# SUMMARY MINUTES OF THE

**\
\
GENERAL AND PLASTIC SURGERY DEVICES PANEL**

**OF THE\
**

**\
MEDICAL DEVICES ADVISORY COMMITTEE**

**OPEN SESSION**

**MARCH 1-3, 2000**

**Grand Ballroom**

**Gaithersburg Holiday Inn**

**Two Montgomery Village Avenue**

**Gaithersburg, Maryland**

**GENERAL AND PLASTIC SURGERY DEVICES PANEL ROSTER**

**March 1-3, 2000**

## Panel Chair

## Thomas V. Whalen, MD

Robert Wood Johnson Medical School at Camden

## 

## Voting Members

Joseph V. Boykin, MD

Columbia Retreat Hospital

Phyllis Chang, MD

University of Iowa College of Medicine

## Temporary Voting Members 

Karen Bandeen-Roche, PhD

Johns Hopkins University

Brent Blumenstein, PhD

American College of Surgeons Oncology Group

Boyd Burkhardt, MD

Adobe Plastic Surgery

Nancy A. Dubler, LLB

Albert Einstein College of Medicine

Stephen Li, PhD

Hospital for Special Surgery

Michael J. Morykwas, PhD

Bowman Gray School of Medicine

John A. Robinson, MD

Loyola University Medical Center

## Consumer Representative

Maxine F. Brinkman, RN, MA

North Iowa Mercy Health Center

# Industry Representative

Cindy Domecus

Conceptus, Inc.

## FDA Personnel

David Krause, PhD

Panel Executive Secretary

Celia Witten, PhD, MD

Director, Division of General and Restorative Devices

Jim Dillard, MS

Acting Director, Division of General and Restorative Devices

Nancy Pluhowski

Panel Coordinator

Stephen P. Rhodes, MS

Branch Chief, Plastic and Reconstructive Surgery Devices Branch

Mr. Phil Phillips, MA

Deputy Director

Office of Device Evaluation

**OPEN SESSION---March 1, 2000**

**Panel Executive Secretary Dr. David Krause** began the Open Session at
8:10 a.m. and read appointments to temporary voting status for Drs.
Bandeen-Roche, Blumenstein, Burkhardt, Dubler, Li, Morykwas, and
Robinson. He also read the conflict of interest statement, noting that a
waiver had been granted to Dr. Li for his interest in a firm at issue
and that matters concerning Drs. Burkhardt, Chang, Li, and Morykwas had
been considered but their full participation allowed. Dr. Krause also
noted that guest speaker Dr. Wendie Berg, who serves as a consultant to
the Radiological Devices Panel, had disclosed a previous relationship
with a firm at issue.

**Dr. Thomas Whalen, Panel Chair**, stated that the charge to the panel
was to make recommendations to the FDA on a premarket approval
application (PMA) for a saline-filled breast implant device and that the
panel members present constituted a quorum.

# 

SPECIAL PRESENTATION TO THE PANEL:

# Least Burdensome Provisions of the FDA Modernization Act

**Mr. Phil Phillips, Deputy Director of the Office of Device
Evaluation,** discussed the meaning of the "least burdensome" provisions
of the FDA Modernization Act (FDAMA) of 1997. He summarized these
provisions as they apply to PMAs and 510ks, noting that FDAMA did not
change the standard for premarket clearance and approval, which remains
a demonstration of reasonable safety and efficacy or a determination of
substantial equivalence to a previously cleared device. Mr. Phillips
looked at FDA implementation of these provisions, saying that efforts
included a January 1999 open meeting, a draft guidance document, and an
industry task force. These efforts produced an interim FDA definition of
"least burdensome" as a successful means of addressing a premarket issue
that involves the smallest investment of time, effort, and money from
the submitters and FDA. He looked at the changes that might result in
FDA philosophy and discussed whether the least burdensome provisions
were in conflict with scientific integrity. Mr. Phillips concluded that
good science includes cost-effectiveness considerations and availability
of resources and that compromise is necessary. He listed mechanisms to
lessen the regulatory burden, which include reliance on nonclinical
testing when possible, reliance on recognized standards, alternatives to
randomized controlled trials, and use of surrogate endpoints. He
concluded that the FDA remains open-minded to alternative proposals for
satisfying regulatory requirements.

**Mr. Stephen P. Rhodes, Branch Chief of the Plastic and Reconstructive
Devices Branch,** welcomed all participants, noting that this was the
first FDA panel to make recommendations on the approvability of any
saline-filled breast implant. Mr. Rhodes stated that there would be
public comment at several points throughout the session, but asked
participants to restrict their comments to saline-inflatable implants
and not to discuss silicone-filled implants.

**Panel Executive Secretary Dr. Krause** asked all participants to
disclose any travel reimbursement, financial ties to companies,
societies, or industries, involvement in lawsuits involving breast
implants, or income derived from surgical procedures or related
complaints.

# OPEN PUBLIC COMMENT

# Individual Speakers

**Ms. Kristine Kitchen** spoke in support of saline-filled breast
implants, citing her lack of problems with implants placed some 20 years
ago to correct a breast deformity. She asked the panel to recommend
approval of the devices in order to keep them on the market and to
notify providers and patients of potential risks and benefits.

**Ms. Patricia Faussett** spoke against approval of saline-filled breast
implants until long-term research has been completed. She cited her
negative reactions of vision impairment, tiredness, and autoimmune
problems after implants, all of which subsided after implant removal.

**Dr. Kathleen A. Melez** presented material on foreign body reactions
to breast implants. She spoke against approval of saline-filled breast
implants, saying they were unsafe and should not be licensed, on the
basis of her experiences as a breast cancer and implant survivor who
later developed foreign body reactions to the implants.

**Ms. Jennifer Gardner** spoke in favor of approval of saline-filled
implants, citing her experience of having saline-filled prostheses
implanted during breast reconstruction surgery following breast cancer.
She spoke of the positive effect on her self-esteem and sexuality and
the importance of restoring a sense of normality to cancer survivors.

**Dr. Tanya Aya Atagi** **of the Washington University School of
Medicine** described her research using standardized instruments to
assess pre and post-operative psychological traits of implant
recipients. She cited evidence that the implants are durable and provide
psychosocial benefits and concluded that it is important to keep the
implants as an option while research efforts continue to reduce risks.

**Dr. Norman Anderson**, an internist and former panel chair, cited his
concerns over the long-term survival of the implant, the degradation of
the silicone shell, and the failure rate of the device over time,
especially at the fold lines. He stated that the implant has the
potential to achieve the highest failure rates of any device presented
to the FDA over time, and he expressed his concern over PMA approval for
devices that may rupture over time and might conceal breast cancers.

**Dr. Fritz Barton, a surgeon,** stated that he spoke on behalf of the
many thousands of patients who say their implants improved their lives.
He described the average patient and spoke favorably of the implant's
effect on their lives.

**Dr. Gwendolyn Lewis** read testimony for three implant survivors who
were too sick or poor to attend, stating that their illnesses were
caused by the saline-filled implants and speaking against the approval
of implants.

**Dr. Cheston Berlin, Jr.,** discussed breastfeeding with implants,
stating that studies he has performed have shown no apparent secretion
of either saline or silicone in breast milk and that there was no
scientific evidence that implants are hazardous to infant health. In
response to panel questioning, he noted that certain types of surgical
incisions might interfere with actual ability to breastfeed.

**Ms. Melinda Cloud** discussed her negative experiences with implant
surgery, saying that it was not a favor to allow women to have implants
that imperiled health and could lead to destitution. She asked the panel
not to recommend saline-filled implants for approval.

**Dr. Howard Ory** made a presentation on breast implants and connective
tissue disease, stating that three blue-ribbon panels had found no link
between silicone gel and connective disease and concluded that breast
implants do not cause connective tissue disease.

**Ms. Patricia Brent**, a mother who breastfed after receiving
saline/silicone-filled implants. Ms Brent discussed her child, who has
suffered from inflammatory disease and digestive disorders, and voiced
her concerns on behalf of mothers who breastfed after implants and
stated that the implants do cause tissue disease in the parent and
feeding problems in the children.

**Ms. Ann Peterson Angus** spoke against approval of saline-filled
breast implants, citing her negative experience with capsular
contracture.

**Ms. Maura McGinn**, a breast cancer survivor and implant recipient,
stated that manufacturers must be required to do research to ensure
safety and said that the decision should be left to women unless there
is incontrovertible evidence to the contrary.

**Ms. Karen Duhala** spoke in favor of allowing saline-filled breast
implants to remain on the market, describing her own positive experience
with a saline-filled implant.

**Ms. Lisa LaCivita** spoke as a consumer advocate for women's choice to
have the implantation of a saline-filled breast implant if they so
desire.

# Consumer Groups and Consumer Information Providers

**Ms. Nicole Cummings** **of Implantinfo.com** described her web site
and read stories from women who described their experiences with breast
implants, largely but not exclusively positive. She stated that because
of the Internet, women are now better informed about what the issues
are.

**Ms. Anne Lowder of the Toxic Discovery Network, Inc.** described her
own negative experience with saline-filled breast implants and stated
that informed choice is the key to making decisions about implant
surgery, which is an elective one. She quoted another member of the
network as saying that the right to choose is meaningless without the
right to know.

**Ms. Lynda Roth of the Coalition of Silicone Survivors** listed the
risks of saline-filled breast implants to cancer survivors, such as more
difficult cancer screening and possible immuno-suppression. She stated
that the manufacturer-supported studies are not impartial and have only
tracked results for five years. She asked that information about
saline-filled breast implants be written by those who are not breast
implant manufacturers and that this information be distributed by all
breast implant providers.

**Ms.** **Eileen Swanson of Survivors of Salines**, a cancer survivor
and breast implant recipient, described her negative experience with
saline-filled implants and requested denial of approval for the PMA. She
stated that the standard allergy testing had not been done, that a
registry of implanted women is needed, and that studies and testing
should be done on implanted women who have become ill.

**Ms. Susan Sherr of the National Coalition of Cancer Survivors**
**(NCCS)** spoke as a personal cancer survivor and on behalf of the
coalition. She stated the NCCS position is that evidence-based science
should be the determinant in any panel review. She stated that women do
not need excessive protection from the FDA and have the right to choose
a breast implant if the data that support safety are available.

**Ms.** **Sybil Niden Goldrich of the Command Trust Network, Inc.**
stressed the need for all available data, noting that some of the data
in the PMAs to be reviewed by the Panel do not support the safety of the
implants. She listed four bioethical issues involving the threshold of
safety and effectiveness for cosmetic surgery, the failure rate, and the
rate of complications such as capsular contracture, numbness, and
infection. She stated that the patient's interest is the only valid
interest in the equation.

**Ms. Cynthia Pearson of the National Women's Health Network** stated
that saline-filled implants have not yet been tested adequately because
there are no long-term, post-five-year data on breakage, complication,
contracture, and reoperation rates, as well as post-mastectomy effects.
She expressed a concern about the loss to follow-up rate, saying that
the data may be flawed because of a selective bias. She felt that
approval without long-term data is a betrayal of the trust women have in
the FDA.

**Mr. Ron Haden of the National Silicone/Saline Implant Foundation**
expressed his concern that the FDA is already biased to approve the PMAs
because the saline-filled breast implants fill a perceived medical need.
He hoped that the FDA would protect the consumer and not approve a
device until safety and efficacy have been proved. He was particularly
concerned with device failure and reoperation rates.

**Ms. Margaret S. Volpe** **of Y-ME** a cancer survivor and implant
recipient, stated that each woman must choose for herself and noted that
the availability of saline implants is very important to breast cancer
survivors to give them reconstructive options. She stressed the
importance of peer support and education for cancer survivors.

**Ms. Anne Stansell of the United Silicone Survivors of the World**
stated that the implants are not medically necessary or life-saving
devices and that the FDA should have warned women about possible
dangers. She charged the FDA to validate the clinical trials before
approval of the PMAs.

**Dr. C. Lin Puckett of the American Society of Plastic Surgeons**
reviewed the history of breast implant surgery. He summarized major
studies and findings from the Institute of Medicine, which he saw as
reassuring in not finding a linkage to autoimmune or connective tissue
disease and as confirming the high level of satisfaction most patients
have with their breast implants. He discussed the risks of deflation and
capsular contracture and stated that there was no evidence that implants
either cause cancer or conceal it from early detection. Dr. Puckett
stated that women should have the right to choose whether they wish to
have breast implants or not.

**Consumer Representative Ms. Maxine Brinkman** read a statement for
**Elizabeth Mullen of the Women's Information Network against Breast
Cancer.** The statement described Ms. Mullen's personal story and
advocated women's right to choose whether they wish to have breast
implants.

**Dr. David Sarwer of the American Society for Aesthetic Plastic
Surgery** stated that the vast majority of implant recipients are
well-adjusted candidates for surgery and will experience significant
psychological benefits from the breast implant surgery.

**Mr. Pierre Blais of Chemically Associated Neurological Disorders**
presented material on his study of 250 explanted devices. He stated that
he felt that the implant design was flawed and that many of the implants
he looked at became infected or septic. He indicated that he felt the
engineering behind the valve and plug design was faulty. He also stated
that breastfeeding would be difficult if not impossible with most breast
implant designs and that the radio-opaque shell can generate false
positives and negatives in mammography.

**Additional Individual Speakers\
Ms. Diane Griffith** asked why the panel is considering a PMA in which
the failure rate of the shell does not meet an acceptable safety
standard. She stated that the labeling does not provide information on
the duration of the shell's integrity.

**Dr. Anne Caspar** discussed women's perceptions of safety of breast
implants, noting that availability and safety of breast implants affect
post-mastectomy choices. Most women do not know that breast implants
have not been FDA approved. She stated that few would have chosen
mastectomies without the implant being available because reconstructive
choices are limited. She felt that breast reconstruction should remain a
choice for those with cancer, but noted that the device has not been
shown to be safe and effective for women who have had cancer and should
not be approved until studies show such safety and efficacy for women
with cancer.

**Ms. Carol Sherman** described her very positive experience with a
breast implant after mastectomy and stated she was grateful that she had
the option of an implant. She stated that she was informed of all risks
and benefits and felt she had returned to normalcy after implant
surgery.

# 

SPECIAL PRESENTATIONS TO THE PANEL:

# Regulation of Saline-filled Breast Prostheses:

**Dr. Celia Witten, Director of the Division of General and Restorative
Devices**, introduced the discussion on regulation of saline-filled
breast prostheses. She reviewed the regulatory history of these devices
up to the call for premarket approval applications for saline-filled
breast prostheses in August 1999. She noted that the guidance document
provides manufacturers with suggested information in the areas of
chemistry, toxicology, mechanical testing, and clinical data. It
suggests that the clinical study include an adequate sample size to
determine a reasonably precise adverse event rate, with a separate
augmentation and reconstruction cohort. Follow-up should last a minimum
of two years premarket with 10 years' total follow-up. The guidance
document suggests follow-up intervals, with a consideration of quality
of life and a screening for connective tissue disease.

Dr. Witten stated that current studies have found no or at most a small
increased risk of connective tissue disease, but these findings are
based on heterogeneous studies. Local complications are not
insignificant and vary widely. A key report from the Institute of
Medicine (IOM) stated that local complications are the primary issue and
noted a deficiency in the literature on product-specific information.

Considerations on Imaging Patients with Breast Implants:

**Dr. Wendie A. Berg, a consultant to the Radiological Devices Panel,**
gave a presentation on imaging patients with breast implants. She noted
that of the two million women with implants, 200,000 (10%) would get
cancer. She discussed mammography with implants and gave survival rates
over various categories. Dr. Berg stated that there is no increased risk
of breast cancer resulting from the implant itself, but it is more
difficult to get an accurate image of the breast with an implant. One
consideration in mammography is that obtaining the best possible view
can involve the use of a double radiation dose with each mammogram
because there is a reduction in the visualized breast with implants.
Other mammographic issues include the fact that implants can hide breast
tissue directly, that adequate compression can be limited because of
contracture, that lesions can be difficult to visualize with implants,
and that scarring and residual calcifications can mimic cancer.

Dr. Berg stated that for her the overwhelming question is whether
diagnosis of breast cancer can be delayed in women with implants. She
noted there are only small studies with minimal data, most of which are
on silicone-filled implants, but results of these studies may be
generalizable to saline-filled implants since silicone-filled implants
are more radiopaque and represent a worst-case situation. In the studies
the majority of patients had only routine mammograms without
displacement. More cancers were palpable at diagnosis than in
nonaugmented women, but the stage distribution and survival were not
different from nonaugmented women. Overall 66 percent of cancers were
visible, but the performance of mammography screening is not adequately
evaluated in the study.

Dr. Berg noted that other imaging methods, such as ultrasound, also have
limitations. She indicated that MRI has higher sensitivity but is
expensive and difficult to perform while nuclear imaging techniques are
not very sensitive, but are still very expensive. She concluded that
there are limitations to normal x-ray mammography for patients with
implants, but there are really no good alternatives.

# 

# OPEN COMMITTEE DISCUSSION\--PMA 990075 FOR MENTOR CORPORATION'S SALINE-FILLED AND SPECTRUM SALINE-FILLED BREAST IMPLANTS

# Sponsor Presentation

**Anthony Gette, CEO of Mentor Corporation,** introduced the presenters
of the PMA.

**Bobby Purkait** gave an overview of the preclinical data and described
the device and its schematics. He noted that a great deal of preclinical
testing was performed using state-of-the-art methods. Potential
extractables were identified and quantified and were found to be at
levels below toxicological concerns. Device materials were found to be
stable and nonbiodegradable. He stated that a thorough battery of
biological testing documented no toxicity issues, and devices and
materials survived mechanical stress testing that exceeds clinical use
conditions.

**Pamela Powell** read the indications for use of the Mentor
saline-filled prostheses. She described the design of the clinical
studies, which included two prospective studies, a three-year and a
large simple trial, and three retrospective studies. Ms. Powell gave the
timeline of all the studies and gave details on the two prospective
study designs. She described the indications, objectives, data
collection, and follow-up of the Large Simple Trial (LST), which
involved 2,347 subjects. On the three-year trial, involving 1,680
subjects, Ms. Powell outlined primary and secondary safety and
effectiveness objectives, data collection and follow-up, site
distribution, and demographic information on augmentation and
reconstruction patients.

**Dr. Bruce Cunningham of the University of Minnesota** presented the
clinical safety findings. He characterized and quantified the clinical
risks defined by the Large Simple Trial (LST) and other clinical data in
the areas of systemic disease, local complications, durability, and
cancer detection and treatment issues. Dr. Cunningham presented results
from three scientific review boards, the Institute of Medicine, the
National Science Panel, and the U.K. Independent Review Group on
systemic disease and breast-feeding. He evaluated the safety endpoints
of the large simple trial and summarized its findings on infection,
capsular contracture, and deflation. On the Saline Prospective Study
(SPS), Dr. Cunningham evaluated the safety endpoints and described
statistical methods used. He showed the breakdown of the different
clinical populations with different clinical objectives and different
complication rates.

Dr. Cunningham also demonstrated the method and extent of physician and
patient information and education on infection, capsular contracture,
and deflation. He placed the clinical risks in perspective with the
medical literature for similar devices and indications, using long-term
data from the ten-year Cunningham retrospective study where available.
He also discussed incidence of reoperation and explantation among
augmentation and reconstruction patients.

On cancer detection, Dr. Cunningham looked at three clinical issues of
implant interference with mammography, delay of cancer detection, and
compromise of clinical outcome and presented data from the SPS study and
population-based research. Dr. Cunningham discussed additional
statistical analyses on factors contributing to deflation and factors
for breast and nipple sensitivity.

Dr. Cunningham concluded that the study data effectively define and
quantify the clinical risks and local complications and that physicians
and patients are fully informed about those factors. He stated that
risks are consistent with those reported in the medical literature for
similar devices and indications and that augmentation patients have a
low risk. Reconstruction patients have higher risks but greater
potential emotional and physical benefits. Revision patients have
experienced similar or somewhat higher complication rates than surgery
for primary implants. He noted that population-based studies have shown
that breast implants do not delay detection or compromise treatment of
breast cancer.

**Dr. Rebecca Anderson of the Medical College of Wisconsin in
Milwaukee** discussed device effectiveness. She described the need for
the device and listed the primary and secondary objectives of the SPS as
evaluation of change in breast size and of patient satisfaction and
quality of life outcomes. These were assessed in augmentation patients
by measuring increase in bra cup size and breast circumference and by
assessing satisfaction with breast attributes and comfort and
satisfaction with breast appearance. In reconstruction patients the
objectives were assessed in terms of increased chest circumference and
increased physical and psychological adjustment and decreased
depression. She concluded that the SPS and the professional literature
demonstrate that the risks and benefits are well defined and documented
and that patients report high levels of satisfaction and improved
quality of life despite possible complications.

**Mr. Purkait** concluded that the preclinical toxicological and
durability/performance assessment had documented safety of the device.
The sponsor's clinical studies document the safety and effectiveness of
the devices and establish long-term durability by 10-year follow-up
data. He stated that the risks were well characterized and that the
device improves the quality of patients' lives and is accompanied by
information and education materials for both patients and physicians.

Questions from panel members focused on fatigue testing, Betadine
washing procedures, complication and reoperation rates, and the
difficulty of teasing out individual practice issues versus device
issues.

### FDA Presentation

**Dr. David Berkowitz** introduced the FDA review team and described the
six styles of the saline-filled and five styles of the Spectrum
saline-filled devices. He read the indications for use and listed the
chemical and toxicology tests, all of which have been completed.
Mechanical testing is incomplete because the data are insufficient for
all the styles listed in the PMA. Dr. Berkowitz also summarized the
medical device reports received from 1997 to 1999 on Mentor devices.

**Dr. Sahar M. Dawisha** gave the FDA clinical overview of the device,
summarizing the clinical studies. These included the Surveillance
Epidemiology and End Results (SEER) program of the National Cancer
Institute, the Large Simple Trial (LST), the Saline Prospective Study
(SPS), and the Mentor Retrospective Study. The SEER study was a
retrospective questionnaire of explant prevalence in the breast cancer
population cohort. The LST was a prospective study of 3,000 to 5,000
patients with one- year follow-up to consider safety endpoints such as
infection, rupture, deflation, capsular contracture, and reoperation.
Dr. Dawisha gave those results by patient and summarized the implant
styles studied. The SPS study was an open-label, prospective study of
1200-1500 patients with three-year follow-up to consider safety
endpoints such as local complications and effectiveness endpoints such
as breast dimensions, patient satisfaction, and quality of life
measures. It also considered connective tissue disease (CTD),
reproduction/lactation at baseline, and breast cancer/breast conditions.
Dr. Dawisha showed cumulative three-year complication rates, reoperative
procedures, reasons for implant removal and three-year cumulative
complication rates after replacement for this study.

The SPS included a subgroup analysis on infection, capsular contracture,
deflation, reoperation, and removal, which showed higher rates of
complication with particular valves or Betadine. Dr. Dawisha also
presented other safety information and effectiveness results from the
SPS. This information showed the cumulative risk of first complication
increases with time and has not leveled off. The cumulative reoperation
and removal rates also have not leveled off over time. The largest
reason for reoperations in augmentation patients are implant removal and
due to complication rather than patient request.

### Ms. Phyllis Silverman of the FDA Division of Biostatistics gave the statistical review, noting that the statistical sections of the PMA are comprehensive and address nearly all the questions requested in FDA's saline-filled breast implant draft guidance document. Her comments were focused on the SPS because it utilizes the devices in question, includes all of the endpoints, and fulfills the recommended follow-up. She noted that complication rates, implant survival curves, and effectiveness parameters must be evaluated from a clinical perspective. Her role was to evaluate the validity of the data rather than to judge the acceptability of the rates. 

### Ms. Silverman noted that statistical power was not an issue and that the sample size was determined by the desired precision of complication rates. Precision was measured by 95% confidence intervals, and the precision met FDA guidelines. She discussed Kaplan-Meier curves and presented three-year Kaplan Meier estimates for primary safety endpoints. She concluded that the data are comprehensive and the analyses consistent with guidelines. Possible biases such as nonrespondent bias, recall bias, or investigator/site bias were acknowledged. She stated that complication-free rates are important for prospective patients and presented Kaplan-Meier estimates of such rates for augmentation and reconstruction patients at one year, two years, and three years. She noted that complications are frequent, with 57% of augmentation patients complication- free at three years as opposed to only 27% of reconstruction patients.

# Panelists Reviews

# Panel Mechanical Review---Dr. Li

Dr. Li's review focused on the possibilities for device mechanical
failure. He agreed with the FDA that all incomplete tests must be
completed, and he added that data are needed on all models and materials
to be marketed. When the material to be used are tested, the gamma
sterilization or other sterilization methods used must be noted. Fatigue
testing shows a high variation in results and should be reanalyzed. The
method of device insertion should be addressed in testing to determine
the effect of load factors. Studies should focus on why and where
deflation happens and on whether reverse diffusion occurs. Leakage
should be addressed, as should the reason the device fails more in
reconstruction patients than in augmentation patients. Dr. Li also noted
that the reoperation rate is very high.

# Panel Clinical Review---Dr. Burkhardt

Dr. Burkhardt stated that the reports of systemic illness and
second-generation effects are largely anecdotal, and that the greatest
concern for these implants is local complications. A major problem is
the failure at fold flaws, with internal abrasion at the end of the
folds. Other local complications include capsular contracture, low-grade
bacterial infections, rippling, and mammography. He thought that fungal
growth in saline is no longer the issue it once was because of modern
filling methods, and that mammography may be made more difficult, but
does not seem to be a major issue in the outcome.

# Panel Statistical Review---Dr. Blumenstein

Dr. Blumenstein thanked the FDA for its presentation of the data. He
stated that the Cox regression analysis is useful but difficult for the
patient to understand, and he recommended a covariate analysis should be
included. He noted several methodological issues: the trials were not
randomized and controlled, and there were no control groups. He listed a
number of data issues related to informative censoring, observing that
there was no analysis to characterize patients not followed at
significant time points. He recommended some alternative presentation of
the relative risks be given to the patients in a more understandable
form.

During the following Panel discussion, the Industry Representative asked
Dr. Li what the company should do to provide more mechanical testing
information. It was suggested that the company should continue the
retrieval analysis.

# Panel Discussion of FDA Questions

The panel concluded that the fatigue and fold flaw testing, at best,
were incomplete because not all models and materials were tested, and
the fatigue and fold flaw testing performed has little or no correlation
with the long-term clinical actualities.

For augmentation patients, the panel was nearly unanimous that the
device is effective within the important constraints of the definition
of effectiveness. There was less agreement on safety, with panel members
expressing some concern about the complication rate but offering
differing interpretations of that as related to safety.

For reconstruction patients, the panel noted that the effectiveness
results as regards the indications are different in this subset in that
this group has different options and also, the sponsor had not
sufficiently assessed quality of life.

A slight majority of the panel felt that additional data should be
collected in regards to the outcomes of the revision patients. There was
an even split within the panel on whether to include the data already
collected on revision patients as a separate cohort in the labeling or
to combine those patients with the reconstruction patients.

The panel agreed that long-term follow-up for 10 years with active
visits would be informative but might not be a realistic goal. All
complications discussed should be tracked until they have reached a
plateau as well as any other complications identified during the
follow-up period. Panel members did not feel collectively that any of
these concerns had to be evaluated by sponsors prior to approval.

Guidelines for surgical practice and postoperative follow-up such as not
inserting the device via a long tube through the umbilicus and not using
Betadine washing were suggested.

# 

# ADDITIONAL OPEN PUBLIC COMMENT

**Lale Goddard,** who had no financial ties but was a plaintiff to a
pending law suit, discussed particulate wear debris generated from
implanted medical devices and requested that the panel not recommend
approval of breast implants without requiring testing for cellular
responses to silicone elastomer particulates. Manufacturers should also
inform doctors and patients about cellular responses to silicone
elastomer shell particles and cytokine production.

**Rosmary Locke, of the DOD Military Hospital Beneficiaries,** a 15-year
breast cancer survivor, noted that the saline-filled implants are the
only unrestricted option left to breast cancer reconstruction patients.
She asked the panel to listen to the IOM recommendations, to use sound
science and reasonable endpoints, and not to restrict saline-filled
implants.

**Dr. Diana Zuckerman of the National Center for Policy Research for
Women and Minorities** stated that she was concerned about the loss of
patients to follow-up and suggested that the information dismissed as
purely anecdotal might be from women lost to follow-up. She thought the
quality of the data reduces the credibility of the report, noting that
of the 17 studies quoted in the IOM report only one looked at saline
breast implants separately. Noting the wide range of views on approval
or disapproval of the implants, she stated she was not in favor of
approval unless the devices were proven safe.

**Jill McClure, whose expenses were paid by the National Alliance of
Breast Cancer Organizations,** said that her comments would be
restricted to the availability of saline-filled breast implants for
reconstructive use only and that her group does not comment on the
cosmetic use of these implants. Saying that saline implants are not
ideal, she expressed a hope that the FDA would look at silicone implants
again but that in the meantime safe saline implants must be made
available to keep options open for women undergoing reconstructive
surgery. The final decision to use implants is up to the woman and the
medical team.

Dr. Whalen thanked all presenters and speakers.

# FINAL REMARKS, PANEL RECOMMENDATIONS AND VOTE

The FDA had no additional comments. The sponsor stated that the data
presented showed the complication rate is not increasing over time,
citing the SPS study in particular.

# Panel Recommendations and Vote

Dr. Krause read the instructions to the panel. A motion was made,
seconded, and passed to recommend the device for approval subject to
conditions. The following conditions were unanimously approved:

1)  That there be additional *in vitro* mechanical testing in
    cooperation with the FDA to address the engineering concerns raised
    in discussion (complete testing of all models and materials intended
    for sale in sterilization conditions, information on shelf aging,
    description of fatigue testing results to show what, where, when,
    and how devices fail, further testing to validate clinical results,
    and further analysis of retrievals done in serum to mimic *in vivo*
    testing).

2)  That the comments regarding the shaped implant in promotional
    material and labeling be revised because there is no evidence
    regarding its more anatomical shape.

3)  That the labeling should discourage peri-umbilical insertion.

4)  That there should be collection of additional revision data.

5)  That risk estimates using true cumulative incidence be reported in a
    way that will be more informative to the patient.

6)  That a reanalysis should be done on characteristics of patients
    dropping out and included in the labeling and that labeling data
    should be presented in a way consistent with peer-reviewed journals.

7)  That long-term follow-up data be collected on patients potentially
    part of an informative censoring pattern.

8)  That the quality of life data on revision patients be dropped from
    the labeling.

9)  That sponsors and the FDA work on the protocol for reasonable
    assurance that patients will be accurately and reasonably informed
    of all risks.

The motion to recommend the PMA as approvable subject to the foregoing
conditions was passed with one dissenting vote.

Dr. Witten thanked all presenters, sponsors, and panel members.

The meeting was adjourned for the day at 9:30 p.m.

**OPEN SESSION---MARCH 2, 2000**

The meeting was called to order at 8:10 a.m. **Dr.** **David Krause,
Panel Executive Secretary**, read appointments to temporary voting
status for Drs. Bandeen-Roche, Blumenstein, Burkhardt, Li, Morykwas, and
Robinson, and Ms. Dubler. Dr. Krause also read the conflict of interest
statement, noting that waivers had been granted for Drs. Li, Burkhardt,
Chang, and Morykwas for their past and present interests in firms at
issue and their full participation allowed.

**Panel Chair Dr. Thomas Whalen** noted that the panel would be
discussing two premarket approval applications and noted that the voting
members present constituted a quorum. He asked the panel members to
introduce themselves.

**Dr. Celia Witten, Director of the Division of General and Restorative
Devices,** provided follow-up to three topics from the previous day's
session. She noted that the 180-day review period begins from the date
the PMA is filed. Dr. Witten also reminded the panel that each PMA must
stand on its own.

## 

## OPEN PUBLIC COMMENT

**Ms. Liz McCloud** related her own unsuccessful experience with a
saline-filled breast implant that ruptured, suggesting that the panel
give greater weight to considerations of local pain, capsular
contracture, and informed consent procedures.

**Dr. Leroy Young of the Plastic Surgery Educational Foundation**
analyzed capsular contracture, deflation issues, failure rates, and
reasons for reoperations. He stated that saline-filled implants are safe
and produce high satisfaction rates, with a complication rate of 1-4%.
He suggested the need for a better informed consent form, a device
registry, analysis of retrieved devices, more research, better
definition of the problem, and a device forum. In answer to questions
from the panel, he recommended that a registry be maintained by
organizations of plastic surgeons.

## 

## OPEN COMMITTEE DISCUSSION\--PMA P990074 FOR MCGHAN MEDICAL'S RTV SALINE-FILLED BREAST IMPLANT

**Sponsor Presentation**

**Dr. Scott Eschbach, president and CEO,** described the company and
introduced the sponsor team.

**Dr. Raymond Duhamel** discussed preclinical studies and testing. He
stated that all elements of the FDA guidance on preclinical testing had
been addressed, and 15 of the 17 test areas are complete. Discussions
continue with the FDA on fatigue and fold flaw testing. He presented
rupture rates, stating that the largest cause of device failure is fold
flaw, but the cause of the folds is still undetermined.

Dr. Duhamel also gave an overview of the four prospective multi-center
studies, the AR90, the LST, the A95, and the R95, noting that the latter
two are ongoing. He discussed patient enrollment, demographics, device
style, and incidence of breast cancer in the implant population. He
presented information on connective tissue disease and local
complications and explained the methodology used to collect these
statistics.

**Dr. Scott Spear** discussed implant removal and replacement, noting
that for augmentation patients the primary reasons for removal were size
and style, leakage, and capsular contracture. For revision patients the
reasons for removal were capsular contracture, leakage, and deflation.
Secondary reasons for surgery are usually procedure-related
complications. He stated that the incidence rates nonetheless supported
reasonable risk/benefit ratios.

**Dr. Marie Pletsch** presented effectiveness data for the sponsors,
saying there was no doubt about the efficacy results. She discussed
quality of life concepts such as physical health, emotional health,
self-esteem, and satisfaction. She concluded that the device has an
excellent risk/benefit ratio, reflecting the high satisfaction rates and
relatively low complication rates.

**Dr. Duhamel** concluded the sponsor presentation with a brief review
of the device benefits.

Questions from the panel to the sponsors concerned valve failure, fold
flaws, connective tissue disease (CTD), missing follow-up data on
quality of life, effect on breast-feeding, safety, and pain data.

**FDA Presentation**

**Dr. Sam Arepalli** introduced the FDA review team, described the
device, and read the proposed indications for use. He presented
preclinical testing information on chemical and toxicology tests, which
were complete. Mechanical testing was complete except for fatigue
rupture and fold flaw tests. He also summarized Medical Device Reports
on the McGhan device.

**Dr. Sahar Dawisha** gave the clinical overview. She summarized the
five clinical studies: the Surveillance Epidemiology and End Results
(SEER) Program of the National Cancer Institute, the Large Simple Trial
(LST), the Augmentation and Reconstruction 1990 study (AR90), the
Augmentation Study of 1995 (A95), and the Reconstruction Study of 1995
(R95). She summarized the SEER study, noting that the main reason for
saline breast implant removal in this retrospective questionnaire of
explant prevalence in the breast cancer population was capsular
contracture. She also described the LST study design, which was a safety
only study of 3,000-5,000 patients with one-year follow-up and presented
the Kaplan-Meier results for infection, deflation, and capsular
contracture rates. Dr. Dawisha described the AR90, which was an open
label, prospective study with five-year follow-up of 300 patients, and
showed patient disposition at five years as well as intra-operative
medications and by-patient five-year cumulative Kaplan-Meier
complication rates. The AR90 study also provided information on type of
reoperation procedure and reason for implant removal through five years,
as well as other safety information. A subgroup analysis on augmentation
patients showed a statistically higher leakage/deflation for leaf valve
and submuscular placement and a numerically higher infection, removal,
and capsular contracture for the leaf valve, which has since been
removed from the market. Effectiveness results showed increased bra and
cup sizes, satisfied ratings and generally improved quality of life
measures.

Dr. Dawisha described the study design of the A95 and R95 studies and
showed the patient disposition at three years for both. She presented
the by-patient cumulative four-year Kaplan-Meier complication rates and
the type of reoperation procedure, as well as the reason for implant
removal through four years and the two-year cumulative complication
rates after replacement for the studies. A subgroup analysis again
showed higher leakage/deflation rates and implant removal rates for the
leaf valve. Other safety information from the study found no changes in
reproductive or lactation problems, no increased breast disease in
reconstruction patients, and a slight increase in breast disease for
augmentation patients. She analyzed new reports of CTD and analyzed
effectiveness results in the AR95 study. Dr. Dawisha concluded that the
cumulative risk of first complication increases with time and has not
leveled off and that there is a cumulative four-year reoperation rate of
24% and a removal rate of 10% for augmentation patients. The largest
cause of reoperations in augmentation patients is implant removal due to
complications. The breast size benefits were evident for augmentation
patients, with quality of life benefits less apparent. Quality of life
generally improved for reconstruction patients.

**Dr. Telba Irony** gave the statistical analysis of the AR90, A95 and R
95 studies, noting there were no claims, targets, or control groups in
the studies, only descriptive statistics to describe safety and
effectiveness endpoints. Sample sizes were previously determined to
achieve precision for the estimates as defined by the length of the
confidence intervals for the adverse event rates. The targeted precision
was achieved. She described the statistical techniques employed to
assess safety, noting that the estimates are very sensitive to biases
generated by loss to follow-up. Quality of life measurements were
appropriate, but statistically significant change in breast or cup size
was meaningless because the breasts were physically enlarged during the
surgery. She noted possible biases of nonresponse, recall, and
investigator/site. Other analyses that could have been performed
included using demographic variables as covariates, checking the
correlation among adverse events, combining the augmentation studies
from 1990 and 1995 and looking at the statistically significant
differences between these studies.

# Panelists Reviews

# Panel Mechanical Review---Dr. Li

Dr. Li was impressed with the sponsors' testing approach but expressed
concern over relating that data to clinical performance. He thought the
fatigue testing deficient and was unclear what the fold flaw data meant.
He stated that he was unclear why sponsors picked the tests they did and
how to interpret the information they provided.

# Panel Clinical Review---Dr. Boykin

Dr. Boykin expressed a significant level of comfort with the clinical
data, saying that the overall studies show some consistency and the
present device with the diaphragm valve design shows some improvement
(less leakage) over the previous model with the leaf valve. He was
comfortable with leakage and deflation rates and stated that the
cumulative rates, although biased, is what is generally seen. He raised
three points: whether there was a replacement policy for the leaf valve
versus the diaphragm design, what measurement issues on quality of life
measures should be considered, and how differences in shape should be
addressed in product labeling.

# Panel Statistical Review---Dr. Blumenstein

Dr. Blumenstein noted his concern about informative censoring in the
data, saying there was no characterization or analysis to show the
percentage of informative censoring. He thought the statistical analysis
should have been performed as cumulative incidence rates. Prevalence
estimates as presented should be dropped. A proportional hazard
regression approach would have been better. He suggested that the
characterization of risk should be redone to sharpen the
characterization between normal surgical complications/adverse
events/device problems/surgeon mistakes. In conclusion he stated that
the method of presentation could be improved.

**Panel Discussion of FDA Questions**

The panel recommended that fatigue testing is important and should be
standardized with sponsor-FDA concurrence. Fold flaw testing may not be
as important as previously thought in assessing long-term rupture or
leakage.

There was a panel consensus that the device is reasonably safe and
effective in both augmentation and reconstruction patients, with some
editorial caveats on how efficacy as studied and designed might not be
as good as they could have been. Safety analysis should distinguish
between complications specific to implants and normal surgical
complications that occur with many surgeries. More data on the cohort of
revision patients would be useful but should not be a condition for
approval.

The majority of the panel thought that a 10-year follow-up period was
the best duration, with a minority saying that five years would be
sufficient. Active follow-up is preferred, with passive follow-up as a
backup position. Complications as defined in the LST should be followed.

The panel was unanimous in stating that sponsors did not need to provide
evaluation on interference with screening mammography or lactation or
effects on offspring as a condition for approval. They stated that these
are, however, important issues that should be included in the device
informed consent form and labeling and on which it is desirable to
accumulate data.

There was a general concern expressed by the panel regarding the need to
improve educational process for physicians. Another concern among panel
members involved the factors inherent in complications regarding
positions and insertions rather than the device itself.

# ADDITIONAL OPEN PUBLIC COMMENT

**Dr. Patricia Lieberman of the National Center for Policy Research**
expressed her concerns over the safety of this device and the one
approved the previous day.

**Dr. Harold J. Brandon of Washington University** gave an analysis of
breast implants from the Washington University Implant Retrieval
Program. He described the breast implant inventory of more than 500
explants and explained the research objectives. He noted that strength
could vary by implant type. He presented data from failure analysis,
noting that failure tends to occur in folds rather than with large-scale
shell degradation.

**Dr. Wendy Anne Epstein,** a patient with Mentor implants, recommended
that women have a baseline mammogram before implantation and have
submuscular implantation to prevent mammographic interference. Saline
implants provide greater radiolucency and thus are better. Although
submuscular implantation requires general anesthesia and nerve damage
remains a possibility, there is less possibility of damage to offspring
or interference with breast-feeding.

# 

# FINAL COMMENTS, PANEL RECOMMENDATIONS AND VOTE

The Agency had no additional remarks. The sponsor thanked the FDA
reviewers and the panel.

The Consumer Representative addressed a remark to sponsors and the panel
asking for responsible promotion and marketing, with no ads targeted to
teenage girls. She noted that ads have no references to possible side
effects.

# Panel Recommendations and Vote

Dr. Krause read the panel voting options. A motion was made, seconded,
and passed to approve with conditions. Those conditions are the
following:

1)  The revision category should be dropped and the two categories of
    augmentation and reconstruction should be considered as the
    indications.

2)  Changes should be made in the labeling and marketing materials to
    eliminate references regarding the proposed anatomical advantages of
    the device pending studies suggesting reasonable scientific evidence
    that such is the case.

3)  Long-term active follow-up should focus on active censoring, with
    the FDA and sponsor to determine an appropriate length.

4)  The risk characterization analysis should be redone with appropriate
    characterization of complications versus adverse events.

5)  An analysis should be provided on censoring and quality of life data
    to characterize the sample and as representative of the general
    population.

6)  Discrepancies between the CTD data presented by the PMA, the FDA,
    and other speakers should be clarified.

7)  Mechanical testing should include testing on the thinist wall and
    the highest potential for failure. Sponsors should work with the FDA
    on acceptable fatigue and fold flaw testing.

8)  A standard operating procedure should be completed and followed for
    looking at explants and to tabulate the model and wall thickness of
    these devices.

The motion was passed unanimously.

# OPEN PUBLIC COMMENT

**Dr. James L. Baker, Jr. of the Aesthetic Surgery Education and
Research Foundation** described the benefits and the psychological
issues involved in breast augmentation. He stated that the benefits are
real and outweigh the risks and described detailed psychological studies
of psychosexual aspects of breast augmentation.

OPEN COMMITTEE DISCUSSION---PMA990077 POLY IMPLANT PROTHESES USA (PIP)

Sponsor Presentation

Dr. Rick Hawk described the history of the company and the device
itself, noting it was a prefilled device with no valve. He defined valid
scientific evidence and listed a U.S. and a French prospective study and
a U.S. surgeon case survey as part of that evidence. He listed the
preclinical testing done on cytotoxicity, sensitization, irritation,
intracutaneous reactivity, and acute systemic toxicity.

Dr. George Burdock presented the preclinical data from the tests listed
above. He concluded that the elastomer is biocompatible and that all *in
vitro* and *in vivo* studies were negative. All findings were also
congruent with the literature such as the IOM report and peer-reviewed
published literature.

#  Dr. Ionana G. Carabin discussed complications from implantation such as deflation and capsular contracture and presented clinical data from the U.S. clinical study, the U.S. surgeon case experience survey, and the two-year French clinical study. She listed indications and contraindications for the device, types of surgical incisions and placement, and types of implant, along with follow-up through October of 1999. 

# Dr. Carabin presented safety/effectiveness data on capsular contracture, displacement, folds, deflation, change in nipple sensitivity, asymmetry, pain, and inflammation for both the augmentation and revision cohorts with various implants and placements. She noted in particular that there was 0% incidence of capsular contracture grade iii and iv for texture implants placed rectopectorally or subglandularly. 

Dr. Carabin also presented material on connective tissue disease and
complications, noting that most of the complications in the cohorts were
rare. Changes in nipple sensitivity and asymmetry were more common, but
were still within the range of reported incidences in the literature.
Quality-of-life data was assessed with self-reported quality-of-life
scales. Data on increase in cup size were also presented.

Dr. Carabin provided data about the U.S. surgeon case experience survey
on 35,000 implants in the United States, some of whom are two or more
years postoperative. This survey showed a relatively low rate of
complications and a relatively high rate (88.5%) of patient
satisfaction.

#### Dr. Margan Goudeau presented further data from the French clinical prospective study on 520 patients to evaluate the complication rate. He listed the indications for use, surgical placement and incision, and contraindications, and presented statistics on follow-up out to 24 months. Dr. Goudeau showed data on augmentation and revision cohorts for deflation, capsular contracture, infection, folds, asymmetry, and nipple sensitivity, showing 0% autoimmune disease, pregnancy difficulty, lactation difficulty, calcification, extrusion, necrosis, pain, or hematoma at 24 months. 

**Dr. Carabin** concluded by noting that 35,000 PIP prefilled saline
breast implants have been marketed in the United States. Preclinical
studies have shown no toxicity, and clinical data have shown low rates
of complications and high rates of patient satisfaction. She also listed
mechanical testing performed and briefly described the tests.

In questions to the sponsors, panel members asked how the current device
differs from that presented a number of years ago. Sponsor
representatives replied that the new shell was thinner and harder.

At this point, the FDA presentation was deferred so that the Open Public
Hearing could be held.

# ADDITIONAL OPEN PUBLIC COMMENT

**Cynthia Pearson, National Women's Health Network**, noted that
consumers would like to see what the unexpected and adverse events are
and what the likelihood is, especially for longer than two years. For
augmentation patients in particularly, it would be reasonable to share
the global number of adverse events because these women do not plan to
go back for a second procedure.

**Diana Zuckerman of the National Center for Policy Research for Women
and Families** noted the public confidence in the FDA to protect health,
even with problematic data. She expressed concern about the higher
dropout rate and smaller sample size in this study and asked the panel
to hold to a standard that makes sense to consumers.

**Tom Hudson of Baylor College of Medicine**, whose expenses were paid
by PIP, gave his results using the PIP implants and discussed how
technological changes in this type of implant had minimized many common
complications and side effects.

**OPEN COMMITTEE DISCUSSION (continued)**

**FDA Presentation**

**Dr. Peter Hudson** introduced the FDA review team and described the
device. He listed the proposed indications for use and reviewed the
preclinical chemistry, toxicology, and mechanical data, noting that many
tests were still incomplete. He also listed the medical device reports
received from 1997 through 1999 on the PIP device.

Dr. Hudson presented clinical information based on the U.S. surgeon case
experience survey, the U.S. clinical study (the Discretionary Postmarket
Surveillance or DPS), and the French Clinical Study. He described all
three of these studies and summarized both their strengths and
weaknesses. Strengths included relatively high numbers of augmentation
patients, while weaknesses included relatively lower samples of revision
patients, problems of bias, and protocol deviations or abnormalities.

**Judy Chen, M.S.,** gave the FDA statistical review of the three
sponsor studies. She presented strengths and weaknesses of all three
studies as well as key data from each. On the postmarketing surveillance
study, she commented on the high proportion of missing data, and the
fact that event time may not be independent of censor time and other
adverse event times. Regarding the French study, she noted the lack of a
protocol and the likelihood of bias in results because censoring was not
appropriately adjusted, missing follow up and complication data, and
possible underreporting effects.

**Dr. Hudson** read the FDA questions for panel review.

# Panelist Reviews

# Panel Mechanical Review---Dr. Li

Dr. Li noted an incomplete device description and incomplete clinical
specifications and analysis. He said that it was not clear what was
being tested chemically or dimensionally. He saw no information on fold
flaw or static rupture and the information on fatigue rupture testing
was confusing. He cited a lack of information and rationale on loading
and felt that the sponsor had not completed the testing that was
specified in the FDA guidance document.

# Panel Clinical Review---Dr. Chang

Dr. Chang noted that the clinical data are a work-in-progress, but
observed that the number of patients in each of the cohorts in the
prospective study is smaller than the number of patients recommended by
the FDA. She felt that the deflation rates cited at two years were good
but asked if data was available for the smooth implant. She recommended
longer follow-up on the folds in the implant and noted a potential
difficulty in fine-tuning the volume of fill, which could cause an
asymmetry problem.

# Panel Statistical Review---Dr. Blumenstein

Dr. Blumenstein stated that the use of true incidence would have been a
better methodology for a later presentation. He also noted that the U.S.
study is not yet complete.

In panel comments, one member noted the potential of the device for
reduced leakage and greater palpability but expressed concerns regarding
the lack of complete product testing. The sponsors replied that
additional data clarifying the follow-up statistics were presented in a
February 2000 PMA Amendment, which had not yet been reviewed by the FDA.

# FDA Questions 

The panel agreed that the carcinogenicity, toxicity, implantation,
pharmacokinetics, biodegradation, and chemical tests listed are crucial
and the data they provide is critical. The engineering material
properties are also critical. The fatigue testing methodology used was
unproven and its relevance was unknown. Further fold flaw information is
critical, and there is a wealth of chemical and physical data not
forthcoming from this sponsor that are essential.

The panel concluded that the U.S. DPS data are essential for the PMA,
but the data as presented are not mature enough to permit an evaluation
of safety and efficacy. Data from the French study cannot stand alone,
and the collection of U.S. data was still in progress. The weakness of
the U.S. Surgeon Case Experience Survey was well described. The data in
each subset of the PMA are inadequate and do not justify an evaluation
of safety and efficacy.

The panel agreed that 10-year post approval follow-up should be a
minimum and the sponsor should strive for active visits, with particular
attention to device failure, leakage, rupture, and asymmetry.

Consistent with its prior opinions, the panel agreed that while the
issues of interference with mammography, lactation, and effects on
offspring are important, information on them is not necessary as a
condition of approval. The panel also agreed that while physician
training is important, it is best left to the head of the training
institutions.

On the risk of asymmetry and the risk of changes in nipple sensitivity,
the panel expressed concern that the data is still incomplete. If rates
prove to be as high as currently noted, they should definitely be listed
in the labeling and informed consent.

# FINAL COMMENTS, PANEL RECOMMENDATIONS AND VOTE

The Agency had no additional comments. The sponsor representative read a
statement saying that changes in design had addressed design defects,
but they would work with the FDA to answer questions and issues raised
by the panel. They added their opinion that their data supported
reasonable assurance of safety and efficacy and met the threshold for
approval.

# Panel Recommendations and Vote

Dr. Krause read the voting options. It was moved and seconded to
recommend the PMA as not approvable because the data were much too
preliminary, especially in the U.S. sources. The motion passed
unanimously. The panel also recommended that the sponsor address
deficiencies such as information needed on smooth versus textured
implants, thickness of implant, and asymmetry of results; and to provide
information from a completed clinical study with adequate follow-up.

Dr. Whalen thanked the panel and all presenters and adjourned the
meeting at 5:47 p.m.

**OPEN SESSION---MARCH 3, 2000**

**Panel Executive Secretary David Krause** opened the session at 8:02
a.m. He read the conflict of interest statement, noting that matters
concerning Drs. Burkhardt, Chang, and Morykwas had been considered and
their full participation allowed. **Panel Chair Dr. Whalen** noted that
the purpose of the day's session was to make recommendations to the FDA
on the content, format and consistency of labeling and informed consent
documents used for saline breast implants.

**Celia Witten, Director of the Division of General and Restorative
Devices,** welcomed all participants, especially those from the public,
to the day's session and invited their comments.

Dr. Whalen introduced the presenters from industry.

# LABELING PRESENTATIONS FROM INDUSTRY

**Scott Eshbach of McGhan Medical** described three routes for
information dissemination to patients and physicians. The first is the
device packaging, which includes the FDA "Information for Women"
document, the informed consent document, the claims processing program
data, the patient device ID card, and an information packet for the
physician. The second is educational material for patients such as
pamphlets on silicone and choices in breast construction and
augmentation and materials for physicians such as instructional
monographs and videos, wall charts, and planning tablets. The third
route is web-disseminated information such as the pamphlets listed
above.

McGhan's advertising philosophy involves product promotional ads with
legally mandated "fair balance" of risks and benefits and reminder ads
without this discussion of risks and benefits in newspapers and
magazines. Medical journals also feature physician-directed articles on
product technical failures. Mr. Eshbach asked the panel to consider
three points: the need for a consistent approach across industry, the
need to cite actual data that are specific to the manufactured devices,
and a phased-in replacement for current labeling.

**Donna Crawford of Mentor Corporation** discussed her company's
approach to communications through its current programs and labeling and
its proposals for new content and expanded communication methods. She
listed communications channels such as a toll-free phone number staffed
by nurses, educational videos, and an interactive web-site. Patient
labeling contains three brochures, the FDA "Information for Women" and
"Options in Breast Augmentation/Reconstruction," all of which she
described. Ms. Crawford listed new initiatives to communicate new
detailed clinical results on both risks and benefits via expanded
web-site communication and focus groups to discern the most effective
methods of communication.

# 

# OPEN PUBLIC COMMENT

# Comments from Professional Societies

**Dr. Shawna Willey of the American College of Surgeons** focused on the
principles of informed consent. She noted that patients must talk to
their surgeons and discuss individualized options. She warned against
unrealistic expectations regarding the duration of the device and
possible complications and recommended that the FDA draft outline might
serve as a checklist for surgeons to review during the informed consent
process. The checklist could also be included with the information
insert in the device packaging. Good understanding of the procedure
should include clear differentiation between risks and complications
that have been proven and those that have not. She opposed a mandatory
waiting period before device implantation on the grounds of questionable
legality, practicality, and needless inconvenience.

**Dr. Mark Jewell of the American Society for Aesthetic Plastic
Surgery** discussed informed consent, suggesting the most comprehensive
approach possible. He thought such an approach should include a
discussion of appropriate indications for surgery, description of the
procedure, alternatives to implants, discussion of inherent
device-specific risks and general surgical risks, and other advisory
information. Such information would cover implications for mammography
and pregnancy, likelihood of breast disease or autoimmune disease,
long-term results, and statistics on revision, replacement, or removal.
Medical risks should be related to familiar risks patients encounter in
their daily lives and explained in a variety of ways. Benefits should
also be discussed. Dr. Jewell did not recommend a waiting period for
breast augmentation because the operation is typically scheduled far in
advance in any case. He also recommended against a waiting period for
reconstruction patient because decisions must be made quickly in order
not to delay cancer treatment. Dr. Jewell provided the panel with copies
of a their proposed informed consent documents.

**Dr. Bailey of the American Society of Plastic Surgeons** noted that
informed consent is communication and is more than a legal process. He
opposed a mandatory waiting period but noted that many doctors impose a
waiting period in any case or refuse patients with the wrong motivations
for surgery.

In answer to questions from the panel, both Drs. Bailey and Jewell
stated that physicians who advertise should not be treated differently
from those who do not and that advertising was not per se a conflict of
interest. With respect to patient understanding of risk, Dr. Jewell
thought it was possible to quantify risk in ways that were meaningful to
patients.

# Comments from Individuals

**Mary McDonough**, **an implant recipient** who said she thought she
was making an informed decision but did not receive true informed
consent, expressed her concern that saline implants are hardly a safe
alternative to silicone implants and that approval with so many
conditions is hardly a clear signal of safety. She recommended
conducting independent research on saline implants and strengthening
informed consent documents to include the absence of scientific
information on breast-feeding and complication rates, the financial
implications, insurability issues, and psychological aspects of surgery.

**Liz Macleod, an implant** **recipient,** stated she was not provided
with proper informed consent and did not know the regulatory status of
breast implants. She felt that patients should know about shell
permeability, gel-bleeding possibilities, risk of multiple surgeries,
and health complications. She would have wanted to know the regulatory
status and been informed about the lack of long-term studies on failure
rates and shell degradation. She noted that it is in the financial
interest of manufacturers and surgeons for the devices to fail, and that
labeling and informed consent are not panaceas. The burden of risk is
unfairly placed on the user, and she reminded the panel of the
Hippocratic Oath versus caveat emptor.

**Lisa Hickey, an implant recipient who had experienced denial of
insurance coverage**, stated that both Mentor and McGhan repeatedly
violated Good Manufacturing Practices and underestimated adverse events.
She suggested that true long-term studies would show that breast size
and patient satisfaction actually decrease over time and that many
long-term problems are not reported in the database because patients do
not return to their doctors. She also reminded the panel that device
failure causes permanent results.

**Dr. Roberta L. Gartside, a plastic surgeon,** shared her experience of
the last 11 years, listing low rates of complications. She discussed the
negative media attention implants have received, saying this was
upsetting and potentially misleading to women who needed to explore all
reconstructive options available after mastectomy.

**Dorothy Stull, a breast cancer and reconstruction patient,** stated
that she had had no problems with her saline implants, she hoped that
saline-filled implants would remain an option because of the advantages
to psychological self-esteem for implant recipients.

**Dr. Saul Puszkin** discussed the immunogenicity of latex and silicone
and the scarring potential of both. He spoke on his lab experience and
discussed the molecular structure of silicone, saying that implants must
have expiration dates because the material will decay.

**Dr. Britta Ostermeyer** discussed adjuvant breast disease in patients
with saline-filled implants. She gave demographics and statistics on her
patients with problems with saline-filled implants, saying that women
need to be aware of the risk of local injury and local response as well
as systemic illness. She recommended that more long-term data be
collected and that surgeons explore patient expectations and explain
potential complications, including health insurance coverage.

**Comments from Consumer Groups**

**Marlene Keeling of Chemically Associated Neurological Disorders**
stated that she had received no informed consent document with her
implant in 1978 and that the current document is written to escape legal
liability. She recommended that a complete list of all chemical and
safety data must be provided and that the product insert, FDA
information, informed consent document, and video explaining
complications all be presented at the initial consultation. Further
recommendations were that a patient identification card with all
information be given at surgery and that a statement that the FDA has
not formally approved the devices should be given to the patients.

**Dr. Diana Zuckerman of the National Center for Policy Research for
Women and Families** stated her concern about the gap between the oral
and written informed consent procedures and her concern about insurance
coverage. She stated that there is a gap between what women are told and
what research shows on advice and options for breast cancer patients,
and a gap between the manufacturers' understanding of their own data and
the FDA understanding of it. She recommended that informed consent
should include photos of what negative consequences can look like, a
listing of what is and is not known on systemic disease, and the
statement that implants change the body permanently.

**Martha Murdock of the National Silicone/ Saline Implant Foundation**
stated that informed consent documents do not contain all the
information that manufacturers have and that manufacturers do not reveal
all they know. She noted that patients do not always get the package
insert and that failure rate tables should be available in all informed
consent documents. She also raised the lack of health and life insurance
coverage for implant recipients.

**Anne Stansell of United Silicone Survivors of the World**, a cancer
survivor and implant recipient, stated her concerns about the lack of
device warranty, lack of device registry, and lack of health insurance
availability. She stated her concern that the FDA did not have full
facts before approval and her feeling that the process of approval was
flawed. She ceded her remaining time to **Marlene Keeling,** who read
the denial of health insurance she had received.

**Amy Allina of the National Women's Health Network** discussed how the
Network is based on the right of all women to make choices based on
complete information. She stated that all available information should
be in the informed consent document and should be substantiated.
Complications, deflation rates, benefits, risks, and photographs of
unsuccessful and successful surgeries should be covered in an easy-to
read presentation.

**Rosmary Locke of the National Alliance of Breast Cancer
Organizations** stated that general information on reconstruction
options and devices should be included in the informed consent document.
A better informed consent would help remove patients' sense of betrayal.
She recommended that all clinical trial information should be included
in a standardized approach. Focus testing should be done to see how
people receive and retain information. Cost of revision surgery and life
expectancy of the implant should be in the informed consent document.
Implants should have a bar code for easier tracking, and patients should
receive a full description of the operation in advance. A device
registry card and patient identification card should be included with
the informed consent document.

# DISCUSSION OF BREAST PROSTHESIS LABELING

**Panelist Presentations**

# Panel Discussant---Nancy N. Dubler, LLB

**Ms. Dubler** noted that the informed consent document was developed as
a way to redress problems in the balance of power in the relationship
between doctors and patients. The doctrine requires a decisionally
capable person who is able to articulate personal values and make valid
choices. Legally it is a risk management technique, not an empowerment
technique. She stressed the need for a new paradigm among manufacturers,
surgeons, surgical organizations, consumer organizations, patients, and
partners on the principles of transparency, awareness of risk, and
availability of independent sources of information. These three
principles should be added to informed consent principles. Transparency
requires that any data should be given to women in the most informative
form possible. The FDA should highlight risk awareness with consumers in
any ways possible, and the authority of the FDA should extend to
promotional material. The FDA should give web-sites as independent
sources of information as part of the informed consent process. Ms.
Dubler added that web-sites might lack quality control but do give both
sides of the information to women.

# Panel Discussant---Maxine F. Brinkman, R.N.

Ms. Brinkman stated that she had listened to dozens of consumers and
groups and would share their comments with the FDA. The consensus was
that informed consent documents should be improved in content and the
consent process should be improved. The challenge is in providing a
nontraditional approach to getting information to consumers. Health care
providers need to learn how to reach consumers better. Specific
suggestions included the following. There should be improved multimedia
access to information, especially improved risks and benefits
information. Photographs of desirable and undesirable results should be
available, and web-sites with hyperlinks should be additional resources.
Detailed instructions for mammography should be given to patients, and
medical costs and issues of insurance availability should be discussed
in advance. Insert material should be duplicated for patients with full
listing of all potential complications. A national registry of all
implants with identification cards for recipients would help facilitate
further information dissemination. Ms. Brinkman also noted that both
manufacturers and the FDA have responsibilities in advertising,
especially in terms of age limits, and that concise physician training
should be available before physicians are able to purchase any product.

# FDA Presentation

**Stephen P. Rhodes, Chief of the Plastic and Reconstructive Surgery
Devices Branch,** summarized the history of the FDA in getting
information to consumers on saline-filled breast implants, from the
Federal Register Notices of 1991 and 1995 to the Breast Implants
Consumer Handbook. He listed the elements of both Federal Register
notices and the patient risk information sheet entitled "Information for
Women Considering Saline-filled Breast Implants." Mr. Rhodes also
described the consumer handbook, which explains the availability and
regulatory status for breast implants and summarizes risk/benefit
factors. The handbook also has information on special medical and
physical considerations and a section on adverse reaction reports. It
lists frequently asked questions and discusses mammographic
considerations. Mr. Rhodes noted that the FDA draft guidance on medical
device patient labeling is still being completed.

Mr. Rhodes also presented an informed decision information template.
After a brief introduction, the document includes a purpose statement, a
brief background on breast surgery and description of the implants, and
a discussion of indications and contraindications. It describes the
breast implant surgery and summarizes clinical results, including
studies, complications, and safety data. Potential risks listed include
general risks, specific risks, and epidemiology on long-term risks.
Additional information would include a warranty, patient assistance
information, and date of printing. Mr. Rhodes concluded with five
questions to the panel.

# 

# ADDITIONAL OPEN PUBLIC COMMENT

**Dr. Kathleen Melez** spoke against advertising and suggested that
studies should be lifelong. She also suggested additional studies on
foreign body reactions.

**James K. Russano of Children Affected by Toxic Substances** expressed
his concern over children whose mothers received implants and later
breast-fed. He noted that the safety of breast-feeding and effects on
health of young girls was never proven. He asked the panel to make a
clear statement that no research was ever done on pregnancy and
breastfeeding and that there were no data on women of childbearing age.
In answer to a panel question, he stated that no women should ever have
breast implants until they are proven safe.

# PANEL DELIBERATIONS AND RECOMMENDATIONS

**Mr. Rhodes** clarified that the panel's charge was to provide
information on what kind of information should be offered in the patient
information template and should accompany the product to explain risks
and benefits. He also asked for guidance on how to present adverse
events.

In general discussion, the panel recommended presenting product-specific
and procedure-specific adverse events and appropriate data to show
incidence in understandable form. Missing scientific evidence should be
noted, and extensive data should be presented in a bulleted text with an
overall summary of adverse events. One recommendation was to use
actuarial estimates with some caveats on informative censoring. Current
materials used in labeling should clarify the high loss-to-follow-up
rate. Other surgical options should be listed and discussed in the
materials. Any information provided in the physician's packaging insert
should also be available to the patient before the operation.
Reoperation should be listed as a risk, and patients must understand
this is a lifelong commitment. Complications should be outlined, and
photographs of bad results should be considered. Any potential for
insurance problems should be carefully noted. Packet information should
also include independent sources of information.

The FDA was strongly urged to work with surgical and medical
organizations to refine the consent process and encourage outcome
analysis of the consent process, and the Consumer Representative will
provide the consumer input she received. Manufacturers should also
analyze whether patients are receiving and understanding the information
provided. Patients should be encouraged to record their interviews with
their doctors to help prevent misunderstandings.

Other comments were that a registry is important for device tracking.
Preoperative mammography is a good idea and should be encouraged.
Advertising should not be allowed to target teenagers.

In discussion of the panel questions, the panel recommended that
discussion of cosmetic benefits in the informed consent or promotional
material should include risks like asymmetry as part of the efficacy
data. Psychosocial terminology should be used in discussion of risks and
benefits. All statements should be backed up with careful wording, and
quality-of-life data should be presented with especially great care.

There was some split on the panel regarding a suggested waiting period
prior to surgery. Some suggested a one-week waiting period for
augmentation surgery and no waiting for reconstructive surgery, but they
did not recommend a mandated waiting time.

The panel listed postoperative symptoms requiring a physician\'s care as
inordinate swelling, redness, drainage, signs of infection, bleeding,
swelling, chills, fever, and so forth. Women should see themselves as
data providers on complications, and there should be a reporting
repository to facilitate data reporting. A national registry would be
useful to track long-term complication rates.

What information a patient should be given regarding differences in
surgical procedures should be left to the professional organizations and
societies.

Additional information that could be included would be results of
chemical, mechanical, or biological testing. Issues of lactation,
mammography, reporting adverse events, complications, and hypo or
hypersensitivity should be discussed.

The panel briefly discussed whether hospitals could require some type of
physician education or credentialing before surgeons could receive
hospital privileges to perform breast implant surgery. However, it was
felt that such hospital regulation would be very difficult to enforce.
It was noted that the FDA can ask manufacturers to have a training
program available but cannot restrict availability to those who do
training.

Drs. Witten and Whalen thanked the panel and all presenters. Dr Whalen
assured all presenters that their tragic stories were heard and
understood. He also thanked panel Executive Secretary David Krause.

The meeting was adjourned at 2:45 p.m.

I certify that I attended the Open Session of the General and Plastic
Surgery Devices Panel Meeting on March 1-3, 2000, and that this summary
accurately reflects what transpired.

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

David Krause, Ph.D.

Executive Secretary

I approve the minutes of the meeting as recorded in this summary.

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Thomas V. Whalen, M.D.

Panel Chair

Summary minutes prepared by Aileen M. Moodie

9821 Hollow Glen Pl.

Silver Spring, MD 20910

30-587-9722

Summary minutes edited by David Krause

June 20, July 14, August 4, and September 11, 2000