> DEPARTMENT OF HEALTH AND HUMAN SERVICES
>
> FOOD AND DRUG ADMINISTRATION
>
> CENTER FOR DEVICES AND RADIOLOGICAL HEALTH
>
> **GENERAL AND PLASTIC SURGERY DEVICES PANEL**
>
> **OF THE MEDICAL DEVICES ADVISORY COMMITTEE**
>
> **OPEN SESSION**
>
> **60th Meeting**
>
> **This transcript has not been edited and FDA makes no representation
> regarding its accuracy**
>
> Tuesday, July 9, 2002
>
> 8:00 a.m.
>
> Gaithersburg Holiday Inn
>
> Two Montgomery Village Avenue
>
> Gaithersburg, Maryland
>
> PARTICIPANTS
>
> Thomas V. Whalen, M.D., Chairman
>
> David Krause, Ph.D., Executive Secretary
>
> VOTING MEMBERS:
>
> Phyllis Chang, M.D.
>
> Michael A. Choti, M.D.
>
> David L. DeMets , Ph.D.
>
> Robert L. McCauley, M.D.
>
> Michael J. Miller, M.D.
>
> TEMPORARY VOTING MEMBERS:
>
> Nancy A. Dubler, LLB
>
> Amy E. Newburger, M.D.
>
> CONSUMER REPRESENTATIVE:
>
> LeeLee Doyle, Ph.D.
>
> INDUSTRY REPRESENTATIVE:
>
> Debera M. Brown
>
> C O N T E N T S
>
> Conflict of Interest and Opening Remarks,
>
> David Krause, Ph.D. 5
>
> **Open Public Comment:**
>
> Ms. Tammy Griffiths 16
>
> Ms. Denise King 21
>
> Ms. Cheryl Valput 23
>
> Ms. Melanie Palmer 26
>
> Joseph Bubinak, M.D. 28
>
> Ms. Kim Hoffman 32
>
> Ms. Margaret Volpe, Y-ME 38
>
> Ms. Mary McDonough 42
>
> Ms. Cynthia A. Pearson, National Women\'s Health
>
> Network (read by Toniya Barron) 49
>
> V. Leroy Young, M.D., American Society of
>
> Plastic Surgeons 54
>
> Laurie Casas, M.D., American Society for
>
> Aesthetic Plastic Surgery 61
>
> Ms. Sheila Crigler, WIN Against Breast Cancer 70
>
> Diana Zuckerman, Ph.D., National Center for
>
> Policy Research for Women and Families 74
>
> Jae Hong Lee, M.D., MPH, National Center for
>
> Policy Research for Women and Families 81
>
> Ms. Susan Pope Helman 87
>
> Ms. Sheila Crigler (for Ms. Elizabeth Mullen
>
> WIN Against Breast Cancer 93
>
> Ms. Cherien Dabis (read by Ms. Mary McDonough) 95
>
> **Panel Update Regarding Post-Approval Conditions**
>
> **of Approval for Saline-Filled Breast Prosthesis:**
>
> **Mentor Corporation:**
>
> Background Information Maher Michael, M.D. 103
>
> Post-Approval Study, Mr. Cliff Kline 106
>
> Focus Group Study, Ms. Donna Crawford 115
>
> Retrieval Study Report, Post-Approval Fatigue
>
> Testing and Post-Approval Real-Time
>
> Shelf-Life Testing, Mr. Ronald Crouther 119
>
> Overall Summary, Maher Michael, M.D. 127
>
> **FDA Presentation:**
>
> Post-Approval Study, Sahar Dawisha, M.D. 165
>
> Focus, Retrieval, Fatigue Testing and Shelf-Life
>
> Studies, Ms. Samie Allen 175
>
> Panel Discussion 179
>
> C O N T E N T S (Continued)
>
> **Panel Update Regarding Post-Approval Conditions**
>
> **of Approval for Saline-Filled Breast Prosthesis (continued):**
>
> **Inamed Corporation:**
>
> Introduction, Ronald J. Ehmsen, Sc.D. 202
>
> Post-Approval Study , Audrey J. Weiss, Ph.D. 203
>
> Focus Group Study, Kim Croyle 220
>
> Retrieval, Fatigue and Shelf-Life Studies,
>
> Mr. Thomas Powell 222
>
> **FDA Presentation:**
>
> Post-Approval Study, Sahar Dawisha, M.D. 241
>
> Focus, Retrieval, Fatigue Testing and Shelf-Life
>
> Studies, Ms. Samie Allen 247
>
> Panel Discussion 253
>
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>
> **Call to Order, Conflict of Interest**
>
> **and Opening Remarks**
>
> DR. KRAUSE: If everybody would take a seat, I would like to start the
> meeting. I would like to say good morning to everybody. Thank you for
> coming. We will try to start the public testimony as close to 8:30 as
> possible for those people who looked at the schedule to see what time
> the public comment period would be. I don\'t want to rush things but I
> want to make sure everybody who wants to speak who is on our list gets
> a chance.
>
> We are ready to continue the 60th meeting of the General and Plastic
> Surgery Devices Panel. My name is David Krause. I am the executive
> secretary of the panel. I am also a biologist and a reviewer in the
> Plastic and Reconstructive Surgery Device Branch, in the Division of
> General, Restorative and Neurological Devices.
>
> I would like to remind everyone to please sign in on the attendance
> sheets which are just outside the door. You can also pick up an
> agenda, a panel meeting roster and information about today\'s meeting
> at the tables just outside the door. The information provided includes
> how to find out about future meeting dates through the advisory panel
> phone line, and also how to obtain meeting minutes or transcripts.
>
> Before turning the meeting over to Dr. Whalen, I would like to read
> today\'s conflict of interest statement. The following announcement
> addresses conflict of interest issues associated with this meeting,
> and is made a part of the record to preclude even the appearance of an
> impropriety.
>
> To determine if any conflict existed, the agency reviewed the
> submitted agenda and all financial interests reported by the committee
> participants. The conflict of interest statutes prohibit special
> government employees from participating in matters that could affect
> their or their employers\' financial interests. However, the agency
> has determined that participation of certain members and consultants,
> the need for whose services outweighs the potential conflict of
> interest involved, is in the best interest of the government.
>
> Therefore, a waiver has been granted for Dr. DeMets for his interests
> in a firm that could potentially be affected by the panel\'s
> recommendations. The waiver allowing him to participate fully in
> today\'s deliberations involves a contract to his employer and his
> consulting services with a competing technology firm. His employer
> receives funding between \$100,000.00 and \$300,000.00 per year on the
> contract that is unrelated to today\'s agenda. For his unrelated
> consulting service, he receives less than \$10,000.00 a year. Copies
> of this waiver may be obtained from the agency\'s Freedom of
> Information Office, Room 12A-15 of the Parklawn Building.
>
> We would like to note for the record that the agency took into
> consideration certain matters regarding Dr. DeMets and Dr. Miller. Dr.
> DeMets reported an interest with a firm at issue, but in a matter that
> is not related to today\'s agenda. Dr. Miller reported that his
> institution has a current related involvement with a firm at issue.
> The agency has determined that these individuals 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 participant should excuse him or herself from such
> involvement and the exclusion will be noted for the record.
>
> With respect to all other participants, we ask in the interest of
> fairness that all persons making statements or presentations disclose
> any current or previous financial involvement with any firm whose
> products they may wish to comment upon.
>
> I would now like to turn the meeting over to the Chairman, Dr. Whalen.
>
> DR. WHALEN: Thank you, Dr. Krause. Good morning. My name is Dr. Thomas
> Whalen. I am professor of surgery and pediatrics at Robert Wood
> Johnson Medical School in New Brunswick, New Jersey.
>
> Today our panel will be making a review and update of previously
> approved premarket applications which were approved in May of 2000.
> Although we are in our second day of business as a panel, I believe we
> have a considerably different audience than we did yesterday, so we
> will ask our panel members to reintroduce themselves to the audience,
> acknowledging that these are panel members who are giving of their
> time to help the FDA in these matters, and I would also ask the FDA
> staff at the table to introduce themselves as well.
>
> Each person is asked to introduce himself by name and state specialty
> and position title, starting on my left with Ms. Brown, please.
>
> MS. BROWN: I am Debera Brown. I am the vice president of regulatory
> affairs for Broncus Technologies. I am also the industry
> representative for this panel.
>
> DR. DOYLE: I am LeeLee Doyle. I am professor of obstetrics and
> gynecology and associate dean for continuing medical education and
> faculty development with the University of Arkansas for Medical
> Sciences, College of Medicine, and I am the consumer representative on
> the panel.
>
> DR. MCCAULEY: Robert McCauley, professor of surgery and pediatrics,
> University of Texas Medical Branch and chief of plastic surgery
> services for the Shriner\'s Burns Hospital in Galveston, Texas.
>
> DR. DUBLER: I am Nancy Dubler. I am an attorney and the director of
> the Division of Bioethics at Montefiore Medical Center, and a
> professor of epidemiology and social medicine at the Albert Einstein
> College of Medicine.
>
> DR. CHOTI: I am Michael Choti, associate professor of surgery and
> oncology, in the Division of Surgical Oncology at Johns Hopkins
> Hospital in Baltimore, Maryland.
>
> DR. NEWBURGER: I am Amy Newburger. I am a dermatologist in private
> practice, in New York. I am an attending physician at White Plains
> Hospital Medical Center. I teach at St. Luke\'s Roosevelt Medical
> consortium in New York.
>
> DR. DEMETS: I am David DeMets. I am professor and chair of the
> Department of Biostatistics and Medical Informatics at University of
> Wisconsin, in Madison. I am a statistician by degree and I have a long
> history and interest in clinical trials.
>
> DR. CHANG: I am Phyllis Chang, associate professor in the Division of
> Plastic Surgery, Department of Surgery, and Division of Hand and
> Microsurgery, Department of Orthopedic Surgery at the University of
> Iowa College of Medicine, in Iowa City.
>
> DR. MILLER: I am Michael Miller, associate professor of plastic
> surgery at University of Texas, MD Anderson Cancer Center.
>
> DR. WITTEN: Celia Witten, division director of the Division of
> General, Restorative and Neurological Devices at the FDA.
>
> DR. WHALEN: Thank you all. I would like to note for the record that
> the voting members present constitute a quorum, as required by 21 CFR
> Part 14. At this point, I would like to turn the meeting back to you,
> Dr. Krause, for a moment.
>
> DR. KRAUSE: Thank you, Dr. Whalen. Just for the record, I would like
> to say that Dr. Miller, Dr. Chang, Dr. DeMets, Dr. Choti and Dr.
> McCauley are voting members on the panel. Ms. Dubler and Dr. Newburger
> are temporary voting members on the panel for today\'s meeting.
>
> I would like to make some brief remarks before we get into the main
> body of today\'s panel discussion. Today is the last meeting for a
> number of our distinguished panelists. It is the last meeting for Dr.
> Whalen, our Chairman, and for Dr. DeMets and Dr. Chang who are voting
> members. I would also like to acknowledge that Dr. Joe Boykin\'s term
> has also ended. He was unable to attend today. These panelists have
> served this panel with distinction for the past four years and I would
> like to thank them for their service. I would like to ask Dr. Witten
> to please make a few remarks at this time.
>
> DR. WITTEN: Thank you. We are very sorry to be saying goodbye to our
> panel members who are with us for the last time today. We rely on our
> panel members for their expertise in helping us make our regulatory
> decisions. Panel members give their time to us to serve FDA and, in
> doing so, serve public health in helping us make good regulatory
> decisions. I am particularly sorry about saying goodbye to the three
> people at the table today.
>
> I have a letter, singed by Linda Sudan, the senior associate
> commissioner for communications and constituent relations, which I
> will read, the same letter to all the panel letters who are leaving:
>
> Dear Dr. Whalen, I would like to express my deepest appreciation for
> your efforts and guidance during your term as a member and chair of
> the General and Plastic Surgery Devices Panel of the Medical Devices
> Advisory Committee.
>
> The success of this committee\'s work reinforces our conviction that
> responsible regulation of consumer products depends greatly on the
> experience, knowledge and varied background and viewpoints that are
> represent on this committee. In recognition of your distinguished
> service to the Food and Drug Administration, I am pleased to present
> you with this plaque, which is not enclosed but will be coming
> separately.
>
> I have the same letter for Dr. Whalen, Dr. Chang and Dr. DeMets and
> also for Dr. Miller. We will be hoping to see you again as consultants
> on some projects in the future.
>
> DR. KRAUSE: Thank you, Dr. Witten. I would like to now turn the
> meeting back over to Dr. Whalen.
>
> **Open Public Comment**
>
> DR. WHALEN: Thank you. We will now proceed with the open public
> comment session of the meeting. I would like to remind everyone who
> wishes to address the panel to please speak clearly into the
> microphone as the transcriptionist is dependent on this means to
> provide an accurate record of this meeting. In addition, if anyone has
> printed copies of their remarks, if they could hand them over to the
> table on my left, to the transcriptionist, that would be deeply
> appreciated.
>
> At this time, Dr. Krause has some additional instructions for those
> who will be testifying before the panel. Dr. Krause?
>
> DR. KRAUSE: Thank you, Dr. Whalen. I have some instructions for those
> of you who will be testifying to the panel this morning. We are
> requesting that all persons making statements during the open public
> hearing of the meeting disclose whether they have financial interests
> in any medical device company, or if their trip to this meeting has
> been paid for by someone else.
>
> Before making your presentation to the panel, in addition to stating
> your name and affiliation, please address the following questions. I
> will read the questions into the record once so that we don\'t have to
> do it when every speaker speaks. The questions are as follows:
>
> Question one, has your travel and/or accommodations been paid for or
> will they be reimbursed by someone else? If so, please state who.
>
> Question number two, please indicate whether you have financial ties,
> including grants or other compensation, with industry or health
> professional societies.
>
> Question number three, please indicate whether you are a party to or a
> witness in a pending lawsuit related to breast implants.
>
> Question four, do you derive a portion of your income from surgical
> procedures using saline-filled implants or from treating patients with
> complaints that they believe are related to saline-filled implants?
>
> I would like to have the attention of all the individuals who have
> registered to speak to the panel today. You have all been put in the
> proper order by Anne Marie. Anne Marie will direct you to the podium
> or, hopefully, she has given you some instructions. At this point, we
> are going to limit everyone to five minutes. At the end of each
> presentation, please stay at the podium in order to give the panelists
> a chance to ask you any questions, if they have any questions.
>
> I would now like to return the meeting to Dr. Whalen.
>
> DR. WHALEN: Thank you, Dr. Krause. We are required by law to allot one
> hour for public testimony. Today, because of the nature of the topic
> that we are dealing with, we have decided to allot two full hours. I
> realize, by the nature of the topic that we are dealing with and from
> the experience that we had as a committee two years ago in dealing
> with the PMAs on this, that there are some very deeply held
> convictions and sentiments about this topic. So, I will apologize in
> advance if I cut you off at the five-minute limit, acknowledging the
> depth of your conviction about what you are speaking about. I am not
> trying to be rude, but simply trying to accommodate everyone who
> wishes to speak on this topic today because of the number of people
> who have come forward wishing to speak.
>
> Also, I have been given an order of speakers that I will follow. I
> understand that there may be some mild confusion about who was to
> follow whom, but please bear with me on this. At the end of going
> through everyone that I have had identified to me being called by
> name, I will have an open announcement for anyone else wishing to
> speak as long as we still have more of that two-hour time period for
> people to address the panel.
>
> Therefore, the first person that I have identified is Ms. Arlene
> Nicole Cummings, from Implantinfo.com. Is Ms. Cummings available?
>
> \[No response\]
>
> Very well. The second one is Ms. Tammy Griffiths, representing
> herself.
>
> MS. GRIFFITHS: Good morning. I would like to thank the committee for
> allowing me to speak today. I come here today of my own accord\--
>
> DR. KRAUSE: Could you excuse me a minute, you weren\'t here when I
> read the questions. There are four questions you need to address
> before you start. Let me read them again: Have your travel or
> accommodations been paid for, or will they be reimbursed by someone
> else? If so, please state who.
>
> Second question, please indicate whether you have financial ties,
> including grants or other compensation, with industry or health
> professional societies.
>
> Number three, please indicate whether you are a party to or witness in
> a pending lawsuit related to breast implants.
>
> Question four, do you derive a portion of your income from surgical
> products using saline-filled implants or from treating patients with
> complaints that they believe are related to saline-filled implants?
>
> If you could just answer those questions before you start. That goes
> for everybody. Thank you.
>
> MS. GRIFFITHS: Sorry about that. No to all of the above questions.
>
> I come here today of my own accord in support of the continued use of
> saline breast implants. My name is Tammy, and I am 38 years old and
> the mother of four children, ranging in ages 5 to 13 years old. I have
> been married for 15 years, and my husband and I own and operate a
> heating and air conditioning company in Texas.
>
> I received a breast augmentation in January of 1999. Breast feeding
> four children had taken a toll on me physically, and the availability
> of breast implants gave me an option. To me, this was, indeed, a gift
> both physically and emotionally that I have never regretted.
>
> Prior to my children, I was very content with my breast size which was
> proportionate to my small frame. However, I was through with my
> childbearing years, and at the age of 34, I was very unhappy with the
> resulting shape of my breasts. Nursing four babies had taken quite a
> toll on my physique. With each child I would swell from my normal 34B
> cup to a 36D cup. Once each child weaned, I would return to the 34B
> cup but each time with less lift texture than I had before.
>
> After my fourth child was through nursing, my breasts were once again
> a 34B only they appeared depleted, flat and shapeless, and they no
> longer felt firm. It was almost as if I had nothing at all. I began
> working at the gym on a regular basis especially concentrating on my
> pectoral muscles, trying to build them back up, but to no avail. Then
> I tried a pair of silicone bran inserts to wear underneath my clothing
> just so that it would appear that I had breasts. However, when I
> looked in the mirror and it was just me, all by myself, I remained
> unsatisfied with my look and began to explore other options. The
> mirror did not lie.
>
> My husband Randy and I began to consider breast augmentation as an
> option. He was, and still is, 100 percent supportive. We both started
> reading everything we could find on the subject. We read medical
> reports; we read opinions both for and against the procedure. After
> research, we considered all the pros, cons, risks, rewards, side
> effects, both physical and emotional. As with any elective surgery, we
> desired to make an informed decision and so we did.
>
> After much discussion, Randy told me the final decision was mine to
> make. He was happy either way and was just satisfied that the medical
> procedure was a safe option. He continued to support me totally. I
> made the decision to have surgery and have never regretted it. I
> located a doctor in my area and again asked many questions.
>
> Once I was satisfied with the doctor, we set a date and the surgery
> was completed without incident. I now have Mentor saline implants. I
> am slightly larger than I was prior to having children but, most
> importantly, I feel better about myself now than I did prior to
> surgery.
>
> I can tell you that this is one of the best decisions or gifts, if you
> will, that I could have given myself. I am now three and a half years
> postop and very happy with my results. I have found myself feeling
> even more confident as a woman when I am in a business suit, a
> swimsuit or just attending a PTA meeting dressed in casual,
> conservative attire. I truly believe I am a wife and a mother who is
> not only well adjusted in her life, but a wife and mother who is also
> self-confident in her physical appearance wherever I happen to be.
>
> In closing, I would like to say that I feel it is most important that
> breast augmentation with saline implants continue to be an option for
> all women, whether they are cancer survivors, whether they need some
> other type of reconstruction, or if they just want something
> different. Given good information and good medical care, saline
> implants are not only a viable solution for a variety of circumstances
> but they are safe as well, in my opinion. Thank you.
>
> DR. WHALEN: Thank you, Ms. Griffiths. Are there members of the panel
> who have any questions?
>
> \[No response\]
>
> Thank you very much. Before the next speaker is called for, just to
> remind people\--I certainly wouldn\'t remember all those four
> questions, so if anyone gets up to the podium and needs a prompt for
> the four questions, just indicate that to me and I will be happy to
> give you the topics of each of the areas that you need to start off
> with. Also, to answer those questions obviously isn\'t part of your
> five minutes. The next identified speaker is Ms. Denise King.
>
> MS. KING: In answer to all of your questions, the answer is no. Thank
> you for the privilege of allowing me to speak today. My name is
> Denise. I am 43 years old and have been married for 22 years. My
> husband and I have 6 children, ranging in ages from 17 to 7 years.
>
> After nursing all of my children, some for as long as 18 months, and
> losing the large amount of weight that I had gained due to six
> pregnancies, my breasts were left deflated, hollow looking. They
> looked as though they belonged to a woman twice my age. It was both
> physically and emotionally uncomfortable to have the upper part of my
> body in this condition because I have worked so hard to maintain my
> weight.
>
> After a lot of thought, research and extensive consultation with a
> board-certified plastic surgeon, after several discussions with other
> women that had had breast augmentation, asking both what they did and
> did not like about implants, on August 7 of 2001, and with the full
> support of my husband, I underwent a five-hour surgery to reconstruct
> my breast with an anchor style lift and under the muscle placement of
> saline implants. I received nothing less than excellent care from my
> physician both before, during and after my surgery.
>
> I have followed my doctor\'s instructions to the letter. I see him
> every 12 weeks so that any possible problems may be detected quickly.
> In the past 11 months I have been asked several times if I have ever
> regretted having the surgery. My answer is that there are no regrets
> because this was something that I did for my self-esteem.
>
> In closing, I would like to say that I believe that every woman should
> have the right to decide for herself whether she wants to pursue
> changing her shape through breast augmentation. It is also my belief
> that women need to have available to them as much information about
> implants and the surgical procedure as possible, enabling them to make
> a well-informed decision. Thank you again for your time.
>
> DR. WHALEN: Thank you, Ms. King. Any questions? \[No response\]
>
> Thank you very much. Next is Ms. Cheryl Valput.
>
> MS. VALPUT: No to all the four questions. Good morning. I would also
> like to thank the committee today for allowing me to speak. My name is
> Cheryl Valput. I am 45 years of age, reside in Ohio with my husband of
> 22 years and two daughters, ages 19 and 16. I am a full-time mom and
> business owner of a real estate company with my husband.
>
> I had breast augmentation done three years ago, in Cleveland, Ohio by
> Dr. Richard Dowden. This was one of the best decisions that I have
> made in my life. I am not a model, a dancer or a movie star but I felt
> that this was something I needed to do for me. I came to this decision
> for myself because I had to balance a difference in my breast size. I
> felt uneven every time I looked in the mirror. I was tired of stuffing
> one side of a bra, making sure I looked normal in a bathing suit. My
> self-confidence was low and I knew that I had a choice in the matter
> to change my appearance.
>
> I did research for over six months and read everything I could about
> breast implants, the good and the bad. I finally decided that I was
> either going to proceed with the surgery or put it out of my mind for
> good. I deserved to look my best and called Dr. Dowden. I have saline
> anatomical McGhan\'s shaped implants under the muscle. I went from an
> A cup to a C cup and finally they were both the same size. Looking in
> the mirror wasn\'t so bad after all.
>
> After surgery I could wear the clothing I desired and my
> self-confidence has been at its best. When you feel so good on the
> inside, it is hard not to feel beautiful on the outside. This is a
> very personal decision I made, along with my husband\'s support every
> step of the way.
>
> For me, to stand and speak in front of the committee today took some
> thought. I don\'t talk about this with everyone. My own parents and
> sisters haven\'t been told about my surgery, but I feel very strongly
> about having the choice of getting breast implants. It is not because
> I am trying to hide anything, but it is a decision that had to be made
> for myself. Taking that choice away from women could not, and would
> not be right. We color our hair; fix our teeth; choose the car we want
> to drive; and change our eye color. We have the right to change our
> breast size and shape if we choose to.
>
> I haven\'t had any complications and I am fully aware of the risk of
> implants. The decision of this must rest on the balance between how
> strongly you want the benefits versus how worried you are about the
> risk. Life is a risk, but I would rather go through life looking and
> feeling this way than without that. Thank you.
>
> DR. WHALEN: Thank you. Again, no questions?
>
> \[No response\]
>
> Thank you very much. Next is Ms. Melanie Palmer.
>
> MS. PALMER: The answer to all your questions is no. Good morning. My
> name is Melanie Palmer. I am 46 years old, from Ohio. I have a
> husband, Tom, and two children ages 15 and 20. Thank you for allowing
> me to speak to day on behalf of women who are seeking the possibility
> of breast augmentation.
>
> Breast augmentation is not only a medical decision but a personal one.
> The perception we have of ourselves defines who we are and how we
> introduce ourselves to the world. Breast augmentation can help
> individuals who feel the need to project a better outward appearance
> and results in increased self-esteem and personal satisfaction.
>
> As with any surgery, there are always risks as there are with breast
> augmentation. When deciding on breast augmentation or any other
> surgery, you need to weigh the benefits and risks as well as
> expectations. You want to make sure you are making this decision for
> yourself and not for anyone else. You must realize something foreign
> is within your breast and that over time complications could happen,
> as with any surgery.
>
> When I approached my husband about breast augmentation he was totally
> supportive of my decision, knowing I had thoroughly researched the
> procedure and having full knowledge of what the pros and cons of the
> surgery could entail. I consulted with two certified plastic surgeons,
> both of whom were equally knowledgeable in their professions, making
> me feel quite secure in my decision.
>
> After all of my research, I was made aware of the fact that my
> implants could rupture and may not last forever. At informational web
> sites, such as FDA.gov and Implantinfo.com, by Nicole, I learned that
> I was at risk for capsular contracture, rippling, infection and other
> complications. Despite these risks, I decided the benefits outweighed
> the disadvantages. This was a personal choice made by me and my
> husband, not by society governing our decision. Once all the options
> and any results were researched it was ultimately my decision.
>
> I still feel the decision of breast augmentation was the right choice
> for me, even though it has only been one year and ten months ago. I
> have no regrets and when asked would I do it again, my answer is a
> definite yes. Has it made me feel better about myself? Yes, in ways
> only a woman can feel from the inside out. Thank you.
>
> DR. WHALEN: Thank you. Are there any questions?
>
> \[No response\]
>
> Thank you, ma\'am. The next speaker, and I apologize if I mispronounce
> your name, is Dr. Joseph Bubinak.
>
> DR. BUBINAK: Thank you, Mr. Chairman and all members of the advisory
> panel. I answer no to all four questions. I am a board-certified
> hematologist and medical oncologist. My undergraduate training led to
> degrees in mechanical engineering and science. I retired from active
> practice two years ago.
>
> One year ago, a former patient with a history of ruptured breast
> implant and a low platelet count called and said she was told that she
> was, quote, full of platinum, unquote. Excessive platinum was found in
> skin, subcutaneous tissue, blood, urine and subsequently bone marrow.
> This interested me because I have treated patients with platinum-based
> chemotherapy since 1976. A low platelet count is a frequent side
> effect. The first chemotherapy agent was cisplatin, which is also
> mutagenic, carcinogenic, leukemogenic and teratogenic. Platinum has
> been found in the milk of patients treated with platinum compounds.
>
> There is little information in the medical literature regarding an
> association of platinum with breast implants. Unfortunately, not
> everyone has a good result. Information obtained from many sources,
> including interviews with patients, physicians and researchers, reveal
> that some implant patients develop a variety of systemic complaints
> including malaise, hair loss, peripheral neuropathy which is sometimes
> disabling, loss of short-term memory, rash and other allergic
> manifestations, respiratory systems, constipation and anorexia, just
> to name a few. In short, these are the same side effects people
> treated with cisplatin cytotoxic chemotherapy experience. Increased
> intensity of systemic complaints commonly follow gross rupture of the
> implant.
>
> I was astounded to learn that the catalyst used to manufacture the
> silicone for silicone gel and silicone elastomer for both gel-filled
> and saline-filled implants was platinum chloride, a highly reactive
> molecule and precursor to the chemotherapy agent cisplatin. The
> chemistry of the polymerization process says that the platinum in
> ideal proportions is reduced to its inactive elemental form. This,
> however, does not correlate with the amount of platinum found in
> tissues both proximate and distant from the implant site.
>
> Two independent researchers now have found platinum in excessive
> concentration in tissues. Capsule formation around the implant, a
> frequent complicating event, tells the world that this device is not
> inert. Even without considering the seepage of low molecular weight
> silicones, the migration of reactive platinum alone can explain
> capsule formation.
>
> One package insert states that the literature suggests that radiation
> therapy may increase the likelihood of capsular contracture, necrosis
> and extrusion. I have witnessed this first hand. In this regard, you
> should understand that platinum-based chemotherapy is commonly used
> explicitly to sensitize the target tissue to the effects of radiation
> therapy.
>
> In conclusion, systemic systems do matter and must be listed as
> potential side effects in the package insert when patients are
> expected to give informed consent. Likewise, reports of symptomatic
> improvement in patients following explantation must also be included.
> Despite almost 40 years of clinical experience, there is not one good,
> solid, prospective epidemiologic study available. The largest study
> that I saw was a retrospective study, just last year, and that study
> showed increased risk for respiratory and brain cancers, and a
> non-significant increased risk for leukemia of various types.
>
> Milk from implanted mothers needs to be tested for bound and unbound
> platinum. Reliable, generally accepted methodology for determining
> free and bound levels of platinum in any tissue must be developed with
> all speed. Analysis for platinum DNA must be made available if other
> critical questions are to be answered. Long-term [ex vivo]{.underline}
> testing of implants, subjected to realistic stresses while immersed in
> physiologic biologically active media at 37 degrees, are needed.
>
> Last, from a pure engineering perspective, considering the failure and
> complication rates, I wonder what reasoning could have led to the
> approval of these devices. Reasonable assurance of safety and
> effectiveness\--no one would argue against the beneficial
> psychological effects a positive body image will give. Safety means
> unhurt, secure from any harm.
>
> I urge this panel to approve only products that are truly safe and
> effective for all who desire them. Thank you.
>
> DR. WHALEN: Thank you, doctor. Any questions??
>
> \[No response\]
>
> Thank you. Next, Ms. Kim Hoffman.
>
> MS. HOFFMAN: My name is Kim Hoffman. I am a party to litigation, and
> my answer is no to the rest of the questions.
>
> Ladies and gentlemen of the panel, I commend you for your due
> diligence in participating in this meeting and ensuring that your
> concerns and recommendations regarding the approval of saline breast
> implants are being handled appropriately. I hope my testimony today
> will outline the importance of your continued diligence and careful
> scrutiny of information that is provided to you, and perhaps you will
> consider that important information has been withheld from you. I am
> happy to provide you with supporting documents, including my testimony
> before the United States Congress last November on this issue.
>
> I am here today to get several issues on record and to make the panel
> aware of information which may affect your opinion of the saline
> implants that were approved two years ago. I am deeply concerned that
> a lot of essential information was withheld from the panel in 2000,
> and I question the accuracy of the data you did receive.
>
> For example, Dr. Bobby Purkait, Mentor\'s director of research,
> testified to the panel about issues involving betadine use with
> implants. If you review his testimony and compare it to information in
> the 1997 FDA 483 inspection report, you will find he misrepresented
> the facts to you.
>
> Furthermore, at the time this panel reviewed Mentor\'s PMA in March
> 2000, Mentor was under an open criminal investigation for allegations
> of serious irregularities in breast implant studies and other issues
> involving the integrity of Mentor and their products. Did the FDA make
> this panel aware of the investigation and the issues involved in the
> investigation? The Chairman of the House Commerce Committee felt this
> important enough to write a letter to the Commissioner of FDA asking
> why the FDA would even proceed to panel under such circumstances.
>
> The story broke in [USA Today]{.underline} in March, 2000. Mentor\'s
> lead counsel made a public statement denying the issue under
> investigation. The false statement made by Mentor\'s representative
> caused extreme fluctuations in stock prices.
>
> Given that Mentor lied to the public about the criminal investigation,
> and the investigation involves allegations of serious irregularities
> in breast implant studies, should this advisory panel trust the
> integrity of the data supplied from Mentor? Why should the FDA trust
> the integrity of the data? Especially since the data that was
> presented was problematic to begin with and because two FDA employees
> with knowledge of the issues involved in the criminal investigation
> recommended the application integrity policy.
>
> Numerous informants have reported product defects and coverups by the
> company resulting in a criminal investigation that was opened nearly
> four years ago and remains open today. All of these issues should have
> been resolved and the criminal investigation concluded before this
> panel was asked to review the PMA data from this company in 2000.
> Since that didn\'t happen, I wanted to make sure you were notified
> about this today.
>
> Many of the allegations that were raised in the criminal investigation
> have implications for the safety and efficacy of breast implants. For
> example, fraudulent manufacturing records subvert the ability of the
> FDA to review certain safety issues like platinum or polyurethane
> contamination, and fraudulent study data subverts the ability to
> review efficacy.
>
> I would like to briefly address the issue of informed consent.
> Unfortunately, patients have not been made aware of the numerous
> problems and violations of good manufacturing practices found during
> FDA inspections at Mentor, in addition to the violations alleged by
> industry insiders. In fact, FDA has been denying the public\'s
> requests for these reports when requested under the Freedom of
> Information Act. I hope the FDA has at least provided these inspection
> reports to this panel, and that in the future this panel will ask to
> review all FDA 483\'s and EIR\'s for a company as part of the PMA
> review process. It is my understanding that Mentor has had yet another
> bad inspection report since the approval of saline breast implants.
> Again, I hope you will ask the FDA for this information.
>
> I would like to end by reading some quotes for a deposition of
> Mentor\'s former vice president of marketing. Ms. Altavilla is talking
> about the difference in contracture rates between smooth and textured
> implants. She states that textured implants significantly reduce the
> capsular contracture rate, from almost 60 percent to almost five
> percent. However, she went on to say that the textured implants had
> another problem, they wrinkled 100 percent of the time with patients.
> My understanding is that wrinkling leads to crease-fold failure.
>
> Does the data supplied to you indicate a 60 percent contracture rate
> with the use of smooth implants? In another unpublished study, done by
> Mentor\'s product evaluations department, it was found that Siltex or
> textured implants have a five times greater deflation rate than smooth
> implants. Does the data you have received reflect that? Do the consent
> forms?
>
> Two years ago members of this advisory panel expressed concerns that
> patients need better informed consent. Unfortunately, the panel itself
> did not have all the information they needed and neither do the
> patients. I think the panel now has to question whether the
> information provided by the manufacturers can be trusted, and must ask
> the FDA what efforts have been made to check whether the data is
> accurate. With all due respect, I urge you to carefully scrutinize all
> information received from Mentor Corporation.
>
> At the last panel meeting, some members marvelled that women wanted
> breast implants despite their high complication rates. Did the panel
> consider that women are not clearly informed about the high
> complication rates? Plastic surgeons at the meeting repeatedly stated
> that the rupture rate was very low, despite clear research data to the
> contrary.
>
> I hope you will review the material I am supplying in the form of
> written testimony, and I hope you will give serious consideration to
> the issues raised and the impact it will have on public health, not
> just for breast implant recipients but for their family members and
> the cost of medical care in this country. Thank you.
>
> DR. WHALEN: Thank you. Any questions for Ms. Hoffman?
>
> \[No response\]
>
> Thank you. Each of the six individuals we have heard from thus far
> have been representing themselves. We now proceed to various
> individuals who have identified that they are speaking on behalf of
> certain organizations. The first is Ms. Margaret Volpe, from the Y-ME
> National Breast Cancer Organization. Ms. Volpe?
>
> MS. VOLPE: As you said, I am representing Y-ME National Breast Cancer
> Organization. Y-ME has received a minuscule amount of funding from
> manufacturers in the past, and the answer to the remainder of your
> questions is no.
>
> Thank you for allowing me to present a statement to the advisory
> panel. Y-ME is committed to providing support and accurate information
> to empower individuals touched by breast cancer so that they can
> select, in conjunction with their healthcare provider, the most
> appropriate options for themselves, including options for breast
> reconstruction. Options give cancer patients some sense of control in
> restoring health and quality of life. Saline breast implants are an
> important option for women who face breast cancer.
>
> Y-ME welcomes the additional data from the manufacturers, and hopes it
> will put to rest the concerns many have expressed about breast
> implants. I was diagnosed with breast cancer in 1995 and had a
> mastectomy and tissue expander. I received an implant in February,
> 1996. Reconstruction meant not worrying about how clothes fit; feeling
> whole again; not being constantly reminded of breast cancer and
> getting on with my life.
>
> I have had no problems or complications with my implant since my
> surgery. While I was eligible for TRAM reconstruction, I didn\'t want
> to endure the major abdominal surgery and painful recovery period. I
> wanted to keep those muscles intact. Many women do not have this
> option at all. They are too thin to have the needed tissue for the
> TRAM reconstruction. Even the latissimus dorsi or back-flap
> reconstruction usually requires an implant.
>
> If implants were not an option we would be reminded daily of the
> mutilation to our breasts. Each woman who has had a mastectomy must be
> allowed to pursue the best option for her, including breast implants.
> At present, a woman who has had TRAM reconstruction on one breast is
> unable to have a second TRAM reconstruction at a later date if she
> should develop cancer in the other breast. It is imperative that we
> continue to have a choice, and for many of us implants are the only
> choice we have.
>
> Y-ME believes the availability of saline implants is very important to
> women who face breast cancer. It is the only uncomplicated option left
> for women who desire an implant as part of their breast reconstruction
> after the FDA\'s 1992 restrictions. It was very difficult for me to
> get the implant I received in 1996 because of FDA restrictions that
> required me to be in a clinical trial.
>
> This panel must abide by the science when evaluating saline breast
> implants. Do not allow yourself to get diverted and side-tracked by
> special interests. The National Academy of Sciences Institute of
> Medicine report was issued, and the science is clear. The IOM
> conducted an exhaustive and definitive review of all the existing
> research and found that there is no evidence that silicone breast
> implants cause cancer or disease. This report also found the same
> results for saline breast implants. U.S. Court\'s National Science
> Panel and several European government scientific panels, including the
> U.K.\'s independent review group, issued similar findings.
>
> Y-ME emphasizes the need for a wide range of treatment options as each
> woman must be able to choose the option that best fulfills her needs.
> Y-ME worked with FDA to produce accurate information and uses the FDA
> and IOM breast implant information booklets when counseling women.
> When it comes to the implant itself, women should understand that no
> medical device lasts forever. Shunts, heart pacemakers, even
> artificial knees and joints have a limited life span and possible
> local complications. Women should be aware of potential rupture and
> the need for replacement.
>
> Adequate informed consent is a key part of the process. Doctors should
> discuss risks and benefits in detail with their patients. Saline
> implants do have a silicone shell, but from the exhaustive research on
> silicone implants, pointed out by the IOM, we also know that there is
> no convincing evidence that silicone produces an immunologic response.
> The IOM states such diseases or conditions are no more common in women
> with breast implants than in women without breast implants.
>
> In closing, I urge the committee to act based on the science alone.
> Breast cancer is a devastating disease. In the effort to resume our
> lives, breast cancer survivors have the right to select appropriate
> and effective medical therapies or devices. Thank you very much.
>
> DR. WHALEN: Thank you. Any questions of Ms. Volpe?
>
> \[No response\]
>
> Thank you, ma\'am.
>
> MS. VOLPE: Thank you.
>
> DR. WHALEN: The next identified speaker was to have been Ms. Sybil
> Goldrich. I understand it was by a videotape and that has not been
> able to be arranged. Is Ms. Goldrich in the audience? If not, next
> then, from the Sheridan Group is Ms. Cherien Dabis.
>
> MS. MCDONOUGH: Ms. Dabis couldn\'t be here today.
>
> DR. WHALEN: You are Ms. McDonough?
>
> MS. MCDONOUGH: I am. So, I am going to do part of her testimony and
> mine, if it is okay with you, and try and cover it all.
>
> DR. WHALEN: It is just that each speaker gets five minutes.
>
> MS. MCDONOUGH: All right, I will do my best. The answer to your
> questions are all no. I actually am not representing any company, I am
> here on my own as well so the answer is no to all of those.
>
> Good morning. My name is Mary McDonough, and for ten years I played
> Erin on the TV show, \"The Waltons.\" After the show ended I chose to
> have breast implants because of the pressure I felt within my industry
> to look a certain way.
>
> It is a decision I now greatly regret. Before going through the
> surgery I did do my homework. I talked to my friends who had had
> implants and I talked to my doctors, and I read the very little
> information that was available at the time. Years later, I now realize
> that I made that decision based on misinformation and I have paid for
> that decision, like thousands of other women, who have faced serious
> complications, ultimately requiring the removal of a breast implant. I
> had my implants in for ten years.
>
> Like most Americans, I believed the FDA and that if a product was FDA
> approved or under a study, it meant every precaution had been taken to
> ensure the safety and effectiveness of the product. This naivete cost
> me my health, if not nearly my life. I have been diagnosed with lupus.
> But I am not naive anymore.
>
> Two years ago I sat in this very room and I learned that the process
> of the FDA that they use to approve products is fundamentally flawed.
> I was shocked to learn that my testimony, given on a Wednesday, was
> irrelevant because the decision had been made on the previous Monday.
> It was a mockery of the democratic process and, frankly, it made me
> very angry. But my anger has now turned to education and that is my
> purpose for why I am here today because I want to share this with you
> as the gatekeepers of America\'s health and safety, what we have
> learned in the past two years.
>
> I will raise questions about the data that was used by this committee
> to approve those products and I will point out gross violations of the
> FDA\'s own policies that allowed this product to move forward, and I
> will call into question the integrity of the manufacturers who
> produced these products.
>
> American women count on the FDA and the advisory committees such as
> this one, and to this day the women have been poorly served on the
> issue of breast implants. I hope that today we can start to rectify
> that. Here are my three points:
>
> First, saline implants were approved in 2000 under a cloud. Mentor
> Corporation had a history of violations and warning letters regarding
> good manufacturing practices and medical device reporting, a history
> that has persisted through today.
>
> McGhan Corporation also has a long history of violations of good
> manufacturing practice and medical device reporting. Since 1992, the
> company has received numerous warning letters from the FDA for
> manufacturing violations that directly relate to implant safety. This
> information is important because it casts doubt on the integrity and
> legitimacy of the manufacturer\'s practices, including their ability
> to conduct valid clinical trials and, since as an advisory panel, you
> solely rely on data produced by the manufacturers, their credibility
> and reliability should be critically important to you. Yet, both of
> these manufacturers were approved in 2000 for saline implants without
> discussion of the history of the manufacturers.
>
> The FDA has an application integrity policy. This policy allows FDA to
> halt or suspend the approval process when there are significant
> questions regarding an applicant\'s data integrity, or if there are
> concerns regarding a manufacturer\'s practices. By invoking this
> policy, it would have been difficult, if not impossible, for these
> manufacturers to bring their PMA applications for approval under the
> FDA guidelines. I question, and perhaps you do too, why this policy
> was not invoked for these two manufacturers.
>
> Second, the data regarding the reporting of adverse events is suspect.
> I have learned that there are serious discrepancies in Medical Device
> Reporting, otherwise known as MDR, for both Mentor and McGhan.
>
> According to Mentor\'s 2000 PMA clearance letter from the FDA, they
> were required to submit MDRs under the identifier P990075 as part of
> the conditions of approval and postmarket surveillance. However, upon
> checking the reporting history, no MDR has been filed under that
> identifier. Mentor has filed MDRs for saline breast implant under
> other identifiers, however. In fact, the majority of MDRs filed by
> Mentor have been under identifier P940039, and that does not
> correspond to any approved PMA in the FDA system.
>
> We have found similar discrepancies with McGhan\'s MDR reporting as
> well. For example, since 1996 167 MDRs have been filed for McGhan
> under identifier K8810444446. This identifier is not a McGhan 510(k)
> number. It belongs to US Dental Corporation\'s Super Pik Massaging
> Pick for Oral Hygiene. That was submitted to the FDA in March of 1988
> and was cleared in May of 1988.
>
> Under this system of surveillance, how are we, or more importantly
> you, the FDA advisors, ever to get accurate information on the
> complications and the failure rates? Six months prior to the approval
> of this product, the manufacturers of these devices were given an
> exemption to report adverse events for saline and silicone implants
> not under the MDR system, but under the new alternative summary
> reporting system. This exemption was made despite the FDA\'s own
> policy not to use this alternative for devices that were approved less
> than two years. Exemptions like this are curious but they also produce
> dangerous results.
>
> Looking at the data from the alternative summary reporting system
> during the years of 1999 to 2001, 34,356 adverse events were reported
> and filed with the FDA through the ASR system for Mentor and McGhan.
> Of those, 30,290 are for saline implants along, 30,000 adverse
> consequences. I can\'t help but think if these were penile implants
> this matter would have been resolved.
>
> Finally, the postmarketing data on saline implants\--
>
> DR. WHALEN: Ms. McDonough, you need to come to a conclusion, please.
>
> MS. MCDONOUGH: Well, I guess you are aware of the adverse events but I
> just wanted to tell you that there were 30,000 adverse events reported
> and it just doesn\'t measure up with this data, and I would like you
> to take a look at that. It is so important for you to know so women
> can know all of the information. If you could read Cherien\'s
> testimony, it is very compelling and I urge you to read it. She was a
> 19-year old girl who got a saline implant for a defection which was a
> tumor in her chest. Through all the manufacturers\' information she
> made this choice and then had a ruptured implant which caused her
> great pain. So, please take a look at that and please look at the
> data, and thank you very much for letting me talk today.
>
> DR. WHALEN: Thank you. Are there any questions for Ms. McDonough? Dr.
> Miller?
>
> DR. MILLER: Thank you for your testimony. What is the Sheridan Group?
>
> MS. MCDONOUGH: I am here on my own today. Cherien is with the Sheridan
> Group. The Sheridan Group is a lobbying firm.
>
> DR. MILLER: Thank you.
>
> DR. WHALEN: The next speaker is Ms. Cynthia Pearson, executive
> director, National Women\'s Health Network.
>
> MS. BARON: Ms. Pearson couldn\'t be here today. My name is Tonia Baron
> and I will be reading a statement on her behalf. I would like to start
> by saying that the answer to all four questions is no.
>
> My name is Cynthia Pearson, and I am executive director of the
> National Women\'s Health Network, a non-profit, non-partisan
> organization that has been dedicated to improving women\'s health for
> more than 25 years.
>
> The Network has been examining the safety of breast implants for more
> than a dozen years, and our primary concern has been the lack of
> safety information. When we first became involved in this issue there
> were no studies of women in the published research literature.
> Although almost a million women had breast implants, no breast implant
> had ever been approved by the FDA.
>
> Today, there are quite a few published studies on the safety of breast
> implants and saline implants made by two manufacturers have been
> approved by the FDA. Nevertheless, the Network remains very concerned
> because there have been more than 150,000 adverse reaction reports to
> the FDA for women with breast implants, and there are still no
> long-term safety studies.
>
> This meeting provides the first opportunity to revisit the FDA\'s
> approval of saline breast implants since they were approved in 2000.
> The manufacturer studies were strongly criticized by the FDA\'s
> advisory committee two years ago because of the poor quality of their
> recommendation. One might expect that the manufacturers would have
> been grateful that their implants were approved despite the high
> complication rates and poor quality of the data and would have,
> therefore, made sure that their five-year studies were better designed
> and analyzed.
>
> Instead, the new studies have many of the same flaws as the previous
> studies, and the response rate is even worse than it was at the PMA
> meeting in 2000. I will not go into details about the statistics
> because that does not seem necessary. Anyone who knows anything about
> research, and many who even know nothing about research, know that you
> can\'t lose 95 percent of your sample and still have a meaningful
> study.
>
> When Mentor Corporation analyzed their five-year follow-up data on
> only 60 of the more than 1200 women who were enrolled in the
> augmentation study, they did a disservice to more than 400,000 women
> who underwent augmentation surgeries since saline implants were
> approved in 2000, to you, the FDA advisory committee members and to
> the FDA. There is no excuse for that kind of shoddy research. In fact,
> it does not deserve to be called research. It is meaningless data.
>
> The fact that Mentor improved their follow-up to 24 percent at the
> six-year mark shows how little attention went into their five-year
> study. But even a 24 percent response rate is much too low to be
> meaningful. A response rate under 50 percent raises more questions
> than it can answer. Are the other women dead or alive? Are they
> healthy and happy or sick and seeking medical care elsewhere? We
> don\'t know the answers to these questions so the data can\'t really
> tell us about the safety of implants.
>
> The McGhan data are a little better. Like the Mentor study, they
> manipulate the data to make it seem that saline implants are safer
> than they really are. Both Mentor and McGhan made note of the women
> who had both their implants removed, but they are not included in the
> complication rate data. Instead, they are apparently excluded from the
> study as if they never existed or, worse, as if they are satisfied
> with their implants or have the same complication rate as everyone
> else.
>
> Even with this highly inappropriate data manipulation, approximately
> one out of every three McGhan augmentation patients are described as
> undergoing additional surgical procedures, an average of more than two
> additional surgeries per patient.
>
> Consumers deserve an FDA that keeps unsafe or ineffective medical
> devices off the market. They also deserve accurate information about
> the long-term safety of medical implants that are intended for
> long-term use. In the case of breast implants, the manufacturers have
> failed to conduct meaningful long-term safety studies and, as a
> result, consumers are continuing to buy implants that are FDA approved
> but are not necessarily safe.
>
> All we do know is that breast implants have an extremely high
> complication rate, higher than any medical product I can think of with
> the exception of a small number of life-saving products used by
> patients who have no other choices. Even the misrepresentation of data
> does not hide that fact.
>
> On behalf of the National Women\'s Health Network, I strongly urge
> this advisory committee to speak on behalf of the millions of
> consumers who are not able to come to this meeting but who look to the
> FDA to protect them from harmful products. If this advisory committee
> does not vehemently criticize these studies and the manufacturers\'
> misrepresentation of their own research and urge the FDA to take a
> stronger watchdog role, breast implants will never be improved and
> accurate and informative research will probably never be conducted.
>
> DR. WHALEN: Thank you. Are there any questions?
>
> \[No response\]
>
> Thank you. Next, we will hear from Dr. V. Leroy Young, from the
> American Society of Plastic Surgeons. Dr. Young?
>
> DR. YOUNG: In answer to the questions, I am a practicing plastic
> surgeon and breast implants are part of my research and part of my
> income. I also receive funding from several of the manufacturers and
> have served as a consultant for several of the manufacturers, and my
> expenses to travel here were paid for by the American Society of
> Plastic Surgeons. I am not involved in any litigation.
>
> What I would like to do with the time that I have is present work that
> the American Society of Plastic Surgeons and the work of the Plastic
> Surgery Educational Foundation has either conducted or funded to try
> to understand the performance of breast implants and the risks and
> benefits that patients derive from them.
>
> I have provided a written copy of the slides which we have here, and I
> will tell you that we have a lot more information available that we
> would be glad to share with you but, because of the limited time, we
> couldn\'t put all of that into a presentation. I apologize that this
> is taking so long.
>
> DR. WHALEN: You might want to start with your remarks because the
> clock is ticking away.
>
> DR. YOUNG: Well, what I want to emphasize about this is that our
> organizations are primarily interested in patient advocacy, research
> and education. We have made a real effort to improve patient advocacy
> in the last two years by initiating a national breast implant
> registry. This was done by Plastic Surgery Educational Foundation
> because we felt that it was the right thing to do for patients. We
> also felt, because there have been lots of concerns, some of which we
> have heard today about the quality of research, that there should be
> independent data that is not sponsored by the manufacturers available
> for patients and for surgeons. This registry provides a source of that
> data, and it provides it in an ongoing, timely fashion and we publish
> it on a regular basis.
>
> This registry, as I said, was founded in July of 2000. At the present
> time we have almost 4000 patients enrolled in it. From this, we are
> learning things about the incisions that are used to insert the
> implants, the type of implants that are being used, the position they
> are placed in but, more importantly, I think we are learning a lot
> about why reoperations occur and how often they occur. From that, we
> are implementing steps to try to decrease the reoperation rate.
>
> In May of this year we also began an international registry that
> includes most of the countries in Europe and South America, and we
> feel that this is important because this is going to let us accrue
> data more rapidly. It will let us make comparisons of different groups
> of surgeons, and it will let us learn about different types of
> implants.
>
> We are also working on informed consent, and we are working on that in
> two ways, by administering a survey in surgeons\' offices and by
> posting the survey on the implant info web site. The beauty of this is
> that it allows women to comment either positively or negatively about
> their results and they are not under the influence of the surgeon\'s
> office when they do that. It is a detailed questionnaire that goes
> over preoperative, postoperative and pre-operation data. From this,
> just as examples, we are learning how the size of the implant was
> chosen and what we have seen from that is that today\'s patients are
> much better educated. They are taking an active role in their medical
> care. As you can see from the slides I provided you, the surgeon and
> the patient decide together about size in 81 percent of the cases.
>
> We are also trying to survey how responsive surgeons are to patients.
> From that, we have provided you data that 79 percent of the surgeons
> prepared the patient for what to expect, and 83 percent took time to
> answer the questions the patient was interested in.
>
> We are also trying to assess did surgeons inform the patients about
> the potential risks. We have heard criticism of that today, and you
> can see that we are getting good data on that and that the majority of
> surgeons are apparently informing patients of most of the risk, but we
> need to work harder to get this to be 100 percent rather than 70-80
> percent.
>
> We are also getting data on the impact on life and we can see that
> there are several positive impacts from that. One of the big issues at
> the last panel meeting was related to pain. One of the things we have
> done is show, in a survey, that a significant number of women who
> don\'t have implants have pain, approximately 48 percent. We have also
> looked at the pattern of pain and how implants affect it. From this
> survey, it appears that implants don\'t affect the pattern of pain but
> in a small percentage, 13-15 percent, it is more severe and it occurs
> more frequently. So, breast implants do have an effect on that.
>
> Another issue was nursing. We have seen from the survey that about
> equal numbers of patients had children and had a history of nursing
> before and after augmentation. The problems that occurred with nursing
> were similar in the two groups of patients but they did not appear to
> be any worse in the patients who nursed after augmentation. So, we are
> getting a lot of useful information from this.
>
> One of our main concerns is the report in the literature that one in
> five women who has an augmentation has a second operation within five
> years. We are trying to decrease that and learn if that is really
> true. We have done one study, which we have just completed, which
> shows that if you apply the principles that we have learned as a
> result of these studies that I am mentioning, we can at least cut this
> rate to ten percent, and we think we can decrease it even further.
>
> Furthermore, we are funding research all over the world. We have two
> studies in Finland now on rupture and local complication, and we are
> looking at the frequency of etiology of reoperations, as I said. We
> have just completed a betadine implant related study, and we have
> funded a Center for Device Retrieval Analysis which focuses on breast
> implants.
>
> PSEF and ASPS are committed to the patients and we are committed to
> understanding these things, and I will be glad to try to answer any
> questions you may have.
>
> DR. WHALEN: Thank you, Dr. Young. Is PSEF separately incorporated?
>
> DR. YOUNG: Yes.
>
> DR. WHALEN: Does it receive any grants or funding from the
> manufacturers of saline breast implants?
>
> DR. YOUNG: It has in the past, yes, indirect funding.
>
> DR. WHALEN: Do you have any idea what the dollar amount of that is?
>
> DR. YOUNG: Early in the \'90\'s I think there was altogether about six
> million dollars. That amount has remained constant over the past ten
> years or so, other than the funding that we received for the betadine
> study which was about \$30,000.
>
> DR. WHALEN: Thank you. Are there other questions for Dr. Young? Yes,
> Dr. Dubler?
>
> DR. DUBLER: Thank you very much for your presentation. I have a
> question. Do you and members of your organization advertise about
> breast enhancement?
>
> DR. YOUNG: Yes.
>
> DR. DUBLER: You do? And what is the goal of that advertisement?
>
> DR. YOUNG: I think in most instances it is to encourage people to
> inquire about it.
>
> DR. DUBLER: To inquire about it, and maybe to go ahead?
>
> DR. YOUNG: If it is appropriate for them, yes.
>
> DR. DUBLER: And, what would you say the goal of an informed consent
> process is?
>
> DR. YOUNG: To educate the patient sufficiently that they understand
> the risks and the benefits of the procedure or treatment so that they
> can make a decision that is appropriate for them.
>
> DR. DUBLER: So, that sounds like an even-handed process.
>
> DR. YOUNG: Yes.
>
> DR. DUBLER: Is advertising and marketing an even-handed process?
>
> DR. YOUNG: No.
>
> DR. DUBLER: Can a person who does one do the other equally well?
>
> DR. YOUNG: I believe so.
>
> DR. DUBLER: Thank you.
>
> DR. WHALEN: Other questions of Dr. Young?
>
> \[No response\]
>
> Thank you. Next, we are to hear from Dr. Laurie Casas, from the
> American Society for Aesthetic Plastic Surgery. Dr. Casas?
>
> DR. CASAS: Thank you. First I will answer your four questions. I am a
> board-certified plastic surgeon and have been in clinical practice for
> 12 years. I have managed hundreds of patients with breast implants
> and, therefore, a portion of my income is derived from breast implant
> surgery. My travel expenses to this hearing were paid for by the
> American Society for Aesthetic Plastic Surgery. I am currently chair
> of the Society\'s communications commission. I have no financial ties
> to any implant manufacturer. I am neither a witness nor a party in a
> pending lawsuit related to breast implants.
>
> I am here today on behalf of the many thousands of patients who tell
> us that breast implants have made a positive difference in their
> lives. I am associate professor of surgery at Northwestern University
> Medical School. I have co-authored a book on breast surgery, and am
> currently a participant in a multi-site investigation of patient
> satisfaction following cosmetic procedures.
>
> Given the proven level of safety and efficacy of breast implants, the
> American Society for Aesthetic Plastic surgery is in full support of
> the FDA\'s approval of these devices, along with the FDA\'s continued
> oversight. Members of ASAPS, who are all board-certified plastic
> surgeons, welcome this oversight for two reasons:
>
> First, to ensure that the collection of data on breast implants is
> ongoing and, second, that women considering the procedure have the
> benefit of the most current information.
>
> Part of ASAP\'s mission is to provide accurate information to the
> public. We do this directly through our web site, and also through our
> members via patient education and informed consent.
>
> Informed consent occurs when patients are provided with all the facts
> and information necessary to make an educated decision to proceed with
> a medical treatment or surgical procedure. Full informed consent is in
> the best interests of both patients and physicians.
>
> ASAP\'s members are patient advocates. We feel that patient education,
> safety and satisfaction are of primary importance. We believe strongly
> that a woman\'s right to choose breast implants is paralleled by her
> right to be fully informed about the risks and the benefits.
>
> The Society offers continuing education to its members, providing
> information to assist them in evaluating and judging the
> appropriateness of their patients\' motivations and expectations.
> Therefore, we believe that patients with inappropriate motivation or
> expectations should be counseled against surgery.
>
> There is a growing body of evidence that suggests that cosmetic
> surgeries, such as breast augmentation, lead to improvement in at
> least three areas of psychological functioning: body image, quality of
> life and depressive systems.
>
> The research arm of the Society, the Aesthetic Surgery Education and
> Research Foundation, has recently funded a multi-site outcome study on
> patient satisfaction following aesthetic surgery. This study will
> provide additional important data on that critical subject.
>
> An increasing number of women today are choosing breast augmentation
> to enhance their appearance, over a million women in the past decade
> alone. Most women seeking breast augmentation come to plastic surgeons
> for two principal reasons.
>
> The first is a woman who finds that her once normal breasts have lost
> considerable volume following pregnancy and lactation and are not in
> proportion to the rest of her body. The second reason a woman comes to
> us for breast augmentation is if she has grown to adulthood with no
> breast development. She feels her breasts are out of proportion.
>
> The change in how she feels about herself after surgery is dramatic. I
> have seen lives transformed by breast augmentation. The typical breast
> augmentation is usually a woman in her 30\'s, most often she is
> married and has children. She is a responsible adult with a family,
> career and normal life.
>
> Women have to overcome tremendous obstacles to have breast
> augmentation, from societal prejudice to a wealth of misinformation.
> The fact that so many seek it out speaks to its strong desire.
> Satisfied patients have created the popularity of this procedure, and
> research has shown that the vast majority of women who have breast
> augmentation would make the same choice again.
>
> The high satisfaction rate, and the determination of so many women to
> undergo a surgery with the knowledge that it is not a perfect
> operation, suggests just how deeply the benefits are felt.
>
> Members of ASAPS believe it is our responsibility as health
> professionals to provide accurate and up-to-date information by which
> a patient can exercise her right to informed consent. We welcome the
> opportunity to work with the FDA and within the FDA guidelines to
> achieve this goal.
>
> The American Society for Aesthetic Plastic Surgery, and its 2800
> board-certified plastic surgeon members and candidates, are committed
> to this process.
>
> DR. WHALEN: Thank you. Any questions for Dr. Casas? Dr. Dubler?
>
> DR. DUBLER: Thank you very much for your testimony. Do you advertise?
>
> DR. CASAS: No.
>
> DR. DUBLER: Do your colleagues in your organization advertise?
>
> DR. CASAS: Yes.
>
> DR. DUBLER: Why don\'t you?
>
> DR. CASAS: I have never had the need to. I have a very busy practice
> and for me, personally, the value of spending the money to market is
> not obvious to me; I don\'t see a value.
>
> DR. DUBLER: Are there any commonly done plastic surgery interventions
> which you don\'t do because you think they are not for the benefit of
> patients?
>
> DR. CASAS: You have to be more specific. I am not sure what you are
> asking.
>
> DR. DUBLER: Liposuction?
>
> DR. CASAS: Could you rephrase the question?
>
> DR. DUBLER: Are there any commonly done plastic surgery interventions
> which are not part of your common practice because you think they are
> not for the benefit of patients?
>
> DR. CASAS: Interventions typically mean you are intervening with a
> past procedure.
>
> DR. DUBLER: I am sorry, surgical interventions.
>
> DR. CASAS: Well, surgical procedures, are there any surgical
> procedures that I don\'t perform?
>
> DR. DUBLER: Correct.
>
> DR. CASAS: Why?
>
> DR. DUBLER: Because you think they generally don\'t help patients, are
> not in the interest of most patients; the data don\'t support their
> effectiveness.
>
> DR. CASAS: You are asking a question that can\'t really be answered. I
> mean, there are thousands of different procedures that we can perform
> as plastic surgeons to mold and reshape the body, and we don\'t have a
> list. You know, there are pros and cons for every different procedure
> and you individualize with each patient. So, it is not like general
> surgery where you have hernia repair, gallbladder\--you know, a list.
> We have thousands of procedures that we perform, small, large,
> somewhere in between, and we individualize.
>
> DR. DUBLER: You said that patients with inappropriate expectations are
> discouraged from having surgery. Why?
>
> DR. CASAS: Because the most important interface that we have with the
> patient is the process of informed consent. So, it is our job and our
> duty to prepare patients for procedures. The interview process is very
> straightforward. The patient presents with a particular body part they
> are not satisfied with. We talk to them about their motivation, their
> present health status, and then provide them with alternatives. On
> that list of alternatives is not to do a procedure, and that is part
> of the informed consent. So, if in the process of informed consent, as
> a physician, we feel that the motivation is inappropriate, their
> health status is not adequate, we would counsel them against the
> procedure.
>
> DR. DUBLER: Are you aware that some of the more recent studies on
> informed consent, the empirical studies, show that patients in general
> think that the informed consent process is to protect the doctor and
> the institution, not really to inform them?
>
> DR. CASAS: I am not aware of those studies.
>
> DR. DUBLER: Thank you.
>
> DR. CHANG: Dr. Casas, I have a question that may be a little difficult
> to answer, but if in the informed consent process, let\'s say in the
> patient brochure, or if every plastic surgeon doing the counseling,
> came right up front and said early data from manufacturers suggests
> that three to five percent of these implants may fail within three
> years, or that one out of five patients may require a reoperation, in
> your opinion would the rate of breast augmentation stay the same, or
> might it go down?
>
> DR. CASAS: It is an interesting question because those are the
> statistics I give patients and they still want breast augmentation and
> breast reconstruction with implants. I think women are looking for a
> choice in changing their body structure, and for the breast we either
> have implants or your own tissue, or a combination of the two. So, we
> are limited by the choices. So, I think patients evaluate always the
> pros and cons of all their choices, at least in my office and my
> practice, and I think ASAPS does that and teaches that in a very, very
> straightforward way. There is absolutely no opportunity in our minds
> that a patient chooses an operation without full informed consent. It
> is critical in the process.
>
> DR. CHANG: Thank you.
>
> DR. WHALEN: Thank you. The next two speakers that have been identified
> to us are both from WIN Against Breast Cancer, Ms. Mullen and Ms.
> Crigler. As I understand it, Ms. Mullen is not going to be present and
> Mr. Crigler was to read her statement. What I am going to ask is that
> Ms. Crigler go ahead with her own remarks at this juncture and then,
> at a later point in time I will call her back, as time allows, to read
> Ms. Mullen\'s statement. Ms. Crigler?
>
> MS. CRIGLER: Good morning. My name is Sheila Crigler, and I am truly
> blessed to be here today to present my perspective on saline-filled
> breast implants. I am in no way receiving financial compensation from
> any implant manufacturer, nor do I have a pending lawsuit.
>
> I am here as an official person for Women\'s Information Network
> Against Breast Cancer, the acronym being WIN. It is a national
> non-profit organization, founded by president and CEO Betsy Mullen.
> Other hats I wear, I co-facilitate Women Reaching Women, a support
> group for breast cancer survivors. Not only do I hope to speak as an
> advocate, but mainly as a breast cancer survivor with saline-filled
> breast implants.
>
> Most of us have heard that life begins at 50. A few weeks after
> turning 50, I received a telephone call from my surgeon at that time
> regarding my recent mammogram. To him, it was a routine telephone
> call, but telling someone you have breast cancer over the telephone is
> anything but to the person on the other end. Life begins.
>
> There were tons of information to plow through; decisions to be made.
> Would I live or die? Intraductal carcinoma [in situ]{.underline}, the
> medical jargon; milk ducts clogged with cancer, the layman\'s jargon.
> My only option was a complete mastectomy. A woman never considers the
> possibility of losing a breast\--more decisions and possible choices.
> A realization was that breasts do not define Sheila but breasts do
> give Sheila definition.
>
> A consultation with a plastic surgeon brought sunshine to a dim
> horizon. I was a good candidate for reconstructive surgery with
> saline-filled implants. More choices. For symmetry, I opted for the
> removal of the remaining healthy breast. This was a very personal
> decision and it is not for everyone. If I could prevent the
> possibility or probability of breast cancer in the remaining breast,
> it was worth it to me to give up my other breast.
>
> The operation was a success, and the real blessing came when it was
> learned there wasn\'t any involvement in my lymph nodes. That meant no
> chemotherapy or radiation. My breasts were gone but I got to keep my
> hair.
>
> It was over a year from the cancer surgery before reconstruction would
> begin. I was amazed to learn some survivors cannot look at themselves
> in the mirror after surgery. Imagine a billboard, as I called it, in
> place of mounds that once defined womanhood.
>
> There are different types of reconstructive surgery, with
> saline-filled breast implants being one of the least complicated in
> regards to length of surgery and recovery. If a rupture were to occur,
> the body will absorb the saline and release it out of the body. The
> lack of choices is what creates problems.
>
> Women need the opportunity to make informed decisions. There is no one
> particular thing that works for everybody. Choices again. A few with
> strong issues against a situation should never be the deciding factor
> for the masses. The need is to inform consumers and not remove
> choices.
>
> My reconstructive surgery was a success and my saline-filled breast
> implants are truly a part of my body by now. It has been almost six
> years since my permanent implants were put in place. That has created
> a completion of a circle. I began with breasts and have ended with
> breasts. Now I can smile at a newly diagnosed patient and show them
> that this is the face of cancer. I can proudly display my
> saline-filled breast implants that say that there is hope.
>
> It would definitely be a travesty if this particular choice were
> removed. Hope is what a person does not have when she tells you she
> would rather die than have her breasts removed. We did not choose to
> have breast cancer but we can choose to have reconstruction. A
> woman\'s right to choose is what is at stake here today. I feel so
> strongly about this issue that I left my mother, who is hospitalized
> in Los Angeles, to make the trip here to express my concerns regarding
> the ongoing study of saline-filled breast implants. Thank you. Are
> there any questions?
>
> DR. WHALEN: Thank you, Ms. Crigler.
>
> MS. CRIGLER: Thank you.
>
> DR. WHALEN: Next is Dr. Diana Zuckerman, from the National Center for
> Policy Research for Women and Families.
>
> DR. ZUCKERMAN: Thank you. The answer to the four questions is no, and
> I donated my time to be here today and traveled in my own car.
>
> My name is Dr. Diana Zuckerman, and I am president of the National
> Center for Policy Research for Women and Families, which is a
> non-profit, research-based organization that explains medical and
> scientific information so that it can be used to improve the health
> and well being of women, children and families.
>
> Our research center works on a wide range of health issues, with
> particular attention to the safety of medical products. Unfortunately,
> as the new research on hormonal replacement therapy has reminded us,
> manufacturers\' claims about medical products are not always supported
> by research. Our goal is to balance the hype by scrutinizing the
> research and determining the facts, whatever they might be.
>
> In the case of breast implants, the more than 150,000 adverse
> reactions that have been reported to the FDA are inconsistent with the
> manufacturers\' claims that implants are very safe and that implant
> patients are so satisfied that even when their implants break all they
> want to do is replace them with a larger size. So, we have used our
> expertise in epidemiology, biostatistics and public health to
> carefully scrutinize the research.
>
> I was at the FDA advisory committee meeting when saline implants were
> approved in 2000. For those of you who weren\'t here, I want you to
> know that the advisory committee expressed a great deal of concern
> about the extremely poor quality of the research and about the
> exceedingly high complication rates. And, I was here to hear the
> shocked gasps in the audience when the advisory committee voted to
> recommend approval despite their very strongly expressed concerns.
>
> The advisory committee recommended approval with the caveat that
> long-term safety data and better studies be required of the
> manufacturers. I am sorry that many of those members are not here
> today because I think they would be very disappointed that the
> manufacturers made many of the same mistakes or misrepresentations in
> their data this time that they were criticized for two years ago. In
> fact, as a former college professor, and I used to teach research
> methods and statistics courses, I would have to say I would flunk
> anybody who would provide a statistical analysis like some of the ones
> that I saw in these studies.
>
> I want to use the words of former members of this advisory committee
> as well as other statisticians. Since we haven\'t had the opportunity
> to hear the data yet this morning, having our public comment before it
> is presented, I wanted to use some of their own words to criticize
> these studies that you are going to be discussing today. For example,
> Dr. Brent Blumenstein, who was the statistician on the advisory
> committee last time, clearly stated that the McGhan presentations did
> not meet the standards of \"good, peer-reviewed articles\" and
> specifically stated that\--I love this one\--\"accuracy is not
> manifest in the presentation of the data.\"
>
> The FDA statistician, Telba Irony, specifically criticized using
> Kaplan-Meier analyses when so many women are lost to follow-up and the
> researchers don\'t know if those who dropped out are similar to those
> who are in the study.
>
> Both these statisticians criticized the large number of patients who
> were lost to follow-up in the studies two years ago. Of course, the
> new data presented today show even more women lost to follow-up.
>
> In the Mentor study two years ago, Dr. Blumenstein criticized the
> company for taking patients out of the analysis if they had their
> implants removed. He said, \"this is an extreme limitation and
> misrepresents the data.\" He then concluded by saying, \"I cannot
> accept the accuracy of any of the data here because of the limitations
> I\'m pointing out. I cannot feel good about any of the data presented
> with respect to accuracy and giving that information to an individual
> patient and having that patient understand what the real risks are.\"
>
> Phyllis Silverman, who was the FDA statistician two years ago, stated
> that, \"because of the approximately 50 percent loss to follow-up with
> the large, simple trial, the ability to draw meaningful conclusions
> from this trial is limited.\" I fully agree with those statements, and
> it is obviously even worse for the new Mentor data which actually had
> 95 percent\--95 percent loss to follow-up at five years, and 76
> percent loss to follow-up at six years. Even if the rates continue to
> get a little higher, and I see that Mentor has made some efforts to do
> so, a response rate under 50 percent cannot provide useful safety
> data.
>
> DR. WHALEN: Dr. Zuckerman, can you come to conclusion?
>
> DR. ZUCKERMAN: Yes, I will speed up but I guess I would respectfully
> request that I get as much time\--
>
> DR. WHALEN: I am sorry, we need to have you conclude. Everybody gets
> their five minutes.
>
> DR. ZUCKERMAN: Yes. I will just address what Dr. Dubler said,
> wondering why the manufacturers were unable to afford good researchers
> to do the research when they have, in fact, spent millions of dollars
> to advertise in every major woman\'s magazine, including those read by
> millions of teenagers.
>
> I have here a letter that was written by two congressmen yesterday,
> asking that members of this committee be given information about two
> things, the National Cancer Institute studies on breast implants and I
> happen to be on the advisory committee for those NCI studies, and also
> ask that you be informed of the criminal investigation and problems
> with inspection reports.
>
> So, I would just turn to you and say, and I will give you a copy of
> that letter, as an advisory committee, if you don\'t insist on better
> long-term research and on accurate reporting of that research,
> teenagers and women will continue to incorrectly assume that breast
> implants are proven safe for long-term use. I am not questioning
> women\'s rights to make choices about their own bodies, but I am
> questioning whether they can make an informed decision when there is
> no really well-conducted safety research. Are there any questions?
>
> DR. WHALEN: Dr. Dubler?
>
> DR. DUBLER: Have you reviewed the materials which surgeons use to
> discuss with patients whether to go ahead with implant surgery?
>
> DR. ZUCKERMAN: Yes, and of course they vary a great deal. One of the
> problems, as you mentioned earlier, is that so many patients think
> that even very clear warnings are really meant for liability reasons,
> not to protect them, not to provide information to them. But we also
> know that sometimes doctors give a written informed consent but what
> they say to the patient is, you know, of course, I wouldn\'t be doing
> this if I didn\'t think it was safe for you; my experience is that
> patients love their implants and most of my patients are very
> satisfied. So, I think informed consent, as we know, is a written
> version and then there is the oral version and they can be quite
> different.
>
> DR. DUBLER: Do you think it would be possible, based on your reading
> of the data that have been produced, to devise an independent,
> interactive, video-based informed consent process that really
> permitted a woman to scrutinize the data from the perspective of the
> skeptical, not the supportive? Would that be a possible process to
> design?
>
> DR. ZUCKERMAN: I think so. I mean, we know that there are limitations
> of informed consent but we have to do a better job than we are doing
> now. I think that your suggestion is an excellent one because I think
> if there was an independent one, particularly if it was a videotape,
> interesting and not these terribly long, boring informed consent
> things that many people don\'t read or don\'t understand or don\'t
> know what to do with, I think that could really make a difference.
>
> I have no doubt that plastic surgeons do warn their patients about
> some of the risks, and I guess my concern is that if they are warning
> about capsular contracture, but they if are not mentioning last
> year\'s National Cancer Institute study showing an increased rate of
> cancers and deaths from certain cancers and respiratory diseases among
> women with saline and silicone breast implants, then I really question
> whether they are getting informed consent currently.
>
> DR. DUBLER: Thank you.
>
> DR. WHALEN: Thank you.
>
> DR. ZUCKERMAN: Yes.
>
> DR. WHALEN: Next is Dr. Jae Hong Lee, also from the National Center
> for Policy Research for Women and Families.
>
> DR. LEE: Good morning. I am Dr. Jae Hong Lee, a physician and the
> senior medical policy analyst at the National Center for Policy
> Research for Women and Families. My response to all four questions is
> no.
>
> The Institute of Medicine report on breast implant safety identified
> reoperations and local complications as the primary safety issue with
> silicone breast implants.
>
> In light of the serious concern regarding reoperations and local
> complications, the post-approval studies recently released by Inamed
> and Mentor are extremely disappointing. Both studies are poorly
> designed and executed, and most likely underestimate the cumulative
> incidence of complications.
>
> I will discuss just a few of the more glaring weaknesses of both
> studies. A major problem shared by both the Inamed and Mentor studies
> is the exclusion of patients who have had all their breast implants
> removed prior to the three- or five-year study interval. One can argue
> that these patients, among the earliest to have all their implants
> removed, are the most important group of patients to study. They
> certainly should be counted as women with complications.
>
> Excluding data from these patients introduces an unacceptable
> post-entry exclusion bias into both studies. Since it seems likely
> that these patients were experiencing complications rates higher than
> those who did not have all their implants removed, the overall effect
> of this exclusion bias will be to seriously underestimate the
> cumulative incidence of complications.
>
> Exclusion of these patients also invalidates the Kaplan-Meier risk
> estimates reported in both studies. One essential condition for using
> the Kaplan-Meier method is the assumption of independence between
> censoring and outcome. In other words, one must assume that the rate
> of local complications and reoperations in the excluded patients was
> similar to those who remained in the study. Since the excluded
> patients had all of their initial implants removed for one reason or
> another, most likely due to complications, this is not a reasonable
> assumption to make. Using the Kaplan-Meier method in this situation
> clearly results in an underestimation of the cumulative complication
> rate, a fundamental flaw in both studies.
>
> The problem is compounded when the reports continue to cite the full
> number of enrolled patients when discussing specific complications.
> For example, the Inamed study enrolled 237 reconstruction patients but
> excluded 97 patients by year five, for an actual follow-up of only 140
> patients. Inamed then reports reoperations in 100 of the 237 patients
> over the five years of follow-up. The question is whey were the
> excluded patients counted in the follow-up cohort? Is the percentage
> of patients with reoperations 100 out of 237, or 42 percent, or is it
> actually 100 out of 140? In contrast, Inamed conveniently excludes the
> breast implant removal patients when calculating their follow-up rate
> for reconstruction patients. They calculated an expected follow-up
> cohort of 175 by excluding 11 patients who had died and 51 patients
> who had all their initial implants removed. As a result, their
> follow-up rate of reconstruction patients was reported as 80 percent,
> or 140 out of 175 patients.
>
> As mentioned earlier, it is highly inappropriate to exclude those
> implant-removal patients from the study cohort. If those patients are
> left in, the expected follow-up cohort consists of 226 patients, not
> 175, and the actual follow-up rate for reconstruction patients is then
> a clearly inadequate 62 percent.
>
> There are also signs that the Inamed study is statistically
> underpowered. For example, Inamed suggests that because most of the
> confidence intervals between five-year and three-year risk rates for
> complications overlap, the true rates may not be higher at five years.
> They imply that it may not be necessary to follow complications with
> overlapping three- and five-year confidence intervals in subsequent
> years.
>
> A more reasonable interpretation of this data is that the study is too
> small and underpowered. Since even a small difference of three percent
> represents over 6000 breast augmentation patients, the post-approval
> studies must be large enough to detect even small differences in risk
> rates.
>
> As bad as the Inamed study is, the Mentor study is even worse. The
> Mentor report acknowledges that low response rate and the differences
> between the responders and the non-responders is a major limitation of
> their study. I would go further and state that most of the data
> presented in the Mentor study is scientifically worthless due to the
> disturbingly low follow-up rates.
>
> Setting aside for the moment the very serious methodological problems
> of both studies, we find little comfort in the reported data. Even
> taken at face value, the complication rates are unacceptably high. For
> instance, Inamed reports five-year reoperation rates of 26 percent for
> augmentation patients and nearly 45 percent for reconstruction
> patients. As a physician, I find these complication rates to be
> completely unjustifiable for a purely elective cosmetic procedure.
>
> The poor quality of the studies clearly indicates that both Inamed and
> Mentor have failed to fulfill all the conditions of their premarket
> approval agreement. Furthermore, the reported complication rates in
> both studies reinforce the Institute of Medicine\'s concern about
> local complications and reoperations. These companies seemingly lack
> the motivation to perform adequate and appropriate safety studies as
> long as they can market and sell their products as FDA approved.
>
> So, what should be done? At the very least, the FDA should require a
> black box warning on all advertisements noting that the manufacturer
> has not adequately completed required five-year safety studies. The
> panel should also recommend that patient consent forms include a
> statement noting the lack of reliable long-term safety data. Another
> option would be to temporarily suspend general distribution of these
> implants until better safety data become available.
>
> The Inamed and Mentor studies leave many questions unanswered, but do
> make clear one important fact, right now, today, there are no adequate
> data demonstrating the safety of saline breast implants. Thank you.
>
> DR. WHALEN: Any questions of Dr. Lee?
>
> \[No response\]
>
> Thank you. Next, we have Dr. Susan Pope Helman on behalf of herself.
>
> DR. HELMAN: Those handouts are a little more detailed than what I am
> going to say. I am shaking, sorry. Good morning. I am Susan Helman. I
> live in Vero Beach, Florida. My reason for being here is to enlighten
> the FDA\'s General and Plastic Surgery Devices Panel regarding the use
> of non-organic platinum in the manufacturing of saline and silicone
> medical devices and how I have been affected.
>
> I will be brief.
>
> DR. WHALEN: I am sorry, I don\'t mean to exacerbate\--
>
> MS. HELMAN: I am sorry, the answer to all those questions is no.
>
> DR. WHALEN: Thank you.
>
> MS. HELMAN: Your handouts include the specific terms and means by
> which my body specimens were tested. I received breast implants in
> 1990 and had them removed in 1992, less than two years. Nine years
> later, in May of 2001, samples of my hair, fingernails, toenails,
> urine, blood, sweat, skin cells and my left axilla lymph node were
> obtained by ExperTox Forensic Toxicology Laboratories in Houston,
> Texas for analysis.
>
> On August 15th, 2001, a bone marrow biopsy was obtained and sent out
> to ExperTox for during a surgical procedure to remove a residual
> silicone capsule remaining in my left breast and lymph nodes in both
> breasts, thoracic area, neck and under my right arm. Samples of these
> tissues were sent to the University of Florida Diagnostic
> Laboratories. The findings from the University of Florida were, one,
> foreign material through all layers of specimens; two, residual
> silicone adhesive; three, foreign body giant cells and vacuolated
> histocytes containing silicone and polyurethane foam; and, four,
> silicone granuloma.
>
> The results from ExperTox Forensic Laboratories are as follows: whole
> blood platinum 1542 pmo 1/L. I don\'t know what these things mean. I
> just know that the level of platinum in a human body should be no more
> than zero. So, I am just going to give you the numbers, if that is
> okay. Whole blood platinum, 1542; urine platinum 0.38; hair platinum,
> 1.59; nail platinum, 2.88; sweat platinum 3.85; bone marrow platinum
> 181.6 upper ug/L. The oxidation states of the excised nodule under the
> right arm were 2+, equaling 42 percent and 4+ equaling 58 percent. I
> just had another bone marrow biopsy taken two weeks ago. I got the
> results yesterday and the number is 325. So, it has gone up from 185.6
> to 325.
>
> In a comparison between this form of platinum and the known platinum
> containing chemotherapeutic agent cisplatin, it is known that
> cisplatin has a cytotoxic and neurologic action on the body and is an
> organic form of a platinum molecule whose properties are less toxic
> than the free form found in my body.
>
> Skin cells from my cheek were also taken for analysis and were exposed
> to the platinum taken out of my body, my own skin cells were exposed
> to platinum taken from my body and the results obtained clearly
> demonstrated acute, significant toxic changes such as vacuolation and
> cell degeneration, and conclusively established that I have sustained
> chronic toxic cellular injury with platinum presently disseminated
> through my entire fluids and tissues.
>
> I can only speak for myself, but I am an example. This is how I have
> been affected and how my body has been affected. My body is basically
> killing itself. There are many women, breast implanted women like me
> in these United States with debilitating illnesses and extreme
> challenges too numerous to even list, but what we would ask is that
> the FDA panel be thorough in your understanding of the manufacture and
> use of saline breast implants since it is my understanding after all
> this that the bags used in these devices contain platinum. Thank you
> so much.
>
> DR. WHALEN: Dr. Helman, it has been ten years since your implants were
> removed? Is that correct?
>
> DR. HELMAN: That is correct.
>
> DR. WHALEN: And, you said in your testimony that at two recent points
> in time there was a rather dramatic increase?
>
> DR. HELMAN: That is correct.
>
> DR. WHALEN: Has any healthcare provider that you have interacted with
> suggested, in view of that data ten years after these were removed,
> that some alternative source of platinum than the breast implants
> might be affecting you?
>
> DR. HELMAN: They said only if I worked in the platinum jewelry
> manufacturing industry or as a motorway, like a turnpike person that
> takes money on the turnpike, or pump gasoline would I even have a
> trace of platinum in my tissues.
>
> DR. WHALEN: But, I mean, a dramatic increase at two points in time.
>
> DR. HELMAN: I asked the toxicologist about it yesterday morning when
> he gave me my new numbers, and he said it is possible that the
> platinum molecules relocated after the removal of the residual capsule
> that was left in my body. He said, because the original bone marrow
> biopsy was done on August 15 of last year and then, of course, just
> two weeks ago, he said it may have relocated. But I am going to be
> tested again in six months.
>
> DR. WHALEN: May I ask what your doctorate is in?
>
> DR. HELMAN: Metaphysics.
>
> DR. WHALEN: Are there other questions? Dr. Doyle?
>
> DR. DOYLE: The question of timing, you said the residual implant was
> removed when?
>
> DR. HELMAN: Last August.
>
> DR. DOYLE: Thank you.
>
> DR. HELMAN: Yes, ma\'am.
>
> DR. WHALEN: Dr. Miller?
>
> DR. MILLER: Thanks for your testimony. Can you tell me about ExperTox?
> How did you select ExperTox in Houston as a place to have your
> toxicology done?
>
> DR. HELMAN: I read a paper that was produced by Dr. Lakissa, along
> with a few other physicians, back in \'99 or 2000 and I phoned him and
> asked him if he would consider doing a toxicological study on me
> because I was sick. I was really sick and I didn\'t know why.
>
> DR. MILLER: Are services like this not readily available where you
> live?
>
> DR. HELMAN: No, they aren\'t. It is my understanding that mass
> spectroscopy\--I have trouble pronouncing these things\--and special
> equipment is not readily available. I think there are a few pieces of
> this equipment throughout the country but they are kind of sparsely
> located.
>
> DR. MILLER: Thank you.
>
> DR. WHALEN: Thank you, Dr. Helman.
>
> DR. HELMAN: Thank you.
>
> DR. WHALEN: I would like to ask if Ms. Crigler would like to return to
> read for the record Ms. Mullen\'s statement.
>
> MS. CRIGLER: The statement that I have for Ms. Mullen is the statement
> from March of 2000, which I am sure anyone here may not remember. It
> would be repetitious. Ms. Mullen was just saying that I could take
> full ten minutes just for expedience sake.
>
> Basically, her statement is mainly as mine in that the saline implants
> gave her quality of life. At that time, Ms. Mullen had immediate
> reconstructive surgery and she, as I, feels that it is really a
> quality of life issue for a cancer patient, much different than an
> augmentation that someone would request for body enhancement which, as
> with any procedure, people have used to excess as far as the
> augmentation. That is my perception. But for a cancer patient, we
> offer a different view as this gives us a different perspective on
> life.
>
> As I stated, when women cannot even look at themselves in the mirror
> because of the mutilation with breast cancer, Dr. Susan Love has
> quoted the only cure is slash, burn or poison. They slash our bodies
> to remove the breast. They poison our bodies with chemotherapy and
> they burn them with radiation. After a woman has gone through any or
> all of these devastating treatments you are looking at an end result
> as to what she did not choose.
>
> The choice comes with an implant for reconstructive surgery. This
> gives a woman a different view of life. She can feel whole again. I am
> sure people have noticed, whether you or anyone on the panel has done
> it, when people observe a female, most times the concentration is on
> their breast for whatever reason. Women feel whole with breast. For
> some women it is a dire need. As we explained, most clothing is
> designed by men for women, but it includes some space for breast,
> whatever size.
>
> I feel that it would really be unacceptable if the study is not
> continued to give women this option for whatever quality of life the
> woman may need at that time. Just have the choice available.
>
> DR. WHALEN: Excepting, of course, the travel question, do you have any
> idea of Ms. Mullen\'s potential responses to the other areas that are
> asked of all speakers? Is there any conflict? Is she involved in
> lawsuits? Is she paid by any company that is interested?
>
> MS. CRIGLER: No, she is not involved in a lawsuit or witness. It is in
> her statement. She is founder, CEO and president of WIN ABC, which is
> the Women\'s Information Network Against Breast Cancer.
>
> DR. WHALEN: Thank you. Any other questions?
>
> \[N response\]
>
> DR. WHALEN: Thank you.
>
> MS. CRIGLER: Thank you.
>
> DR. WHALEN: If Ms. McDonough is still present in the room and if she
> wishes to read for the record Ms. Dabis\' statement, and if she can
> also begin, if you know it, with what Ms. Dabis\' answers would be
> with lobbying companies she works for, and the like.
>
> MS. MCDONOUGH: She doesn\'t work for a lobbying company.
>
> DR. WHALEN: Oh, I am sorry, I thought you said that in response to a
> question.
>
> MS. MCDONOUGH: No, my response to the question was that I came here by
> myself and I was reading my own testimony, as is true with Cherien. If
> she had been here this morning, she would have been here on her own
> and by herself.
>
> DR. WHALEN: So, the Sheridan Group has nothing to do with either of
> you?
>
> MS. MCDONOUGH: That is correct.
>
> DR. WHALEN: Thank you.
>
> MS. MCDONOUGH: That is correct. Thank you for clarifying that. To the
> best of my knowledge, all of the answers to the questions, the four of
> them, are no.
>
> My name is Cherien Dabis. I wanted to be here today to present to you
> information for women who have receive and will ever receive saline
> breast implants.
>
> I was born with cystic hygroma, a rare benign tumor of the skin
> consisting of a collection of abnormal lymph vessels. At birth, a
> tumor the size of a grapefruit was perched on the left side of my neck
> and interwoven with the delicate nerves and blood vessels in my neck,
> chest, arm and underarm. A series of surgeries at birth removed the
> growth, but also necessitated the removal of surrounding tissue, skin
> and muscle, leaving me with excess scar tissue and half a pectoral
> muscle. The scar tissue hindered the range of motion of my left arm.
> As I developed, the asymmetry of my chest became more and more
> apparent. My left breast was significantly smaller than my right. What
> I saw as a deformity led me to hate my body. So, I decided that when I
> was old enough I would pursue reconstructive surgery.
>
> At age 18 I underwent tissue expansion, followed by stage-two
> reconstruction with breast implants at Christ Hospital in Cincinnati.
> My plastic surgeon recommended silicone gel implants, but I had done
> my homework. I read about the problems women had with silicone
> implants which, in 1992, led the FDA to restrict their use,
> ironically, making silicone implants only available to women who were
> born with defects or those having undergone mastectomies.
>
> I assured my doctor that I did not want silicone implants. He
> discounted my concern, but told me that the saline implants were a
> safer option. If it leaks, he said, it is only salt water. It will
> dissolve, leave your body and you will be unharmed. But chances are
> that it won\'t leak. It will last forever unless you suffer some major
> trauma to your chest, such as a car accident. My doctor tried to
> convince me to have both of my breasts implanted. I refused. I simply
> wanted to correct my defect.
>
> In Mary of \'96, my chest was implanted with a McGhan style 168
> saline-filled breast implant. Another custom-made implant was inserted
> in my arm to fill the cavity that resulted from my birth defect. I
> thought at the time this implant was also saline-filled.
>
> Nearly four years later I began to experience periodic pain and
> burning in my chest and arm. The burning and pain eventually worsened
> and my left arm became more and more immobile. I knew something was
> seriously wrong. I was experiencing painful capsular contracture. My
> doctor thought I would never be able to improve the range of motion in
> my left arm. Her recommendation was to surgically remove the implant.
>
> During the few weeks following my initial appointment, the pain and
> burning in my chest worsened. I could not sleep at night because I
> could feel the implant moving around, shifting and painfully poking
> me. Then I had the ultimate breast implant nightmare. I stepped out of
> the shower on June 1, 2000. I knew it had happened to me. My breast
> was gone.
>
> One week later I was in an outpatient operation room, terrified. After
> five hours of surgery to remove the implants, I woke up to find out
> that Dr. Feng had removed one deflated saline breast implant and the
> other device in my body which had been a solid silicone block.
>
> My insurance did approve the procedure, but I still had to pay 20
> percent up front, which amounted to \$2000, and I was required to stay
> in a hotel room for five days so that the doctor could monitor my
> progress and remove my drains. The total cost of my trip was \$3000. I
> had to take out a loan in order to pay for what the insurance had not
> covered.
>
> Had I known the additional physical and emotional consequences of
> receiving breast implants, I would have made a different decision.
> When I opted for reconstructive surgery I did my homework. I read what
> little research was out there. Only now do I know that the research
> that was available was conducted by the manufacturers.
>
> As a young woman and a consumer, I ask you to require and enforce the
> most stringent guidelines on the integrity of applications and of the
> manufacturers submitting applications for device marketing approval
> and clinical trials. I ask that long-term follow-up on the adverse
> events be demanded of all manufacturers, with close oversight by FDA.
> Only through this process will consumers ever have access to accurate
> surveillance data on complications and failure rates of breast implant
> devices.
>
> Until there is incentive for manufacturers to make better, safer and
> more effective devices, women will continue to risk their health,
> their future, and possibly their lives by choosing these FDA approved
> medical devices. Thank you.
>
> DR. WHALEN: Thank you. I realize that was a reading of a statement but
> does anybody have any questions?
>
> \[No response\]
>
> Thank you.
>
> MS. MCDONOUGH: Thank you very much.
>
> DR. WHALEN: We have a brief amount of remaining time so if there is
> anyone, who has not yet addressed the panel, who wishes to address us
> in this public session, would you please so indicate by raising your
> hand right now? I see none.
>
> This is a convenient time for us to take a break. I have 10:07. We
> will reconvene here at 10:25 and resume our activities.
>
> \[Brief recess\]
>
> DR. WHALEN: I would like to remind the public observers at this
> meeting that while this portion of the meeting is, of course, open to
> public observation, public attendees may not participate unless
> specifically requested by a member of the panel.
>
> Before we begin the first presentation from industry, I would like to
> ask Dr. Celia Witten to make some brief remarks about what the conduct
> of our day\'s activities is going to be.
>
> DR. WITTEN: Thank you. I just want to describe what we are going to be
> doing for the rest of the day. I will start with just mentioning
> something that I think everybody here probably already knows, which is
> that at the time that we approved the two saline breast implant PMAs
> several years ago, we asked the sponsors to continue to study their
> product in the form of several conditions of approval, which have been
> outlined in the panel packet.
>
> The purpose of the meeting today is to give the sponsors an
> opportunity to describe their progress in those studies to date, and
> there will also be an FDA presentation on each of those studies.
> Following that, there is an opportunity for the panel to comment on
> the data and the studies as presented.
>
> We think it is very important that the panel get an opportunity to see
> what the data is that the sponsors have generated to date, and also
> for the public to get an opportunity to see this data. This is
> important information and will be incorporated into the sponsors\'
> labeling as part of an ongoing effort to make sure all the information
> is available to physicians and patients.
>
> I would like to thank everybody here on the panel in advance for your
> discussion of the data, and I would like to thank the members of the
> public, who gave presentations this morning already, for their input
> as well.
>
> DR. WHALEN: Thank you, Dr. Witten. So, as we proceed, as long as the
> day flows as we anticipate, we will have one of the sponsors give
> their presentation before lunch. There will be three speakers, and I
> would ask the panel members to make note of any questions they have
> for any of those speakers. Then, following all three speakers we will
> ask them to entertain our questions. Following that question and
> answer period and comments, we will have FDA\'s presentation for that
> particular sponsor\'s presentation, followed, in a similar fashion, by
> questions, answers and comments. We will then have a general
> discussion on that particular status. Then, we hope to break for lunch
> and then duplicate that for the other sponsor following lunch.
>
> I would ask that we begin with Mentor Corporation\'s presentation,
> with the three speakers who are going to address us.
>
> **Panel Update Regarding Post-Approval Conditions of**
>
> **Approval for Saline-Filled Breast Prosthesis**
>
> **Mentor Corporation**
>
> DR. MICHAEL: Ladies and gentlemen, good morning. My name is Maher
> Michael. I am the medical director and vice president of clinical and
> regulatory affairs for Mentor Corporation.
>
> We are here today to update the panel members and FDA staff on the
> status of the conditions of the post-PMA approval for Mentor
> saline-filled and Spectrum mammary prostheses.
>
> First, I would like to give you an overview of Mentor\'s saline
> prospective study which constitutes the basis of our approved PMA.
> There were 1680 patients enrolled in this study. That study was
> designed for a three-year patient follow-up. The devices that were
> used were 30 percent smooth and 70 percent textured. The last patient
> was enrolled in September of 1995. The PMA was approved by FDA on May
> 10 of 2000, with some conditions.
>
> The first condition was the post-approval study, and the purpose for
> that study was to extend the patient follow-up from three years to ten
> years to collect longer-term safety data. That study was not designed
> really to collect any patient satisfaction data. Today, five-year data
> will be presented by Mr. Cliff Kline, director of clinical programs.
>
> The second condition was the focus group study, and the purpose for
> that study was to evaluate the effectiveness of the patient brochure
> in communicating information to prospective patients about risks and
> benefits of breast implants. The status of that study will be
> presented by Ms. Donna Crawford, director of corporate regulatory
> affairs.
>
> The third condition was the retrieval study, and the objective of that
> study was to better understand causes of deflation and further analyze
> the failure modes.
>
> The fourth condition was the fatigue testing study, and the purpose of
> that study was to characterize fatigue resistance of the devices using
> methods, as requested, in the breast implant guidance document.
>
> The fifth, and last, condition was the real-time shelf-life testing,
> and the purpose of that study was to support our four-year shelf-life
> data submitted in our PMA, and to extend the real-time shelf-life
> testing to five years.
>
> The status of the last three conditions will be presented this morning
> by Mr. Ron Crouther, vice president of advanced development.
>
> Now I would like to present Mr. Cliff Kline who will present and
> discuss the post-approval study. Thank you.
>
> MR. KLINE: Thank you, Dr. Michael. Good morning. As Dr. Michael said,
> I will be presenting the five-year clinical results for Mentor\'s
> post-approval study, or PAS, on our saline-filled and Spectrum mammary
> prostheses.
>
> I will first briefly discuss study design and the chronology of our
> efforts to contact and follow-up on the majority of patients. Then, I
> will provide five-year complication data.
>
> The objective of the post-approval study was to assess the long-term
> ten-year safety for Mentor saline-filled and Spectrum breast implants
> by assessing the cumulative incidences of capsular contraction,
> deflation, breast pain, reoperations and explantations.
>
> Patients were included in this study if they had participated in the
> saline prospective study and they consented to participate in this
> post-approval study. They were excluded if they had died, had all
> their implants removed or discontinued by choice.
>
> Patients could either complete a mail-in questionnaire or they could
> elect to be seen by their physician. The questionnaires are sent to
> each patient once every year around the anniversary date of her
> surgery.
>
> Mentor has conducted extensive and varied efforts to contact and
> follow-up with all potential patients, and I would like to share these
> efforts with you now.
>
> We received PAS protocol approval in May of 2000. During July we
> contacted all saline prospective study investigators and confirmed
> with them that Mentor would contact their patients directly. Three
> physicians did deny us direct access to their patients so those
> patients were not contacted about participating in the study.
>
> Prior to the first mailing, we worked with the participating sites to
> confirm the patients\' addresses. We also used the National Change of
> Address database, NCOA, to update this information. We then initiated
> a patient mailing of informed consents and questionnaires, and at the
> end of 2000 we did a second certified mailing to those patients who
> had not responded, the non-responders.
>
> You will hear me using those two phrases throughout the presentation,
> responders and non-responders. Responders are those patients on whom
> we have data, whereas noon-responders are those patients who we have
> not yet had success in contacting.
>
> In 2001, we continued to collect an analyze the data as well as send
> out annual questionnaires. We increased our efforts to contact
> non-responders by using the nationwide 411 telephone directory.
>
> This year, we continued to collect and analyze the data as well as
> mail out annual questionnaires. We have increased our contact and
> follow-up rate by approaching investigators who have non-responders
> and, if they were successful in contacting these patients, we provided
> financial incentive. We also began to correspond with non-responders
> via FedEx, which allows tracking and verification of patient
> signatures. We did this by using the ChoicePoint nationwide database
> to identify all possible addresses for the non-responders, and then we
> followed up by sending, via FedEx, packets to all these addresses.
>
> These extra efforts have resulted in increased contact and follow-up
> in 2002. As noted in FDA\'s memo to panel, Table 5(a), currently the
> augmentation patient contact rate is 75 percent and the reconstruction
> contact rate is 91 percent.
>
> This graph shows the improvement in patient follow-up from March to
> May of this year. Augmentation improved from 54 percent to 64 percent
> and reconstruction from 73 percent to 79 percent. The rates are
> different for contact and follow-up because these two are defined
> differently. Contact rate is made up of all patients whom we have been
> able to get a hold of, whereas follow-up rate only includes those
> patients on whom we have data. So a patient is counted as contacted
> whether she says yes or no to participating in this post-approval
> study, but she is only counted in the follow-up if we have data.
> Please note that the complication data in this presentation are from
> the March, 2002 data set.
>
> Before I address complication rates, I would like to address the issue
> noted in FDA\'s memo to the panel regarding responders and
> non-responders. When we analyzed the study data we did find that
> non-responders were significantly different in some demographic and
> operative characteristics. Adjustment for these differences showed
> essentially no change in the cumulative rate of complications at five
> years. Therefore, Mentor concludes that responders adequately
> represent the entire study population at five years. This analysis is
> currently being reviewed by FDA.
>
> The complication rates were calculated via Kaplan-Meier analysis. This
> is a statistical method used when 100 percent patient follow-up is not
> available, and it provides an estimated probability of a complication
> at a given time period.
>
> The remainder of this presentation is divided into the augmentation
> and reconstruction cohorts. I first want to talk about the
> augmentation patients. They are defined as a patient who is normally
> healthy and at least 18 years of age or older, and desires breast
> enlargement. The average age of augmentation patients in the saline
> prospective study at the time of surgery was 32 years of age. Almost
> half were married. The remainder, 30 percent, were single, and 22
> percent were widowed, divorced or separated, and 80 percent has at
> least some college education.
>
> This table details both the three- and the five-year cumulative
> Kaplan-Meier rates, as well as 95 percent confidence intervals for the
> complications of reoperation, explantation, capsular contracture,
> implant deflation and breast pain. For each of the complications at
> five years the cumulative rate increased. For example, reoperation
> went from 13.2 at three years to 20.2 at five years. Capsular
> contracture, 9.0 to 10.1. This is expected as this is a cumulative
> rate. That is, occurrences of complications that occurred in years
> four and five were added to the three-year cumulative rate.
>
> But it is important to note that for reoperation, explantation and
> breast pain there was no significant change in the complication risk
> rate per year during this five-year time period. The risk rate to the
> patient for capsular contracture, Baker grades 3, 4 and unknown,
> decreased. Only for deflation was there an increased risk rate per
> year.
>
> If we compare this five-year deflation rate to the published
> literature, we can see that the post-approval study rate is within the
> range of published literature which is 0-27 percent. As you can see,
> the rate for explantation also falls within the published rate.
> Reoperation and capsular contracture actually fall slightly under the
> published rate. Literature rates for breast pain were not captured.
>
> This table details the top ten reasons for reoperation. The first
> column is categorized by number of reoperations by breasts; the second
> column, reoperation by patient. So, 52 patients of 198 patients and 98
> breasts of the 343 breasts had capsular contracture as a reason for
> reoperation. The top three reasons in both columns are patient
> requested size exchange, leakage/deflation and capsular contracture.
>
> Explants, which are a subset of reoperations, are discussed in this
> table. This details the primary reason for explantation at both three
> and five years if the rate occurred at a rate greater than five
> percent. The primary reason at both three and five years was patient
> request for size exchange.
>
> Now, before I discuss the reconstruction data, I would like to more
> specifically define a reconstruction patient. This is a patient
> undergoing breast reconstruction as a result of breast cancer or
> congenital deformity. She could be expected to face a more extensive
> initial surgery and require additional treatment such as radiation
> therapy, or chemotherapy. Skin coverage over the implant, as well as
> achieving symmetry is more difficult than in augmentation patients.
>
> Saline prospective study demographic data shows that at the time of
> surgery a woman had an average age of 46 years. Approximately
> two-thirds of the women were married, and almost three-quarters of the
> women had some college education.
>
> This table details the three- and five-year Kaplan-Meier rates, as
> well as the 95 percent confidence intervals for reoperation,
> explantation, capsular contracture, breast pain and implant deflation.
> Again, this represents a cumulative rate so the five-year rates are
> higher than those at three years. Please note that the five-year
> numbers are updated, whereas the three-year numbers are those as
> presented at the 2000 panel.
>
> At five years there was no increased risk rate per year for any
> complication, while there was a decreased risk rate per year for
> implant removal, explantation, and reoperation, as well as capsular
> contracture Baker grades 3, 4 and unknown.
>
> If we compare these rates to those in published literature, we can see
> that three of the five rates were within the range from the
> literature. While reoperation did have rates above those in published
> papers, it is important to note that the patient risk rate per year
> actually decreased at five years.
>
> We would also like to note that the cumulative three-year rate, as
> presented in our saline PMA, was 40.2 percent. So, in the intervening
> two years the rate has increased less than three percent. Literature
> rates for breast pain were not captured.
>
> This table details the top ten reasons for reoperation. Again, the
> first column represents the percentages as categorized by number of
> reops by breasts, and the most commonly reported reasons were capsular
> contracture, asymmetry and patient request. The second column, by
> patient, the top three reasons were capsular contracture, asymmetry
> and leakage/deflation.
>
> This table details the primary reasons for explantation surgery at
> three and five years. As you can see, the primary reason was capsular
> contracture.
>
> In overview, patient contact and follow-up rates have increased. The
> responders adequately represent the entire study population through
> five years. The risk rate per year for the complications discussed
> decreased or stayed the same for four of five complications in the
> augmentation cohort and all five of the complications in the
> reconstruction cohort. For deflation, in the augmentation cohort the
> rate was within published literature.
>
> In summary, Mentor\'s saline-filled and Spectrum implants continue to
> perform in a safe and effective manner. As presented today, the
> complication rates are comparable with published rates. We will
> continue to follow patients through ten years and seek to continue to
> increase the total number of responders.
>
> Thank you. I would now like to present Ms. Donna Crawford.
>
> MS. CRAWFORD: Thank you, Cliff. Good morning. My name is Donna
> Crawford. I am director of corporate regulatory affairs for Mentor
> Corporation.
>
> I will be discussing the focus group study or the patient informed
> decision brochure. Mentor conducted this study as one of the
> post-approval conditions of saline breast implant PMA.
>
> There were four major purposes of the focus group study. The first was
> to determine whether the patient brochure effectively communicates
> information about the risks and benefits associated with breast
> implants.
>
> Secondly, it was important to assess whether the information in the
> brochure is presented in an understandable way and is clearly
> understood by prospective patients.
>
> Thirdly, we wanted to identify any unintended effects of the brochure
> and also any unanticipated effects of the brochure.
>
> Finally, we wanted to obtain patient suggestions for improvement and
> identify any additional information needed by the patients.
>
> The focus group study was conducted under an FDA-approved protocol by
> an independent research group by the name of Communications Sciences
> Group. Four focus group discussions were held, two in Dallas and two
> in San Francisco. The focus groups consisted of reconstruction
> patients or patients considering augmentation. There were eight to ten
> individuals in each focus group, and each group was balanced across
> age, employment status, income level and educational level.
>
> Data were collected in two ways. First, the participants were asked to
> read the brochure and complete a self-administered survey prior to
> participating in the focus group interviews. Secondly, the focus group
> interviews were led by a moderator who followed a discussion guide
> which was part of the focus group study protocol.
>
> Some of the key findings of the study are as follows. In general, the
> educational and informed decision objectives of the brochure were met.
> The majority of women had a good understanding of the risks and
> benefits associated with breast implants after reading the brochure.
> Eighty-eight percent of the respondents reported that they had learned
> new information about breast implants after reading the brochures, and
> 85 percent felt better able to ask their doctors questions about
> breast implants after reading the brochure.
>
> Most respondents felt that the brochure, on the whole, was clear and
> understandable, with the possible exception of the clinical data
> tables. Most respondents rated the brochure highly on comprehension
> and relevance, and 88 percent felt that the information in the
> brochure was useful to them.
>
> The study identified only one possible unintended effect of the
> brochure, and that was that some of the respondents felt that
> complication rates were not to be taken at face value because they
> were overstated in order to protect the manufacturer.
>
> Both the focus group discussion and the survey results found that the
> brochure was effective in conveying information, and 73 percent said
> that the information in the brochure was not confusing, and only six
> percent of the respondents felt that the brochure was confusing. There
> was some difficulty in understanding the meaning of cumulative risk
> rates and interpreting the data tables.
>
> The major suggestions for improvement had to do with improving the
> layout and format of the brochure; adding explanatory information to
> the data tables; choosing the content order to group augmentation data
> together and reconstruction data together; and adding a glossary and
> table of contents. The additional information amounted to small points
> of clarification only.
>
> In response to the focus group findings and suggestions from FDA, the
> following changes were made: A table of contents and glossary were
> added. The clinical study section was revised to separate augmentation
> and reconstruction data; and to simplify and explain the data tables.
> Some minor wording changes were made to improve the clarity. For
> example, an introductory paragraph was added to the clinical study
> section to explain how Mentor\'s clinical study data may relate to
> each patient\'s own experience. Sentences were added prior to each
> clinical data table to explain what the numbers in the table mean and
> how they were calculated.
>
> The brochure is in the process of being revised to add the five-year
> follow-up data from the post-approval study. The revised brochure will
> be available on the Mentor\'s web site and a printed version will be
> available in approximately six weeks following FDA approval.
> Therefore, this condition of approval has been fulfilled.
>
> I would now like to introduce Mr. Ron Crouther.
>
> MR. CROUTHER: Good morning. My name is Ron Crouther. I am vice
> president of advanced development for Mentor, and I would like to
> present interim results on three studies, our explant retrieval study,
> our post-approval fatigue testing, and also our real-time shelf-time
> testing.
>
> First on the explant retrieval study, the objective of this study was
> to retrieve 300 devices that were explanted because of deflation and
> perform appropriate analyses to determine the mode of failure. The 300
> devices were selected to cover a range of saline device types, that
> is, smooth and textured devices, various shapes, and devices
> containing our two valve types, diaphragm valves and Spectrum kink
> plug valves.
>
> Upon receipt of the explanted devices, we first captured the device
> descriptive information and clinical information. This included device
> type, date of manufacture, time [in vivo]{.underline} and time of
> surgery. All devices were then visually examined and additional
> microscopic examination of the surface of the defect area was
> conducted to better characterize the type of failure mode. Leak
> testing was performed, as was necessary, to confirm that all leak
> sites had been located. The last phase of our testing was physical and
> mechanical property testing.
>
> We provided an interim report on 38 devices to the FDA in August of
> 2001. We completed our study of 310 devices and submitted the final
> report in our May, 2002 annual report. Because we have just submitted
> the final report and the FDA has not had adequate time to complete its
> review, the presentation today is based only on the interim report on
> 38 devices.
>
> This table summarizes the failure modes we saw on the 38 devices for
> both smooth and textured devices. The first failure mode is material
> separation, a term which Mentor has used for many years to describe a
> tear or split in the device without very significant abrasion or
> thinning at the site of the defect. Material separation is the primary
> failure mode of our Siltex devices. As supported by a wider study of
> Siltex devices, most material separation failures do exhibit evidence
> of folding at the site of the defect, often compound folding in which
> the outer surface of the implant is in tension causing the split to
> propagate from the outside in.
>
> The second failure mode is smooth crease-edge opening or crease-fold
> failures on smooth devices. These are similarly related to folding
> and, in contrast to material separation defects, do exhibit very
> obvious abrasion and thinning at the failure site.
>
> Sharp-edge openings can be duplicated by puncture with a surgical
> instrument and are very likely indicative of iatrogenic damage. We
> also had two reported cases of leaking valves, however, one could not
> be confirmed and, if you will notice, the numbers in the left-hand
> column do not add to 19 as we had one Spectrum kink plug valve device
> in which the tubing was not fully withdrawn per our instructions for
> use, and when the tubing was withdrawn the device did not leak.
>
> To summarize, the failure modes that we saw in this interim report
> reflect what we have seen in our clinical study information, as well
> as our product evaluation or complaint database. There is evidence of
> folding present in a majority of the failures that did not exhibit
> evidence of instrument damage. Again, Mentor\'s final report covering
> the 310 devices is under review by the FDA. The general findings in
> that study are similar to what we saw in the preliminary report.
>
> The next topic I will briefly discuss is Mentor\'s fatigue testing of
> our saline-filled breast implants. Fatigue testing involves cyclic
> compression testing for our implants up to 10 million cycles and
> utilizes an apparatus that is schematically represented here. The
> sample is located here, between two flat platens, one of them fixed
> and one of them movable. The movable platen oscillates up and down to
> apply the compressive force to the implant. The implant is immersed in
> a saline bath that is kept at 37 degrees Celsius.
>
> We had two phases and two objectives to our fatigue testing. The first
> objective was to create AF/N curves, that is, applied force versus
> number of cycles to failure for the various device types. There were
> four device types chosen for the study. Along the Y axis we have the
> applied force; along the X axis are cycles to failure. As you can see,
> as you decrease the applied force the device will withstand more
> cycles until failure.
>
> The second phase of our testing was to conduct long-term fatigue
> testing and calculate fatigue safety factors for each of the four
> device types. The fatigue safety factors are calculated according to
> the formula you see here. I am not going to try to point to it, but it
> is the force to achieve 10 million cycles without failure, what we
> call our run-out load, divided by the estimated device load during
> walking, which we conservatively estimate to be two times the device
> weight. The safety factor chosen for this, in consultation with the
> FDA, was greater than or equal to 2.
>
> The protocol was approved by the FDA. Four device types were chosen
> for the study. Those four were the smooth and Siltex round diaphragm
> valve devices, smooth round kink valve devices and contour tall
> profile devices. The tested devices include all sterilization methods
> that we currently use and that are approved by the PMA.
>
> We chose for the testing the smallest devices of each device type as
> those typically have our thinnest wall thickness. We also made special
> runs of those devices in which we ran at the absolute minimum of our
> tolerance extreme for shell wall thickness as well as texture layer
> thickness. As such, this device configuration represents worst-case
> physical testing as defined in the FDA\'s breast implant PMA guidance
> document.
>
> These are the results to date for three of the four devices completed.
> This is the phase one testing, which was the generation of the AF/N
> curves. Again, along the Y axis we have load amplitude; along the X
> axis we have cycles to failure. It is a logarithmic scale so, again,
> 10,000, 100,000, a million and so forth. The three devices are the
> smooth Spectrum device, the Siltex diaphragm valve device and the
> smooth diaphragm valve device. So, for example, for the Siltex
> diaphragm valve device a load amplitude or force applied of 50 lbs
> requires approximately one million cycles to generate failure.
>
> Based on this phase one testing, as well as other experimental data, a
> run-out value of 10 lbs was chosen for our second phase of testing,
> which was the long-term fatigue testing. Again, the goal of that was
> to withstand the 10 million cycles without failure at the 10
> laboratory load level. We have successfully completed testing on three
> of the devices. Again, if we calculate a safety factor based on the
> formula here, the run-out load of 10 lbs is divided by the estimated
> device load during walking, or two times the device weight. Since we
> chose the same size device for each of the three device types, 125 cc
> device in each case, the device weights were very close to the same
> thing, so ten divided by two times the device weight for all three
> devices turns out to be 16.7. Again, if you recall, our acceptance
> criterion was a safety factor greater than 2.
>
> To summarize, three of the four device types have been completed. The
> fourth is scheduled to begin shortly, probably within about the next
> month to month and a half. AF/N curves have been generated, and
> fatigue safety factors have been calculated for three of the four
> devices, which far exceeds the protocol requirements, again using
> worst-case test samples.
>
> The last topic I would like to discuss this morning is our real-time
> shelf-life testing. As Dr. Michael mentioned, this was twofold in
> terms of objectives. First, to support our current shelf life of four
> years and then, secondly, to extend that shelf life out to five years.
>
> The testing is being performed under an FDA-approved protocol. Seven
> device types are included in the testing in order to cover small and
> large devices; all packaging types and sizes; all sterilization
> methods; and all different device and component configurations.
>
> The testing includes mechanical and shell tensile property tests,
> which include tensile and elongation, tension set, joint strength and
> valve competency tests. The packaging seal peel strength, microbial
> challenge and dye penetration tests are performed to ensure
> maintenance of sterility.
>
> Our status is that all devices have been tested at the time zero time
> point, with all devices meeting all specifications, and the four-year
> testing will be completed in the year 2005. The five-year testing will
> be completed in the year 2006.
>
> This concludes my presentation, and I would now like to reintroduce
> Dr. Michael.
>
> DR. MICHAEL: The overall summary of our presentation this morning is
> that we presented five-year data for the post-approval study, and we
> will continue to follow all our patients through ten years, and we
> will continue to update the agency in our annual reports.
>
> For the focus group study, the study has been completed. For the
> retrieval study, we have completed the study. It is under FDA review.
> Fatigue testing, we tested three out of four styles. The last style is
> scheduled to start six weeks from now. Lastly, the shelf-life testing
> is ongoing through five years.
>
> Mr. Chairman, panel members, FDA staff, I would like to thank you for
> your attention and, after FDA\'s presentation, we would be glad to
> answer any questions you may have. Thank you.
>
> DR. WHALEN: Actually, if you wouldn\'t mind, we will ask you to answer
> some questions before FDA\'s presentation and then perhaps again.
>
> DR. MICHAEL: That is fine.
>
> DR. WHALEN: If I could start off, Ms. Crawford, the focus groups had
> relatively small numbers as most focus groups do, but it was unclear
> to me what the composition of that group was vis-a-vis thinking about
> having the implant, having had the implant, having had it and having
> had it removed.
>
> MS. CRAWFORD: Yes, the augmentation focus groups consisted of patients
> who were considering augmentation. The reconstruction focus groups
> were primarily patients that had already had reconstruction with
> breast implants.
>
> DR. WHALEN: And all of them were still in place?
>
> MS. CRAWFORD: Yes.
>
> DR. WHALEN: Dr. Dubler, do you have any questions about the focus
> group results?
>
> DR. DUBLER: Yes, I have one question about the focus groups, that is
> that it seemed to me that one of the findings was that they really
> didn\'t understand the data sets and what they said. Would you agree?
>
> MS. CRAWFORD: There was some confusion about exactly what the meaning
> of what a cumulative risk rate was, and there was some confusion in
> terms of the data tables, which often switched from identifying data
> by patient, some by implant, some by total patient population. We have
> addressed that and made clarifications to the data tables to address
> that confusion.
>
> DR. DUBLER: Have you left them in table form?
>
> MS. CRAWFORD: Yes, the data tables still are included in the brochure,
> yes.
>
> DR. DUBLER: Have you translated them into reasonable lay language, or
> simply left them in the table form?
>
> MS. CRAWFORD: It is in table form by patient and each table has at
> least a couple of sentences of introduction to explain what the
> numbers are.
>
> DR, DUBLER: I have another question about the presentation. Would it
> be appropriate to ask it now?
>
> DR. WHALEN: Yes.
>
> DR. DUBLER: I believe it was Dr. Michael who stated that there were
> three exclusions from your follow-up cohort.
>
> DR. MICHAEL: It was Cliff Kline in his post-approval study
> presentation.
>
> DR. DUBLER: The three exclusions were patients who had died? What were
> the three exclusions, please?
>
> MR. KLINE: The three exclusions were patients who had died, had their
> implants removed or had withdrawn by choice, discontinued by choice.
>
> DR. DUBLER: Discontinued what?
>
> MR. KLINE: They elected not to participate in the post-approval study
> when we asked for their participation and consent.
>
> DR. DUBLER: I see, and what percentage of your cohort was represented
> by those three categories, total cohort?
>
> MR. KLINE: I would have to look and determine those numbers by those
> three groups. I don\'t have that information available at the moment.
>
> DR. DUBLER: Why did you decide to exclude patients who had removed the
> implants? One would think that they would be an important source of
> information.
>
> MR. KLINE: You are exactly right, in that we captured all
> complications, including removal, and reported those complications
> today. After a patient has her breast implants removed, she no longer
> has a study device in her body and, therefore, she is no longer
> studied. But, of course, until the device is removed we do study her
> and collect and report on all complications.
>
> DR. WHALEN: Dr. McCauley?
>
> DR. MCCAULEY: I just have a question related to the focus group study.
> Did these groups have group leaders, and if they did, how were they
> chosen?
>
> MS. CRAWFORD: There was a moderator that was an employee of
> Communications Sciences Group that followed the discussion guide that
> was part of the protocol. There wasn\'t a leader of the focus group
> participants per se, but there was a moderator who conducted the
> discussion among the focus group participants.
>
> DR. MCCAULEY: After your separation out of the data, was there
> significant improvement in the confusion level or decrease in
> confusion that some of the participants expressed?
>
> MS. CRAWFORD: Well, since we did the focus group study on the original
> version of the brochure before the data were separated out, we
> haven\'t gotten feedback on the brochure with the data separated. So,
> I can\'t answer that question. It was primarily so that somebody
> undergoing reconstruction would not have to sort through the
> augmentation data that wasn\'t applicable to them.
>
> DR. WHALEN: Dr. DeMets, would you have any questions or comments about
> the statistics that were presented to us, or any particular vantage
> point on the percent follow-up that they have vis-a-vis other clinical
> studies in a population similar to this?
>
> DR. DEMETS: Yes, I actually have two sets of questions, one for Mr.
> Crouther and one for Mr. Kline. You said that you recovered 310
> implants and those reports have been done and submitted. Why is that
> we aren\'t privileged to see that today?
>
> MR. CROUTHER: We just submitted those to the FDA with our annual
> report and it is still under review by the FDA.
>
> DR. DEMETS: Is there some regulatory reason why we can\'t see that
> data? I mean, you are giving us 38 and there are 310, or something,
> that are available.
>
> DR. WITTEN: We usually review data and send it to the panel before it
> is presented in a panel session.
>
> DR. DEMETS: All right. On the time to failure, how many actual samples
> are tested in that? Is it one sample from each of the devices?
>
> MR. CROUTHER: No, for the long-term fatigue testing a minimum of
> three, and for the AF/N curves three also.
>
> DR. DEMETS: Did you calculate or compute any time to failure? You only
> have three but you presented your data on how many cycles it took, but
> is there some way you can translate that into failure time?
>
> MR. CROUTHER: Not directly into failure time. The 10,000 cycles,
> again, was agreed to with the FDA and 10,000 cycles represents walking
> for eight hours a day at a rate of one Hertz or one cycle per second.
>
> DR. DEMETS: The remainder of my questions are for Mr. Kline. Can you
> explain to me in a little more detail the process that you went
> through to capture information from the patients just to get
> responses?
>
> MR. KLINE: Certainly. In terms of how we got the patients to agree to
> participate or not?
>
> DR. DEMETS: Just the process. I am not understanding the process that
> you went through because the response rate is low relative to
> standards that I am used to. So, I am trying to understand what you
> did do.
>
> MR. KLINE: Well, once we did get protocol approval through working
> with FDA, we then contacted first the investigators to see what
> information they had on the patients because, as you know, a patient
> population can move. So, once we determined first from the
> investigators that they wanted us to contact the patients directly, we
> then worked with them to get the addresses. Once we had the updated
> addresses from them, we then also checked with NCOA to make sure that
> the doctor\'s address was verified by NCOA. Then we began to
> correspond via mail with the patients. The SPS study only had patients
> consented for the three-year study. That is why in the first mailing
> we included a questionnaire as well as a consent to ask them to
> participate in the study through ten years. So, the first step, once
> we had the address was to see if the patient would consent to
> participate in this additional follow-up.
>
> DR. DEMETS: Was there a reason that you didn\'t ask the investigators
> themselves\--not the investigators, the surgeons to collect this
> information from their patients as opposed to doing it directly from a
> mailer?
>
> MR. KLINE: It was an option, and we asked each doctor if they wanted
> to contact the patients themselves or they wanted Mentor to, and they
> all elected\--except for the three that declined any contact with
> their patients\--us to be their representative and to contact the
> patient directly.
>
> DR. DEMETS: And, was the questionnaire such that the patient would be
> able to fill out all of the items accurately?
>
> MR. KLINE: Yes, once they got the questionnaire, the form was fairly
> basic but also had an explanation as to what we were asking them to
> do. There was a letter accompanying that as well as, of course, the
> informed consent in the first mailing. If they had any questions, they
> could call us. There was a phone number for them to call.
> Additionally, if there was something that was incorrectly filled out
> on the form, the clinical research associate working on that study
> would contact the patient directly and get clarification.
>
> DR. DEMETS: Do you have any insight as to why the response rate is
> what it is?
>
> MR. KLINE: Well, the response rate, as we have heard today, has
> improved. We will continue to work to improve the number of
> responders. I would say that many of the patients are transient\--not
> transient but have moved from their location where they were being
> seen by their doctors as part of the SPS study. The doctors sometimes
> did not know where they were at, or thought they knew and it turned
> out that they didn\'t. So, some of it was just finding the patients,
> which is one of the ways that we improved follow-up by using the
> ChoicePoint database, which is a database which gives more current
> addresses than even NCOA. Then, using that as well as FedEx, we were
> able to track the patients down and determine, if there were three
> addresses for one patient, which address was the correct one, if any,
> and then work with the patient.
>
> DR. DEMETS: Do you have any sense of what you think you can get this
> response rate to be, and what a target should be?
>
> MR. KLINE: Well, I don\'t. I don\'t want to give a hypothetical
> because we don\'t know, but we are continuing to work even as we speak
> to improve the contact and follow-up rate.
>
> DR. DEMETS: Do you have a sense of what a target rate should be?
>
> MR. KLINE: Well, as in an FDA guidance document, for a two- or
> three-year study we would hope 80 percent. Obviously, at ten years I
> would estimate we would like to have 60 percent. We are obviously
> somewhere in between there and are working to improve both contact and
> follow-up.
>
> DR. DEMETS: So, you think an 80 percent response rate at five years
> and a 60 percent at ten years would be adequate for your purposes?
>
> MR. KLINE: Yes, 80 percent at two to three years and 60 percent at ten
> years.
>
> DR. DEMETS: Do you have any sense of what a typical clinical trial
> expects in follow-up response rates?
>
> MR. KLINE: Just talking about the breast implant studies today, the
> breast implant study guidance document indicates 80 percent follow-up
> at least at two to three years and, of course, we are enrolling
> adequate patients in other breast studies for adequate follow-up for
> ten years.
>
> DR. DEMETS: Well, I will comment later but I worry a lot about the
> adequacy of even those response rates given the potential biases that
> exist, and those biases can be very powerful.
>
> I would like to follow-up on a comment or a claim that you made that
> the responders are the same as the non-responders. Could you detail
> that? That is a strong statement you make and I am trying to
> understand that.
>
> MR. KLINE: That is a very good question, and I would like to have Dr.
> Eugene Poggio, managing vice president and executive director of
> biostatistics and epidemiology at ACT, address that since he is a
> biostatistician and can more correctly address your question. Is that
> okay?
>
> DR. WHALEN: Sure.
>
> DR. POGGIO: My name is Gene Poggio and, as Cliff indicated, I am
> managing vice president of biostatistics and epidemiology at APT
> Associates Clinical Trials. We are under contract to Mentor to do data
> management and statistical analysis for both the original SPS study
> and the follow-on post-approval study.
>
> I have no personal financial connection with Mentor, aside from the
> fact that the firm I am employed by has contractual arrangements. My
> travel was paid through that contract by Mentor. I am not involved in
> any lawsuits whatsoever, and I certainly derive no income from implant
> surgery.
>
> With regard to the issue of response/non-response, the way we dealt
> with that is we took all the information we had on baseline
> characteristics and operative characteristics and conducted logistic
> regression. This was done separately for the augmentation cohort and
> the reconstruction cohort. We used logistic regression to identify
> variables that were significantly related to response/non-response. I
> should say that for purposes of that analysis, response/non-response
> was defined as participating in the PAS versus not participating in
> the PAS, and didn\'t deal with loss to follow-up before that.
>
> Through that, we identified some variables that were related. For
> example, for augmentation it was age and annual income, and for
> reconstruction it was several variables, some operative
> characteristics and some demographics. Having identified those
> variables, we then stratified the population by that set of variables,
> conducted a Kaplan-Meier analysis within each stratum and then
> computed a weighted average of the Kaplan-Meier estimates with the
> weights being the initial number of patients in each stratum. The
> result was numbers that were remarkably close to the original
> estimate. The largest deviation of the adjusted number to the original
> number was half a percentage point.
>
> DR. DEMETS: So, what percent of those risk factors that you identified
> explained the response/non-response rate?
>
> DR. POGGIO: What was the total percent explained?
>
> DR. DEMETS: I know it is not easy to answer in a logistic regression
> but in analysis of variance you could do that. There are such
> measures, by the way.
>
> DR. POGGIO: I don\'t know the answer to that question.
>
> DR. DEMETS: So, suppose it didn\'t explain much, would your analysis
> or your adjustments be useful? You are making a claim that these two
> groups are the same so I am challenging that.
>
> DR. POGGIO: I guess my statement would be that we did everything we
> could to adjust for it. We looked at the information we had about
> baseline variables, both demographic characteristics and operative
> characteristics. We looked at which ones related to
> response/non-response and then adjusted for those. It is obviously
> conceivable there is some other variable that we don\'t have access to
> that could explain part of it.
>
> DR. DEMETS: I am not sure who wants to answer this, but there was a
> comment that there was no follow-up of those patients in whom the
> implant was removed. Somewhere else it was said that you used a
> Kaplan-Meier methodology to censor that observation. There are some
> assumptions that are required to employ the Kaplan-Meier method about
> censoring. Can you comment on how that was investigated in the study?
>
> MR. KLINE: This is Cliff Kline. Dr. Poggio can explain how the
> Kaplan-Meier was used in this setting.
>
> DR. POGGIO: I think you are referring to some of the earlier comments
> that we excluded patients with explants.
>
> DR. DEMETS: Let me be specific. The assumption is that the censoring
> mechanism is independent of the process that is going on. So, I am
> trying to understand how you came to that conclusion.
>
> DR. POGGIO: Let me make clear at the outset that patients that were
> explanted were certainly kept in the analysis up until, if you will,
> the day after they were explanted. If we had data after that, all that
> data was reported to the FDA. In order to be conservative, we didn\'t
> feel patients were at risk for the complications once the implant was
> removed. You are not really at risk for capsular contracture after
> removal. So, if we were to include them after that point the estimates
> would actually go down, and we didn\'t think it would be appropriate
> to do that.
>
> In terms of the issue of the censoring, yes, obviously the underlying
> assumption in Kaplan-Meier is that the people who aren\'t censored
> look like the people who are censored\--rather, the other way around.
> Obviously, the adjustment we made was a refinement on that in that we
> don\'t assume that the censored people look like all of the uncensored
> people. We assume they look like the uncensored people in the stratum
> that we defined by the variables that we stratified.
>
> DR. DEMETS: I am still not sure I fully understand the statement you
> are making. The other issues I want to ask about have to do with if
> you censor the patients at the time of the implant being removed, do I
> understand that complications that may take place after that point are
> not captured? I mean, we have heard this morning\'s testimony that
> some of these complications can occur\--
>
> DR. POGGIO: They are captured in the data provided to the FDA, in data
> listings. They are not included in the analysis because we don\'t
> feel\--I mean, it was really my decision. We didn\'t keep them in the
> Kaplan-Meier because we don\'t feel they are appropriately included
> predominantly because those patients are not at risk for most of the
> complications with the device no longer in place.
>
> DR. DEMETS: That is an assumption, it seems to me.
>
> DR. POGGIO: I guess if you asked a surgeon if they could have capsular
> contracture, a new case of capsular contracture after the device was
> removed, I would assume they would support that.
>
> DR. DEMETS: But my question was not about that; it was about other
> complications.
>
> DR. POGGIO: As I said, we didn\'t feel they should be included in the
> analysis because they are certainly not at risk for many of the
> complications.
>
> DR. DEMETS: Which is what the data are trying to understand, if they
> are there. Aren\'t you precluding that if you take them out?
>
> DR. POGGIO: If I include them in I assume that they are at risk and,
> in fact, I think that would lower the estimated complication rates.
> You could do a special analysis to look at that question. I would be
> very reluctant to include them in a principal analysis when I no
> longer think they are at risk.
>
> DR. DEMETS: It seems to me that you get rid of some of the
> complications if you don\'t follow them beyond that censoring point.
>
> DR. WHALEN: If I could interject, would it be a more graphic example
> to state that deflation would be rather ridiculous to continue to
> measure in someone who has had an explant because it is hard to
> deflate something that isn\'t there? Indeed, if they kept those
> patients in the denominator it would dramatically lower the deflation
> rate falsely.
>
> DR. DEMETS: I am thinking about other kinds of complications.
>
> DR. WHALEN: I am only trying to interject to say that it seems to me
> that there have to be different sets of data of complications, ones
> that could continue with the implant in place and ones that would not.
>
> DR. POGGIO: And, remember that the ones we are looking at are
> deflation, capsular contracture, explantation which, obviously could
> only happen if they had a reimplantation. Obviously, breast pain
> could. But my view is it would be reasonable to look at that as a
> separate issue but I still would be very reluctant to include it in a
> principal analysis because they are not at risk for some of the
> complications, and certainly much lower risk for some others.
>
> DR. DEMETS: My last question is about the table at five years that you
> compare to three years, the denominators are different. In fact, they
> are larger at five years than at three years. Can you explain that?
>
> DR. WHALEN: Could you give a number that you are looking at so we can
> make sure we are looking at the same thing?
>
> DR. POGGIO: It is certainly true that we did get additional three-year
> data in the PAS study also.
>
> DR. DEMETS: It is your slide 19 in your presentation. At five years
> you report 211 patients, at three years you report 138. There are
> several like that but that is one.
>
> DR. POGGIO: Sure. In that table the N under five years, which is 211,
> indicates the number of implants that had reoperations, whereas at
> three years the number of implants involved in reoperations was 136.
> Therefore, the denominator increases because we had more implants
> involved in reoperations.
>
> DR. DEMETS: So, are we looking at comparable groups?
>
> DR. POGGIO: You are looking at 211 explants at five years and 136
> explants at three years. So, there are obviously more explants as time
> goes on.
>
> DR. DEMETS: Thank you.
>
> DR. WHALEN: Dr. Dubler?
>
> DR. DUBLER: Could I ask one more question, please, about the focus
> groups? I am very concerned about how the resurgery rate is presented
> and defined. So, can you tell us, and this may be unreasonable, how
> that was explained in your first \"informed consent\" or what I prefer
> to call disclosure document, and after your focus groups how you might
> have restated that? So, if there is a table about the chance of
> resurgical interventions?
>
> MS. CRAWFORD: Yes, I am looking at the version of the brochure that we
> did the focus group study on right now. There is a section on
> reoperations. It does give the three-year risk rate of reoperation by
> patient and by implant.
>
> DR. DUBLER: So, there is a table?
>
> MS. CRAWFORD: There are tables.
>
> DR. DUBLER: And what do you say about the tables? Are there
> declarative sentences?
>
> MS. CRAWFORD: Prior to the tables, for example, it just indicates that
> the following are the cumulative risk rates, first occurrence for the
> following complications.
>
> DR. DUBLER: So that is the text? Could you read us the particular
> language?
>
> MS. CRAWFORD: Certainly. I just want to make sure I am looking at the
> right place here. The question at the heading of the section is what
> were the three-year cumulative complication risk rates of first
> occurrence? Then the sentence following that says the cumulative risk
> rate of first occurrence which occurred in at least one percent of the
> patients are shown in the following tables, including all levels of
> severity, mild to severe. Then it lists the complications. This
> particular section is talking about augmentation and it lists the
> complications that were found in augmentation patients.
>
> DR. DUBLER: Are there any other declarative sentences that surround
> the table?
>
> MS. CRAWFORD: Not in the original version.
>
> DR. DUBLER: And in the version that was modified by the focus groups,
> is it very different?
>
> MS. CRAWFORD: Yes, the column by implants was eliminated, and there
> were some explanatory sentences. I don\'t have that right in front of
> me at this moment, but that was added. In the introduction of the
> whole section on cumulative risk there were a couple of sentences
> explaining how the risk rate can be interpreted and what it means to
> the patient.
>
> DR. DUBLER: Let me ask anyone to answer the following question, what
> is your chance of going back in for surgery, what is your five-year
> chance of going back in for surgery after receiving a breast implant?
> That is my question. What would you say to me? What is your percentage
> chance?
>
> DR. MICHAEL: Are you talking about augmentation?
>
> DR. DUBLER: I want to know how you would translate that table.
>
> DR. MICHAEL: Are you talking about the augmentation group or the
> reconstruction?
>
> DR. DUBLER: Either one, take your choice; augmentation. What is the
> chance that you are going to have another surgery in the next five
> years?
>
> DR. MICHAEL: Well\--
>
> DR. DUBLER: What percentage chance?
>
> DR. MICHAEL: Let me mention something here for the augmentation group,
> in one of the tables that was presented this morning 30 percent of
> reoperations in the augmentation group was the patient\'s choice for
> change of size. In the reconstruction group 16 percent was the
> patient\'s choice for a larger size or a different size, and 15
> percent in that cohort was expected because that was stage
> reconstruction. So, one-third out of that.
>
> DR. DUBLER: I want to say to you I know I may want to decide to change
> my size but, given all of the factors that lead to surgery, what is
> the chance, including my changing my mind\--what is the chance that I
> am going to have another surgery in the next five years?
>
> DR. MICHAEL: Based on what we presented in our data this morning, the
> chance, if using the same mix of the product that was used in the SPS
> study, at five years the probability of having a deflation is 9.7
> percent.
>
> DR. DUBLER: That is not what I asked you. What is the chance in the
> next five years, for any reason, that I am going to have to have
> surgery again? What do your data show?
>
> MS. CRAWFORD: It shows that there is a 20 percent risk rate at five
> years, and the way that is explained in the patient brochure is that
> 20 out of 100 patients will experience at least one reoperation during
> five years. That is how it would be explained. There is an example
> given, and to translate that to a reoperation number, that is how it
> would read.
>
> DR. DUBLER: So, your statement is that there is a 20 percent chance in
> the next five years that you will have to have another surgery.
>
> MS. CRAWFORD: That is how it would be interpreted. For example, the
> brochure right now gives an example for a cumulative risk rate of two
> percent for infection. That means that approximately two patients out
> of 100 will experience at least one infection sometime during the
> first year. So, since our five-year risk rate was 20.2 percent for
> reoperation, that is how it would be interpreted.
>
> DR. DUBLER: Thank you.
>
> DR. WHALEN: Can I just interject, more in comment, if a third of your
> reoperations are patient choice for a different size, would it not
> perhaps be more appropriate to say there is a 20 percent chance I am
> going to have another operation; there is a 14 percent chance I am
> going to have to have another operation? Since the wording you use was
> I am going to have to have another operation?
>
> DR. MICHAEL: I would like to take a couple of minutes to introduce Dr.
> Roger Freedman. He is a clinical instructor\--
>
> DR. WHALEN: For what purpose?
>
> DR. MICHAEL: To elaborate on that issue of the percentage of
> reoperations based on his experience in practice.
>
> DR. WHALEN: I don\'t think that is necessary. Thank you. Dr.
> Newburger?
>
> DR. NEWBURGER: I have a question for Mr. Kline regarding the attempts
> to contact patients to participate in the post-marketing study. How
> long is the questionnaire that they are sent?
>
> MR. KLINE: One page.
>
> DR. NEWBURGER: How many questions on that one page?
>
> MR. KLINE: Of course, we ask them to verify that their name is spelled
> correctly, but there is a question on capsular contracture,
> explantation, reoperation. So, there is just a very small list of
> questions to specifically ask them about the complications we are
> collecting.
>
> DR. NEWBURGER: Is there any incentive to the patient to return the
> questionnaire?
>
> MR. KLINE: Yes, there is.
>
> DR. NEWBURGER: And what would that be?
>
> MR. KLINE: I don\'t recall the exact amount. It is minimal. It would
> be somewhere under \$30.
>
> DR. NEWBURGER: And, how do you explain your protection of patient
> confidentiality?
>
> MR. KLINE: Well, that is explained both in the original letter they
> get as well as the informed consent that they sign which, of course,
> indicates that we will try to protect their confidentiality; it may
> not be able to be done if, for example, a government agency such as
> FDA needs to review these data.
>
> DR. WHALEN: Dr. Doyle?
>
> DR. DOYLE: I have a question regarding the reoperations. How are these
> women included in the further data? Is that reoperation considered a
> new start, or is it a continuation of the patient? Also, I am confused
> about your three-year and your five-year cohorts of women. They are
> not necessarily the same patients, is that correct?
>
> MR. KLINE: To answer your second question first, all post-approval
> study patients were originally SPS, saline prospective study patients.
>
> DR. DOYLE: But the people who answer at five years and the people who
> answer at three years are not necessarily the same group of patients.
> As you might ordinarily expect where you have attrition, that those
> who were left at five years would have answered at three. In this you
> have two separate groups actually who all started together but the
> five years may not be in the three-year data and the three years may
> not be in the five-year??
>
> MR. KLINE: I would agree with that, but most of the patients\--as the
> panel members saw\--that were present two years ago, our follow-up
> rates were a little bit higher so most of the patients that were
> reported on at the three-year PMA were also included in this study.
>
> DR. DOYLE: But some of your five years were not included in your three
> years.
>
> MR. KLINE: Pardon?
>
> DR. DOYLE: Some of your five years were not included in your three
> years.
>
> MR. KLINE: There were a couple of patients that we were able to
> collect additional information on that we didn\'t have three-year
> information on at the time of the PMA.
>
> DR. DOYLE: Okay, and what about how you handled the patients with the
> reimplantations? Do they start at year one or do they continue?
>
> MR. KLINE: They continue unless the reoperation\--as I said, explants
> are a subset of reoperations, obviously if they are explanted they are
> no longer\--
>
> DR. DOYLE: No, these are the ones who were reimplanted. They start out
> as year one or continue?
>
> MR. KLINE: They continue.
>
> DR. WHALEN: Are there any questions by any of the panel members about
> the biomaterials presentation? Dr. Miller?
>
> DR. MILLER: I just have a couple of questions on that. Ten million
> cycles in that machine, how many years of walking does that represent?
>
> MR. CROUTHER: That is one year of walking eight hours a day, one
> second per cycle.
>
> DR. MILLER: How do you feel that system, that test that was
> devised\--I know it was all agreed upon by FDA, but how do you feel
> that actually simulates what that implant is experiencing, especially
> considering the fact that so many failures occurred at the site of a
> fold? Do you think that testing in this way is a good simulation of
> what the implant experiences?
>
> MR. CROUTHER: It is a good simulation of some of what an implant
> experience is; it is not a good simulation to duplicate a fold failure
> like a material separation defect.
>
> DR. MILLER: Which is how most fail.
>
> MR. CROUTHER: Correct, most of the textured devices that are
> non-instrument damaged devices fail that way.
>
> DR. MILLER: The other question I had is that several of the presenters
> this morning suggested that there are materials released from the
> device that may be toxic, and platinum was mentioned several times
> today. Is it fair for me to ask about your response to the
> manufacturing methods that employ platinum, and is this a concern that
> you have about the presence of such trace materials?
>
> MR. CROUTHER: I am going to ask Phil Yang, who is our corporate vice
> president of technology submissions, to answer that question.
>
> MR. YANG: Phil Yang. We have done a risk analysis based upon what we
> know. We do a specific analysis for I believe 20 heavy metals, of
> which platinum is one. We do do that. That is compared against what is
> in the literature for toxicity data. So, we do compare that. That is
> all part of the PMA.
>
> DR. MILLER: When you determined those materials are released, do you
> look at an implant subjested perhaps to a type of environment as
> described in your mechanical study?
>
> MR. YANG: We can\'t do that because probably we would find metals from
> the platens themselves. So, we do it on sterilized, finished devices
> from the package because that is what would go into a patient.
>
> DR. MILLER: Is it possible that a device subjected to the environment
> [in vivo]{.underline} would have a different profile of release of
> trace elements?
>
> MR. YANG: It is possible. The problem becomes when you try and analyze
> for them, you then have to somehow correct for what the patient
> contributed to that device. That becomes very complicated. We tried to
> do that in some cases but the techniques that we use are not
> designed\--things like proteins get in the way. So, it is hard to do.
> It is not impossible to do that; some people have tried to do that but
> the question is how good is the analysis, and that has always been a
> question.
>
> DR. MILLER: Thank you.
>
> DR. WHALEN: Dr. Choti?
>
> DR. CHOTI: Just a couple of questions, Mr. Kline. One, just to clarify
> again the follow-up of the two different cohorts that you looked at,
> you showed a five-year follow-up rate in the new analysis of 60
> percent, 50-60 percent on average I think, depending on whether it was
> reconstruction or augmentation. What was the three-year follow-up
> given the new follow-up that you have, a better follow-up, and how
> does that compare to the original PMA data? In follow-up to that, when
> you compared the three-year to the five-year, why did you use the new
> follow-up data rather than the original PMA data?
>
> MR. KLINE: The follow-up in the PMA was approximately 70 percent for
> both cohorts.
>
> DR. CHOTI: Three years?
>
> MR. KLINE: Yes, at three years, the PMA submission at three years. The
> analysis that we did does include all data, whether it is five-year or
> updated three-year. So, the analysis is on all the data that we have.
> The numbers for the PMA and the numbers that I showed for the
> three-year columns were just for consistency\'s sake. The three-year
> numbers submitted in the PMA just varied slightly because of some new
> patient data that we got.
>
> DR. CHOTI: The other question is regarding the textured versus the
> smooth. In the clinical data, did you look at differences in
> deflation, capsule and reoperation between the two groups? Also, what
> were the relative percentages of the two types?
>
> MR. KLINE: We did look at the difference in deflation rates between
> smooth and what we call Siltex or textured product. The rate for
> smooth products, for all products was approximately 5-6 percent and
> the rate for Siltex was approximately 11-12 percent.
>
> DR. CHOTI: As the population as a whole of the two types, what did you
> have in the group?
>
> MR. KLINE: We presented that in Dr. Michael\'s first slide, 30 percent
> smooth and approximately 70 percent textured.
>
> DR. CHOTI: And how was that changed near the end of the trial or more
> currently?
>
> MR. KLINE: You are exactly right, with the current mix of product,
> with the product mix that we had in the study those were the rates.
> You know, doctor preferences have changed. At this point it would be
> appropriate to bring up Dr. Freedman to discuss the current preference
> mix that he uses in his own practice. As Dr. Michael was explaining
> before, Dr. Freedman is a clinical instructor for plastic and
> reconstructive surgery at George Washington University. He is a
> clinical assistant professor for plastic and reconstructive surgery at
> Georgetown University, and a consultant to the Department of Plastic
> and Reconstructive Surgery for the NIH.
>
> DR. FREEDMAN: My name is Roger Freedman. Approximately 35 percent of
> my practice is breast surgery
>
> DR. WHALEN: I am sorry to interrupt, but could you identify with the
> questions?
>
> DR. FREEDMAN: Oh, I am sorry. I am not involved in any suits. I have
> provided my own travel today. I do put in breast implants and I am
> also involved in the core gel breast implant study provided by Mentor.
> So, I do get some compensation for that study.
>
> My practice consists of approximately 35 percent breast surgery, which
> encompasses all aspects of both cosmetic and reconstructive breast
> surgery. My implant usage is pretty consistent with that of the norm
> for the nation, which is probably 98 percent to 99 percent smooth
> round, with a rare case of using textured today.
>
> I think people have appreciated that there is more of an incidence of
> rippling in the textured implant which, therefore, then gives a
> potential for fold failures which you were addressing earlier and,
> therefore, by switching over to the smooth round and placing these
> implants under muscle, that muscle is then providing pressure on the
> implant which has a tendency to help smooth out that implant even
> more. That is consistently the norm today.
>
> The issue then is the issue of filling an implant. There are
> recommendations, nominal recommendations by the manufacturer. It has
> been appreciated that if you under-fill an implant to maintain a
> softer implant there is a higher incidence of rippling and, again, a
> higher incidence of fold failure. So, that is not the current norm so
> people typically, including myself, fill them to their nominal value
> or slightly overfill those implants, but not beyond the
> recommendations of the manufacturer. The numbers that I personally
> experience in my practice are less than those which are quoted in this
> report.
>
> DR. CHOTI: So, can you tell us again the difference of smooth versus
> the textured in the study as far as the complication rates?
>
> MR. KLINE: We stratified for deflation, and for deflation smooth is
> approximately 5-6 percent deflation rate, whereas our textured
> product, Siltex, is 11-12 percent through the five years.
>
> DR. CHOTI: Other parameters? Reoperation, capsular formation?
>
> MR. KLINE: I don\'t have that information available right at the
> moment, but we could certainly look at it and provide it to FDA.
>
> DR. WHALEN: Dr. Chang?
>
> DR. CHANG: Even though the data was not presented, can anyone give me
> an answer with regard to the explanted implants that were examined?
> Was there any relationship between thickness of the shell in those
> that were explanted and that did not have surgical sharp
> instrumentation?
>
> MR. CROUTHER: Not within a population of a given type. You know, our
> textured devices are thicker, for example, than our smooth devices,
> but I am assuming you are talking just about the textured, did those
> where we had fractures exhibit lesser wall thickness? And, there was
> no evidence of that, nor was there any correlation with physical
> properties.
>
> DR. CHANG: My second question is that previous testimony from public
> comment just mentioned some questions about investigators about good
> manufacturing practices so I would ask the sponsor if there are any
> outstanding questions or communication with the FDA regarding
> improvement in good manufacturing practices that are outstanding at
> this time.
>
> MR. CROUTHER: I will ask Clark Sheriff, from Mentor, to discuss that.
>
> MR. SHERIFF: Good morning. I am Clark Sheriff, vice president of
> regulatory compliance for Mentor Corporation. At this point there are
> no outstanding issues with the FDA. The last inspection was this last
> February. There was a comprehensive GMP inspection by the agency, in
> Dallas, and the few issues that they brought up have been all
> addressed satisfactorily.
>
> DR. CHANG: Thank you.
>
> DR. WHALEN: Dr. Dubler?
>
> DR. DUBLER: If I heard the previous discussion correctly, the textured
> implants have twice the deflation rate, approximately twice the
> deflation rate as the smooth. Is that correct? Is there any point in
> the brochure that makes a statement that says our textured implants
> have two times the deflation rate as the smooth?
>
> MS. CRAWFORD: No, that is not currently in the brochure. Most of this
> information was developed after the brochure was printed. We can
> certainly work with FDA in determining what is appropriate to add to
> the brochure at this point.
>
> DR. DUBLER: So, there is no statement that reflects those data?
>
> MS. CRAWFORD: That is correct.
>
> DR. WHALEN: Thank you. We will now proceed to the FDA\'s presentation
> with Ms. Allen and Dr. Dawisha.
>
> **FDA Presentation**
>
> MS. ALLEN: Good afternoon. FDA will now summarize the status of the
> conditions of approval for Mentor\' saline-filled breast implant PMA.
> For your convenience, we have provided you with a hard copy of FDA\'s
> slides.
>
> There are five conditions of approval: post-approval study; a focus
> group study; a retrieval study; fatigue testing; and shelf-life
> testing. Dr. Sahar Dawisha will present the status of the
> post-approval study and I will present the status of the remaining
> four conditions of approval. I will now hand it over-expression to Dr.
> Dawisha.
>
> DR. DAWISHA: It is still morning so I can say good morning. I am a
> medical officer and I had reviewed and presented the breast implant
> information back in March of 2000. As you recall, at that time one of
> the conditions of approval was that the sponsors provide long-term
> safety information on their products.
>
> To meet this condition, Mentor Corporation has been conducting a
> post-approval study which is an extended follow-up of the patients in
> the saline prospective study, which was originally designed as a
> three-year study, out to ten years postop in an abbreviated protocol.
>
> As you just heard this morning, this protocol consists of annual
> mailing or a physician visit, and the endpoints of interest in the
> study include implant deflation, implant removal and reason for
> removal, additional surgery and reasons for surgery, presence and
> grade of capsular contracture, and breast pain related to implants.
>
> As just discussed by Mentor, the protocol was approved in May of 2000,
> which is when the PMAs were approved. Mentor began contacting their
> investigators in July of 2000, asking them to contact their patients
> or allow the sponsor to contact them. The initial patient mailing
> began in October of 2000. The database that we are going to be
> discussing today was closed in March of 2002.
>
> It is FDA\'s goal to update the patient labeling, the physician
> package insert and the summary of safety and effectiveness, which I
> will refer to as the labeling, every few years to reflect the current
> complication information. We plan on updating the labeling to reflect
> the five-year data that I am going to be discussing in the next few
> slides.
>
> Before discussing the post-approval study or PAS study results, I
> would like to briefly review the saline prospective study patient
> accounting. Recall that the saline prospective study served as the
> basis for the PMA.
>
> The number of patients living and with implants by the end of the
> saline prospective study, as shown on this table, was 1252 for
> augmentation and 375 for reconstruction. By the end of the saline
> prospective study and before the start of the post-approval study in
> October\--so, there is about a five-month period there\--there were a
> few additional patient deaths and implant removals, making 1250
> augmentation and 351 reconstruction the number of patients available
> for participation in the post-approval study. You will see these
> numbers in a subsequent table.
>
> With that background, we can now discuss the patient accounting for
> the post-approval study patients over time, which is shown in this
> table for augmentation. Based on the actual follow-up, divided by the
> expected follow-up where we define expected follow-up as the
> theoretically due minus deaths and removal of all implants during the
> interval, the follow-up rate is shown here for five years through ten
> years postop. For example, the follow-up rate at five years is 5
> percent, 24 percent at 6 years, 45 percent at 7 years, etc.
>
> Because some patients had exceeded their five-year follow-up visit at
> the time of the start of the PAS and because the sponsor has recently
> improved their efforts to contact patients, the follow-up rates beyond
> six years are superior to that at five years.
>
> The bottom row of this table shows the number and percent of patients
> with any data at any time, where a returned questionnaires are counted
> for all previous time points. For example, using this method the
> follow-up rate at five years is 54 percent at five and six years.
>
> The patient accounting information for the reconstruction patients in
> the PAS study are shown on this table. As you can see, the follow-up
> rate for reconstruction patients is superior to that for augmentation
> patients in the previous slide. For example, the rate at five years is
> 52 percent, at six years 59 percent, and at seven years 54 percent.
>
> Because of the low follow-up rate, FDA has been working with the
> sponsor to improve patient contact efforts, which are summarized in
> this table. Of the patients expected for participation in the PAS,
> which is shown in row 1, some patients were excluded, in row 2,
> primarily because a few physicians didn\'t want to participate in the
> PASS, which reduced the number of patients to whom packets were
> mailed, which is shown in row 3.
>
> Taking augmentation as an example, of the original cohort of 1250
> patients, approximately half, which is shown in row 12, have agreed to
> participate in the PAS, and 777 patients have some data reported at
> least once in the PAS, which is shown in row 15.
>
> Of the 351 reconstruction patients, approximately two-thirds of the
> original cohort, which is shown in row 12, have agreed to participate
> in the PAS, and 265 have some data reported at any time, which is
> shown in row 15.
>
> Rows 6 and 7 are of interest because they reflect the patients whom
> the sponsor is pursuing to continue to contact.
>
> Because of concerns with missing information and how this would impact
> the results, the sponsor was asked to determine whether and to what
> extent there was bias in the results due to missing information from
> patients who were considered non-responders, and whether and how the
> complication information should be adjusted to reflect missing
> information from these patients.
>
> The results of this analysis are currently under review by us, and
> additional information has been requested and is ongoing to further
> clarify this issue.
>
> What I can discuss are the results of preliminary analysis to answer
> these questions in which the baseline demographic and surgical
> characteristics were compared between patients who were and were not
> responders.
>
> There were no significant differences with respect to race, ethnicity,
> marital status, incision size and obesity, defined as a body mass
> index of greater than or equal to 24.
>
> For augmentation, there was a significant difference with respect to
> age at the time of implantation, with responders older than
> non-responders.
>
> For reconstruction, there were significant differences with respect to
> surgical approach, implant placement and surface texturing. Again,
> these analyses are still being developed.
>
> I will now discuss the safety results from the data that we have
> available from the responders, first for augmentation and then for
> reconstruction.
>
> Table 5 summarizes the cumulative Kaplan-Meier risk rate of first
> occurrence and the corresponding 95 percent confidence interval of
> complications at three and five years for the augmentation patients.
> These values represent the cumulative risk of having the first
> occurrence and do not capture repeat occurrences.
>
> The three-year rates shown in this table reflect the data from the
> saline prospective study that appear in the current labeling, and the
> five-year rates are an update based on the post-approval study.
>
> While the cumulative risk rates at five years are higher than at three
> years for all the complications shown here, it is only for
> reoperation, implant removal and implant deflation where the
> confidence intervals are not overlapping, suggesting that the rates at
> these time points are significantly different.
>
> I would like to point out that we had not asked Mentor to do any
> statistical analyses comparing whether the rates were different at one
> time point to another. However, they have a slightly different
> interpretation where they found an increased risk only for implant
> deflation and a decreased risk for capsular contracture. They reached
> these conclusions based on a separate analysis where the risk of each
> complication was estimated over time for patients who had not had the
> complication, and then linear regression was used to determine whether
> there was a statistically increased or decreased risk at five years.
>
> Again, we did not ask Mentor to do these analyses and the Kaplan-Meier
> shown here are what are in the current labeling and will be included
> in the updated labeling.
>
> The reasons for reoperation in the augmentation patients are shown in
> this slide based on the number of reoperations. If more than one
> reason was reported, then all the reasons are included in this table.
> Note that the current labeling reports the types of reoperation
> procedures, again, because these were physician elicited responses
> rather than the reasons for reoperation, which is what was elicited on
> the questionnaire.
>
> The three-year information shown here was provided by the sponsor at
> our request to show the progression from three to five years. I have
> combined the rows for the purposes of projecting the slide, as
> described in the footnotes below the table.
>
> Through five years there were 343 reoperations or additional
> procedures reported in 198 patients, involving 312 implants. On a per
> reoperation basis, the three most common reasons for reoperation at
> five years are cosmesis, and this includes wrinkling, ptosis,
> asymmetry and aesthetic revision, approximately 36 percent; followed
> by patient request for a size or shape change, 28.6 percent; and
> followed by leakage/deflation, 19.2 percent.
>
> The primary reason for implant removal at three and five years is
> shown for augmentation in Table 7. If more than one reason was
> reported, the same hierarchy was used as that reported in the current
> labeling.
>
> Through five years, implant removal was reported for 211 implants in
> 132 of the augmentation patients. The four most common primary reasons
> for implant removal at both three and five years was patient request
> for a size or shape change, approximately 30 percent, which was equal
> to the number of leakage/deflation, also approximately 30 percent;
> followed by asymmetry, wrinkling, ptosis or scarring, 18.5 percent;
> and then followed by capsular contracture, 14.7 percent.
>
> Moving on to the reconstruction information, the by-patient
> Kaplan-Meier values are shown in this table, with the three-year rates
> based on the current labeling and the five-year rates representing the
> updated information.
>
> While the risk rates are slightly higher at five years compared to
> three, the confidence intervals are overlapping for these time points,
> suggesting no differences. Note that the overlapping confidence
> interval is least superimbosable for the complication of implant
> deflation compared to the other complications.
>
> The reoperation information, which excludes planned procedures, is
> summarized for reconstruction patients in Table 9. As with
> augmentation, the three-year information was recently provided by the
> sponsor and is not in the current labeling. Through five years there
> were 232 reoperations reported in 162 patients, and occurring with 196
> implants.
>
> On a per reoperation basis through five years, the three most commonly
> reported reasons are cosmesis, which includes wrinkling, asymmetry,
> aesthetic revision and ptosis which is 31 percent; followed by
> capsular contracture, approximately 29 percent; and followed by a scar
> or wound revision, 25.4 percent.
>
> The implant removal information is shown in this slide for the
> reconstruction patients. Through five years, implant removal was
> reported for 135 implants in 112 of the reconstruction patients. The
> three most common primary reasons at both three and five years is
> capsular contracture, leakage/deflation and infection.
>
> This concludes the post-approval study presentation for Mentor and Ms.
> Allen will now continue with the focus study results.
>
> MS. ALLEN1: The ultimate goal of the focus group study was to improve
> the existing patient brochure. Mentor already described how an
> independent study was conducted to obtain feedback regarding their
> patient brochure. They also described some of the key findings from
> that independent study.
>
> FDA considered the independent study reports submitted by both Mentor
> and Inamed and required the same types of changes for both companies,
> if applicable. The primary changes to Mentor\'s patient brochure were
> as follows:
>
> They made significant modifications to the lead-in as well as to the
> content of the safety tables because most women had difficulty in
> understanding the safety data. They stratified augmentation and
> reconstruction information, and they added a table of contents and a
> glossary.
>
> Mentor incorporated all requested changes into the patient brochure
> and received FDA approval. Therefore, FDA considers this condition of
> approval fulfilled. Mentor has just submitted a revised patient
> brochure and package insert that reflect five-year post-approval data.
> After FDA review and approval of this supplement, Mentor will finalize
> them for public and product use.
>
> The purpose of the retrieval study is to determine modes of failure.
> This information may lead to changes in manufacturing design
> specifications, mechanical testing requirements, and/or labeling.
>
> In their 2001 report, Mentor submitted limited data on 38 explants
> collected over a four-month period. Mentor provided clinical or
> physician observations collected at the time of explantation. They
> provided laboratory observations, or device failure characteristics,
> such as smooth and sharp crease-edge opening. These were noted with
> respect to whether the device was deflated or non-deflated.
>
> Based on the limited number of retrieved implants, Mentor made no
> conclusions regarding whether the device failure characteristics were
> representative of a true failure or the result of an artifact, such as
> shipment, excessive handling or the method of explantation.
> Accordingly, no hypotheses regarding modes of failure were provided in
> that report.
>
> Mentor submitted a final report of the retrieval study which is under
> FDA review. Therefore, FDA considers this condition of approval still
> open.
>
> The purpose of the fatigue testing is to determine the fatigue
> strength of Mentor\'s product line. These data provide additional
> information on the expected long-term performance of the device. T r
> are 12 styles across the saline-filled and Spectrum families. Mentor
> chose styles 1400, 1600, 2600 and 5000PT as representative of their
> entire product line.
>
> Mentor completed fatigue testing on three of the four styles. The
> resulting endurance load limit was 10 lbs at 10 million cycles run-out
> for those three styles tested, which did meet the acceptance criteria.
>
> As part of the test report, Mentor also supplied the ultimate static
> rupture results for those three styles. The results were over 600 lbs
> for all three styles, which shows that the implants failed at static
> loads much greater than that expected during mammography, which is
> about 55 lbs.
>
> FDA expects Mentor to submit fatigue test results for style 5000PT as
> part of their 2003 annual report. Accordingly, FDA considers this
> condition of approval still open.
>
> The purpose of the shelf-life testing is to support a five-year
> expiration date on the package label. Mentor\'s shelf-life protocol
> involves real-time package integrity and mechanical testing performed
> at year zero or baseline at years four and five.
>
> In their 2001 annual report, Mentor provided an interim report with
> year zero data. The results were adequate. However, this report did
> not include style 5000PT data. An updated report of year zero testing
> with style 5000PT data has been submitted and is under FDA review.
>
> FDA expects Mentor to submit an updated report of shelf-life testing
> year-four data in 2005 and year-five data in 2005. Accordingly, FDA
> considers this condition of approval still open.
>
> This is an overall summary of Mentor\'s five conditions of approval.
> The post-approval study will remain open until ten-year data are
> provided.
>
> The focus group study is complete. Mentor has already revised their
> patient labeling to reflect the focus group study findings.
>
> The retrieval study is currently open, however, Mentor has submitted
> the final report and it is under FDA review.
>
> The fatigue testing is complete on three of the four styles. Testing
> on the fourth style is expected to be submitted in the 2003 annual
> report.
>
> The shelf-life testing will remain open until five-year data are
> provided.
>
> I will now turn it over to the panel for discussion.
>
> **Panel Discussion**
>
> DR. WHALEN: Thank you. Questions of Ms. Allen or Dr. Dawisha from the
> panel?
>
> DR. DEMETS: I have a question.
>
> DR. MCCAULEY: I do too.
>
> DR. WHALEN: Dr. McCauley, I heard you first.
>
> DR. MCCAULEY: Based on the focus group study, initially the brochure
> revealed that one out of four of the focus group participants did not
> understand the data, or it was confusing, and the brochure was
> revised. But this was not taken back to the focus groups to see if
> they understand that data before it is approved? Is that not true?
>
> MS. ALLEN: That is correct. The protocol was for that first feedback
> on the existing brochure, approved back in May, 2000. There are no
> plans right now to go back and conduct a second focus group study.
>
> DR. MCCAULEY: Then how do you know if the consumer understands the
> data?
>
> MS. ALLEN: Good question. We worked with ODE and OHIP, Office of
> Health and Industry, in order to provide input on making it more in
> layman\'s terms. I don\'t know, maybe Mentor can provide more input on
> that.
>
> DR. WITTEN: I would say we think we addressed the issues that were
> raised by the focus groups. As Ms. Allen mentioned, we have someone in
> another office who looks at patient labeling specifically for us to
> address issues related to it being understandable to the patient or to
> the consumer.
>
> DR. WHALEN: Dr. Doyle?
>
> DR. DOYLE: I am concerned about the follow-up rate, whether the data
> is even viable given the low follow-up rate. In addition to that, 20
> percent of the patients have reimplantation and they are considered in
> the group that goes out to five years rather than starting over as a
> new implant. Wouldn\'t that give falsely low complication rates at
> five years because these women may have only had the implant at one,
> two or three years and their second implant, yet, I think I understood
> that they are within the group that has been carried out to five
> years.
>
> DR. DAWISHA: If a patient undergoes a revision, gets their implants
> removed and gets a second set of implants, as far as I know, they are
> not included in the Kaplan-Meier values because they are considered
> revision patients and we have reported them separately in the
> labeling, as a separate group that gets complications following
> revision.
>
> DR. DOYLE: Perhaps I misunderstood but I thought when I asked Mentor
> this question they said they were left back in the data. Maybe I
> misunderstood.
>
> DR. DAWISHA: Well, they continue to follow the patients and they
> report the study results to us, but they are in a separate table in
> the labeling. They are reported as patients who have complications
> following revision.
>
> DR. WHALEN: Dr. DeMets?
>
> DR. DEMETS: Yes, I am bothered by the response rate. I appreciate the
> challenges and difficulties of follow-up in any study, any clinical
> study that is done. Having said that, I am still troubled I guess as
> much as my predecessor Dr. Blumenstein was by the response rate, and
> what you can make of any kind of strong conclusion based on that kind
> of response rate.
>
> There has been some comment by both the FDA and the sponsor about
> comparing responder and non-responder at baseline. That is nice. Maybe
> it is necessary, but it is hardly sufficient because the real
> assumptions have nothing to do with that. The real assumption has to
> do with the outcomes. Are the outcomes in responders the same as in
> the non-responders? Suppose it turned out that the patients who
> didn\'t respond all had bad experiences and were so angry that they
> threw the questionnaire in the trash, that is the kind of bias that
> you worry about and until you can begin to address that you never know
> with the non-responder is introducing a bias or not. So, that is why
> it is such a problem.
>
> That is why in good clinical trials the response rate that you go
> after is in the higher 90\'s because nobody believes that non-response
> is independent of what is going on. If we did that, we wouldn\'t
> pursue mortality trials to have almost no loss to follow-up. So, I am
> really troubled by this, much, as I said, as Dr. Blumenstein was. I
> think this issue of comparing responders and non-responders at
> baseline is nice.
>
> The second point about that is when you do any kind of an adjustment
> procedures, logistic regression or anything else, they add a little
> bit but, you know, they don\'t explain much. If those regression
> models explained a lot of the outcome, then those adjustments would be
> meaningful but they don\'t explain much, I am guessing. We don\'t
> know; we didn\'t hear that data, but they don\'t explain much.
> Therefore, the adjustments are sort of a very modest correction and,
> you know, analysis can never correct for flawed designs. We need good
> design and a low response rate is one of those kind of design problems
> we all wrestle with in a trial.
>
> So, I am very troubled by this response rate. But I guess my question
> is, given the passion that the patients undergoing this procedure
> have, it seems like we ought to be able to get 99 percent response
> rates. So, I am puzzled by why we are where we are.
>
> DR. DAWISHA: Well, I would just like to add I think we share your
> concern. I am glad you brought up the issue of the responders and
> non-responders and whether or not they have suffered a complication. I
> had indicated that the analyses are under way and we actually asked
> the sponsor that specific question, whether having a complication at
> an earlier time predicted whether someone was or wasn\'t a responder.
> I mentioned in my presentation that the analyses are continuing. That
> is one of the analyses. I guess what we do with that data and how we
> adjust the data or how much sort of remains to be seen. But we
> certainly share your concern as well.
>
> DR. WHALEN: Dr. Choti?
>
> DR. CHOTI: Dr. Dawisha, it still is not clear to me. You mentioned
> certain things that you asked Mentor to provide you or certain
> analyses. Did you specify in this what the response rate should be,
> what your minimal expectation for a follow-up is? I guess the bottom
> line is are you happy, are you satisfied with the data that you have
> gotten? You say you are currently working with it, reanalyzing it so
> we don\'t have the final but is this kind of sufficient to address the
> concerns of the panel in 2000, the data you got?
>
> DR. DAWISHA: Well, I think our goal is to update the patient labeling
> and the labeling information, and we would like the labeling to be the
> most valid information that we have. Certainly, you know, we are not
> happy with the low follow-up rate. We are sort of stuck between do we
> put this information in the labeling and update it, or do we not put
> it in. I think our position is that we would rather at least put the
> information that we have in the labeling, explaining what the
> limitations are, just so that at least that information is available
> to patients.
>
> DR. CHOTI: I guess my question though is were there some specific
> metrics that you requested in this follow-up data set, and were those
> met, follow-up being one? I mean, it is possible that they could ramp
> up the effort even more to get better follow-up data if necessary, if
> it was specified that this is the information we need at this
> follow-up time. Was there some specific information requested of them?
>
> DR. DAWISHA: There were no specific follow-up target rates that we had
> asked the company to follow. The breast implant guidance document has
> some general guidelines, one of which is that we expect follow-up to
> be about 60 percent at ten years. That is based not just on this
> product but several other types of products. We are lucky to get 50
> percent follow-up at ten years for those types of studies. So, no,
> there was no set follow-up rate. There was no target set for the
> sponsors. We certainly would like to see high follow-up rates out to
> ten years but we may not.
>
> DR. DAWISHA: Dr. Dubler?
>
> DR. DUBLER: Back to my current interest, which is this reoperation
> rate. On Table 8, which is the Kaplan-Meier risk rate for
> reconstruction, the five-year risk rate, as I read it, is 43 percent.
>
> DR. DAWISHA: That is right.
>
> DR. DUBLER: In your revision of the informed consent document that you
> were provided, is that rate stated in that document in any way?
>
> DR. DAWISHA: You mean the patient labeling?
>
> DR. DUBLER: No, in the brochure, the company brochure. It is my sense
> that patients read labels, the really savvy ones, but a lot of them
> will rely on the company brochure, and after the focus groups you have
> seen a revision. Correct?
>
> MS. ALLEN: The company has already submitted the supplement with the
> labeling with the focus groups findings and we approved that. But they
> have just recently submitted an updated package insert and the patient
> brochure with the five-year post-approval data.
>
> DR. DUBLER: And does that say 43 percent of patients who have
> reconstruction will have surgery in the next five years?
>
> MS. ALLEN: Yes, it does.
>
> DR. DUBLER: It does?
>
> MS. ALLEN: Yes.
>
> DR. WHALEN: Seeing no other questions at this point, thank you. We
> will go into the concluding discussion. I would like to do this by
> asking everyone at the table to make their comments about what we have
> just heard and, since you were last at the microphone, we will start
> with Dr. Dubler.
>
> DR. DUBLER: This has been a puzzle to all of us for the last decade.
> Clearly, a woman does have a right to choose. The problem is that she
> has had the right to choose between procedures that don\'t appear, by
> their own data, to be terrific. So, then the right to choose has got
> to be supplemented by information that makes that choice a truly
> informed one.
>
> I am impressed, someone gave us the statistic that the industry had
> spent six million dollars supporting one of the industry
> organizations. We did hear that figure, didn\'t we? That is a lot of
> money. And, I would think with one fraction of that money and some
> creative people we could come up with a process that would bring
> together various independent groups that analyze the data and the
> company that analyzes its own data, and agree upon the data that a
> woman had to confront in a form that wasn\'t the Kaplan-Meier adjusted
> risk rates, which no lay person, quite frankly, understands, and come
> up with a script which could then be put in an interactive video
> format. We could think of lots of creative ways of making an informed
> consent process independent of the physician, who is likely to say,
> \"yes, of course, I have to give you this but, hey, I do this all the
> time; I think it is terrific. I gave my 16-year old breast implants
> for her birthday.\"
>
> There are ways of ensuring that this prospective patient, indeed,
> focuses in the most constructive circumstance on the data that she has
> to consider. Once she has considered that, so be it. But there are
> ways of presenting it, of designing it, of agreeing on what has to be
> presented that I think we are technically capable of doing. I think
> that a written brochure, handed out by the surgeon who does this and
> thinks it is really quite a good process, is a very 18th century way
> of thinking about what to do. We could do a lot better, and I would
> hope that the FDA would work with the companies to devise really
> creative, new, independent solutions to the problem of helping a woman
> confront and analyze the data in terms of her own values.
>
> DR. WHALEN: Dr. McCauley?
>
> DR. MCCAULEY: I agree. I think the entire issue we are dealing with
> here is about choice. In order to really make a proper choice you have
> to have informed consent, and that informed consent has to be based on
> reliable data in terms of complications or problems that the patient
> may experience.
>
> I think that when we start looking at data, herein lies the problem
> and I can appreciate the fact that certainly for implant surgery, not
> only in plastic surgery but even in orthopedics, the follow-up can be
> not quite as reliable as some patients with cancer problems, as you
> have mentioned. However, I think it is imperative that we really try
> to push the envelope here to try to get as much follow-up as we can in
> terms of percentage on these patients that have undergone these types
> of procedures.
>
> The other issue relates to integrity and perception. I think this has
> been a problem of some consumer groups that have spoken to us earlier
> this morning. I am happy to hear that the issues related to good
> manufacturing practices have been addressed and this is no longer an
> issue.
>
> However, I think it is imperative that the FDA continues to work
> closely with Mentor to try to improve the data collection, and also to
> improve the statistical analysis. Certainly this issue of responders
> versus non-responders is a crucial issue I think, and I am not sure
> how that can be resolved but I think it is something that we really
> need to take into account.
>
> The last point I wanted to make really relates to consumer education,
> and I think that if we take on a project or the FDA takes on a project
> that states that what you have to do is appropriate for a study, then
> for closure would be to take that information back to the focus groups
> to see if they understand truly what the risks are. It is a matter of
> concern, having a proper consent and information for the patient to
> make a proper choice.
>
> DR. WHALEN: Dr. Doyle?
>
> DR. DOYLE: I resonate with the idea that the breast implants really
> represent a choice for women. I have a sister who went through
> reconstruction surgery for cancer so I know that this is a very
> important choice for women to be able to make. I also believe that the
> informed consent process needs to be based on accurate information and
> that the important thing is that the informed consent contain all the
> information to make a choice.
>
> I am actually not sure an interactive video is going to alter the fact
> that once a woman understands what the risks are that they are still
> not going to make this choice. I don\'t think we can protect people
> from wanting to do something once they understand what the risks are.
> So, I believe the informed consent process is the key here.
>
> DR. WHALEN: Dr. Miller?
>
> DR. MILLER: If I could just try to provide some perspective on this,
> when I look at what is going on, we have an unusual problem with the
> breast implant in that we are trying to balance a benefit/risk ratio
> where the benefit is extremely subjective to the patient, and even
> within a particular patient it can change over time. So, getting a
> handle on that side of the equation is very difficult. The risk is
> difficult to get a handle on.
>
> It is difficult to study this. You can\'t do it as nice and cleanly as
> you can a drug where you have a limited number of patients and a
> limited number of follow-up time. It is difficult to conduct a study
> for ten years in patients who are basically healthy, patients who
> don\'t want to consider themselves patients, who want to disappear
> into the landscape as soon as they have their implants.
>
> I mean, these are all challenges to doing this. I think that we have
> to be careful in how we look at addressing this in terms of methods
> that we have become very comfortable with in looking at other
> problems. That is one thing.
>
> On the other hand, we have to do the best possible job we can do. I
> share everyone\'s sentiment about the inadequacy of the studies, the
> follow-up. Those need to be done in an unassailable fashion so that
> this is laid to rest, so that we are not discussing this five years
> from now. I think we are all weary of discussing this, and I think a
> study can be designed where we address this.
>
> I don\'t know what the follow-up rate is for pacemakers but I know it
> is pretty darned good. I mean, if you have a patient with a pacemaker
> that was put in 15 years ago, you call up a number and the person on
> the other end of the line practically knows the entire life history of
> that person who had that pacemaker. Maybe that is an extreme example
> because of the nature of that device, but I think that something needs
> to be done to not permit three physicians to say I won\'t participate
> in this study. I mean, if they won\'t participate maybe they
> shouldn\'t have access to the implants. I mean, if you have the
> implant you have to, as a responsible citizen of the medical
> community, participate in confirming how these implants are used and
> whether they are safe or not and effective. If you don\'t want to
> participate in that, then perhaps you shouldn\'t place any implants.
>
> I think those sorts of things could possibly be done. But I want to
> avoid the tendency to treat this like other medical problems because
> it is very unique. I guess that is my main philosophical point.
>
> DR. WHALEN: Dr. Chang?
>
> DR. CHANG: I think two years ago the advisory panel and finally the
> final decision of the FDA was to keep the option of having saline
> implants available to women for augmentation or reconstruction. It
> wasn\'t a decision made without controversy, and it is certainly on
> the record that there have been many reservations regarding process,
> statistics and other questions which have led to the conditions for
> premarket approval.
>
> Today is an update of presentation of sponsors trying to meet these
> conditions of approval and they are in process. I would urge sponsors
> to continue to examine the physical properties of their product to try
> to decrease the preliminary studies of safety, to continue to make
> improvements and weigh what are the benefits of lessening implant
> failure with perhaps increasing thickness, comparing to the benefits
> of pliability and cosmetic effect and perception of pliability. So,
> that is one question and request that I would make of the sponsor.
>
> The other question, I would second Dr. McCauley\'s comments regarding
> the focus group. Again, follow-up is necessary to be sure that what we
> presume to be understandable by the lay public is, indeed, understood
> in terms of reading information provided to them so that they can make
> that informed decision.
>
> I am astounded, but maybe I shouldn\'t be, that reported comments by
> members of the focus group felt that these statistics were not true;
> that these numbers were merely presented as a disclaimer by the
> manufacturing and that this really couldn\'t happen and won\'t happen
> as an individual makes a decision of choosing the saline implant. So,
> there is some issue of credibility in terms of presenting this data.
>
> However, I feel that statistically speaking in terms of percentage of
> follow-up being on the far extreme of what normally is acceptable in a
> scientific clinical study, it is some data to give us an idea of what
> happens to these implants after three and five years. So, there is
> some data and, despite good efforts of sponsor to collect this,
> perhaps higher remuneration, perhaps a larger bonus for returning the
> survey might increase the numbers. Be that as it may, we would say
> these are scientifically suspect data just because of the numbers of
> responders, but there are some numbers and I think that they should
> continue to be made available to consumers.
>
> Finally, my comment is that, yes, continued efforts should be made to
> carry out to ten years to find out what happens with these implants,
> but ultimately I don\'t think we are really going to get an answer
> until there is a report by an independent registry that has, again,
> good follow-up on the people who are registered to see what happens to
> these implants.
>
> DR. DAWISHA: Dr. DeMets?
>
> DR. DEMETS: Well, I have already said some of the things I have been
> thinking about. I am obviously not going to quarrel with the issue of
> the right to choice and assess the risk/benefits, but I worry about
> information that those decisions and thoughts are based on.
>
> I would only urge I guess the FDA and the panel to appreciate how
> sensitive results can be to issues of non-response, to excluding
> patients, to censoring patients from follow-up. I am a professional
> statistician and I am still amazed and astounded at times at the power
> of these biases that work in data. So, I think that we really need to
> set a higher standard for something that has been so controversial, so
> much discussed and is so important.
>
> I think that if we don\'t do something different than we are doing
> now, at the ten-year mark we will still be arguing just as much as we
> are arguing now. Sixty percent as a target at ten years, I guaranty
> you, is going to bring more controversy and discussion because 40
> percent non-response is overwhelmingly an opportunity for bias to
> enter into any kind of results.
>
> The trouble with numbers, if you produce tables such as we have today
> and put 95 confidence intervals on them, is that they take on a
> credibility that they sometimes don\'t deserve because of the power of
> the biases that are at work. So, I am not saying we should not present
> the data that we have, but there is a danger to it of misleading the
> perhaps less sophisticated readers of those tables.
>
> But I would go back to where I started, that is, the response rates
> that we are observing here and perhaps other devices are simply not
> acceptable if the decisions really depend on the data that comes out
> of those surveys. So, we may have to challenge ourselves across the
> board and certainly in this arena with all the interest and importance
> this has to do a lot better than the target we set for ourselves.
>
> DR. WHALEN: Dr. Newburger?
>
> DR. NEWBURGER: As my colleagues at the panel have expressed their
> discomfort with what has been presented, and have constructive
> suggestions on how to ameliorate the situation, I join their concerns.
> Augmentation mammoplasty is the second most frequently performed
> plastic surgical procedure in the U.S. Something upward of 300,000
> were done this last year, 2001. It is mind-boggling to me that we have
> so little data available on a procedure that was done in 300,000
> individuals in one year. The rate is going to increase geometrically
> as it has been. This is from the American Society of Plastic and
> Reconstructive Surgery web site, by the way.
>
> So, I would hope that the efforts to get more accurate follow-up on
> increasing the numbers of patients in this study would be done to the
> point of maybe sending investigators to really look for the patients.
> I am also concerned that the products appear to have a high rate of
> product failure. I think that the high reoperation rate wouldn\'t be
> acceptable in other type of prosthetic devices. I question two
> standards. Perhaps because this is considered to be cosmetic, it is
> not held to the same exactitude that other prostheses are.
>
> DR. WHALEN: Dr. Choti?
>
> DR. CHOTI: I echo the comments of my fellow panel members. It was
> clear in the review two years ago there were concerns when this was
> approved, and I commend the FDA and the industry on working on the
> conditions of approval. I think we have learned a lot based on the
> data of these conditions. Yet, it is astounding, particularly the
> post-approval study, how weak the data is still. As we heard, in spite
> of how common this procedure is, we still are faced with a procedure
> and device that clearly is important, and it is clear I think that we
> do not have sufficient data or good enough data.
>
> So, I really do echo what has been said, that coming up with better
> registries, independent data collection so that we really can have the
> real answers rather than the data we have been working with today, and
> I am concerned that it is not going to be improving that much with
> continued follow-up.
>
> It is interesting that these products have problems. I mean, we are
> learning that there is device failure. The performance is not as good
> as we would like to see. So, I think there is clearly a mandate to
> continue to improve this product. These devices are placed in healthy
> individuals. So, I think it is very important to continue the effort
> to improve the product which is clearly fraught with problems.
>
> So, I think I really do echo the statements that have been made both
> regarding informed consent and the data that is available.
>
> DR. WHALEN: Dr. Witten, for FDA\'s purposes has this discussion been
> adequate?
>
> DR. WITTEN: Yes, thank you.
>
> DR. WHALEN: We, therefore, will stand adjourned for lunch and at 1:30
> sharply we will reconvene.
>
> \[Whereupon, at 12:40 p.m., the panel was adjourned, to reconvene at
> 1:30 p.m.\]
>
> A F T E R N O O N P R O C E E D I N G S
>
> DR. WHALEN: I would like to welcome everyone back. I would remind the
> public observers at this meeting that while this portion of the
> meeting is open to their public observation, public attendees may not
> participate except at the specific request of the panel.
>
> We are now ready to continue our panel meeting with Inamed
> Corporations presentation.
>
> **Inamed Corporation**
>
> DR. EHMSEN: Good afternoon, Dr. Witten, Dr. Whalen, members of the
> panel, FDA representatives and all those in the audience. I am Ron
> Ehmsen, vice president of clinical and regulatory affairs for Inamed.
> I should point out that what had previously been McGhan Medical
> Corporation is now operating as Inamed Aesthetics, which is a business
> unit of Inamed Corporation.
>
> My colleagues and I are here today to present an update on several
> conditions of approval that were associated with PMA number P990074
> which covers McGhan\'s saline-filled breast implants. That PMA was
> approved by FDA on May 10, 2000 for breast augmentation in women over
> 18 years of age and for breast reconstruction.
>
> There were five conditions of approval. First was a post-approval
> study; second, a focus group study aimed at clarifying or trying to
> understand whether the patients themselves had any questions about the
> brochures that were provided to them to help them make a choice. Third
> is a retrieval study. Fourth is fatigue testing and fifth is
> shelf-life testing.
>
> We will break up the presentation into several parts. Dr. Audrey
> Weiss, our senior manager of clinical research, will present the
> results of the post-approval study and then we will move on from there
> with Kim Croyle, our senior regulatory affairs specialist, and Tom
> Powell, our director of technologies. Audrey?
>
> DR. WEISS: Thanks, Ron. Inamed\'s first condition of approval was to
> conduct a post-approval study to identify long-term outcomes
> associated with McGhan\'s saline-filled breast implants.
>
> First I would like to review the data that formed the basis of the
> original PMA that was submitted. The original PMA included data from
> three years of follow-up, three-year post-implant information from two
> five-year clinical studies. Additionally, women enrolled in these
> studies also had begun to complete some of their three-year follow-up
> visits. So, limited four-year data was also available at that time.
>
> The two clinical trials were the 1995 augmentation study which, for
> short, I will refer to as the A95 study. In that study, 901 patients
> were enrolled between 1995 and 1996 for primary augmentation. The
> second study was the 1995 reconstruction study, which I will refer to
> as the R95 study for short. That study had a very similar protocol to
> the A95 study and enrolled 237 patients for primary breast
> reconstruction. Almost all of the patients enrolled in the R95 study
> had had mastectomy following breast cancer, and there was a handful of
> patients in that study who had had prophylactic mastectomy. All of the
> patients in both the A95 and R95 studies had not had previous breast
> implants prior to enrollment.
>
> The post-approval data collection is being conducted in two phases,
> and the objective of the study is to obtain long-term safety
> information through ten years post-implant on the same 1100 women who
> were enrolled in the A95 and R95 studies. Again, at the time of the
> original PMA complete three-year follow-up information was available.
> All women had completed three-year follow-up.
>
> So, the post-approval data collection we actually are conducting in
> two separate phases. The first phase has been completed, and involved
> continuing to follow those 1100 women enrolled in the A95 and R95
> studies under the same protocols as those studies had been conducted
> under through three years post-implant. Specifically, the protocol
> involved women coming in to see their physician for a follow-up visit
> in the office. The four-year and five-year follow-up information that
> forms the phase one of the post-approval data collection was based on
> this method of data collection. Complete five-year information is now
> available. All patients have completed the five-year follow-up visit
> and the five-year data is what I will present today.
>
> The second phase of post-approval data collection is currently in
> process. This phase involves continuing to follow those same 1100
> women who were enrolled in the A95 and R95 studies using a mail survey
> protocol that will follow them from six to ten years post-implant. On
> the anniversary of their original implant surgery, patients will be
> sent a mail survey to complete regarding the status of critical safety
> outcome variables, including reoperation and implant
> leakage/deflation. Again, that phase two is in process and we are
> currently mailing surveys to patients fort he six- to ten-year
> follow-up information.
>
> The remainder of the presentation will focus on the five-year
> follow-up information from phase one. First, I would like to present
> the follow-up compliance information for patients enrolled in the A95
> and R95 studies.
>
> First, what I have done here is actually included the follow-up
> compliance rate at each of the required follow-up intervals, which was
> annually through the five years in the A95 and R95 clinical studies.
> The data that was presented for the original PMA was three-year data
> which was based on 83 percent patient compliance for the augmentation
> cohort and 88 percent follow-up compliance for the reconstruction
> group.
>
> For the post-approval phase the follow-up compliance rate has remained
> at 80 percent or higher. At five years the follow-up compliance rate
> was 81 percent for augmentation patients and 80 for the reconstruction
> patients.
>
> Next, I would like to present the information obtained for specific
> local complications that were assessed in the A95 and R95 studies. The
> specific complications that I will present are reoperations, implant
> replacement/ removal, leakage/deflation, capsular contracture,
> infection, and a variety of other complications that were included in
> the protocols and, for completeness, we have included them here today.
> These include complications such as surgical-related outcomes
> including hematoma, seroma, and skin and nipple related complications.
>
> I should point out with this complications that these are not
> additive. The same patients who are included in the reoperation rate,
> for example, may also be included in implant replacement/removal since
> implant replacement/ removal is a subset of reoperations. Similarly, a
> patient may undergo a leakage/deflation and also be included in the
> risk for implant replacement/removal. So, they are independent risks
> and are not additive.
>
> Again, the method used for data collection was a physical examination
> by a physician at an office visit, according to the original protocol
> for the A95 and R95 studies. The analysis method utilized was a
> cumulative risk based on the Kaplan-Meier product limit method with 95
> percent confidence intervals computed. The cumulative risk that you
> will see in the following graphs is represented as a failure rate
> curve which, you will see, increases or stays level over time. It will
> never go down because, as we add additional events in over time the
> risk can only increase.
>
> What you will see in the cumulative risk curves is the summation of
> all events that occurred up to the particular time point being
> reported, and each of the time points that were assessed in the study
> is presented.
>
> What I will do now is go through each of the specific complications,
> reoperations, implant replacement/ removal, leakage/deflation,
> capsular contracture and infection and report on the risk information
> obtained through five years post-implant.
>
> First, this graph represents the cumulative risk of reoperations for
> the augmentation and reconstruction patients. Again, the risk is being
> presented for each of the time points that were assessed in the study,
> and you can look at this as a cumulative risk through the time point
> presented in the graph. The white line represents the cumulative risk
> for the augmentation patients and the yellow line represents the
> cumulative risk for the reconstruction patients.
>
> For example, with reoperations the cumulative five-year risk for
> augmentation patients is approximately 25 percent and the cumulative
> risk of experiencing at least one reoperation through the five-year
> time point is approximately 42, 43 percent.
>
> Next, what I would like to do is breakdown what types of reoperation
> procedures patients underwent. The reoperations reported here include
> any type of operative procedure to the breast or chest area, for
> example, implant replacement/removal and biopsy/lump removal, for
> example, is included here.
>
> The next graph will break down for all those patients who underwent
> reoperation what those reoperations were. This pie chart represents
> the breakdown of all of the reoperations for augmentation patients.
> What you can see here from the red wedge is that the largest
> proportion, the largest number of reoperations were implant
> replacement/ removal. That could be removal with or without
> replacement of the device.
>
> The second most common type of reoperation performed for the
> augmentation patients was a capsule procedure, for example,
> capsulotomy or capsulectomy.
>
> For reconstruction patients, the breakdown of the types of reoperation
> procedures is as such. Again, implant replacement/removal is the most
> common type of reoperation performed, followed by, in the purple
> wedge, scar revision or wound repair, and then capsule procedures.
>
> What I will do next is drill down into this chart a bit and look
> specifically at the most common type of reoperation, which is implant
> replacement/removal, and look specifically at risk through five years
> of that particular reoperation and then look at reasons why patients
> undergo implant replacement/removal.
>
> First, this graph represents the cumulative risk through each of the
> time points indicated, ending with the five-year time point, of
> implant replacement/removal for augmentation and reconstruction
> patients. Through five years, the risk of experiencing an implant
> replacement/ removal was approximately 11 percent for augmentation
> patients and approximately 28 percent for reconstruction patients.
>
> The next two graphs will look at these patients who have undergone
> implant replacement/removal and look specifically at why patients
> underwent the device replacement/removal.
>
> First for augmentation patients, the most common reason why patients
> undergo replacement/removal is seen with the red wedge, which is the
> patient\'s own choice to change the size or the style of the device.
> The second most common reason for device replacement/removal is
> leakage/deflation of the device.
>
> For reconstruction patients the predominant reason for undergoing
> implant replacement/removal is capsular contracture, followed by the
> patient\'s choice to change the size or style of the device, and then
> leakage/deflation.
>
> The next slides that I will present break out these particular
> complications that have been represented in these graphs and look
> specifically at the risk to patients of experiencing various
> complications, including leakage/ deflation, capsular contracture and
> infection.
>
> This graph represents the cumulative risk through five years for
> augmentation patients and reconstruction patients who experienced a
> leakage/deflation. As you can see, the risk is virtually identical for
> both augmentation and reconstruction patients, and is approximately
> six percent through the five-year time point.
>
> For capsular contracture, the five-year cumulative risk for
> augmentation patients is approximately ten percent and approximately
> 35 percent risk through five years for reconstruction patients.
>
> Next is the risk of infection following implant surgery. For
> augmentation patients through five years the risk of experiencing an
> infection is approximately one percent and for reconstruction patients
> approximately five to six percent.
>
> The remaining graphs that I will show for the local complications that
> were assessed in the A95 and R95 studies are actually summaries of the
> cumulative Kaplan-Meier risk curves that you see here. We had another
> approximately 20 or so complications that were assessed in the A95 and
> R95 studies, and for completeness I have included them here. Each one
> of them, you can imagine, has a Kaplan-Meier risk curve, just like
> those complications presented here. However, for brevity, what I have
> done is include them on a bar chart that summarizes only the five-year
> risk rate, which would be the highest possible risk through five
> years.
>
> For example, this graph includes six implant-specific complications,
> and what you see with the white bar is the risk through five years for
> augmentation patients, and the yellow bar, the risk through five years
> for reconstruction patients.
>
> For example, the risk of experiencing asymmetry for an augmentation
> patient through five years is approximately 12 percent, and for
> reconstruction patients approximately 40 percent.
>
> In discussions with clinicians, they have indicated that this is to be
> expected given that with reconstruction patients they are trying to
> match a reconstructed breast that has had mastectomy with a normal
> non-reconstructed breast on the other side.
>
> Also reported here are cumulative five-year risks for capsule
> classification, implant extrusion, implant malposition, implant
> palpability and wrinkling.
>
> The next graph reports the five-year cumulative risk for augmentation
> and reconstruction patients for various surgical-related complications
> that were assessed in these studies. As you can see from this graph,
> all of these surgical-related risks occurred at well less than ten
> percent, actually under seven percent for the five-year cumulative
> risk. Presented are delayed wound healing, hematoma, scarring,
> irritation/inflammation, lymphadenopathy, pneumothorax and seroma.
>
> The next graph presents the cumulative five-year risks for various
> skin and nipple-related complications that were assessed in the A95
> and R95 studies. Presented are the risks for loss of nipple sensation,
> nipple paresthesia, skin paresthesia, skin rash, tissue/skin necrosis
> and breast pain.
>
> The next graph that I will present looks very similar to this, however
> it differs in two very important ways. Following implant replacement,
> we continued to follow patients and look at any outcomes following the
> replacement, and this graph looks at the cumulative risk of some
> specific complications following device replacement.
>
> The two critical differences in this graph that I would like to point
> out from the ones that you have seen previously are, first, that the
> risk presented here is at three hears following replacement. Patients
> were able to be revised any time through the five years. So, limited
> follow-up information is available for patients, for example, who were
> explanted at year four. We would only have one year of information
> following the device replacement. So, we were only able to calculate a
> valid risk with the information available for three years following
> the replacement in the study.
>
> The second difference in this graph is that, unlike the previous risk
> information presented which was on a by-patient basis, this analysis
> is based on a by-device or by-implant basis. This was selected because
> patients could have one side revised rather than both sides. So, it
> made the most sense to look specifically at an analysis by the
> replaced device.
>
> The complications presented here are of second replacement removal
> following replacement removal. The risk here, you can see, is
> approximately 18 percent three years following replacement for
> augmentation patients and approximately 28 percent for reconstruction
> patients; risk of leakage/deflation following device replacement; risk
> of capsular contracture and risk of infection following a replacement
> surgery.
>
> Next, I would like to present information obtained on reports of
> breast cancer post-implant and connective tissue or autoimmune disease
> reports. First for breast cancer, of the 901 enrolled augmentation
> patients, there was one post-implant report of breast cancer which
> occurred 27 months after implant surgery. For reconstruction patients,
> there were 24 post-implant reports of breast cancer through five years
> post-implant. All of these 24 reports occurred in patients who
> previously had had breast cancer, which was the reason why they
> enrolled in the study initially. The cancer may have recurred in the
> same breast that originally had the breast cancer or in the
> contralateral side.
>
> Next, connective tissue and autoimmune disease information, the method
> of data collection for connective tissue and autoimmune diseases was
> that a patient would self-report to her physician that she had a
> particular connective tissue or autoimmune disease. Based on the
> self-report by the patient, the physician would attempt to contact a
> diagnosing physician, attempt to obtain a diagnosis by the
> rheumatologist for example. If the physician was able to obtain a
> diagnosing physician\'s report we term that here a confirmed report.
> In other words, there is a physician diagnosing the patient with the
> particular connective tissue or autoimmune disease. If the patient
> self-report was not able to be confirmed by a diagnosing physician\'s
> report, we list that here as an unconfirmed report. It is still a
> patient\'s self-report of the disease but the doctor has been unable
> to obtain a diagnosing physician\'s report. That may be due either to
> the patient never obtained the diagnosis or is not able to be
> contacted, for example.
>
> Additionally, and I do not report that here, there have been some
> cases of self-reports by patients that have been found to be false
> reports, where the patients initially reported a particular connective
> tissue or autoimmune disease and subsequently indicated that they
> actually either had a different type of diagnosis or did not have a
> connective tissue or autoimmune disease at all.
>
> For the augmentation group, there were 7 confirmed reports of
> connective tissue or autoimmune disease and 13 unconfirmed reports. Of
> the 7 confirmed reports, 3 were Grave\'s disease, 2 were
> hyperthyroiditis and 2 were chronic fatigue syndrome or fibromyalgia.
>
> Among the reconstruction patients there was one confirmed report of a
> connective tissue or autoimmune disease and four unconfirmed reports.
> The one confirmed report was a diagnosis of Grave\'s disease.
>
> Last, I would like to present information obtained concerning patient
> satisfaction with their breast implants. At each follow-up interval
> with their physician, patients were asked whether they were satisfied
> or dissatisfied with their breast implants and breast implant surgery.
> The following graph presents the results from each annual follow-up
> visit so it includes data from the original PMA through three years,
> as well as the post-approval data at four and five years. It indicates
> the percentage of patients who indicated that they were satisfied with
> their breast implants.
>
> For the augmentation cohort, you can see that the percentage has been
> at 95 or 96 percent of patients at each annual follow-up visit,
> including five years post-implant, with 95 percent of augmentation
> patients indicating they were satisfied.
>
> For reconstruction patients the percent of patients indicating they
> were satisfied has remained at around approximately 90 percent, with
> 88 percent indicating they were satisfied at three years post-implant
> and 89 percent indicating they were satisfied at five years
> post-implant.
>
> To conclude the information pertaining to the post-approval study,
> Inamed is conducting its post-approval study in two phases. The first
> phase has been completed and involved continuing to follow patients
> enrolled in the A95 and R95 studies out through five years
> post-implant, according to those original study protocols which
> involved physician examination of the patient at an office visit.
>
> The second phase is ongoing, and Inamed is in the process of obtaining
> mail surveys from patients who will self-report on the status of their
> breast implants out through ten years post-implant.
>
> Next, I would like to turn the presentation over to Kim Croyle, senior
> regulatory affairs specialist with Inamed, who will talk about the
> second condition of approval, which is the focus group study.
>
> MS. CROYLE: Thank you, Audrey. Good afternoon, panel.
>
> In order to meet the second PMA condition of approval, Inamed
> contracted with Kaplan West Qualitative Research Organization to
> conduct a focus group study in order to obtain women\'s opinions and
> assessment of our patient brochure.
>
> The research objectives of the focus group study were to obtain
> women\'s feedback regarding the quality of our patient brochure, and
> to propose qualitative changes to improve the patient brochure, based
> on the study findings.
>
> There were six focus groups consisting of 8-13 women each, three
> groups for augmentation, which consisted of two groups of women who
> had had, or who were considering, or had considered breast
> augmentation; one group of women who had previously had breast
> augmentation. Additionally, we had three reconstruction groups, two
> groups of women who had considered or were considering breast
> reconstruction, and a third group of women who had previously had
> breast reconstruction.
>
> The key findings in discussion with the patients who were
> participating and the women who were considering these surgeries were
> that the brochure was informative, and also was helpful to them and
> answered most of the patients\' questions. So, we had a lot of
> positive feedback, particularly regarding the fact that the brochure
> did provide them with potential risks and complications, the surgical
> procedures. It proposed questions they could ask their surgeon about
> their surgery. The impact the implants might have on mammography, and
> their other interest was knowing about the style and size options
> available.
>
> An additional finding of the assessment from all these women was that
> the brochure was so comprehensive and extensive that it created some
> confusion. There was a lot of information for them to have to, you
> know, review and assess. Their key comments were difficulty in
> understanding and interpreting the clinical tables. Most of the women
> found it king of daunting to understand the tables. Finding, within
> the brochure, relevant sections was important to them. Also,
> difficulty in understanding how the brochure was actually organized,
> where they would find the information they needed and the graphic
> presentation.
>
> As a result of their comments and feedback, we have incorporated
> changes to the patient labeling and provided that to FDA. Part of the
> changes that we have implemented are revisions to the clinical tables
> to make them easier to understand and clearer. We have created
> separate sections for augmentation and reconstruction because the
> women who provided feedback on this point wanted to find the surgery
> that pertained to them, whether it be augmentation or reconstruction.
> We also added a table of contents and a glossary of terms, and we
> modified the graphic presentation for ease of use. This condition of
> approval the FDA has determined we have completed.
>
> Now I will pass the microphone to Tom Powell.
>
> MR. POWELL: Good afternoon. The third condition of approval involved
> an effort to determine mode of failure of saline implants. The
> objective of this retrieval study was to use reported and observed
> information to understand and identify possible mode of implant
> failure.
>
> In the eight months from July of 2000 to March of 2001, over 2000
> saline devices were returned as deflated and were evaluated. This
> quantity represents in the neighborhood of a half percent of the
> devices that were sold.
>
> Evaluations included detailed visual examinations, the interpreting
> physicians\' reports and performing appropriate testing, such as
> shell, material, mechanical tests.
>
> From this effort, failure characteristics were identified and grouped
> into the following categories: smooth-edge opening, shell openings
> associated with a crease or fold, which is indicative of a true device
> failure as this characteristic is nearly always associated with
> deflation.
>
> Sharp-edge opening, openings in the device shells where there is no
> associated crease. The reason for this characteristic is yet
> undetermined and may be a true failure or an artifact from handling,
> and are associated with both reported deflated and non-deflated
> retrieved implants.
>
> Valve delamination, a characteristic where 50 percent or more of the
> valve bond area is lost. For devices where valve observations
> confirmed physician reports, this may be representative of a true
> device failure. However, based on lab identification of valve
> delaminations on non-deflated retrieved implants, this characteristic
> may be the result of an artifact.
>
> Leaky valve, this characteristic is identified by a device
> demonstrating leakage upon return evaluation. The reason for this
> characteristic is unknown and may be most likely a result of an
> artifact as it is frequently associated with non-deflated retrieved
> implants found in the lab to have a leaky valve.
>
> Additionally, another group of devices was identified as returned
> devices reported as deflated where lab evaluation could not confirm
> the deflation characteristic. These devices were determined by lab
> evaluation to be functional and the devices in this group made up
> approximately 10-15 percent of returned reported deflated implants.
>
> The next condition of approval was continued activity on fatigue
> testing, responding to past concerns. These were testing of minimum
> thickness products; controlling the compression by load values rather
> than the displacement technique previously employed; and testing of
> the individual units rather than simultaneously testing multiple
> units.
>
> Specific equipment was purchased to address these concerns and a
> protocol was accepted. The smallest size was selected as worst case
> where the load is concentrated over the smallest area. The test
> duration was accepted at either device failure or at 6.5 million
> cycles. The acceptance criteria was accepted to be all samples passing
> the anticipated [in vivo]{.underline} load of 5 lbs, all samples pass
> ingredients twice the anticipated [in vivo]{.underline} load, and
> evidence that the anticipated [in vivo]{.underline} load is past the
> inflection point, or elbow point, defined as the intersection of the
> best-fit log curve with the linear best-fit curve from test values.
>
> Results demonstrated that all criteria were met. All samples passed at
> both 5 lbs and 10 lbs, and the endurance limit or the threshold force
> below which an implant can undergo the run-out number of cycles
> without failure was determined to be 20 lbs. The ultimate static force
> value was used in determining the inflection point and the [in
> vivo]{.underline} load anticipated at 5 lbs was clearly underneath the
> inflection point of 44 lbs for smooth products and 48.5 lbs for
> textured implants.
>
> The last condition of approval was to initiate a real-time study to
> support a five-year shelf life. Currently, saline implants have
> approval for a four-year shelf life at Inamed.
>
> To support this five-year dating, all test product was subjected to
> shipping simulation and testing of both packaging and product is
> ongoing. For packaging performance, four test criteria is evaluated,
> and those are those up on the screen. The results for the year zero
> are also up there. For product performance seven categories are tested
> and, again, the results for year zero have all passed and testing is
> ongoing.
>
> I will turn the microphone back to Ron.
>
> MR. EHMSEN: Thank you, Tom and Kim and Audrey also. Just to quickly
> summarize, the five-year follow-up, as part of the post-approval
> study, has been completed and the years six through ten are in process
> at this point.
>
> The focus group study has been completed. The final report for the
> retrieval study is being prepared and will be submitted to FDA very
> shortly.
>
> The fatigue testing has been completed, and the baseline or year zero
> values for shelf life testing have also been completed, and this will
> continue on for a period of five years.
>
> I would like to open the floor to questions at this time. We are
> joined to today by Dr. Scott Spear, who is professor and chief of the
> Division of Plastic Surgery at Georgetown University, who may be able
> to address clinical questions if you have any; also, Joanne Kune, our
> director f regulatory affairs at Inamed. We also have several key
> members of our technical staff, Meggy Backstrand who is our senior
> biostatistician and contributed greatly to the preparation and
> organization of this data, Farhan Jahab, who is our group leader for
> device analysis, and Mike Taylor, our process validation group leader.
> So, if you have any questions, we would be happy to try to answer
> them.
>
> DR. WHALEN: Thank you. If I could begin, perhaps Dr. Weiss, you
> described in one of your slides that was labeled implant-specific
> complications\"and I have a couple of questions. One was labeled
> implant malposition and just looking at those two words, I would have
> thought that would have been on the next slide in terms of a surgeon
> complication rather than the device. Could you elaborate on what
> implant malposition is? In other words, if somebody comes out with
> breast augmentation at their right knee, that seems to me to be the
> surgeon and not your device. How do you explain that?
>
> DR. WEISS: I am actually going to defer this to Dr. Spear to answer.
>
> DR. SPEAR: My recollection is that we wanted to be as encompassing as
> we could in terms of things that could be related to the implant so,
> for example, an implant could be put in the right position but,
> because of its properties or characteristics, it might displace
> itself. So, although it could be surgeon related in terms of making a
> space where it shouldn\'t be made, it could also be device related.
> So, I think it is just meant to be as generous as possible.
>
> DR. WHALEN: So, if it was in the right place when I finished is sort
> of like it was dry when I closed?
>
> DR. SPEAR: It could be.
>
> DR. WHALEN: The same sort of thing? Thanks. On that same slide, Dr.
> Weiss, what is implant palpability?
>
> DR. WEISS: Implant palpability would be that you could actually feel
> the device through the skin.
>
> DR. WHALEN: So, the ones that you have on your slide are ones where
> you can\--
>
> DR. WEISS: The surgeon noted it as a complication, that they could
> actually feel the device through the skin.
>
> DR. WHALEN: So, it is moderately subjective.
>
> DR. WEISS: It would be based on physician assessment.
>
> DR. WHALEN: Correct. Finally, Dr. Weiss, my last question for you, in
> the patient satisfaction data that you reported, those are percentages
> of patients with implants remaining in place?
>
> DR. WEISS: Correct.
>
> DR. WHALEN: Other questions? Dr. DeMets?
>
> DR. DEMETS: As a follow-up of some of the follow-up studies, do I
> understand that no patients were excluded from your analysis? I
> didn\'t hear you comment on that. The patients that you started out
> with, they are all in the Kaplan-Meier curves for example? There were
> no patients excluded?
>
> DR. WEISS: That is correct, no patients were excluded.
>
> DR. DEMETS: And how did you handle the situation for the issue of
> censoring that we discussed earlier today for patients who had the
> implant removed?
>
> DR. WEISS: There was no specific correction that was taken into
> account in the Kaplan-Meier analysis. The follow-up compliance rate
> was at 80 percent or above. So, we did not do any type of bias
> analysis at this point.
>
> DR. DEMETS: So, any complication that took place in a patient in whom
> the implant was removed, at least it counts up until that point in
> time in all the graphs? For some outcomes it is not relevant; for some
> it might be.
>
> DR. WEISS: Correct, if the patient was lost to follow-up or was
> explanted of all study devices at a particular point, her data up to
> the time that she either dropped out of the study or had all of her
> devices explanted was included. If she was replaced with another study
> device, the outcomes associated with the replacement continued to be
> followed and those were reported here.
>
> DR. DEMETS: While I think that your response rate is certainly pretty
> good, 80 percent, for reasons I said earlier it may not be good enough
> because of the kind of attention that this device is drawing. But do
> you have any sense of the potential bias that might be in the
> non-responders? You can\'t do a very thorough job of this, but have
> you looked at this at all?
>
> DR. WEISS: I don\'t have anything specifically for this study. I know
> that in some of our other studies we have found that some of the
> reasons why patients have not returned for follow-up visits have
> included being unable to because they are out of the country, for
> example, or have been in an accident. So, we have had some information
> to suggest some reasons why patients don\'t return.
>
> DR. DEMETS: If I understood you correctly, the information up to the
> five years was obtained through patient visits to their surgeon and/or
> the clinical site?
>
> DR. WEISS: That is correct. It was a visit to their same physician
> with whom they had enrolled in the A95 or R95 studies. Or, potentially
> a follow-up physician if the patient moved to another area, for
> example, she could see another physician in her area.
>
> DR. DEMETS: And, do I understand that you are proposing for the five-
> to ten-year to do more of a questionnaire?
>
> DR. WEISS: Correct. The six- to ten-year follow-up is being obtained
> via a mail survey to those patients.
>
> DR. DEMETS: Thank you.
>
> DR. WHALEN: Questions for Ms. Croyle, you reported your focus groups
> were confused about the clinical tables. Have you taken some actions
> to redesign that data presentation? Confusion is sort of a
> non-descript word. Can you elaborate a little further on that?
>
> MS. CROYLE: Confusion may not be the most accurate term. A lot of
> women are not familiar with looking at that type of information. It is
> just something they typically won\'t look at unless they are in
> academia or they have a job where they are utilizing tables. I think
> it was more just an understanding, comprehension issue.
>
> DR. WHALEN: In that regard, I know each PMA stands on its own and,
> therefore, every update stands on its own so I don\'t want to be
> comparing one to the other, but there was the opinion voiced earlier
> that when people looked at some of the data for the other sponsor,
> they just couldn\'t believe it was that high and they just thought
> they were covering their own derrieres in that regard.
>
> MS. CROYLE: We did not have any of that kind of feedback. That was
> information we did not receive.
>
> DR. WHALEN: So, phrased another way, was it the perception of your
> independent contractor doing your focus groups that women looking at
> your complication rates grasped what that meant?
>
> MS. CROYLE: They grasped what we were trying to do; it was just
> daunting. Based on the review, they were allowed to read the brochure
> prior to the interviews, and most of the feedback from many women, not
> all\--I actually sat in and viewed most of these focus groups in the
> two-way mirror, and most of them just said I don\'t really need this.
> It is not very helpful to me. It is not the sort of thing I would
> utilize. Other women would say I would need to study it further; I am
> not sure what these tables are telling me.
>
> DR. WHALEN: Dr. Choti?
>
> DR. CHOTI: Ms. Croyle, regarding the focus group, you had some
> comparison groups. You had some augmentation focus groups prior to and
> then a group of women after, as well as the reconstruction. I am
> curious whether you saw any differences between the different focus
> groups.
>
> MS. CROYLE: I would say the main observation of those who had
> reconstruction or augmentation was that they very much appreciated
> that this information was available. Many of them had had surgery
> quite a few years previously and they felt that if they had all this
> additional information at that time it would have been helpful. So, it
> was mostly positive feedback from those who had had the experience.
> There were a few who said, you know, if I had had this knowledge I
> might have made a different decision, but it was primarily that it was
> more informative and helpful.
>
> DR. CHOTI: Another question to Dr. Weiss, it is interesting that when
> looking at the local complications I would have expected, if anything,
> the number to go up, that is, the shape of the curve to be different
> than an asymptotic curve. At least the reoperation curve was kind of
> asymptotic, higher number in the first year than the second and so
> forth, which perhaps may be related to exchange of implants, and so
> forth. But even with deflation one might expect that to go up over
> time, greater in the fourth year, the third, the fourth and the fifth
> year than in the first year. If I recall, your curve was quite linear.
> Any speculation as to why we are seeing that?
>
> DR. WEISS: Not really. I don\'t have any suggestions as to why that
> may be occurring. I will defer to Dr. Spear again.
>
> DR. SPEAR: I don\'t claim to be a biomaterials expert, but I think we
> heard about this issue of the inflection point with these devices, and
> I think the expectation is that they will wear at a fairly linear rate
> up to some point, at which point the failure rate we expect will
> accelerate. It is just that at five years it doesn\'t accelerate. It
> might be at ten years or 15 years, or 25 or 30 years. I don\'t know if
> Tom has any comment about that.
>
> MR. POWELL: I think it would be hard to assess a time expectancy of
> this implant because of the flexibility and the forces of the body
> counteract that to some extent and fix it in place. So, it is a very
> challenging area for investigation, but I would not really have a good
> response to that question at this time.
>
> DR. CHOTI: I do want to compliment you on what I thought was very
> clearly presented.
>
> DR. WHALEN: Dr. Dubler?
>
> DR. DUBLER: I have two questions. First on the focus groups, when you
> went back to them, you had your focus groups redesign your brochure
> and then brought it back. Is that correct?
>
> MS. CROYLE: No, the focus group studies were conducted to revise the
> approved labeling for the PMA.
>
> DR. DUBLER: All right. And, you said that people found the tables
> confusing, or whatever word we are now using.
>
> MS. CROYLE: Right. Difficult.
>
> DR. DUBLER: Difficult, fine. Have you removed the tables and
> substituted\--
>
> MS. CROYLE: No, the tables are still there because they certainly
> contain key information, but the language, the explanatories
> introducing the tables have been expanded and we have worked with the
> FDA quite some time on trying to make that much more comprehensive for
> the patients.
>
> DR. DUBLER: So, even if you don\'t read the table, you will get the
> information?
>
> MS. CROYLE: You will certainly get a brief gist of the contents of the
> table, yes.
>
> DR. DUBLER: My second question, and I am not sure to whom to address
> it, is that the data for your R95 have substantially greater
> complication rates than for your A95. Speculation why? Is the
> reconstruction happening too soon? It is so startling in all of the
> data that I wonder if you have begun to think that perhaps ways of
> changing surgeon practice might reduce those high rates. I am a little
> puzzled about why they are so high.
>
> DR. WEISS: I will ask Dr. Spear to address this.
>
> DR. WHALEN: If he can figure out how to change surgeon practice, he
> will get the Nobel Prize.
>
> DR. SPEAR: I wish we could. Actually, it is not surprising from the
> clinical point of view. It is pretty much expected. In fact, if you
> want to get technical, since these are per-patient complications and
> many reconstructions are unilateral, the data is probably even more
> disparate because the per-device complication is probably even higher
> in reconstruction than it is in augmentation because there are two in
> augmentation and in reconstruction there is only one device.
>
> But, you know, they are two operations. There is underlying scar
> tissue. There is often radiation involved. It is a much more
> technically challenging situation, and it is a fluid situation.
> Frankly, the standards of practice in 2002 are different than they
> were in 1999 or 2000 because of changing patterns of treatment of
> breast cancer. So, it is to be expected that the complication rate
> would be higher.
>
> What is very interesting from an academic point view is that the one
> complication rate which is the same is the failure rate, which is not
> specific to the underlying environment that is device specific. The
> failure rates are actually identical.
>
> DR. WHALEN: Dr. Newburger?
>
> DR. NEWBURGER: Have you noticed any difference in the failure rates of
> the implants related to the positioning of the implants? In other
> words, is there less of a leakage rate if it is inframuscular as
> opposed to supramuscular? Is there any complication rate that you can
> relate to positioning? For example, the skin and nipple complication
> rates are reasonable. Are these related to periareolar positioning?
>
> DR. WEISS: That was not a focus of the study, to look at differences,
> although there was a secondary analysis that had been conducted at the
> time of the original PMA that looked at submuscular versus
> subglandular placement on certain select variables, including
> leakage/deflation and at the time that data, I believe, three-year
> rates were available and there was no difference observed at that
> time.
>
> DR. WHALEN: Ms. Brown?
>
> MS. BROWN: First I would like to compliment the company on getting 80
> percent follow-up out to five years. Getting patients back to the
> doctor\'s office I think is probably a pretty big challenge so I
> compliment you on that.
>
> I was intrigued by the satisfaction rate of 90-95 percent in the
> context of reconstructive contracture rates of 35 percent, if I
> understood that correctly, and augmentation contracture rates of 10
> percent, and leakage/deflation rates a little less than 10 percent in
> both those populations. I just find that really interesting, that
> patients were that satisfied when they are having those kinds of rates
> of contracture and leakage. I was curious as to the 5-10 percent who
> weren\'t satisfied, if you have some thoughts on why they weren\'t
> satisfied, either the contracture patients, the leakage patients.
>
> DR. WEISS: I don\'t specifically have that information with me. We did
> have the physician ask if the patient was not satisfied, why she
> wasn\'t and she would provide a reason, and I don\'t have a synopsis
> of that information, but they could list a complication, for example,
> as a reason.
>
> MS. BROWN: I also thought it was a good indication that perhaps the
> informed consent process is working if 90-95 percent of the time
> patients are saying they are satisfied after five years.
>
> DR. WHALEN: I would like to thank the sponsor then and ask that Ms.
> Allen and Dr. Dawisha again come forward for the FDA presentation.
>
> **FDA Presentation**
>
> MS. ALLEN: Good afternoon. FDA will now summarize the status of the
> conditions of approval for Inamed saline-filled breast implant PMA.
> For your convenience, we have provided you with a hard copy of FDA
> slides.
>
> There are five conditions of approval, a post-approval study, a focus
> group study, a retrieval study, fatigue testing and shelf-life
> testing.
>
> Dr. Sahar Dawisha will present the status of the post-approval study
> and I will present the status of the remaining four conditions of
> approval. I will now hand it over to Dr. Dawisha.
>
> DR. DAWISHA: Good afternoon. Recall that the A95 and R95 studies,
> which the PMA was based on, were five-year studies with three-year
> data presented to the panel back in March of 2000.
>
> The sponsor has now followed this patient cohort for the total of the
> five years of the study, and they are going to be following the
> patients in an abbreviated protocol for the remainder of the five
> years, for ten years. The database was closed for this update in
> August of 2001, and I am going to be discussing augmentation, followed
> by reconstruction.
>
> Table 1 shows the patient follow-up at five years for augmentation on
> an by-patient basis. The percent follow-up of 81.1 percent, which is
> defined as the actual follow-up of 686 patients divided by the
> expected follow-up of 846 patients, is shown here, as well as the
> reasons for withdrawals.
>
> This slide summarizes the by-patient cumulative Kaplan-Meier risk
> rates for selected complications with corresponding 95 confidence
> intervals. The three-year data in this table is what is currently
> reported in the approved labeling, and the five-year data is the
> updated information which is going to be included in the updated
> labeling.
>
> Compared to three years, the rates at five years are slightly higher,
> however, the confidence intervals are overlapping. The exception to
> this is for the complication of implant removal where the confidence
> intervals are not overlapping, suggesting a significantly increased
> cumulative rate at five years compared to three. I will be discussing
> implant removal in more detail later in the presentation. Just to note
> that infection is not included here. The five-year Kaplan-Meier rate
> for infection was one percent.
>
> The number and types of additional surgical procedures performed in
> the augmentation patients is shown through four years, which is what
> is currently reported in the labeling, and through five years as an
> update.
>
> Through five years, there were a total of 463 additional surgical
> procedures performed at 293 reoperations in 224 of the 901
> augmentation patients enrolled in the study. Of the 224 patients
> undergoing reoperation, the majority, 82 percent, underwent one
> reoperation. Through both four and five years, implant removal for any
> reason with replacement was the most commonly performed additional
> surgical procedure, constituting approximately one-third of the
> procedures. It was 30.3 percent through four years and 33.7 percent at
> five years.
>
> This is followed by capsule procedures, specifically capsulotomy,
> which constituted the majority of the capsule procedures. There was
> about three-quarters of the capsule procedures at both four and five
> years.
>
> Of the 1800 augmentation implants that were enrolled in the A95 study,
> there were 166 implant removals, or 9.2 percent, through five years
> for any reason. On a by-patient basis, there were 10.9 percent of
> patients who had an implant removed through five years for any reason.
>
> The primary reason for implant removal, using the same hierarchy as in
> the currently approved labeling, is shown on this slide. I have
> combined categories for the purpose of projecting the slide, as noted
> in the footnotes below the table. Patient request constitutes
> approximately less than half of the primary reasons for implant
> removal through both four and five years. It is 43.2 percent at four
> years and 42.2 percent at five years. The majority of these patient
> requests for an implant size or shape change.
>
> Of the complications, leakage or deflation constitutes the most
> frequent primary reason, approximately 33 percent at both four and
> five years.
>
> For those patients who underwent implant removal with replacement,
> i.e., who had a revision and had follow-up, selected complications
> follow-up implant replacement are shown on this table at two years,
> which is what is currently reported in the labeling and at three years
> which is the updated information. Although the Kaplan-Meier rates are
> higher at three years than at two years, the confidence intervals are
> overlapping, suggesting that the rates are not significantly
> different.
>
> I would like to point out that for implant removal and/or replacement
> the overlap is minimal, suggesting that the rate at three years is
> approaching the limit of being significantly higher than at two years.
>
> The sponsor provided updated information pertaining to breast disease
> and connective tissue disease, however, I am not going to be
> discussing these results.
>
> We now move on to the reconstruction data. The patient follow-up for
> the reconstruction patients is shown on this table through five years.
> Again, the percent follow-up, which is the actual follow-up divided by
> the expected is 80 percent.
>
> The next table shows the by-patient cumulative Kaplan-Meier rates of
> first occurrence through three years, which is what is currently
> reported in the labeling, and through five years, which is the updated
> information for selected complications. Although the rates at five
> years are slightly higher than at three years, the confidence
> intervals for all these complications are overlapping, suggesting no
> significant differences. Note that the reoperation rate here excludes
> planned procedures as part of stage reconstruction.
>
> Table 8 summarizes the number and types of additional surgical
> procedures excluding planned procedures through four years, which is
> what is reported in the current labeling, and through five years,
> which is the updated information. There were a total of 159 additional
> surgical procedures performed and 126 reoperations in 100 of the 237
> percents enrolled in the R95 study. Of the 100 patients undergoing
> reoperation, the majority, 81 percent, underwent one reoperation.
> Through both four and five years, implant removal for any reason, with
> replacement, was the most commonly performed additional surgical
> procedure, constituting approximately 30 percent of the procedures
> through five years. This is followed by skin or scar revision or
> removal, 27.7 percent, and followed by implant removal without
> replacement, 13.2 percent.
>
> Of the 316 implants in the R95 study, there were 70 implants which
> were removed, which is 22.2 percent, through five years for any
> reason. On a by-patient basis, there were 26 percent of patients who
> underwent implant removal through five years for any reason. The
> primary reason for implant removal in this group, using the same
> hierarchy as in the currently approved labeling, is shown here, and
> through both four and five years capsular contracture constitutes the
> largest primary reason for implant removal, approximately 26 percent
> at four years and 31 percent at five years. This is followed by
> patient request for a size or shape change, approximately 23 percent
> at four years and 21 percent at five years. Then, followed by
> leakage/deflation, 16 percent through four years and 17 percent
> through five years.
>
> For those patients who underwent implant removal with replacement,
> i.e., who had a revision and then had follow-up, selected
> complications are shown here. Although the Kaplan-Meier rates at three
> years are higher than at two years, the confidence intervals are again
> overlapping, suggesting that the rates are not significantly
> different.
>
> This concludes my presentation and now Ms. Allen will continue with
> the focus group study results.
>
> MS. ALLEN: The ultimate goal of the focus group study was to improve
> their existing patient brochure. Inamed already described how an
> independent study was conducted to obtain feedback regarding their
> patient brochure. They also described some of the key findings from
> that independent study.
>
> FDA considered the independent study reports submitted by both Mentor
> and Inamed and required the same types of changes for both companies,
> if applicable. The primary changes to Inamed\'s patient brochure were
> as follows: They made significant modifications to the lead-ins, as
> well as to the content of the safety tables because the majority of
> the women found the information confusing. They stratified the
> augmentation and reconstruction information. They added a table of
> contents and a glossary, and they modified the graphics to read
> easier.
>
> Inamed incorporated all requested changes into the patient brochure
> and received FDA approval. Therefore, we consider this condition of
> approval fulfilled. Inamed has just submitted a revised patient
> brochure and package insert that reflect the five-year post-approval
> data. After FDA review and approval, Inamed with finalize them for
> patient and product use.
>
> The purpose of the retrieval study is to determine modes of failure.
> This information may lead to changes in manufacturing design
> specifications, mechanical testing requirements, and/or labeling.
>
> In their 2001 report, Inamed submitted data on over 2400 explants
> collected over an eight-month period. They provided clinical or
> physician observations collected at the time of explantation. They
> provided laboratory observations or device failure characteristics,
> such as smooth and sharp crease-edge openings. These were noted with
> respect to whether the device was deflated or non-deflated. They also
> provided material property test data.
>
> Inamed made numerous conclusions regarding whether the device failure
> characteristics were representative of a true failure or the result of
> an artifact. These were summarized by Inamed earlier and provided in
> your panel memo.
>
> Inamed made on hypothesis regarding a mode of failure. That is, based
> on smooth-edge openings being a characteristic found more in smooth
> shells, failure may be caused by fold flaw and repetitive abrasion of
> both sides of the shell.
>
> Inamed will submit a final report of the retrieval study in their 2002
> annual report. Therefore, FDA considers this condition of approval
> still open.
>
> The purpose of the fatigue testing was to determine the fatigue
> strength of Inamed\'s product line. These data provide additional
> information on the expected long-term performance of the device.
>
> Of the five styles in their product line, Inamed performed fatigue
> testing on styles 68 and 168 as representative of their entire product
> line. The resulting endurance load limit was 20 lbs at 6.5 million
> cycles run-out for both styles, which met the acceptance criteria.
>
> As part of the test report, Inamed also supplied the ultimate static
> rupture results for those two styles. The results were over 1600 lbs
> for both styles, which shows that the implants failed at static loads
> much greater than that expected during mammography, which is 55 lbs.
> FDA considers this condition of approval fulfilled.
>
> The purpose of the shelf-life testing is to support a five-year
> expiration date on the package label. Inamed\'s shelf-life protocol
> involves real-time package integrity and mechanical testing performed
> at year zero, or baseline, and annually through five years.
>
> In their 2001 annual report, Inamed provided an interim report with
> year zero data. The results were adequate. FDA expects Inamed to
> submit an updated report of shelf-life testing annually until the
> desired five-year expiration date is supported. Therefore, FDA
> considers this condition of approval still open.
>
> This is an overall summary of Inamed\'s five conditions of approval.
> The post-approval study will remain open until five-year data are
> submitted. The focus group study is complete. Inamed has already
> revised their patient labeling to reflect the focus group study
> findings. The retrieval study is currently open, however, Inamed will
> submit the final report in July, 2002. The fatigue testing is
> complete. The shelf-life testing will remain open until five-year data
> are submitted.
>
> I will now turn it over to the panel for discussion.
>
> DR. WHALEN: Thank you both Ms. Allen and Dr. Dawisha. Let me add, Dr.
> Dawisha, if I had had someone with your gift of lucidly turning
> numbers into knowledge in med school, I might not have developed a
> life-long passionate hatred of biostatistics. So, thank you very much.
>
> \[Laughter\]
>
> Are there any questions of the FDA members? Yes, Dr. DeMets?
>
> DR. DEMETS: Although the sponsor didn\'t say this directly, you
> certainly allude to the fact that because the confidence intervals
> overlap there was no significant difference, which is technically true
> but the other side of the story is was the study big enough to have
> sensitivity to find differences of that size? So, I am not quarreling
> with the general gist or your comment, but I think the only caution in
> pushing that statement too far is, yes, they may not be statistically
> different but it could be that the difference is there and you just
> can\'t see it with the size of the study, or maybe there isn\'t a
> difference. That is just a caution, and I think somewhere in all the
> discussion we need to have some discussion or comment on the size of
> the study, the precision that they are able to find for the different
> outcomes, whether it is failure rate or other kinds of complications.
>
> DR. DEMETS: Yes, I would agree. We actually did not ask the sponsor to
> do statistics for that reason. That is why I didn\'t present
> statistics but we were just sort of trying to make some sort of
> comparison of time trend analysis.
>
> **Panel Discussion**
>
> DR. WHALEN: Other questions?
>
> \[No response\]
>
> Thank you very much. We would like now to have discussion by each of
> the panel members, the last go around the table for this particular
> presentation. I think it is only fitting that at our last meeting Dr.
> Chang has the last words so we will start with Dr. Miller and then
> work our way around the table. Dr. Miller?
>
> DR. MILLER: I guess I would like, first of all, to compliment this
> afternoon\'s presentations. I certainly feel much more satisfied with
> the data presented this afternoon, and reassured by it.
>
> I think I would like to emphasize as we consider these things that
> this is a unique set of patients and unique problem, and looking at
> single things like reoperation, which ordinarily we would consider
> something undesirable for most surgical procedures, for most
> procedures like this, reconstruction procedures or esthetic
> procedures, it is almost expected that there will be other procedures
> performed to achieve the desired result. So, looking at that as an
> isolated category and considering it a complication per se is not
> really interpreting it properly. So, I just would like to be cautious
> about that.
>
> The other thing I would like to point out is that the satisfaction
> levels being high, despite a 40 percent incidence of reoperations,
> just points out this sort of elusive side of this problem, the benefit
> perceived by the patient. Ordinarily, a reoperation would lower a
> person\'s satisfaction with what they are going through perhaps, and
> it does at the time, but patients perceive a tremendous benefit from
> having these procedures, even with multiple procedures. So, we have to
> remember that as we consider the risk/benefit ratio on the use of the
> implants. But this kind of data is very helpful to get an idea about
> what the risks side of the equation is.
>
> DR. WHALEN: I should just state if you two are more comfortable not
> being in the center, since you have already completed, feel free to
> adjourn, but we are delighted to have you where you are as well. Ms.
> Brown?
>
> MS. BROWN: This is my first panel meeting at which the breast implants
> have been discussed, so I don\'t have the benefit of the history of
> being at the last meetings. One of the things I am very pleased to see
> was a requirement and was actually fulfilled is the evaluation of the
> patient brochures, the focus groups, because adequately informing the
> patients of the risks as well as the benefits of the procedure seems
> to be a key to ensuring future satisfaction of patients. I guess I
> would take that as an indication that that is probably a reasonably
> successful process of the patient brochure informing the patients
> because the satisfaction rates have been pretty high in spite of the
> complication rate.
>
> So, I would just exhort the companies to continue to keep an eye on
> that patient brochure process, keeping that information up to date.
>
> DR. WHALEN: Dr. Doyle?
>
> DR. DOYLE: I would like to thank the presenters this afternoon for a
> very clear presentation. My only concern is that they have gotten such
> an excellent follow-up rate with the procedure they have been using to
> date, which is the physician visit, and they are now going to switch
> to another procedure. I would wish, if it were at all possible, that
> they try to continue to go through the physician because the follow-up
> rate, I fear from other studies, will fall off drastically for the
> next five years, and it is so important to have those data in the
> longer-term follow-up. If it were at all possible, I would hope that
> they would be able to continue to go through the physician because I
> think that this kind of data set\--this is an amazingly good follow-up
> for this particular type of group of women.
>
> I think it is interesting, as Dr. Miller noted, that the patients are
> satisfied even though there is a high complication rate, I think
> similar to some of the injectable contraceptives where there was 80-90
> percent breakthrough bleeding and, yet, the satisfaction was very
> high. So, it speaks again to the fact that is an individual\'s
> decision and, as long as they have the right information on which to
> make that decision, I feel that they have the right to make it and I
> would continue to urge that we give them the correct data.
>
> DR. WHALEN: Dr. McCauley?
>
> DR. MCCAULEY: I would like to basically echo some of the comments that
> have already been made. I think Inamed is to be congratulated on their
> presentations and their clarity, and also the follow-up that they have
> been able to sustain at five years on their patients.
>
> I would only suggest that at least with the focus group study, after
> revisions are made in those brochures, to actually take those back to
> those patients for follow-up just to make sure that the changes that
> they perceived to be resolved or clarified the brochure a little bit
> better are actually the same as what the patients actually think. I
> think that is an important but I think overall it was an excellent
> presentation. I think their data actually resolve some of the issues
> that were of tremendous concern prior to their presentation.
>
> DR. WHALEN: Dr. Dubler? I am the only survivor of the \'92 hearings
> and the hearings two years ago and today, and it is heartening. I
> thought the PMA data that were presented two years ago were excellent
> and today\'s follow-up has been equally excellent, and I thank you for
> that.
>
> For the FDA, I would suggest, and I don\'t know how we would do this,
> but these data and the patient brochure are the basis for an informed
> consent process but they are not the informed consent process. That
> has to go on with the physicians, and I don\'t know if there is any
> way of trying to affect, change or help that process to evolve into
> one that uses these data and truly empowers patients. Maybe that is
> beyond what the FDA can consider, but there is such a nice platform
> now to help women think about this decision that it would be excellent
> if we could take that to the next step, if the FDA could encourage
> that process of informed consent to go forward. So, I thank you for
> the data. They are very helpful, and for a clear presentation.
>
> DR. WHALEN: Dr. Choti?
>
> DR. CHOTI: Although many of the points have been clarified this
> afternoon, I still think it is important to emphasize what we have
> been talking about all day, and that is, this is a common operation
> being performed with placement of this device with increased
> frequency, often in healthy women, and there is still a significant
> paucity in data to help both the physician and the patient make
> informed decisions.
>
> Although this data certainly was presented quite clearly, I think I
> would still encourage the increase in quality, follow-up data,
> preferably independently collected, longer-term follow-up. Also, I
> agree with using that information as well as continued focus groups to
> continue to improve informed consent because it is still not clear
> whether this information is really being understood by the woman who
> is getting these implants put in.
>
> DR. WHALEN: Dr. Newburger?
>
> DR. NEWBURGER: I appreciate the seriousness with which Inamed has
> taken the FDA\'s directives, and the thoroughness with which the
> follow-up studies have been applied. I hope that Inamed will apply the
> same thoroughness to improving product performance to have less
> leakage developing, less reactivity of the implants because still,
> when you look at the rate of leakage of 10, 11 percent over five
> years, this still translates, at the current rate of implantation,
> into between 20,000 and 30,000 women having this complication and them
> having to have a reoperation. So, I hope you will apply the same
> thoroughness and diligence in further perfecting the product. But
> thank you very much.
>
> DR. WHALEN: Dr. DeMets?
>
> DR. DEMETS: Well, I would like to echo the sentiments of my previous
> colleagues speaking. I was very pleased, for example, that the
> follow-up was based on clinic evaluations. I share Dr. Doyle\'s
> concern that if you switch procedures it may drop. Obviously, there
> are some practical matters that have to be taken into consideration.
>
> I have already said my comment about response rates. I think this is a
> substantial improvement in the right direction. I think because of the
> sensitivity and the interest of this particular study and this device,
> my own personal view is that an 80 percent response rate is probably
> not good enough to get rid of some of the concerns because with 20
> percent non-response there is plenty of room for bias, and I can\'t
> predict which way the bias will go. It could go in favor of or against
> the device because it is very hard to predict those kind of things.
> But 20 percent is a lot of room. If you have 80 percent now at five
> years, I worry about what it will be at ten years even if you didn\'t
> change procedures, and I worry even more if you do.
>
> So, I guess my recommendation or at least suggestion to the sponsor is
> to work even harder to get those rates up. I think it will serve you
> well in the long-run to address controversies and questions that are
> bound to come.
>
> I guess this is my last meeting so I am allowed to not follow the
> rules totally, but if I were in the business of breast implants in any
> way, I think I would demand that some kind of registry\--if there are
> 300,000 of these per year, it would be of benefit of the
> investigators, patients, sponsors and even the FDA to have some
> national registry of these kind of patients so we really get the kind
> of numbers and the kind of follow-up and the conditions that if you
> get into the registry you have to stay in the registry so we good,
> complete\--otherwise, this controversy will be here five years from
> now just as sure as it is right now.
>
> That would be a general plea to everybody. It is an important area,
> obviously, and everybody cares about this, so that would be my general
> plea.
>
> Finally, and a personal comment, I just want to thank the panel for
> allowing a biostatistician to survive four years amongst a group of
> surgeons, and occasionally pay attention to what I say or at least the
> points I am trying to make. So, I thank the panel for tolerating me
> for four years, and for the FDA allowing me to be a member of this
> committee.
>
> DR. WHALEN: Dr. Chang?
>
> DR. CHANG: In March of 2000 I felt that McGhan Medical Corp. had done
> its homework in presenting data for its PMA evaluation. I believe that
> Inamed has shown due diligence in the follow-up and presenting the
> data as part of its approval conditions. So, I want to commend the
> sponsor for the data that they have presented today.
>
> A continued plea, and I would echo what Dr. Newburger says, is let\'s
> not rest on our laurels. I make an appeal to sponsor to continue to
> use its energies and resources to improve on the rate of leakage and
> deflation. And, whether this includes physician education, a warning
> not to under-inflate to try to prevent the folding that can occur
> because of position usage, that may be an important part of decreasing
> the rate. Regardless of this, again, there is room for improvement but
> I do want to congratulate the sponsor for doing an excellent
> presentation today, and I would like to thank FDA again for the
> opportunity to participate these past few years on the panel.
>
> DR. WHALEN: Thank you. Dr. Witten, is the discussion satisfactory to
> FDA?
>
> DR. WITTEN: Yes, it is.
>
> DR. WHALEN: Thank you. Let me add a thanks to all of those who
> testified, particularly this morning during the public session. I
> realize many of them took their own time and some of them their own
> financial resources to bring a very impassioned and heartfelt message
> to us, and I assure you we did hear what you had to say to us and have
> taken that into consideration.
>
> I would like to thank all of my fellow panel members, from very solid
> new additions to the panel to always stalwart temporary panel members,
> and give special thanks to Drs. Chang and DeMets for their service
> elbow to elbow with me for the past few years.
>
> Finally, let me give my profound thanks to the FDA. Between 12 years
> active and 16 years reserve service in the United States Navy, I have
> somehow developed a moderately cynical attitude towards the
> government\--hard to believe. Despite that, the FDA has consistently,
> at every level\--scientific review, leadership, professional,
> administrative and support\--always done an impeccable job, and they
> have done it in a fishbowl. It has to be this way; it should be this
> way, but every watchdog group and every congressional member of the
> Hill is watching you guys every time you use a pencil eraser. So, my
> hat is off to you.
>
> Having completed our business, this meeting of the General and Plastic
> Surgery Devices Panel is adjourned.
>
> \[Whereupon, at 2:55 p.m., the panel was adjourned\]

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