoperation in a patient who you
> have implanted something to change their breasts necessarily as a
> complication, because you cannot make the breast like it was
> originally, and putting the implant in, you have introduced an element
> to try and create the final product of a shape.
>
> Now, rarely, and I tell my patients this, is this going to be done
> perfectly with one go-around, and it depends how high your
> expectations are and how close to the perfect idea you want your
> result to be that will determine how many operations you are going to
> require.
>
> So, some of the patients, the higher standards of expectations require
> the most operations, but in doing them, it does not represent a
> failure for that patient, it\'s a continued pursuit of that patient\'s
> goals. So, that clouds a little bit the data when we just consider
> reoperation a failure. I disagree with that view.
>
> One final comment is I think that these devices, placing one of these
> devices is deceptively simple. As a surgeon, it seems so simple. You
> create an incision, you create a pocket, you put a device in, and you
> are done. This invites a host of surgeons of all types to decide to do
> this procedure.
>
> There are technical issues with putting an implant in properly to
> avoid wrinkles, to place it properly, to not cut it with a needle, all
> these things, to properly inform your patient, to follow them
> responsibly. These are things which make a successful operation and an
> unsuccessful one.
>
> Not every surgeon is really cut from the same cloth in this regard. I
> think that perhaps some element of considering who is qualified to
> place these devices should be considered in terms of considering their
> safety and efficacy.
>
> Thank you.
>
> DR. WHALEN: Dr. Anderson.
>
> DR. ANDERSON: As a breast cancer surgeon, I came here this morning
> thinking that what I thought I knew, I believe in the efficacy. If you
> have handled a silicone versus a saline implant, there is no question
> that silicone is a better implant.
>
> I believe in the right to choose. I think my patients should have that
> right to choose. Life is not without risk, so there are risks that
> come with all of the things that we do, there is no reason that this
> should be an exception.
>
> The problem that I have hit, I must say that it was the presentation
> of the company that actually made me back off from my confidence in
> the device, because I didn\'t hear the answers to the questions that
> we were looking for in terms of the local complications of these, and
> also addressing these possible systemic effects in very small groups
> of people, because at a minimum, I don\'t think we can say that it is
> impossible, but at a minimum, we need to be able to say to our
> patients, well, this only happens in X percent, because then we can
> properly inform the patient that this is what your risks are.
>
> So, we need that from you. What I also didn\'t hear from the company
> were guidelines about how these should be used. When the question came
> of what do you do, are we supposed to take them out at 10 years, do
> you wait until they rupture, there was no answer, and that should have
> been thought through upfront.
>
> So, on the one hand, if this device is approved by the committee,
> then, we need to have a real plan about how the follow-up is done, how
> the data is collected, and not window dressing, but something that is
> enforceable and realistic.
>
> On the other hand, if we don\'t approve this device at this time,
> then, it is the obligation of the FDA to be very clear about what it
> is that these people are supposed to do to prove that this device is
> efficacious, because it does sound like they actually followed the
> rules of what was laid out by the FDA.
>
> So, if we are going to pull back on it now, we can\'t do that multiple
> times.
>
> DR. WHALEN: Dr. Li.
>
> DR. LI: My comments are basically circled around the same worries
> everybody else had, which is rupture and gel bleeding, so to those two
> regards, let me cover four areas - the manufacturing issues,
> extractables, mechanical testing, and retrievals.
>
> Because we don\'t seem to understand or be able to duplicate the issue
> of rupture, this kind of raises the question of what is important and
> what is not important, so in the absence of actually knowing what
> causes the rupture, it kind of brings everything into question.
>
> Some of this data, the company may already have, the FDA may even have
> it. I am just going by what I could find and glean out of the data.
>
> For instance, Dr. Chang mentioned the thickness of the implant, so
> given a particular style of the implant, the thickness could vary a
> factor of 4 just for any given style, from 18,000ths to 80,000ths, so
> certainly one would think that the 80,000ths thickness wall would be
> the preferred one because diffusion would be more difficult, however,
> from the fraction mechanics point, a thicker implant doesn\'t
> necessarily guarantee you better rupture, in fact, depending if it\'s
> permanent set, a thicker wall actually may work against you in terms
> of rupture, so it is just not clear, out of these rupture mechanisms,
> what the influence of thickness is.
>
> The other thing that is not discussed is the sizes of these implants.
> We have talked about different models of implants, but for every
> model, there are a variety of sizes. I think the volumes vary by a
> factor of 4 almost, anywhere from 100 or 90 up to 750 milliliters, and
> the effect of thickness combined with volume has not been broken out.
>
> Again, one wonders in a classic fraction mechanic test, do these
> design issues play a role in the rupture.
>
> As far as manufacturing consistency goes, they propose using
> mechanical tests like penetrometers or modulus mechanical testing to
> give an indication of crosslink density, which they appear to have
> done for the shell, at least given a particular crosslink density.
>
> They seem to have a penetrometer reading that reflects that crosslink
> density, but I am unclear if they know what the sensitivity is of
> changes of crosslink density to the penetrometer data.
>
> For instance, if the number of crosslinks per molecule tripled, would
> you still get the same penetrometer reading or would you not? It is
> unclear to me that the mechanical tests are actually a good indication
> of changes in crosslink density, and it doesn\'t appear, at least in
> the data that I saw, that their testing of the crosslink density of
> the gel is nearly as extensive as they are of the two base layers.
>
> Extractables. This is the gel bleeding concept. This, you did a
> substantial amount of work that, just as a body of literature, just
> confused the heck out of me, for two reasons. One, as has been pointed
> out, the extracting conditions are not in-vivo conditions.
>
> One of the problems is that I found at least four different solvents
> used in these extracting tests depending on when they were done and
> who did them. There was hexane, there was dichloromethane, there was
> isopropanol, there was ethanol. In some cases, the batch of implants
> done where the lot of implants was made under a label of an
> experimental production lot, they weren\'t pulled out of the regular
> lot.
>
> Now, maybe they were the same, and maybe not, but certainly the
> workers making those implants knew they were making a set of implants
> that were going to be tested differently than the regular batch, so
> that certainly raises the issue of was that lot particularly good,
> particularly bad, or was it, in fact, representative of all the rest.
>
> Depending on the solvents you used, you have got a wide range of
> molecular weights, and you also got a different set of molecular
> entities. You have got both linear silicones, you have got cyclic
> silicones.
>
> Now, because we don\'t really know what these local and broader
> effects are, we actually have no idea which are the most biologically
> important ones - is it the low molecular weight, is it the high
> molecular weight, is it the linear, is it the cyclic or the diphenyls,
> we actually have no clue. Circumposed on that is we have no idea what
> the dose-response is, if there is one, for these materials.
>
> As far as epidemiology goes, it seems to me, as the
> non-epidemiologist, and I know just enough statistics to be dangerous,
> their assessment that there doesn\'t seem to be any systemic effect is
> based on a large number of groups, however, we do know there are a
> subset of patients where these implants have ruptured, in fact, in
> many cases, we have heard that sometimes the implant stays ruptured in
> the patient for some length of time.
>
> I haven\'t seen any breakout of what happened, what the epidemiology
> of that subgroup is over time, so maybe if you look at the whole
> thousand women where small fractions of them have ruptured, you can\'t
> see it, but if you actually followed one particular group that you
> know had ruptured, I don\'t know if that breaks out or not.
>
> The mechanical testing, they have satisfied the ASTM and FDA
> requirements, but just as a comment to the rest of my panel
> colleagues, neither of those groups of tests are performance-related
> criteria. In fact, the ASTM guidelines almost in every particular test
> says you ought to do these to ensure that you making the right thing,
> but if you make them this way, we don\'t really guarantee you, you
> will get better performance.
>
> Now, this isn\'t the fault of the sponsor or the FDA, that is just the
> nature of the ASTM tests. My problem with the mechanical tests is they
> don\'t seem to reflect our clinical experience. In your fatigue tests,
> you can\'t seem to break them, but patients seem to do it kind of
> regularly. Your fatigue tests would say it is impossible to break
> these things during mammography, yet, at least we have a series of
> patients who appear to have done it at that time.
>
> There doesn\'t seem to be any attempt to actually verify or solidify
> your hypotheses of where these cracks come from or these ruptures come
> from. Typically, the approach in this is that cracks either occur
> where the implant is weakest, or they occur where the stresses are
> highest, and I have seen really no engineering or modeling in a
> classical sense to demonstrate that, in fact, what the increase is in
> stress out of fold, and something that has a very low modulus, it
> could be the increase in stress at the fold is minimal or not, but I
> haven\'t actually seen that calculation.
>
> Again, that would be a function of thickness. So, although it seems
> kind of intuitive that if you have a fold, it ought to be easier to
> tear, that may not be true if you have something very soft and pliable
> like an elastomer.
>
> So, the problem with the mechanical tests is there seems to be a
> disconnect between the testing and the actual failures that we are all
> worried about, in this case, rupture.
>
> That brings us to the last comments I want to make on the retrieval.
> So, first, let me congratulate on you for even attempting to do the
> retrieval stuff. I have been doing this for 10 years and it\'s a very
> difficult thing to do, and I think it is great that you attempted to
> do that.
>
> Now, that being said, let me criticize it. The data seems to be at
> least reported, if not collected, with kind of a bias toward the
> outcome. In other words, you may have collected more data than you
> presented, which seems to be the case. For instance, I heard that
> there was weights of these implants taken, but I didn\'t see any of
> that data in my panel packet.
>
> So, the problem is the data doesn\'t seem to be a general study of
> looking at all the factors that one could measure on retrievals, and
> then trying to associate those factors with rupture, for instance,
> factors that are not described, at least in my panel packet, are the
> size of the implant in addition to the model, the length of
> implantation of that particular device, the actual direction of the
> crack and the length of the crack, and if there is any association
> between the length of implantation and whether or not there was a
> crack.
>
> Kind of arguing against the fact that it\'s surgeon-induced is that
> some of the models appear to have cracks on the anterior of the
> implant, and other models had cracks on the posterior of the implant,
> so unless the surgeons are going to tell me somehow these two
> different styles have a different surgical technique, it is a little
> hard to imagine why, in one particular model, the cuts seem to be on
> the front and the others, they seem to be on the back.
>
> Again, the biggest bias comes, in my view, it comes from kind of the
> smooth versus sharp edge rupture description. That, in the kindest
> terms, is a very non-classical approach to implant failure. In fact,
> unless you can do some modeling or demonstrate to me these two, in
> fact, have different mechanisms occurring, in fact, they could be
> manifestations of the same failure mode, but because of the direction
> of stress or the location of stress, one appears to be curved and one
> appears to be straight, so it just basically puts in a question of I
> actually don\'t understand at all what is going on there.
>
> There seemed to be an inconsistent collection of data and some of the
> implants, they seem to be weighed and other ones they weren\'t
> weighed, but there was no assessment, for instance, if an implant was
> ruptured, was there an assessment of okay, well, you know, the implant
> now weighs half of what it did or maybe it only weighs less than what
> it did.
>
> I am not even sure what the variation is in brand-new implants. If I
> got 100 style 10\'s, I don\'t really know what the weight variation is
> in that. I don\'t know if it\'s inconsistent or if that is something
> that you can actually measure in the retrieved components.
>
> Lastly, there seems to be a general belief that as the implant stays
> in longer, the number of mechanical problems seemed to increase, and
> that whole area hasn\'t been addressed at all. So, if that is the
> case, two things come to my mind, either it\'s a fatigue issue and the
> longer it is in, it actually just sees more number of cycles, the
> other, more insidious mechanism could be, in fact, that there is some
> kind of chemical change going on in the implant, which some people
> reported as kind of a stiffness or a color change, or a physical
> change in the material of the implant, and again, that is a whole area
> that we just have no idea about.
>
> So, there is a tremendous amount of testing that left me no better
> understanding of why these things rupture or, in fact, even a
> discussion of actually how much they rupture, or why, and then this
> issue of the gel bleeding.
>
> The extraction data is interesting, but it is so far from the in vivo
> condition, I am not really sure what to do with it.
>
> DR. WHALEN: As chair of this panel today and in the past, I don\'t
> often articulate my analysis or opinions on matters that are being
> considered. My job is somewhat more mundane to do things such as keep
> us on time, for which I get an F today.
>
> However, I would like to, on the one hand, congratulate Inamed,
> because I think they did a phenomenal job in answering the questions
> that FDA asked them to answer. I remain astounded at the questions
> that FDA asked them, and with all due respect to this being the normal
> process and we never ask for more than two years, et cetera, that has
> been articulated and is the situation as it stands, we have been
> getting decubitus ulcers today over a matter of a product that was
> taken off the market a decade ago for concerns about long-term issues
> in these patients, a decade has passed, and we sat here today talking
> about two and three year data, and I am just flabbergasted by that,
> that we are going to be asked to give a cogent answer to safety and
> effectiveness when the data wasn\'t asked for, nor was it given.
> That\'s my opinion.
>
> With that in mind, let us go into the questions, please, Commander
> Allen, if you would present those questions and guide us through them,
> and each of the panel members will be giving a brief insight into how
> they feel about each of those questions, following which I will
> attempt to give a synopsis of the panel\'s comments to Dr. Witten,
> question by question. No. 1.
>
> **Open Panel Discussion and Questions**
>
> CDR ALLEN: FDA is going to seek the panel\'s input on the following
> seven questions.
>
> No. 1. Please discuss the adequacy of the information to determine the
> safety of this product with respect to asymptomatic rupture.
>
> Please start your discussion.
>
> DR. WHALEN: We will start going around the table first with Dr.
> Newburger.
>
> DR. NEWBURGER: I don\'t feel that there is information available to us
> to determine the safety of the product with respect to asymptomatic
> rupture. There certainly is a difference in symptoms associated with
> rupture in that augmentation patients seemed to be much more
> symptomatic than reconstruction patients.
>
> I am thinking that that may be in light of the scarring that one would
> expect to see at the surgical implant site with the reconstruction
> patients, but I am not comfortable with addressing that question. I
> don\'t have information that makes me comfortable discussing any
> safety.
>
> DR. WHALEN: Dr. Boulware.
>
> DR. BOULWARE: Can I clarify that with what was asked for them in terms
> of a timeline?
>
> DR. WHALEN: You certainly can.
>
> DR. BOULWARE: Because I think in terms of a short-term two to three
> year, I think they have answered that and the data is adequate, but
> the question has become greater, I guess, with the long-term outcomes
> for this.
>
> So, I am comfortable, I guess, with the short-term data, but not the
> long-term, but I want to be fair to the company in that. I don\'t know
> what was asked of them in terms of providing information about safety
> with respect to asymptomatic rupture relative to implantation time.
>
> Does that make sense?
>
> DR. WHALEN: Thank you.
>
> Dr. McGrath.
>
> DR. McGRATH: Good question. Are we going to stop and answer that
> before I say anything or after?
>
> DR. WHALEN: I personally consider that an answer in and of itself
> saying the short term, yes, long term, no, and then I will try to put
> that into the synopsis to Dr. Witten, and she clearly has a right to
> reject the answer that I give her.
>
> DR. McGRATH: Okay. The only thing I would add to it then, if it were
> short term, and they were responding to a request for three-year data,
> it sounds like not much of it was three-year data, most of it is
> one-year data in point of fact, as we understood it today, therefore,
> that is another issue that comes up that it really isn\'t even
> three-year data at this point in time.
>
> DR. WHALEN: Dr. Witten.
>
> DR. WITTEN: Perhaps I should clarify the question before you all go
> around and answer it, and that is that yes, the sponsor was asked,
> what the sponsor did was they proposed a 10-year study and proposed to
> come in to FDA with two-year data, which is what they have done.
>
> But our question to you in the end is going to be is there enough
> safety information to provide reasonable assurance of safety and
> effectiveness. So, what is in their application is their study, their
> preclinical testing, which we have heard about the limitations of, the
> information from the literature giving us some idea of the long-term
> performance of these implants as they have been reported in the
> literature, not specifically to this implant, so we are going to be
> asking you whether the information is adequate to determine reasonable
> assurances, to provide reasonable assurance of safety and
> effectiveness.
>
> So, I think you are going to also need to tell us whether this
> short-term study, coupled with the other information, will be enough
> to provide reasonable assurance of safety for this product.
>
> DR. WHALEN: In view of that elucidation, Dr. Boulware, Dr. McGrath, do
> either of you have any further comment or can we move along?
>
> DR. McGRATH: No.
>
> DR. WHALEN: Dr. Leitch.
>
> DR. LEITCH: Well, to say the safety of an asymptomatic rupture, by the
> aspect that it\'s asymptomatic, it is not bothering the patient at the
> moment, so in that point, I think is where they are in this study
> because it is early on, that those ruptures are not causing the
> patient\'s problems currently, so really, the question is not so much
> what is the safety of an asymptomatic rupture, as what is the
> long-term outcome of a rupture that is identified in the asymptomatic
> state, what is the long-term outcome of that.
>
> Data wasn\'t presented to that other than the data that is being
> reported with respect to systemic symptoms and signs which there seems
> to be general consensus that a lot of these concerns that people had
> about connective tissue disorders are not highly associated with
> breast implant patients, but what other people have asked here is,
> well, if you cull that down to those with rupture, what is the rate of
> that.
>
> So, while in the short term, I think the sponsor has presented what
> they should, we do need the long-term follow-up, which I think is what
> we are saying here, that if approval were to occur, that the follow-up
> data must be required and rigorous for that long term and posing to
> the sponsor a question that they can answer, so that they can generate
> this data for the long term.
>
> DR. WHALEN: Dr. Chang.
>
> DR. CHANG: It is hard to change the rules in midstream or to try to
> predict the future without having the information, so to answer the
> short-term question, rates of 2.7 percent were given for ruptures by
> MRI studies, and in collecting or looking at extracapsular rupture,
> the sponsor testifies that there have been no extracapsular, no
> findings grossly on clinical examination by surgeons of extracapsular
> gel leakage.
>
> So, it\'s a qualified yes, but it begs the question of what happens to
> again patients with ruptures long term, if they had a rupture, it was
> asymptomatic, and the patient kept it in for a year and had this
> amorphous gel in a subpectoral plane for one year, we haven\'t had the
> opportunity to examine any data of what happens to those patients, so
> I think we are asked to make a conjecture without data.
>
> DR. WHALEN: Dr. Choti.
>
> DR. CHOTI: I think with respect to this question, I think we don\'t
> have adequate information regarding the safety with regards to
> asymptomatic rupture. I think, if anything, the information is of
> concern.
>
> I think rupture is bad, and I think asymptomatic rupture is bad, as
> well, even though it\'s not asymptomatic, I think it\'s likely there
> is a concern that is associated with higher risk of extracapsular
> rupture perhaps.
>
> So, it brings up other issues in addition, well, the other point is
> that it is higher in the reconstruction patients perhaps, it appears
> to be, and why is that the case, and is it less safe in the
> reconstruction patient for that reason.
>
> Also, other issues somewhat less related to safety are the screening
> issue, how then do we follow patients at risk for asymptomatic rupture
> and who pays for the costs.
>
> So, I think that I do have concerns that the information provided
> brings up concerns of safety, and it is not adequately addressed.
>
> DR. WHALEN: Dr. Blumenstein.
>
> DR. BLUMENSTEIN: The number of events is too small and the follow-up
> is too short.
>
> DR. CONANT: I agree.
>
> DR. LAWRENCE: I would echo the same and say that it is much more
> critical for a women in the childbearing years.
>
> DR. WHALEN: Dr. Lieberman.
>
> DR. LIEBERMAN: I would say that I agree, there are too few events and
> we also have to keep in mind that only about a third of the patients
> were screened with MRI, so the rate of asymptomatic rupture in the
> whole population is really much higher than what we know.
>
> I don\'t think we know in particular what I would call the shape of
> the curve, does it increase linearly, does it at a certain point, does
> the rate of rupture go way up, and that is very important in terms of
> thinking about monitoring these women and about recommendations about
> replacement after certain periods of time, and all the other issues
> that have been raised related to that.
>
> We also don\'t know the consequences of detecting an asymptomatic
> rupture sooner rather than later, is it more likely to result in
> extracapsular silicone, and what is the importance of that, so we
> don\'t know that either.
>
> So, I think that we have a lot more that we need to learn.
>
> DR. WHALEN: Dr. Manno.
>
> DR. MANNO: I think I pretty much agree with everybody so far. There is
> insufficient information on the short term, there is only one year\'s
> worth of data completely analyzed and part of the third year group,
> and nothing on the long term. So, I think there is insufficient data.
>
> DR. WHALEN: Dr. Olding.
>
> DR. OLDING: This question really asked about the safety. In the short
> term, as far as we know, since they are all intracapsular rupture, we
> can\'t really question or we don\'t have any evidence that there is
> any short-term problem with that.
>
> We don\'t have the long-term evidence, but at least right now I would
> have to assume that the safety short term is certainly verified, and I
> am not certain about the long term.
>
> DR. WHALEN: Ms. Brown.
>
> MS. BROWN: May I ask the company a quick pointed question?
>
> DR. WHALEN: Well, since you brought it up, for this particular
> instance, we will. In the question period, we would prefer not to do
> that. That was during the open panel discussion, but since you have
> brought it up, if there is a quick question that they can give a quick
> answer to, go ahead.
>
> MS. BROWN: I hope they can answer quickly. Can you comment on the
> relationship between disease and extracapsular rupture quickly?
>
> DR. WHALEN: If you can do that, boy, you should get an award. If you
> go to the podium, please.
>
> DR. McLAUGHLIN: We will answer this in terms of this issue of this
> alleged relationship between extracapsular rupture and fibromyalgia,
> and I apologize for the overheads, but that is what we were told we
> have.
>
> \[Slide.\]
>
> The FDA summary of this issue of fibromyalgia relative risk estimates,
> I believe is mistaken. The Wolfe and Anderson paper, in 1999, the
> correct relative risk in that paper is 1.22, not 6.1, and in our
> papers that we did in Sweden and Denmark, the Nyren paper and the
> Kjoller paper, the correct relative risk is 1.0 and 1.2.
>
> For the Nyren paper, that is because we had a medical review and we
> excluded cases that weren\'t really fibromyalgia, and we also used the
> control group that we chose for the study, and in the Danish study,
> the Kjoller study, or as they say in Denmark, \"Keeler,\" we used the
> control group that we chose for the study.
>
> The Wolfe and Anderson, the 6.1 is in error because three of the six
> fibromyalgia cases in this risk ratio had their fibromyalgia before
> their breast implantation, so it\'s uninformative as to the
> association.
>
> DR. WHALEN: Thank you.
>
> DR. LIEBERMAN: Could I ask one quick follow-up? Is that for all
> fibromyalgia and all implants? That doesn\'t particularly address the
> extracapsular silicone.
>
> DR. McLAUGHLIN: No, we have other slides.
>
> \[Slide.\]
>
> This slide shows the percentage of women with fibromyalgia by implant
> status in a paper by Dr. Brown and colleagues, and you see that in the
> intact implants, it is about 15 percent had fibromyalgia. Ironically,
> in the intracapsular rupture, the lowest rate was to be found, which
> is the 8 percent, and then in the extracapsular rupture, they have a
> 25 percent rate of self-reported fibromyalgia.
>
> DR. WHALEN: What was the length of follow-up in that paper?
>
> DR. McLAUGHLIN: This is a cross-sectional survey, so they weren\'t
> following anybody, they just interviewed them.
>
> DR. BROOK: Some of the cases might have been diagnosed before
> implantation in this study, as well.
>
> DR. WHALEN: How long were the implants in?
>
> DR. McLAUGHLIN: Sixteen years, the average was about 16 years.
>
> So that what happened, if you compare the extracapsular rupture rate
> to the intact implant rate, which I think is the more traditional
> epidemiologic comparison, you don\'t get a significant difference.
>
> In the Brown paper, what happened was the intracapsular rate, the
> lowest rate, was put in with the control comparison, which then
> produced a statistically significant difference.
>
> \[Slide.\]
>
> We tested this hypothesis in a study, a similar study in Denmark, and
> this slide shows that in the intact implant, the percentage of women
> with fibromyalgia was less than 1 percent. For the intracapsular
> rupture, it was 1.4 percent, and for the extracapsular rupture, of
> which we had 23, not one woman had fibromyalgia.
>
> DR. BROOK: The average age of the implants was 14 years.
>
> DR. WHALEN: The comments need to be at the microphone by the person
> answering the question, please. For any question of the sponsor, we
> will have one person answering the question.
>
> DR. McLAUGHLIN: So, I, as an epidemiologist, and someone who has
> published over 45 papers in the field of the epidemiology of breast
> implants and their health outcomes, I don\'t think the relationship
> between fibromyalgia and extracapsular rupture has been established at
> all.
>
> DR. WHALEN: Ms. Brown, does that answer your question?
>
> MS. BROWN: Yes, thank you.
>
> DR. WHALEN: Thanks. Ms. Gilbert.
>
> MS. GILBERT: I will hold my questions in regards to this, because I
> don\'t think there is enough information even going through what they
> just went through, but frankly, I don\'t think the\--the short term,
> yes, one year, yes. For long term, no, I don\'t think we have enough
> information.
>
> DR. WHALEN: Dr. Miller.
>
> DR. MILLER: I think that we don\'t know the rate of rupture beyond one
> year, but we also don\'t know the implications of rupture should it
> happen. There certainly doesn\'t seem to be any health risk with the
> implants that can be demonstrated, so I mean it\'s hard to know what
> to say about silent rupture.
>
> I mean it is silent, it\'s asymptomatic, we don\'t know how often it
> happens, we don\'t know the implications. It would be nice to know,
> but I don\'t know if that is a safety issue. I don\'t see anybody
> being harmed by a silent rupture. I mean I don\'t like having a
> ruptured implant in a patient, but I am not convinced that they are
> harmed by it.
>
> So, is it safe? It hasn\'t been proven unsafe.
>
> DR. WHALEN: Dr. Anderson.
>
> DR. ANDERSON: I am going to disagree in a qualified way with the
> majority of the panel. I think we do have long-term data, it\'s not in
> the company\'s study. We heard reference to the Mayo Clinic study,
> which has 7.8 years follow-up for the implant group, and in the
> Nurses\' Study, it was 9 years, and these are not prospective studies,
> but there was no difference between control and intervention groups.
>
> So, I think there is more data, it is just in the literature as
> opposed to what was cited here. I agree that getting more data is
> better than having less.
>
> DR. WHALEN: Dr. Li.
>
> DR. LI: I will just answer from a device standpoint. It really just
> echoes what everybody else said, that it appears that the rupture rate
> is really kind of unknown beyond one year. It\'s unlikely it will get
> better with time, so I am a little taken aback that I don\'t know how
> we can answer the safety question when we are not quite sure how to
> answer the simplest question of how much they rupture.
>
> DR. WHALEN: Dr. Dubler.
>
> PROF. DUBLER: I have been a lawyer hanging out in medicine for 27
> years, and it is rare that something shocks me, but I sat on the panel
> in \'92, and that was 11 years ago. How we could have come from 11
> years ago, where we were going to collect data, to a point where we
> have a year\'s data simply boggles the mind.
>
> I am sure from what I have heard today that it\'s some combination of
> FDA and sponsor relationship, but I simply don\'t understand it.
>
> I am also shocked by a second point, and that is that clearly, the
> rupture of these implants is a very serious issue, and yet the company
> over the 11 years, the sponsor over the 11 years between the first
> hearings and now, has made no attempt to make this a better implant,
> so that it might have a lower rupture rate.
>
> So, having said I am shocked, I feel like Claude Raines at the end of
> Casablanca, but given that and given that I don\'t think we have
> anything more than a year\'s data on asymptomatic rupture, I would say
> that we can\'t make a determination on safety.
>
> DR. WHALEN: Dr. Witten, in regard to Question No. 1, relating to the
> adequacy of information to determine safety of the product with
> respect to asymptomatic rupture, there is not an entirely homogeneous
> response to that issue.
>
> I think that the panel pretty much uniformly feels that there is, in
> the short term, really measured as one plus or minus years, that there
> is adequacy of information to assure that it\'s safe at that juncture.
>
> Going beyond that interval of time to a longer term, there is some
> discordancy of opinion as to whether or not there is any data to
> demonstrate that, but there is also some elements of thought on the
> panel that it remains open-ended as to whether or not if, indeed,
> there is a higher rupture/leakage rate longer term, what, if any,
> implications that has for the individual patient.
>
> So, for the short term, it is demonstrated to be safe. I would say for
> the long term, the majority opinion is that that remains a question to
> be answered.
>
> Does that answer the question adequately?
>
> DR. WITTEN: Yes, thank you.
>
> DR. WHALEN: Commander Allen, Question No. 2.
>
> CDR ALLEN: No. 2. Please discuss the adequacy of the literature and
> the preclinical testing to determine the safety of this product with
> respect to long-term and general health effects.
>
> DR. WHALEN: Thank you.
>
> We will start with Dr. Boulware.
>
> DR. BOULWARE: I am actually reflecting back down at the bottom of the
> definition of safety that the FDA has given us to use. In considering
> the literature that has been out there from the IOM, other large
> epidemiologic studies, I am actually very comfortable with this, that
> they have met the safety issue.
>
> DR. WHALEN: Dr. McGrath.
>
> DR. McGRATH: That last sentence you asked us about preclinical testing
> and about literature. Preclinical testing was done according to the
> usual formulas, as I understand it, for ASTMS standards, so I am happy
> with that.
>
> As far as the literature goes, we could go through each of these
> categories and discuss them, but to just lump them all together,
> again, we haven\'t heard it presented today, but certainly out there
> in the historical published literature, and that pulled together by
> other very concerned medical groups that have looked at this, the
> Institute of Medicine and the other mega-analyses have not suggested
> that there is any risks in terms of cancer risks and connective tissue
> disease, and so forth, so I agree with Dennis on that, safety on
> historical data, and yes also on the preclinical testing.
>
> DR. WHALEN: Dr. Leitch.
>
> DR. LEITCH: I would agree that with respect to systemic illness and
> the literature and preclinical testing that has been done, that we
> have good evidence for the safety. I think again one of our main
> issues remains the local complication of implant rupture in the long
> term.
>
> DR. WHALEN: Dr. Chang.
>
> DR. CHANG: With one reference to a published literature that suggests
> that peri-areolar incisions may cause increased difficulty with
> breastfeeding, there is yes to both questions.
>
> DR. WHALEN: Dr. Choti.
>
> DR. CHOTI: I am not sure I can say that with such confidence. I think
> the preclinical testing, while encouraging, I don\'t think reflects
> necessarily some aspects of the clinical safety that we have discussed
> regarding the gel bleed and the mechanical strength, so I am not sure
> it addresses all the issues about long-term safety.
>
> As far as the literature, again, I think that all the data is not
> there. So, I still have some concerns about long-term safety based on
> both preclinical testing and the adequacy of the literature.
>
> DR. WHALEN: Dr. Blumenstein.
>
> DR. BLUMENSTEIN: I have been around medical studies and clinical
> trials long enough to know that we are always surprised. I just don\'t
> think that the data collected from these two modes are sufficient, and
> I can think of a lot of reasons, for example, you can\'t ask
> laboratory animals how they feel, so I don\'t think this is adequate.
>
> DR. WHALEN: Well, you can, but they won\'t give you an answer.
>
> Dr. Conant.
>
> DR. CONANT: I also am concerned about the laboratory, the preclinical
> testing for things like gel bleed and gel migration, that they really
> don\'t mimic the in-vivo circumstances, so I am not sure I have enough
> data either for long term.
>
> DR. WHALEN: Dr. Lawrence.
>
> DR. LAWRENCE: I think as a general comment that there is probably not
> enough information to answer all these questions, some are more
> significant than others, but I am concerned, as was mentioned earlier,
> about some of the animal information and the way reproductive and
> teratogenic effects were assessed, so I don\'t think we know that
> answer.
>
> DR. WHALEN: Dr. Lieberman.
>
> DR. LIEBERMAN: I think there are some things about long-term effects
> that we don\'t know. I am not sure that all of them are knowable or
> can be known in terms of considering approval.
>
> There are some suggestions about some kinds of cancer, but again, I
> think we know it is probably not very big, connective tissue disease,
> maybe there is a subgroup where there is an effect, but the overall
> literature is very reassuring.
>
> I think we don\'t know a lot about gel migration and extracapsular
> rupture, so there are clearly still some questions that we don\'t have
> all the answers to.
>
> DR. WHALEN: Dr. Manno.
>
> DR. MANNO: I pretty much agree with what has been said, however, I
> have some concern, and it may be my lack of understanding of the
> historical, the literature, that has been given here, but it is my
> impression, if you are going to use historical data in terms of
> controls, I got the feeling that we are dealing with non-Inamed
> specific implants, and we are comparing apples and oranges because the
> uniqueness of the Inamed device is the construction of the outer or
> the components of the shell, and that the gel is different than has
> been used before.
>
> So, we are looking at a whole new ballgame where that is concerned. I
> could stand to be corrected if I am wrong in my interpretation.
>
> DR. WHALEN: Could I just follow up and maybe I wasn\'t listening to
> you right, so I will apologize upfront, but in regards specifically to
> the literature end of it, do you feel that is adequate or not in
> answering the long-term question?
>
> DR. MANNO: It is not specific towards the product that we are
> discussing, we don\'t have enough information.
>
> DR. WHALEN: Thank you.
>
> Dr. Olding.
>
> DR. OLDING: Again, we are talking comfort level here, and I would ask
> those members of the panel who are not comfortable with the adequacy
> of the literature, what would, in their own minds, make them
> comfortable with the literature. I think it\'s an individual thing and
> it is difficult when you try to look at a lot of different articles
> that are not, as other panel members have said, are specific, but when
> there appears to be an overwhelming support or refuting of some
> particular general item to be discussed, then, I think one has to pay
> attention to that, therefore, I am, by and large, comfortable with the
> adequacy of the literature and also with the preclinical testing.
>
> DR. WHALEN: Ms. Brown.
>
> MS. BROWN: With respect to the literature, I agree with Dr. Olding,
> and with respect to the preclinical testing, the company, I believe
> has complied with the pre-agreed-upon standards that FDA had issued,
> so I believe the preclinical data, according to that standard, is
> adequate.
>
> DR. WHALEN: Ms. Gilbert.
>
> MS. GILBERT: I agree, but I disagree. I think there is a lot of
> information, and I think that this Question 2 outlines a lot of other
> areas that we don\'t have answers to, so I think we need more
> information.
>
> DR. WHALEN: In terms of the literature part or the preclinical part?
>
> MS. GILBERT: In terms of the literature part, yes.
>
> DR. WHALEN: Thank you.
>
> Dr. Miller.
>
> DR. MILLER: I think the literature is pretty convincing that there is
> no systemic health long-term problems, and the preclinical testing
> appears to be in accordance with what was required for them to do.
> Even though it does leave some question open in terms of whether the
> tests\--if the tests that are done don\'t mirror what happens in vivo,
> then, perhaps the tests that are done need to be modified, but that is
> not what has been required of the company.
>
> So, I think that both preclinical testing and the literature are
> consistent with safety.
>
> DR. WHALEN: I am sorry, repeat that.
>
> DR. MILLER: That they would be safe based on those criteria.
>
> DR. WHALEN: Dr. Witten wants to say something.
>
> DR. WITTEN: Yes, I just want to comment, maybe just because I am from
> FDA that it bothers me, the use of the terms \"required\" and
> \"agreement,\" since neither of them are really the case. We have
> guidance, and that means we provide our recommendations to sponsors,
> and we have discussions with them about what our best recommendations
> are about testing to address the issues in that application, but it is
> not requirements, and \"agreement\" has a specific meaning to us,
> where we have an agreement that if they do this, that will get them
> their approval.
>
> Maybe it\'s just a minor technical FDA point, but I just wanted to
> clarify our terminology that we have provided guidance.
>
> MS. BROWN: And I apologize for mischaracterizing that.
>
> DR. WHALEN: Dr. Anderson.
>
> DR. ANDERSON: I don\'t see that additional laboratory animal studies
> or studies of the material are going to answer our questions. The
> questions are clinical ones. These are already being put in women
> around the world, and so I think we need to stay in the clinical realm
> from here, and I think the literature is adequate, as well, so I am
> satisfied with both the literature and the preclinical testing.
>
> DR. WHALEN: Dr. Li.
>
> DR. LI: I believe the preclinical testing that was done was necessary,
> but not sufficient to predict the safety of this device given that we
> don\'t know the mechanism of the rupture. So, they are necessary in
> the fact that they followed the guidance documents, but as we now have
> discussed, the guidance document does not necessarily allow you to
> predict clinical behavior.
>
> So, I don\'t think that the preclinical testing actually addresses the
> safety issue of the product.
>
> DR. WHALEN: Dr. Dubler.
>
> PROF. DUBLER: The large epidemiological analyses seemed to me to
> answer some of the questions that have been posed over the last years
> about association with connective tissue disease. I am concerned that
> we don\'t know what the chilling effect of implants might be on a
> woman\'s decision to seek mammography, and there have been some issues
> raised about the ability to interpret the results, number one, and to
> engage in more focused interventions.
>
> So, with some discomfort, I would say yes, the literature is adequate.
> I have no ability to comment at all on the preclinical studies.
>
> DR. WHALEN: Thank you.
>
> Dr. Newburger.
>
> DR. NEWBURGER: I believe the sponsor has fulfilled answering Question
> 2 and that the preclinical and literature search, testing and search,
> are adequate.
>
> DR. WHALEN: Thank you.
>
> Dr. Witten, in regard to the second question which addresses the
> adequacy of the literature and preclinical testing in determining
> safety of the product with respect to long term and general health
> effects, there again is not a unanimous opinion of the panel.
>
> About half of the panel in regard to the preclinical testing, perhaps
> more the clinicians than others, reflective of the earlier discussion
> of the perhaps non-linkage of in vitro and in vivo data, remain
> somewhat hesitant to say that that would directly correlate to
> evidencing safety, but others are reassured by it.
>
> In the same light, there are many who feel that the literature does
> adequately address some of the long-term complications, if not most of
> the long-term complications, but others remain hesitant to commit to
> that being demonstrated.
>
> DR. WITTEN: Thank you.
>
> DR. WHALEN: Question No. 3.
>
> CDR ALLEN: Given these data shown in the bullets above and that the
> augmentation patient generally has breast implant surgery at a younger
> age which includes childbearing years compared to other indications,
> is there reasonable assurance that the device is safe for augmentation
> patients?
>
> DR. WHALEN: We begin with Dr. McGrath.
>
> DR. McGRATH: Since you gave us three bullet points, I am going to go
> ahead and break it into the three bullets points as I comment.
>
> The first one, is there reasonable assurance that it is safe with
> regard to the local complications as have been reported in the
> studies, today, I am going to say no to that, and I am basing that on
> the fact that there is a 20 percent reoperation over three years and
> that 70 percent of those reoperations are for complications, not for
> patient choice. Therefore, I think there are issues here about safety.
>
> No. 2. With regard to the asymptomatic/silent rupture information, do
> we have reasonable assurance that the device is safe based on the fact
> that approximately 30 percent of the patients, and so forth, have
> data, we have sort of addressed this already with the first question.
>
> I think the answer from many of us was that we don\'t know. We don\'t
> know enough information with that snapshot in time. We don\'t yet
> really understand the prevalence of asymptomatic rupture over time,
> the best way and most cost effective way to detect it, and the
> implications of this in young people.
>
> The third bullet point, is there reasonable assurance the device is
> safe based on published historical literature and the animal data to
> address the long-term effects, to that I would say yes, these studies
> are large. Someone mentioned that they are not necessarily Inamed\'s
> products, but I think that we have to remember that the incidence of
> these problems, these long-term problems are so small that it has to
> be pooled data from many different sources trying to give us the
> information, so I don\'t see that as a difficulty.
>
> The only thing that I would focus on particularly in the young group
> is the issue of mammography, and we certainly have information from
> the long-term studies although I don\'t think it was drawn out here
> today, that mammograms with extra views, as was mentioned before, can
> detect changes in the breast in younger patients, and we clearly have
> good historical evidence that breast cancer is detected at just as
> early a stage in patients with breast implants. So, I would yes to the
> third bullet point.
>
> DR. WHALEN: Dr. Leitch.
>
> DR. LEITCH: Well, I would just like to preface my remarks by saying,
> you know, we go on this Question 4, and I am not trying to answer
> Question 4, but my comments sort of reflect those two things.
>
> Certainly, patients who have implants reconstruction for breast cancer
> can be of childbearing age, so I think this distinction of
> childbearing age should kind of go under both groups.
>
> I think, as Dr. McGrath has said, we have talked over and over again
> about the local complication rate and reoperation issues that are
> related to local issues, so those issues are of concern, and certainly
> in an augmentation patient where she is not \"required\" to have the
> surgery to restore her to her original state as a reconstruction
> patient would have, her motivations to undertake augmentation in this
> circumstance where she has a risk of having reoperation, may not make
> it as valuable to her in that circumstance.
>
> So, I think we still have questions about these local issues. Again,
> on the third point of the literature about long-term health effects, I
> think I agree that we demonstrated that well, and just to reiterate my
> point, I would not separate out so much these patients with respect to
> younger age because we do have childbearing patients in the
> reconstruction age.
>
> DR. WHALEN: Dr. Chang.
>
> DR. CHANG: I see Question 3 as do the benefits to health far outweigh
> the probable risk, and with the caveat that the patient has adequate
> instructions for its use and is truly informed about the local
> complications, so two bullets, I say yes, and that is, first local
> complications, rates for this PMA are comparable to the historic local
> complication rates of the saline implant presented three years ago.
>
> We don\'t take even a 1.2 percent rupture rate lightly, but it is
> within the range of a previous study with saline implants, which have
> passed muster. Bullet 3, I have already stated I believe the published
> historical literature does address concerns about systemic disease.
>
> Bullet No. 2 is qualified because of lack of long-term data. So, that
> is the part that is inadequate.
>
> DR. WHALEN: Dr. Choti.
>
> DR. CHOTI: Well, obviously, this question is trying to tease apart the
> first two questions and asking the question specifically regarding
> augmentation. The question is can it couch by saying younger patients,
> childbearing, so that perhaps we don\'t get brought into the moral
> issues of the risk/benefit regarding the indications for augmentation
> versus reconstruction.
>
> So, in my mind really, regarding safety, they are equal whether it\'s
> reconstruction or augmentation, and I don\'t thing necessarily the
> younger age or childbearing should impact that much. As I mentioned,
> generally, I am concerned about the local complications in either
> group, I am concerned about asymptomatic and silent rupture in this
> group, as well as reconstruction, as well as historical and
> preclinical data.
>
> Perhaps the one difference is that younger patients, there are some
> issues regarding informed consent. Perhaps for this indication it is
> somewhat more difficult and since there are risks, and the patient
> really needs to understand carefully the risks, one needs to think
> about in the younger augmentation patient, the motives as it relates
> to are they really understanding the risks before they take this on.
>
> DR. WHALEN: Dr. Blumenstein.
>
> DR. BLUMENSTEIN: I find myself having to think about the efficacy here
> and the balance between efficacy and risk, and I don\'t have much
> question that this device is efficacious in a subset of the people in
> which it is applied to. It is the subset that has the risks in which
> it is not efficacious or at least not immediately so, and so balancing
> those two factors is where I am having difficulty coming up with a yes
> or no answer, I have to say no.
>
> DR. WHALEN: Dr. Conant.
>
> DR. CONANT: I feel very strongly that I shouldn\'t be separating out
> the indications for this procedure and treating them differently
> except for the duration and longevity of how long that implant may be
> in there, and therefore the younger patients come into question, and I
> am concerned again about the long-term follow-up for local
> complications, for silent ruptures, and that we just don\'t have that
> data particularly when maybe we will be looking at these\--we could be
> looking at these young women for many years.
>
> I am also concerned about the ability to truly provide informed
> consent without longer term follow-up, particularly to educate a young
> woman choosing implants when she may not have a clue about her
> lactational interests 10 years later, or the importance of breast
> cancer screening.
>
> So, I would say no.
>
> DR. WHALEN: Dr. Lawrence.
>
> DR. LAWRENCE: I think in this situation that it is not a matter of why
> it was done, the risks seem to be the same for women in the same age
> group, however, the risk/benefit ratio varies depending on your
> interpretation of benefit.
>
> I think that the literature is still lean on the long-term outcome of
> rupture and the long-term outcome of any offspring.
>
> DR. WHALEN: Dr. Lieberman.
>
> DR. LIEBERMAN: I have great concern about the local complications
> especially in a young woman who is going to have this implant for a
> long time and probably going to have to have, even if nothing goes
> wrong, repeated surgeries for replacement since they don\'t last
> forever.
>
> On the other hand, even with that concern, given that the bar has been
> set and the rates are similar to saline, and given issues of choice
> for women, I have to say that it is probably acceptable if we can get
> really good informed consent.
>
> On the second bullet, I think there is a lot we don\'t know about
> asymptomatic and silent rupture, and I am concerned about that, and I
> would have to say no.
>
> For the published literature, as I said, there are probably some
> sub-areas and some subgroups where we don\'t have information, we
> definitely need more information, but I think that is going to need to
> come from large epidemiologic studies, not from the sponsor.
>
> DR. WHALEN: Dr. Manno.
>
> DR. MANNO: I think effectiveness is a non-issue here. I think it is
> pretty broadly presented that I can recognize the effectiveness of the
> implant. I agree with Dr. Lieberman on the first question. I think we
> don\'t have enough information on the long-term aspects of the
> asymptomatic rupture.
>
> I think other than what I have already mentioned on the third point,
> what I have already mentioned on what I see as problems with the
> offspring in the reproduction when we lack that little bit of
> information.
>
> DR. WHALEN: Dr. Olding.
>
> DR. OLDING: My comments pertain to Question No. 3 and No. 4, because
> I, like some of the other panelists, cannot separate these two out for
> any reason.
>
> I believe that, to address the third bullet first because for me,
> it\'s the easiest, I believe that there has been good historical
> literature and animal data.
>
> The first bullet, local complication rates, I am concerned about the
> local complication rates, but in the long term we haven\'t shown that
> those local complication rates, other than in and of themselves, and
> the problems which they create by being present at that time, don\'t
> really cause any long-term problems.
>
> I would ask myself the same thing I asked of an earlier question of
> the other panelists, what would make me comfortable or happy to answer
> the second bullet, and I think that it answers itself. I think that I
> would be much more comfortable with some more screenings.
>
> DR. WHALEN: Ms. Brown.
>
> MS. BROWN: With respect to local complications, it seemed that the
> largest concern was reoperation. It is a concern we are already living
> with, with the saline-filled implants, so I think that if we are
> willing to accept the reoperation rate for saline implants, we should
> be willing to accept it for this.
>
> With respect to long-term data, actually tomorrow I would be
> interested in clarification from the company, not tonight, tomorrow,
> clarification on what their long-term data collection plan is for the
> 10 years, because I thought I saw almost two different plan
> presentations, and I am very curious as to what the real plan looks
> like, but I think that is very important.
>
> Then, with respect to the definition of what constitutes reasonable
> assurance of safety, built into that definition is when accompanied by
> adequate instructions for use and warnings against unsafe use, so I do
> think that for the augmentation patient, it is very important that
> they get good informed consent.
>
> DR. WHALEN: Ms. Gilbert.
>
> MS. GILBERT: I think this is a personal issue. I am not going to go
> down the three bullets. I am going to say is there reasonable
> assurance that the device is safe for augmentation patients, no. I
> don\'t think that women understand, nor should they accept the fact
> that when they get reconstruction or augmentation surgery, that they
> are going to be on a merry-go-round of surgery after surgery after
> surgery. I mean they need to be handed those facts upfront.
>
> I mean the high reoperation rate speaks for itself. That is all I can
> say.
>
> DR. WHALEN: Dr. Miller.
>
> DR. MILLER: I think the local complications are well characterized by
> the current studies. I think that if a patient is informed of what
> their risks are, that those risks don\'t necessarily outweigh the
> benefits in that person\'s mind. If the person will receive high
> benefit from the procedure and understands the risks and wants to
> proceed, then, I think that is a valid choice.
>
> So, I would say yes on No. 1, I would say yes on No. 3 because of all
> that we have talked about, and because of the yes on the No. 3, I
> would say yes on No. 2, because we don\'t know the implications of the
> rupture, so if long term there is no health effects seen with breast
> implants, in some ways, if they rupture, if they don\'t rupture, there
> is no long-term health effects seen. In terms of the safety, I am not
> sure that it bears on the safety.
>
> DR. WHALEN: Dr. Anderson.
>
> DR. ANDERSON: FDA has provided us with four studies that address
> nursing problems with women with implants. I think that in the
> childbearing years question, it is an informed consent issue, and
> should be stated explicitly in the consent form that women who have
> breast implants may have trouble breastfeeding in the future.
>
> DR. WHALEN: Dr. Li.
>
> DR. LI: Actually, I have nothing to add.
>
> DR. WHALEN: Dr. Dubler.
>
> PROF. DUBLER: It is wonderful to watch the focus and the cadence of a
> discussion change. When we sat on this panel, some of us, and we
> considered the saline implants, we were challenged by a member of the
> public to say how could you possibly approve them given the rupture
> rate, on the one hand, and the local complications and resurgical
> intervention rate.
>
> I was comfortable then, and I am not comfortable now. It seems to me
> that the one year data that we have don\'t provide us sufficient
> information on bullet 1 and 2, and the published epidemiological
> studies answer bullet 3, and I would give that answer both for No. 3
> and No. 4.
>
> DR. WHALEN: Dr. Newburger.
>
> DR. NEWBURGER: I agree with Dr. Dubler and without a prospective
> long-term study, I am uncomfortable about the impact of what will
> ultimately turn into probably extracapsular silicone, and without that
> information, and this isn\'t something that I saw in the literature
> search, without that information, I don\'t see how a patient can
> really give an informed consent.
>
> DR. WHALEN: Dr. Boulware.
>
> DR. BOULWARE: I have nothing further.
>
> DR. WHALEN: Before giving the synopsis to the answer to Question No. 3
> to Dr. Witten, I would like to ask the panel\'s indulgence and advice.
>
> With the possible exception of Dr. Anderson, it was my sense from all
> of your answers to Question No. 3, that that would be the answer to
> Question No. 4, that we are not discriminating again with the possible
> exception of Dr. Anderson, with some warnings about the breastfeeding
> population, that we are not discriminating on the question of safety
> between the augmentation and reconstruction population.
>
> I open the floor to anybody who disagrees with that.
>
> DR. CHANG: I would change one bullet. Rather than saying yes to two
> bullets on 3, it is yes to the third one because I am just too
> uncomfortable with the rate of 45.9 percent reoperation rate with
> breast reconstruction.
>
> So, I think that is an inordinately high number, so that is my
> question. That doesn\'t change my answer in terms of should a person
> needing reconstruction, should they have the option. I believe they
> should have the option, but I am sure that I am convinced that that is
> absolutely safe.
>
> DR. WHALEN: Dr. Li.
>
> DR. LI: My only addition to Question 4, I don\'t disagree with what
> you said, Dr. Whalen, the only issue I would want to bring up with
> Question 4 on reconstruction, is that we don\'t appear to understand
> why the rupture rate appears to be higher in the reconstruction, so we
> should not be surprised if, as the study goes on, that, in fact, the
> increase in rupture as more and more patients are studied, it actually
> doesn\'t go up linearly between the augmentation and the
> reconstruction group.
>
> DR. WHALEN: Dr. Leitch.
>
> DR. LEITCH: Well, the other thing, the point Dr. Miller made, which I
> think we do have to really take into account, on the reoperation rate
> on the reconstruction patients is that those reoperations can be part
> o the completion of the reconstruction, and I think it was noted
> somewhere in our booklet that it might have been coded that removal
> with replacement was actually taking out the expander and placing the
> permanent implant at that time, so again, that\'s the stepwise process
> which the patient would be informed about in advance.
>
> So, I think if you just look at it and say, oh, my gosh, look at all
> these operations, they have to be presented that it is a stepwise
> process in many circumstances, and that accounts, I think, for, you
> know, maybe 20 percent of these reoperations, so just to make that
> point.
>
> DR. WHALEN: Before going on to the next comment, let me admit my
> abysmal failure in my judgment because obviously, people look at these
> two questions differently, so I will answer No. 3 and then we will go
> on to No. 4.
>
> My interpretation had been that everybody was being consistent with
> the first two bullet points with Question No. 1, in that there was no
> agreement upon that, and everybody was being consistent with the third
> bullet point about historical data in that there was no agreement with
> that, and all of your analysis for this augmentation population fell
> into that same line of thought, so that there was a discordancy in the
> degree of safety for the augmentation population.
>
> For Question No. 3, Dr. Witten, does that satisfactorily answer your
> question?
>
> DR. WITTEN: Yes, thank you.
>
> DR. WHALEN: We have already had some comments about Question No. 4,
> and we are just going to go through everybody else who hasn\'t yet
> answered, and anybody who wants to add to what they have already said.
>
> We will just start over at that end with Dr. Miller and work our way
> down the table.
>
> DR. MILLER: I think the reconstruction patients are already a
> different kind of patient, and when you talk about safety, the way it
> is defined here, it is really a balance between the risks and the
> benefits.
>
> A reconstruction patient, many of them, those who elect to have
> reconstruction, the benefit is high, so you can tolerate perhaps a
> higher complication rate because the ratio is what we are talking
> about here.
>
> I do many operations that have a 45 or 50 percent complication rate,
> which sounds horrendous, but when you consider the alternative to
> those operations, it becomes very acceptable. We shouldn\'t accept a
> 45 percent incidence of problems with these operations, we should
> always strive to lower that, but that doesn\'t mean that they are not
> safe operations. We just have to improve them, but they are still safe
> because the balance of risks and benefits is acceptable.
>
> I think the reconstruction patients, we can tolerate a little higher
> risk of problems, and I want to reiterate the issue of the reoperation
> in these patients, it is difficult to group all those reoperations
> together as a problem, because many of these patients have revisions
> by their choice, some want to exchange an implant. You are more prone
> to capsular contracture, and it is very visible with the very thin
> tissues over the implant.
>
> I have been tempted all evening to speculate as to my theories as to
> why you may have larger rupture rates visible with these implants, but
> I will refrain from that, unless you want me to, but I won\'t prolong
> the evening.
>
> But I would say yes on all three of the bullet points, that it is a
> safe procedure by the criteria of balancing the risks and the
> benefits, and the complications are well known and can be explained to
> the patient.
>
> DR. WHALEN: It follows logically, but just for the simplicity and in
> view of the hour and my current mentation, if we just focus on is it
> safe for the reconstruction population, because that subsumes the
> other bullet points, and it is quite clear you are saying yes in that
> regard.
>
> DR. MILLER: Yes.
>
> DR. WHALEN: Dr. Anderson, anything further?
>
> DR. ANDERSON: Can you come back to me?
>
> DR. WHALEN: Okay. Dr. Li, anything further?
>
> DR. LI: No, nothing more.
>
> DR. WHALEN: Dr. Dubler.
>
> PROF. DUBLER: Nothing further.
>
> DR. WHALEN: Dr. Newburger.
>
> DR. NEWBURGER: No questions.
>
> DR. WHALEN: Dr. Boulware.
>
> DR. BOULWARE: Yes, yes, yes.
>
> DR. WHALEN: I will just take that to be stuttering since I just wanted
> one yes.
>
> \[Laughter.\]
>
> DR. WHALEN: Dr. McGrath.
>
> DR. McGRATH: The same as for augmentation, just one issue, and that is
> that since you don\'t need to do mammography in the reconstruction
> group, I think that that eliminates some concerns that one might have
> about visibility of the breast tissue and also the question of whether
> mammography can injure the implant.
>
> DR. WHALEN: Anything further, Dr. Leitch?
>
> DR. LEITCH: No.
>
> DR. WHALEN: Or Dr. Chang?
>
> DR. CHANG: No.
>
> DR. WHALEN: Dr. Choti.
>
> DR. CHOTI: Just one point about the two different groups. I personally
> think that they should be, you know, the approval is comparable, yes,
> the risk/benefit is different between the two different groups, but
> that should be the informed consent aspect, the patient should make
> that decision based on their risk/benefit, but for approval, I think
> the safety profile should be comparable for both the reconstruction
> and the augmentation group, and I still have concerns in this group,
> as well.
>
> DR. WHALEN: Dr. Blumenstein.
>
> DR. BLUMENSTEIN: No comment.
>
> DR. WHALEN: Dr. Conant.
>
> DR. CONANT: I have the same response to 4 as 3, but I just wanted to
> ask for some guidance. Through Question 3, I heard a couple of people
> comment, saying that, well, we think it\'s okay for saline implants,
> so because the complication rate is no more, then, it must be okay.
>
> I thought we weren\'t supposed to be considering that as a comparison,
> but looking at this independently. Can you provide some guidance?
>
> DR. WHALEN: I will defer to Dr. Witten.
>
> DR. WITTEN: Well, I think that really relates to that product is
> approved and what the clinical experience is with it, and if that
> helps people put it in perspective, then, I think that\'s your
> prerogative, if it helps you put it in perspective to give an answer,
> then, that is up to you.
>
> DR. CONANT: Thanks.
>
> DR. WHALEN: Dr. Lawrence.
>
> DR. LAWRENCE: No additional comment.
>
> DR. WHALEN: Dr. Lieberman.
>
> DR. LIEBERMAN: Nothing further.
>
> DR. WHALEN: Dr. Manno.
>
> DR. MANNO: Nothing further.
>
> DR. WHALEN: Dr. Olding.
>
> DR. OLDING: Nothing further.
>
> DR. WHALEN: Ms. Brown.
>
> MS. BROWN: I did have a comment just with respect to informed consent
> for this patient population. If there is any way to address the issue
> of reoperation as a function of the process as opposed to
> complications, I think that would be helpful, so if a patient could
> know that X percent were due to the fact that a tissue expander is
> being removed as opposed to there has been a problem with the implant,
> if hat makes a sense.
>
> So, I think that would be helpful in the informed consent decision.
>
> DR. WHALEN: Ms. Gilbert.
>
> MS. GILBERT: I know it\'s late, but I have concerns about this. Do I
> think it\'s safe? Yes, for a short period of time. Do I think patients
> are being educated? Absolutely not, no, I don\'t.
>
> I myself went through this. I didn\'t get all the facts. I didn\'t
> have all the information in front of me. I don\'t think that we are
> giving women the information they need to make an informed decision.
>
> It may be safe for the short period of time, but long term, no.
>
> DR. WHALEN: Dr. Witten, in regard to the question of there being
> reasonable assurance that the device is safe for reconstruction and
> revision patients, I would state that there is a larger element of
> support for safety among panel members than there was for augmentation
> patients, although there remain some significant elements of
> reservation based upon the same tenets of the data that have been
> previously discussed.
>
> DR. WITTEN: Thank you.
>
> DR. WHALEN: Question No. 5.
>
> CDR ALLEN: Based on the patient satisfaction and health status/quality
> of life data, has Inamed adequately demonstrated reasonable assurance
> of effectiveness of the implants for each of the augmentation,
> reconstruction, and revision indications?
>
> DR. WHALEN: Starting with Dr. Leitch.
>
> DR. LEITCH: Yes, I would agree that they have.
>
> DR. WHALEN: Dr. Chang.
>
> DR. CHANG: Yes.
>
> DR. CHOTI: Dr. Choti?
>
> DR. CHOTI: Yes, I do.
>
> DR. WHALEN: Dr. Blumenstein.
>
> DR. BLUMENSTEIN: Yes.
>
> DR. CONANT: Yes.
>
> DR. WHALEN: Dr. Lawrence.
>
> DR. LAWRENCE: Yes.
>
> DR. WHALEN: Dr. Lieberman.
>
> DR. LIEBERMAN: Yes.
>
> DR. WHALEN: Dr. Manno.
>
> DR. MANNO: Yes.
>
> DR. WHALEN: Dr. Olding.
>
> DR. OLDING: Yes.
>
> DR. WHALEN: Ms. Brown.
>
> MS. BROWN: Yes.
>
> DR. WHALEN: Ms. Gilbert.
>
> MS. GILBERT: Yes.
>
> DR. WHALEN: Dr. Miller.
>
> DR. MILLER: Yes.
>
> DR. WHALEN: Dr. Anderson.
>
> DR. ANDERSON: Yes.
>
> DR. WHALEN: Dr. Li.
>
> DR. LI: Yes.
>
> DR. WHALEN: Dr. Dubler.
>
> PROF. DUBLER: Yes.
>
> DR. WHALEN: Dr. Newburger.
>
> DR. NEWBURGER: Yes.
>
> DR. WHALEN: Dr. Boulware.
>
> DR. BOULWARE: Yes.
>
> DR. WHALEN: Dr. McGrath.
>
> DR. McGRATH: Yes. Dr. Boulware and I are laughing because we are
> looking at page 27 and page 63, which are the summary of the selected
> health status/quality of life measures, and for every parameter they
> are statistically different in the pre- to two-year post-implant
> score, but every single one, they are worse. Am I not mistaken, are
> these not the quality of life information that we are talking about
> here? So, I can\'t say that I think that it has been shown in the data
> that has been submitted by Inamed.
>
> On the other hand, I think there is historical literature out there
> that hasn\'t been discussed here or presented, but definitely supports
> that there is a positive benefit to patients from having these
> implants for both augmentation and reconstruction.
>
> DR. WHALEN: Dr. Witten, the overwhelming preponderance of the panel,
> which may be reflective of the fact that it\'s 25 minutes to midnight,
> is that efficacy has been established for this with one salient
> observation by a panel member that perhaps some of the data does not
> overwhelmingly demonstrate that, but some other elements of data do.
>
> DR. WITTEN: Thank you.
>
> DR. WHALEN: Next.
>
> CDR ALLEN: No. 6. Given the information in Question 1, please address
> the following with respect to the labeling for the device:
>
> First, provide your recommendations for the frequency and method of
> screening for asymptomatic rupture, given that prospective screening
> for asymptomatic rupture is not currently routinely performed..
>
> Second, provide your recommendations for the necessity of explantation
> of asymptomatic implant ruptures.
>
> DR. WHALEN: Dr. Chang.
>
> DR. CHANG: I am going to take my cue from Dr. Spear\'s comments during
> the sponsor\'s presentation, that monitoring every two to three years
> would be very reasonable.
>
> Is it necessary to explant a known rupture? In order to avoid
> potential for extracapsular migration and just the thought of the gel
> being outside of the capsule, and being slimed, I think yes.
>
> DR. WHALEN: Just fill us in with regard to the method of the
> screening. You have stated the frequency, but I don\'t believe you
> stated the method.
>
> DR. CHANG: Screening by follow-up by the physician.
>
> DR. WHALEN: Dr. Choti.
>
> DR. CHOTI: This is an extremely hard question to answer. I mean we
> have not been shown any data to provide you any guidelines regarding
> these recommendations. We have heard some testimony. Some said that
> patients are examined every six months, one comment made annual
> screening, who pays for it, and so forth.
>
> I think, although there is no evidence, I think it is reasonable to
> recommend annual screening, and as far as the recommendation for
> explant, again, we don\'t have any good evidence, but I am concerned
> that rupture is bad and probably even if it\'s asymptomatic, it should
> come out.
>
> DR. WHALEN: Dr. Blumenstein.
>
> DR. BLUMENSTEIN: This is an opportunity to do a randomized clinical
> trial embedded in this study where you would give the woman who has
> discovered to have an asymptomatic rupture the chance to be randomized
> to have it explanted or not.
>
> Explantation requires additional procedures, whereas, not explanting
> it avoids those procedures. It seems like it might be a reasonable
> choice and a reasonable randomization to do, assuming that there is
> going to be an increase in the number of asymptomatic ruptures
> discovered over the next few years as this study progresses, I think
> it is possible that there might even be enough sample size to do
> reasonable statistical testing.
>
> Even if it is not, it could be a descriptive study with comparable
> groups. I would also, at the same time, increase the surveillance
> frequency to six months. To me, as I inspect all of the things that
> bother me the most about what I have been talking about tonight, and
> answering these questions, and so forth, it\'s these asymptomatic
> ruptures that bother me the most and what the significance of them
> are.
>
> So, I feel like the opportunity to do an embedded randomized clinical
> trial of the consequences of explantation versus not, is going to give
> us an awful lot of data.
>
> DR. WHALEN: Dr. Conant?
>
> DR. CONANT: This really is a very tough one, being an imager. To
> Bullet No. 1, I am not sure we have the data from Inamed with this
> implant, or for these implants. However, if we look at other data that
> shows approximately 50 percent rupture at a ten-year point, in a
> perfect world, you would want these women to have some sort of
> screening which I think, at this point in time, I think is M.R. But I
> can\'t see requiring\--possibly recommending, that. It is very
> expensive. I am not sure that insurance will pay for that, so I have
> real problems with that and I don\'t have a good answer to it.
>
> In terms of recommendations, I disagree about a randomized trial
> because women are not going to let you randomize them with this and I
> am very sorry, but I cannot imagine that. However, anecdotally from my
> experience, I have seen quite a few women who I have, on many
> sequential years told them, your implants are ruptured. There is free
> silicone. And they do not want to do anything about. And it stays very
> static for a very long time.
>
> However, in those women, it is never going to get better and it is
> only going to get possibly worse. It may stay the same but it is
> complex. It is scarring to remove it, often and these women need to be
> told about their status.
>
> I think the right thing to do is recommend explantation. However, I
> think many women won\'t do it because if it looks good, it doesn\'t
> bother me, I am not going to do anything about it. But I think
> recommending is correct, explantation. Complex answer. Sorry.
>
> DR. WHALEN: Dr. Lawrence?
>
> DR. LAWRENCE: If we had an ideal way to screen that was relatively
> inexpensive we could really make a more intelligent response to this
> question although, with mammographers becoming more efficient,
> perhaps, in the near future, we will be able to do it with ultrasound
> or something a little less expensive than MRI.
>
> It certainly is appropriate to counsel any woman with an implant as to
> the risk of rupture and the understanding of that. If a randomized
> controlled study is going to be done, we don\'t want to spoil its
> possibility of getting through the research committees by saying we
> know that everybody needs to have it removed.
>
> DR. WHALEN: Dr. Lieberman
>
> DR. LIEBERMAN: I think this is the hardest question. I have to agree
> with Dr. Blumenstein. This is the place where I have been most
> bothered and the thing where we have the least adequate information.
> But, given that we know that eventually these \"wear out\" is the term
> that is being used, I think it would be prudent to recommend screening
> probably on a yearly basis at least until we have some more
> information and we can gauge things and a few of those recommendations
> could be changed.
>
> We also don\'t know the significance of an asymptomatic rupture
> although, on the face of it, it would seem logical to remove it and
> replace it. But it is very difficult with the limited information we
> have to make good recommendations.
>
> DR. WHALEN: Dr. Manno?
>
> DR. WITTEN: Excuse me. Before you go on. It is Dr. Witten. Could you
> just also state the method of assessment that you would recommend for
> this screening?
>
> DR. LIEBERMAN: Yes. I\'m sorry. I guess MRI is the standard right now
> and I think that is what we have to do since that is the only way to
> pick up asymptomatic ruptures.
>
> DR. WHALEN: Dr. Manno?
>
> DR. MANNO: I would think that MRI screen should be done at a minimum
> of one, three, five, and it definitely should be done at ten, because
> we don\'t know the real life of these things and when the trouble will
> be developing. That would be my response for that first question
> there. I think the\--I am having thought problems here. I don\'t know
> if I am having an autoimmune response with loss of memory, or it is
> the lateness of the hour. It probably is a little bit of both.
>
> At any rate, I think that, in terms of the necessity for expantation,
> I think that it is interesting to me that it was pointed out that
> there are patients that, in spite of knowing they have a rupture,
> won\'t have the implant removed in some instances.
>
> I think there has to be good information and education for the
> patient. There is not a whole lot you can do if they won\'t submit to
> having them removed. But they do have to have the information provided
> that some of the complications that they may develop won\'t be seen
> for a long period of time, a matter of years.
>
> So I am kind of ambivalent whether there should be just automatic
> removal of the implant. I guess I am just kind of in the middle of the
> road on that and it is a little out of my area.
>
> DR. WHALEN: Dr. Olding?
>
> DR. OLDING: It sounds like equipoise to me. I will answer the second
> part of this first because it is the easiest of the two and I can
> maybe respond to it, that is provide my recommendation for the
> necessity of explanation of the asymptomatic patient.
>
> We know that there are\--at least in the studies presented, there have
> been a relatively small number of extracapsular rupture and a lack of
> long-term side effects relating to that. So, therefore, for me, this
> one becomes simply a matter of choice, a woman\'s choice. We present
> the data as we know it. We give them the alternative whether or not
> to.
>
> So, to me, this is really toward the second part of the\--
>
> DR. WHALEN: Could I just ask you, Dr. Olding, is it safe to, then, say
> that, as regards to the specific question of its necessity, you are
> saying no.
>
> DR. OLDING: Correct. It is not an absolute necessity. The first one, I
> don\'t know if I can really answer that. I would have liked to have
> had some additional guidance from the sponsor\'s studies. I am not
> sure we have that, but what we do know is that the rate of rupture
> increases with time. So, whatever I would recommend, or we would
> recommend, or whomever would recommend, for the first time period, I
> would continue to recommend that same methodology.
>
> I stated before, I think it is very difficult for me, as a clinician,
> to determine whether or not a patient is ruptured from my examination.
> So I think it has to be more than simply my examination, but I don\'t
> know how much more.
>
> DR. WHALEN: Ms. Brown?
>
> MS. BROWN: I have no comment.
>
> DR. WHALEN: Ms. Gilbert?
>
> MS. GILBERT: I think annual exams by a woman\'s physician or plastic
> surgeon should definitely\--I mean, you should definitely maintain
> your relationship with that provider, especially if you are not seeing
> a specialist in this field that can tell you if there is something
> going on that you need to be alerted to.
>
> I also think MRI is something that a lot of women should be aware of
> as an option, three, five, seven years because we don\'t know the
> rupture time line there. The second question, explantation, yes,
> because I think that is something that should happen. I don\'t think
> that we have the confidence or the knowledge to make an informed
> decision on whether or not there are long-term side effects. We don\'t
> have that information.
>
> DR. WHALEN: Dr. Miller?
>
> DR. MILLER: I think a yearly or even every-other-year physical exam is
> good for follow up followed by an MRI if you suspect a rupture on
> physical exam. And if I confirm a ruptured implant in a patient, I
> generally remove it. I insist that we remove it, but that is probably
> an emotional thing because we don\'t know the implications of a
> ruptured implant.
>
> That is the problem. There is no long-term health problems associated
> with the implants that we can detect. And so, if the implant ruptures,
> it is not associated with a long-term problem. We are not sure what it
> is associated with, if anything, but it is more pleasing to get it
> out.
>
> DR. WHALEN: Dr. Anderson?
>
> DR. ANDERSON: I feel more strongly than that, that if we know of a
> rupture, we should recommend that it be removed because an
> asymptomatic rupture can progress to becoming a symptomatic rupture
> which is the problem that we are trying to get the handle on.
>
> So, if we remain neutral, well, you could take it or not take it out,
> well, who in the world would take it out. Why would I do that if the
> recommendation is not being made. In my car, it is recommended I
> change the oil every 5,000 miles. It is actually my decision about
> whether I act on that or not, but that is their recommendation.
>
> In terms of the screening, how do we screen for this, I think we have
> to defer to the plastic surgeons about how that screening is done. I
> think suggesting MRI is unrealistic. It is way too expensive a test
> for this. But it is prudent to suggest breast exams at one-to-two-year
> intervals because that is what we recommend for routine breast-cancer.
> So I think that we should stay with breast-examination recommendations
> that are the same as what we do for women without implants which is
> clinical exam every one to two years. It depends on which source.
>
> DR. WHALEN: Dr. Li?
>
> DR. LI: I will defer to my surgical colleagues.
>
> DR. WHALEN: Dr. Dubler?
>
> PROF. DUBLER: Really, I have to defer to my clinical colleagues to set
> what would be the appropriate medical approach and procedure. But
> having said that, it implicates immediately what we say to patients
> and it underscores the lack of our data at this point to permit us to
> craft that message. So I see a message that says if you sign up for
> augmentation or reconstruction, it really does mean a series of
> surgeries, not one, with the danger of rupture and if it is a silent
> rupture, we recommend strongly that it be removed.
>
> If you are really a prudent patient, you will get an MRI. The notion
> that the cost, in terms of public policy, would affect the clinical
> standard is a difficult one for me. So I think that No. 6 is difficult
> because it raises some hard clinical issues on which we don\'t have
> data, but it is additionally difficult because it demonstrates how
> very difficult it is going to be to craft a message that is specific
> enough and raises sufficient issues to alert a women to the dangers
> but not so overwhelming that people simply stop listening.
>
> DR. WHALEN: Dr. Newberger?
>
> DR. NEWBERGER: I think it becomes even more important now that the
> long-term data isn\'t available in terms of reactions to implant
> rupture, extracapsular types of rupture. In terms of monitoring these
> patients, I think they should be seen on a yearly basis by their
> physicians. MRIs are certainly the gold standard. But, if you have an
> MRI at one year, at three years, and so on and so forth, I calculate
> with the current rate of augmentation and reconstructive procedures
> that, four years from now, there will be over 1 million MRIs done just
> for the care and feeding of these breast implants. And that really
> does seem overwhelming to our healthcare system.
>
> So I would be content with just MRI indicated if the physician feels
> there is evidence for rupture.
>
> DR. WHALEN: Explantation?
>
> DR. NEWBERGER: Again, there isn\'t data to guide us. It does get worse
> over time if there is a rupture. I have certainly seen that, over
> time, silicone gel will go in some unusual locations. I would
> recommend that, as soon as an asymptomatic rupture is found, that the
> implant be removed.
>
> DR. WHALEN: Dr. Boulware?
>
> DR. BOULWARE: I am not very confident in the sensitivity of MRI in
> terms of picking up asymptomatic rupture. I am also not very confident
> that asymptomatic rupture really progresses on or that we have data
> that progresses on to be symptomatic. I would have no recommendation
> for screening for this other than the usual postoperative care and
> would not recommend explantation at this point for asymptomatic
> rupture.
>
> DR. WHALEN: Dr. McGrath?
>
> DR. McGRATH: Everybody else has said it better than I but, at this
> point, I cannot answer Part A. I think any recommendation for a
> diagnostic test has to be data driven and I just simply don\'t have
> longitudinal data about the incidence of rupture to tell me how
> significant a problem this is and how it should be monitored.
>
> In answer to the questions from some at this end of the table about
> leaving it up to the clinicians and physical examination, by
> definition, then, asymptomatic rupture would be one that neither you
> nor the patient would diagnose by physical exam and that these are
> ones that are being picked up now by a diagnostic test.
>
> I would be hard-pressed to advise a patient without any information to
> spend her cash for this and I certainly wouldn\'t want to have to be
> put in the position of going to the health-insurance industry or to
> Medicare to explain why they should pay for MRIs for patients when we
> don\'t have any data about the incidence of asymptomatic rupture and
> so forth over the long term.
>
> As far as B goes, I would say yes.
>
> DR. WHALEN: Dr. Leitch?
>
> DR. LEITCH: Well, this is the reason the MRI study needs to be
> completed is that we would be able, I think, to provide an answer for
> one with respect to that mode of screening for rupture. So I think it
> would be great for that portion of the study to be completed out to
> the ten-year point. Of course, this one- and three-year business, that
> is where the risk of rupture is lowest. But the more years out you
> get, the higher risk there is so the greater yield you would have from
> doing those studies.
>
> But, before that is finished, then I would suggest the annual exam by
> the physician. If the breast is preserved\--in other words, if it is
> an augmentation patient or a symmetry procedure in a patient who has
> breast cancer, that they should have mammography. If they have breast
> cancer, they should be having mammography annually.
>
> If they are without breast cancer but 40 years of age, they should
> have mammography annually. If the mammography gives a hint that there
> could be an implant problem, which sometimes there can be even without
> extracapsular extension, then that could prompt the clinician to
> recommend further screening interventions to assess that probability.
>
> Then, with respect to the issue of identified implant rupture that is
> asymptomatic, I generally would recommend removal of that implant if
> the patient\'s health status is otherwise good. I mean, you are
> talking about the person having surgery with its attendant risk as
> well, so, you know, you have to put that in the context of their
> general health conditions as to whether, again, that risk/benefit
> ratio is there.
>
> The primary reason would be to prevent the local complications of an
> extracapsular extension of that rupture and the difficulties it could
> pose for the patient in the future.
>
> DR. WHALEN: Dr. Witten, in regards to Question 6, with the first part
> being recommendations for frequency and method of screening for
> asymptomatic rupture, there was not a strong consensus of the panel. I
> would say that the majority favor simple physical examination and the
> majority, I had a head count of seven recommended that that be on an
> annual basis.
>
> However, that being said, there were one or two salient observations
> being made that it is certainly not at all established how sensitive
> physical examination alone would be in detecting asymptomatic rupture.
>
> As far as other methods being utilized, the most preponderant one
> discussed was that of MRI. Concerns were raised about its cost, some
> concern raised about its particular sensitivity in detecting this and
> further concern raised about the very significance of even detecting
> what that sort of finding might mean if, indeed, it is picked up.
>
> There is, therefore, perhaps, less consensus about this first arm of
> this question than any other question that we have thus far dealt with
> tonight.
>
> The second part was the recommendation for the necessity of
> explantation of asymptomatic ruptures and, by my count, I found seven
> panel members saying they should be removed, three saying they should
> not and three being rather on the fence about that. So the
> preponderance was that they should be removed but, again, there were
> some reasonable questions raised as to what the significance of such
> ruptures are and I think there were some very good issues raised about
> how you would convince somebody with an asymptomatic rupture to
> undertake the explantation to begin with.
>
> Does that answer your question?
>
> DR. WITTEN: Yes.
>
> DR. WHALEN: Even though we are at midnight, I would prefer to go on to
> Question 7 since we are in the question mode, since that is our final
> question. Commander Allen?
>
> CDR ALLEN: With regard to the proposed postapproval study plan, first
> please comment on the method of data collection, the mailed survey,
> from the six- to ten-year time points and, second, please describe any
> other specific endpoints which should be captured as part of the
> postapproval study.
>
> DR. WHALEN: Dr. Choti?
>
> DR. CHOTI: Well, I think that follow up longer than ten years should
> be recommended, perhaps by examination and/or whatever screening
> methods we recommend. As far as the specific endpoints, I mean, I
> think where guidelines really aren\'t based on sufficient data, it is
> still not clear with rupture rates exceeding 70 percent at 20 years,
> should there be a time in which implants should be recommended to
> removed regardless of rupture just because\--it is still unclear.
>
> But I think if the consensus is that they should stay until which time
> there is evidence of rupture, which it sounds like is probably
> reasonable based on the data, then I think guidelines should be
> removed if there is any sign of rupture and routine explant in that
> situation and routine evaluation, perhaps, with examination.
>
> DR. WHALEN: Dr. Blumenstein?
>
> DR. BLUMENSTEIN: I don\'t have much to add. I think that active follow
> up is going to be better with respect to compliance than a mailed
> follow up. I just wanted to say one more thing. It is a shame that,
> with all the device experience in Europe, that we don\'t already have
> the data that addresses these issues.
>
> DR. WHALEN: Dr. Conant?
>
> DR. CONANT: I also think the follow up needs to be extended longer
> than five years and I think direct follow up is important. I would
> like to see the completion of the MR study at least out to ten years.
> In terms of other specific endpoints, I would like to have the
> population of ruptured cases confirmed, ruptured cases better
> evaluated as to intra- and extracapsular and potential systemic
> problems.
>
> And then I would also like to know farther out the increase or the
> additional surgical procedures these women undergo to try to figure
> out what that curve is, whether it is exponential or linear or
> whatever.
>
> Thanks.
>
> DR. WHALEN: Dr. Lawrence.
>
> DR. LAWRENCE: I don\'t feel that a mail-in kind of questionnaire is
> adequate for the kind of information that we wish to have available
> for the full ten years. So I would vote for continuing the process as
> it is now and looking at endpoints such as rupture and need for
> additional surgery and, of course, for those women who bear children
> with an implant, that we have absolute follow up on those children.
>
> DR. WHALEN: Dr. Lieberman?
>
> DR. LIEBERMAN: I agree. I think that a full ten years needs to be done
> with in-person follow up and also to continue the MRI screening
> because asymptomatic rupture seems to be the place where all of us are
> having the most difficulty in terms of getting a handle on its
> significance.
>
> I think also following up the history of the reoperations, the
> long-term health effects in the women and, if possible, their children
> would be helpful.
>
> DR. WHALEN: Dr. Manno.
>
> DR. MANNO: I am not comfortable at all with the mailed-survey
> approach. I think it should be face-to-face with the physician
> approach accompanied by the MRIs until we get a better handle on the
> long-term stuff.
>
> In terms of other endpoints, I would suggest that, if this is approved
> that we would be trying to capture some information on these interim
> visits that will continue, that, in terms of any pregnancy since a
> previous visit and the outcome of the pregnancy in terms of live
> births, total number of children, any complications with the pregnancy
> or the delivery and any health or developmental problems of the child.
> I think this should be added to the questions asked of these people.
> This is just with the child-bearing age.
>
> Oh, one other thing that I forgot to bring up earlier that might be of
> value in there is ask if there are any chemical contraceptives used in
> these people in the child-bearing age.
>
> DR. WHALEN: Dr. Olding?
>
> DR. OLDING: Like the rest of the panel, I agree that you need to have
> more than a mailed survey and I think it should be examination by the
> treating physician through the ten-year period. I have nothing to add
> about B.
>
> DR. WHALEN: Ms. Brown?
>
> MS. BROWN: I think the ten-year period is appropriate. When I look at
> the list of complications that have been reported by the company to
> date, a lot of these\--actually, all of them appear to me to be
> complications that the patient could self-report. So I think that a
> survey or a phone questioning could be appropriate, maybe with a
> physician visit somewhere at the end of that ten-year period might be
> appropriate.
>
> DR. WHALEN: Ms. Gilbert.
>
> MS. GILBERT: Well, I think the ten-year period is something that I
> would like to stress but, also, when it comes to data collection, can
> we be creative about this? I think that the patients really need to
> take an active role and I don\'t think a mail-out survey really does
> that.
>
> I mean, what is the return rate? Why aren\'t there more women
> participating in this? What does it take and why aren\'t more
> companies investing in this? It really restores the confidence of the
> patient in regards to these devices. So I would definitely encourage a
> stronger approach when it comes to getting more women actively
> involved and understanding their role in research.
>
> Also, endpoints; just the ten-year. I really think that it is
> important that women\--that we learn more about this ten years.
>
> DR. WHALEN: Dr. Miller?
>
> DR. MILLER: I think I agree with the comments that were made about the
> need for ten-year data and for physical visits and physical
> examination. I would like to see the current stage just continued on
> through ten years with the patients that are entered already.
>
> I like the idea of the controlled trial regarding what to do with the
> asymptomatic ruptures. I think that might be something worth
> considering.
>
> DR. WHALEN: Dr. Anderson?
>
> DR. ANDERSON: Agree with need for ten-year follow up, agree with
> concern about mail data collection.
>
> DR. WHALEN: Dr. Li?
>
> DR. LI: I would like to see long-term follow up as well out to the
> ten-year period, but I would definitely like to be able to answer the
> questions we seem to be asking for a decade now, what is the rupture
> rate, silent or otherwise, and what are the clinical consequences of
> those rupture rates. I think it would be a shame to collect data from
> the ten years and not be able to answer those question.
>
> The other thing I would add about other specific endpoints is, despite
> my criticism of the retrieval programs that I provided earlier, I
> think, in the long run, the retrievals will probably be your best
> indication to the mechanisms of rupture. So, to continue to gather as
> many retrievals as you can, but I would probably take a more biased,
> more generalized approach, failure-approach, method to analyzing those
> retrievals.
>
> DR. WHALEN: Dr. Dubler?
>
> PROF. DUBLER: Yes. I agree with the last two comments. My problem is
> one of the framing of the question. Inamed provided a brief
> description of their postapproval study plan. In the best of all
> worlds, which this is not, we would have ten years worth of data to
> support the panel\'s comments and evaluation of the implant process
> and product.
>
> But we don\'t. And I just don\'t know if the one-year, basically
> one-year, data we have is sufficient to get us to an approval that
> gives us an postapproval study plan. It might be a preapproval study
> plan.
>
> DR. WITTEN: Yes. I was going to say that the question could be taken
> more generically to be read as what type of study, longer term, do you
> think would be appropriate for these implants. So you could just
> answer that question, then.
>
> PROF. DUBLER: I think that we need to collect data and we need to add
> very clear endpoints of the rupture rate, especially the silent
> rupture rate, and to learn more about the surgical revisions since I
> think we know something about them but not as much as we should.
>
> DR. WHALEN: Dr. Newberger?
>
> DR. NEWBERGER: I agree with my colleagues on the left side of the
> table here and I would like to ask for the possibility of another
> endpoint along with the retrieval of explanted breast prostheses which
> is is it possible to get samples of the tissue from the capsule, or
> even a small amount in a punch biopsy extracapsular, this might be
> helpful in analyzing the outcomes of some of these patients down the
> line. It shouldn\'t be technically very difficult at all.
>
> DR. WHALEN: Dr. Boulware.
>
> DR. BOULWARE: I am worried that if we do mail-in self-reported data,
> we will be facing this same problem five years from now with
> confounding data which we cannot interpret. So I don\'t think that is
> adequate. I would agree with Dr. Li and Dr. Newberger about the
> explanted retrieval data as well as, perhaps, the capsule biopsy at
> the time of explant.
>
> DR. WHALEN: Dr. McGrath?
>
> DR. McGRATH: I agree also about long-term follow up and, again, I am
> not quite clear as we are talking this, you are saying what other
> specific endpoints. Well, I am not quite clear what endpoints would be
> the endpoints that would be the ones that would be in the process to
> start with because there is bunch of others that you could think about
> adding beside the ones that Dr. Li and my colleagues on the left have
> suggested. Certainly health status, quality of life, needs to be
> looked at, again, since the only data we have is at two years and it
> is confusing, to say the least.
>
> A lot of other things could come out. For instance, before we had a
> discussion about fibromyalgia and how it was self-reported. I mean,
> there are certainly a lot of opportunities here if you are going to do
> this to get some of that into a different setting so that you could
> really look at some of these systemic symptoms more effectively.
>
> DR. WHALEN: Dr. Leitch?
>
> DR. LEITCH: I agree with all the panelists who suggested that the
> follow up should continue to the ten-year point with physician
> examination, which I would recommend on an annual basis. I think that
> six- to ten-year period actually offers the point in time of the
> greatest opportunity to identify problems which, to the patient, may
> be asymptomatic but, on questioning the patient or by examining the
> patient, it may be evident that she has a complication of the implant
> with respect to rupture.
>
> So, again, that is a high-yield time and I think that that does demand
> the physician participating and the follow up. And then the things
> that Dr. McGrath has mentioned for the follow up of the patients I
> think is important. I would continue the MRI follow up out to the ten
> years, at least in a cohort of the patients that are followed and,
> absolutely, those patients are identified to be ruptured should be
> evaluated for their follow up specifically with detailed follow up to
> find out what happens to them in additional surgical procedures that
> are done.
>
> I also, which I forgot to say earlier, don\'t think it would be crazy
> to do a randomized study of what to do with the asymptomatic rupture
> identified on MRI because, like I said, it is our gut feeling to get
> it out because you don\'t think it ought to be there and the potential
> local complications, which is more my concern.
>
> But, again, with the benefit of having surgery versus not, that could
> certainly be looked at in a randomized trial.
>
> DR. WHALEN: Dr. Chang?
>
> DR. CHANG: I have already expressed my concern based on data presented
> three years ago, that mail-in surveys are not very successful in
> getting a high compliance rate. I believe ten years is reasonable
> follow up especially to get the completion for the MRI data.
>
> DR. WHALEN: Dr. Witten, despite the lateness of the hour, there was a
> wonderfully harmonious thumbs-down to the mail survey. Certainly, the
> preponderance of opinion expressed by the panel members was that hard
> data should be collected for at least ten years and perhaps beyond
> that and the same would apply to the MRI study.
>
> The type of data should be collected face-to-face and endpoints that
> should be considered to be included within this include, certainly,
> the rupture rate, the explantation rate, what may happen to the
> capsular tissue itself and the extracapsular tissue, whether the
> ruptures are intra- or extracapsular, a defined set of systemic
> problems that should be rigorously surveyed for, whatever surgeries
> were employed and the effects upon both the pregnancy of any woman who
> has an implant and their children and whatever health of developmental
> problems the children might experience if they are born to a mother
> who had an implant place.
>
> Does that answer your questions, Dr. Witten?
>
> DR. WITTEN: Yes. Thank you.
>
> DR. WHALEN: If it does, I would like to point out that there is no
> resident member of the panel so we don\'t have to send anybody home at
> noontime tomorrow, fortunately. That being said, we can adjourn for a
> brief nap and be back here at 7:30.
>
> \[Whereupon, the proceedings were recessed, to be resumed at 7:30
> a.m., Wednesday, October 15, 2003.\]
>
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