PUBLIC CITIZEN: Petition to halt FDA's decision on allowing silicone gel breast implants back on the marke

http://www.citizen.org/publications/release.cfm?ID=7289

Petition to halt FDA's decision on allowing silicone gel breast
implants back on the market (HRG Publication #1682)

November 3, 2003

Dockets Management Branch
Food and Drug Administration
5630 Fishers Lane, Room 1061 (HFA-305)
Rockville, MD, 20852

Hand Delivery [or By Facsimile]

Docket No. _________________

CITIZEN PETITION

The National Organization for Women, Public Citizen's Health Research
Group and the National Women's Health Network submit this petition
under 21 C.F.R. 510.30 and 10.35 to request that the Commissioner of
Food and Drugs stay its review of and decision on any and all
Premarket Applications (“PMAs”) for silicone gel-filled breast
implants until the actions described below are taken with respect to
such implants.

A. Action Requested.

This petition requests that the Commissioner of Food and Drugs refrain
from completing the review of the PMA submitted by Inamed Corporation
(“Inamed”) for McGhan silicone gel-filled breast implants, until an
amendment to such PMA is submitted to the Food and Drug Administration
(FDA) responding to the deficiencies identified in this petition and
consisting of adequate data demonstrating a reasonable assurance of
safety or effectiveness of such implants. This petition further
requests that, pursuant to 21 C.F.R. 14.7 (2), “the Commissioner will
expedite the review of the petition and make a reasonable effort to
render a decision before the action concerned in the petition.”

B. Statement of Grounds.

1. The Core clinical study in the Inamed PMA does not include
adequate data to provide a reasonable assurance of safety,
particularly data substantiating the long-term safety of silicone
gel-filled breast implants in relation to rupture, gel migration and
increases in connective tissue disease signs and symptoms as seen at
two years follow-up. The panel decision to recommend approval with
considerable and unfeasible postapproval conditions including labeling
requirements to warn of the limited safety data is tantamount to a
complete denial of choice – since an informed choice can not be made
in the absence of data that demonstrates even minimum standards of
safety.

The Inamed PMA purports to demonstrate the safety and effectiveness of
McGhan silicone gel-filled breast implants in seven styles for breast
augmentation, reconstruction and revision. The application relies
largely upon a Core clinical trial. There was also an “adjunct” study
that collected safety (local complications data) and an AR90 study
that collected safety and effectiveness data on saline-filled and
silicone gel-filled implants. The adjunct and AR90 clinical studies
are incomplete, underpowered and of inadequate duration to
substantiate that the implants are safe for their intended uses.

The clinical data in the Core clinical trial is based only on one
complete year of follow-up and the partial completion of follow-up at
2 and 3 years for several parts of the study. Therefore, the data
fails to address substantial long-term problems that can affect
women’s health. Because silicone gel-filled breast implants were
first commercially distributed before enactment of the 1976 Medical
Device Amendments, the FDA is aware of historical data on the type of
complications that are associated with these devices and the
timeframes in which they occur. Both anecdotal and scientific evidence
demonstrates that the onset of the majority of complications occur
after a considerable period of latency.

Because of the late onset of local, regional and systemic
complications, substantial evidence of long-term complications, and
the long and controversial history of these devices, Inamed’s core
clinical trial and other studies did not produce sufficient clinical
data to provide a reasonable assurance of safety. Nevertheless, the
limited data reflect high complication and reoperation rates: 20.6%
reoperation and 7.5% removal/replacement rate for augmentation
patients and 45.5% reoperation, 25.3% removal/replacement and 6.3%
rupture rate for reconstruction patients.

As one member of the General and Plastic Surgery Devices Panel stated
in the panel’s October 14 - 15, 2003 meeting, “A decade has passed and
we sat here today talking about two and three-year data. I’m
flabbergasted.”[1] Another member of the panel observed “it simply
boggles the mind” that the PMA did not substantiate greater safety,
effectiveness and durability after years of experience with such
health complications and device failures.

The panel was ambivalent in its assessment of the adequacy of Inamed’s
literature review of long-term risks of cancers, connective tissue
disorders, reproductive or teratogenic effects, interference with
breast feeding or detection of tumors through mammography. Inamed
publicly conceded at the panel meeting that its preclinical mechanical
data is not clinically meaningful. Absent substantiating clinical
experience with its products, the company’s reliance on historic
literature, consisting of case reports and studies of non-Inamed
product, and on preclinical animal testing fails to provide a
reasonable assurance of safety.

The FDA has publicly acknowledged that “there are additional safety
issues that apply to the silicone implants that do not apply to the
saline implants, such as silent rupture and gel migration, which will
need to be evaluated.”[2] Research has consistently demonstrated
that the onset of the majority of complications related to silicone
gel-filled breast implants occur between seven to ten years and,
unlike saline breast implants, are often not detected by women for
many years after they occur. Research conducted at the FDA by S.
Lori Brown, Ph.D., verified the latency of developing complications
associated with silicone gel-filled breast implants, including rupture
and gel migration.[3] Indeed the Summary Panel Memorandum, dated
September 12, 2003, prepared by the FDA’s Inamed PMA Review Team
noted, “one consequence of implant rupture is gel migration.”
According to the memorandum, “there are several studies that report
that, in some cases, there is gel migration outside of the fibrous
scar capsule (extracapsular rupture) following rupture. Cases of
distant migration of gel to breast, axillary lymph nodes, abdomen,
groin, arms, and fingers have been reported, some with serious
consequences and deformities (e.g., extensive migratory granuloma
formation and contracture, and scarring from gel extrusion and
ulceration) described as a result of gel migration.”

These long-term adverse medical consequences specifically include an
elevated risk of an immunological response, potentially contributing
to the development of systemic illness following long-term
implantation of silicone gel-filled breast implants. Recently
published and ongoing research continues to demonstrate the real
potential of an immunological response to long-term implantation of
silicone gel-filled breast implants, particularly in the presence of
significant rupture or verifiable gel migration. Research at the
National Institutes of Environmental Health Sciences and published
research by the FDA has demonstrated the presence of immunological
responses to silicone gel-filled breast implants including a
significant association with fibromyalgia.[4]

The Core clinical study reconstruction and augmentation cohorts
demonstrated increased frequencies of connective tissue disease signs
and symptoms through year 2 of patient follow-up. When asked by the
advisory panel whether the association between connective tissue
disease and silicone breast implants was “closed”, Dr. Sahar Dawisha
of the FDA responded that the question of a relationship “has not been
resolved at this time.” (emphasis added)

2. The Inamed PMA fails to provide adequate data on the rate of
asymptomatic or silent rupture of silicone gel-filled breast implants,
making a complete assessment of the resulting safety consequences
impossible.

According to the Summary Panel Memorandum dated September 12, 2003,
“in their review, Inamed provided no discussion of the significance of
implant rupture. Because implant age is a factor in rupture, it is not
clear whether later generations of implants have improved with respect
to rupture, since these implants have not achieved the age of earlier
generations.”

As one method of investigating asymptomatic rupture, more than 108 of
221 patients from the reconstruction cohort (48 percent) and 166 of
331 patients from the augmentation cohort (50 percent) in the Core
study were intended to be subject to serial MRI screening to determine
asymptomatic or silent rupture.[5] Complete MRI screening data was
completed one year post-operatively for all three indications of
augmentation, reconstruction and revision, and partial three-year data
was available for the augmentation cohort. Only 2 implants from the
reconstruction cohort were followed to the second screening at three
years. As such, the panel concluded that there was limited data and
no relevant information on asymptomatic rupture.

The absence of this longer-term data from the PMA makes a rigorous
assessment of safety impossible. Of the 15 implant ruptures reported
by Inamed at the time of database closure, a majority of nine (60
percent) were initially detected by MRI screening and were
asymptomatic. And with less than half of the reconstruction patients
enrolled in this screening subset, FDA recognized that “had a larger
proportion of patients undergone MRI screening, the rupture rate would
likely be higher.”

As a result, the design and execution of the Core study clearly
understates the frequency of asymptomatic or silent rupture.
Additionally, published literature on silicone gel-filled breast
implant rupture, although not specific to Inamed, substantiates the
fact that rupture rates increase significantly with implant age, with
between 26 percent (median implant age of 12 years) and 55 percent
(median implant age of 16 years) of such implants assessed by MRI for
evidence of rupture.

These deficiencies were also clearly identified by the General and
Plastic Surgery Devices Panel, whose members discussed extensively the
absence of reliable information on asymptomatic rupture. There was a
panel consensus that Inamed had failed to provide adequate information
to provide a reasonable assurance of safety with respect to such
ruptures. The Inamed PMA consequently lacks adequate safety data on
the rate of asymptomatic or silent rupture of the McGhan silicone
gel-filled breast implants.

3. The Inamed PMA includes little if any clinical data in support of
the safety or effectiveness of two of the seven proposed styles of
silicone gel-filled breast implants.

The FDA’s summary memorandum for the General and Plastic Surgery
Devices Panel baldly acknowledges that the Inamed Core clinical study
“does not include Style 10 or 20, which are two implant styles for
which Inamed is seeking approval. This is the primary clinical data
set for this PMA.”[6] Although Inamed claims that data is available
from the adjunct study to support the safety and effectiveness of
these two styles, which differ in important design features as volume,
shell surface, shape and profile from the other five styles, the
adjunct study cannot provide more than 1 month of actual data
underlying the use and observation of these two styles. The adjunct
study was initiated in 1998[7] and closed in August of 2003. According
to Inamed Styles 10 and 20 were introduced into the adjunct study in
July of 2003.

4. Unreliable mechanisms of post-marketing surveillance and proposed
conditions of use susceptible to noncompliance cannot provide the
clinical data or remedy deficiencies in the Inamed PMA to provide a
reasonable assurance of safety.

In the absence of actual clinical data in the Inamed PMA, the proposed
reliance on mechanisms of post-marketing surveillance which have
historically yielded incomplete or unreliable data, and on conditions
of use which are highly susceptible to noncompliance, cannot provide
the clinical data to provide a reasonable assurance of safety, nor
remedy the deficiencies of the Inamed core clinical study. Dr. Lori
Brown from the FDA acknowledged in her presentation to the panel
“surveillance is not the equivalent of a clinical study.”[8]

Inamed proposed a series of postapproval conditions to the General and
Plastic Surgery Devices Panel that would consist of loosely monitored
post-market surveillance and provider education programs that would
serve marketing and promotional purposes more than they would assure
patient safety. The proposal to require annual MRIs to detect
implant rupture was attenuated into an ineffectual “strong
recommendation” rather than an actual condition of use of the devices.
Celia Whitten from the FDA acknowledged at the advisory panel meeting
that the FDA does not have the ability to provide oversight of
postapproval conditions to ensure compliance.

The FDA’s historic post-market surveillance of breast implants has
been inadequate and the agency has acknowledged that it is unrealistic
to rely upon such scrutiny to generate data that could supplant
long-term safety data collected through rigorous clinical
investigation. As early as 1995, the Center for Devices and
Radiological Health (CDRH) determined that breast implant
manufacturers did not need to identify the age of the device in
reporting adverse events. As a result, the failure rate and
susceptibility to complications are not discernible for different
“generations” of breast implants in patients and on the market.

As of March 13, 2003 erroneous reports – filed under incorrect
identifiers by both Inamed and Mentor Corporation (“Mentor”) – were
removed. Whether these reports have been refiled under the correct
identifiers has not been determined. Moreover, as divulged during the
FDA’s criminal investigation of Mentor, the problems of inadequate
manufacturer adverse event reporting, the use of incorrect identifiers
for hundreds of such MDRs, the FDA’s waiver of filing of additional
MDRs for issues that were “well characterized”, and the significant
loss of patients to follow-up for saline-filled breast implants were
not remedied by the FDA, nor was the potential recurrence of such
problems fully addressed by the agency. Unless the FDA can undertake
steps to dramatically improve and ensure the accuracy of adverse event
reporting by breast implant manufacturers and user facilities,
reliance on this method of surveillance is not a satisfactory method
of assuring the safety of silicone gel-filled breast implants.

C. Conclusion.

For the aforementioned reasons of law, regulation and policy, the
Commissioner should refrain from completing the review of and the
decision concerning the Inamed PMA for silicone gel-filled breast
implants, until a PMA amendment is submitted responding to the
deficiencies identified in this petition.

D. Environmental Impact.

The action requested in this petition will have no impact on the
environment.

E. Certification.

The undersigned certifies that, to the best knowledge and belief of
the undersigned, this petition includes all information and views on
which the petition relies, and that it includes representative data
and information known to the petitioner that are unfavorable to the
petition.

___________________________

Kim Gandy
President
National Organization for Women

Sidney M. Wolfe, MD
Director
Public Citizen, Health Research Group

Cynthia A. Pearson
Executive Director
National Women's Health Network



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[1] Dr. Thomas Whalen, acting chairman of the panel, quoted in the
Associated Press, October 15, 2003.

[2] Letter from Amit K. Sachdev, Associate Commissioner for
Legislation, Department of Health and Human Services, to Senator
Edward M. Kennedy, July 2, 2003.

[3] Brown SL, MS Middleton, WA Berg, MS Soo, G Pennello. Presence of
rupture of silicone gel breast implants revealed on MR imaging in a
population of women in Birmingham, Alabama. American Journal of
Roentgeonology; 175: 1057-1064, 2000.

[4] Brown SL, Duggirala HJ, Pennello G. An Association of Silicone-Gel
Breast Implant Rupture and Fibromyalgia. Current Rheumatology
Reports, 2002; 4:293-298.

[5] Dr. Sahar Dawisha (FDA), Inamed Clinical Summary memorandum,
September 12, 2003, pp 36-37.

[6] FDA Inamed PMA Review Team, Summary Panel Memorandum, September,
12, 2003.

[7] Dr. Sahar Dawisha (FDA), Inamed Clinical Summary memorandum,
September 12, 2003.

[8] FDA presentation to the advisory panel, October 14, 2003, Slide
87.