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Inamed Corporations McGhan SiliconeFilled Breast Implants

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Title: Inamed Corporations McGhan SiliconeFilled Breast Implants


1
Inamed CorporationsMcGhan Silicone-Filled
Breast Implants
  • October 14-15, 2003

2
FDA Presenters
  • CDR Samie Allen, USPHS
  • Sam Arepalli, Ph.D.
  • David Berkowitz, Ph.D., V.M.D.
  • Sahar Dawisha, M.D.
  • Telba Irony, Ph.D.
  • S. Lori Brown, Ph.D., M.P.H.

3
Device Description, Mechanical Testing, Retrieval
Study, Shelf Life Overview
  • Samie Allen

4
Device Description
  • Styles 10, 20, 40, 45, 110, 120 153
  • Round shaped
  • Standard, moderate, high, full profiles
  • Smooth textured (Biocell) surfaces
  • Single lumen except Style 153
  • Components shell, patch, filler, silicone
    adhesive

5
Mechanical Testing
  • Gel Cohesion
  • Gel Bleed
  • Fatigue

6
Gel Cohesion Testing
  • Gel Cohesion Testing of Final Gel
  • ASTM F703 (lt4.5cm no gel separation)
  • Results passed
  • Penetrometer Testing of In-Process Gel
  • No standard (internal specification)
  • Results 49.2 (39.5-56.0)

7
Gel Bleed Testing
  • Gel Bleed Testing
  • ASTM F703
  • Results 0.0152 g/cm2 for Style 40
  • 0.0048 g/cm2 for Style 110

8
Fatigue Testing
  • Fatigue Testing of Total Device
  • No ASTM standard
  • Results 55 lbs for Style 40 30 lbs for
    Style 110
  • Ultimate Static Results
  • 1245 lbs for Style 40
  • 1861 lbs for Style 110

9
Retrieval Study
  • From 7/31/00 to 10/1/02, 339 gel explants
  • Physician Observations
  • Laboratory Observations
  • Mechanical Testing
  • Sharp-edge Analyses

10
Retrieval Study (cont.)
11
Shelf Life
  • Device and package testing
  • 2.5-year shelf life date on package label
  • (2 years real ½ year accelerated)

12
Conclusions Mechanical Other
  • Gel Cohesion Testing
  • Gel Bleed Testing
  • Fatigue Testing
  • Retrieval Study
  • Shelf Life

13
Chemistry Overview
  • Sam Arepalli, Ph.D.

14
Device Materials
  • Shell, middle (barrier) layer
    Diphenyldimethyl-siloxane copolymer, 15 mole
    diphenyl
  • Shell, inner/outer (base) layers
    Diphenyldimethyl-siloxane copolymer, 5 mole
    diphenyl
  • Patch, outer layer Peroxide cure silicone
    elastomer
  • Patch, inner (barrier) layer Dimethyl,
    methyl-trifluoropropylsiloxane
  • Silicone Gel Two-part platinum cure gel
  • Silicone adhesive Oxime cure RTV silicone

15
Extent of Crosslinking
  • Shell 3.4 crosslinked units/molecule (Sol
    Fraction Method)
  • Gel 3.5-7.5 mm (Penetrometer)

16
Volatiles
  • Shell 1,1,1 trichloroethane (279 µg)
  • Isopropyl alcohol (251 µg)

17
Extractables
  • Gravimetric analysis
  • Gel permeable chromatography
  • FTIR analysis
  • Qualitative and quantitative analysis

18
GC-MS Analysis
  • Cyclicoligosiloxanes up to D10 not detectable.
  • Higher cyclic and linear oligosiloxanes
    concentrations comparable to those of
    saline-filled breast implants.

19
Metal Analysis
  • Shell Sn (0.05 ppm) Pt (3.3 ppm)
  • Patch Sn (6.6 ppm) Pt (2.6 ppm)
  • Gel Sn (0.06 ppm) Pt (4 ppm)

20
Silica Analysis
  • Amorphous silica (X-ray diffraction)
  • No free silica present (Electrospectroscopy)

21
Conclusions - Chemistry
  • Shell and gel tested separately
  • Degree of crosslinking
  • Volatiles
  • Metals
  • Extractables
  • Gravimetric analysis
  • GPC
  • FTIR
  • GC-MS

22
Toxicology Overview
  • David Berkowitz, Ph.D., V.M.D.

23
Six Testing Categories
  • Pharmacokinetics
  • Biocompatibility
  • Subchronic Toxicity
  • Reproductive and Teratogenicity
  • Immunotoxicology
  • Genotoxicity and Carcinogenesis Testing

24
Pharmacokinetics
  • 30 days after implantation, only 0.06 of
    radiolabeled Gel left the implant site.
  • Lower molecular weight siloxanes (e.g., D4 and
    D5) diffuse out of the implants at a slow rate.

25
Biocompatibility Testing
  • Cytotoxicity
  • Irritation and Sensitization
  • Acute Systemic Toxicity
  • Implantation Testing (Subchronic Toxicity)
  • Hemolysis
  • Pyrogenicity

26
Reproductive Teratogenicity - Shell Testing
Results
27
Immunotoxicity
28
Genotoxicity
  • Bacterial Mutagenesis
  • Mammalian Cell Forward Mutation Assay
  • Chromosomal Aberration Assay
  • Mammalian Cell Transformation Assay

29
Carcinogenicity
  • 2-year studies including gross and microscopic
    pathology.
  • Gel Longer time to tumor and longer survival
    time than polyethylene control.
  • Shell Shorter survival time than sham and
    control. Differences attributable to foreign
    body carcinogenesis.

30
Clinical Data Overview
  • Sahar M. Dawisha, M.D.
  • Medical Officer

31
Summary of Studies
  • Core StudyStarted 1999.
  • Adjunct StudyStarted 1998.
  • 1990 StudyStarted 1990.
  • All open label, prospective, multicenter.
  • Yearly F/U in Core Study 1990 Study.
  • All collected local complications.

32
Core Study
  • Majority of Safety and Effectiveness data.
  • Augmentation, Reconstruction, Revision.
  • Yearly F/U to 10 years after implantation.
  • Only study with prospective MRI screening for
    asymptomatic rupture in 34 of 940 total
    patients.
  • Only study with QOL and CTD signs/symptoms
    collected.

33
Adjunct Study
  • Intended to make the implants available for
    reconstruction and revision indications.
  • Collected local complications at 1, 3, and 5
    years after implantation surgery.
  • Unlimited sample size.
  • Enrollment is ongoing.

34
1990 Study
  • Majority of patients augmentation indication.
  • Yearly F/U to 5 years.
  • Data from 4 of 11 styles presented.

35
Core Study Results
36
Core Study Demographics Age
37
Core Augmentation Cohort
38
Patient DispositionCore Augmentation
  • 494 Patients (987 devices) enrolled.
  • 90 of 489 expected patient F/U at 2 years.
  • 81 of 398 expected patient F/U at 3 years.
  • 1 Death
  • 13 Implant Removals
  • 76 Lost to Follow-up

39
By-Patient 3-Year Cumulative KM Complication
RatesCore Aug
40
ReoperationCore Augmentation
  • 248 Additional procedures in 112 reoperations
    through 3 years in 94 of the 494 patients
    (19.1).
  • Capsule related 79 of 248 procedures (31.9).
  • Removal with replacement 51 of 248 procedures
    (20.6).

41
Reasons for Implant Removal through 3 YearsCore
Aug
42
Asymptomatic Implant Rupture ScreeningCore
Augmentation
  • 166 Patients (331 implants) enrolled.
  • At 1 year 139 patients (87) of expected
    underwent MRI screening.
  • At 3 years 83 patients (64 of expected)
    underwent screening.
  • Total of 145 patients (289 implants) who had at
    least one MRI screening.
  • 3 Implants reported ruptured.
  • Silent rupture rate 1.2 (0.0, 2.6) through 3
    years, by-implant.

43
Implant RupturesCore Augmentation
  • No MRI Screening/Symptomatic Ruptures
  • 2 implants (out of 698) ruptured.
  • 2? Additional implants reported as intact.
  • Unknown asymptomatic rupture rate.
  • Overall by-implant rupture rate 0.6 (0.1,
    1.1) through 3 years
  • 3 Asymptomatic/silent 2 Symptomatic.
  • Excludes potential silent ruptures in No MRI.
  • Excludes 2 additional symptomatic ruptures.

44
Other Safety InformationCore Augmentation
  • No increase in reports of reproductive or
    lactation problems.
  • 32 post-implant breast disease reports 1
    malignant, 29 benign, 2 unconfirmed.
  • 12 post-implant abnormal mammogram reports 1 no
    disease 11 benign.
  • 1 New CTD Rheumatoid Arthritis.

45
CTD SummaryCore Augmentation
46
EffectivenessCore Augmentation
  • Most patients completing 2 years of follow-up
    reported being satisfied, but declines in mean
    satisfaction over time.
  • Mean General QOL measures worsened over time.
  • Some Specific QOL measures improved (TSCS, Body
    Esteem--Total, Sexual Attractiveness, and
    Weight) while others declined over time
    (Rosenberg Self Esteem, Body Esteem-Physical).

47
Core Reconstruction Cohort
48
Patient DispositionCore Reconstruction
  • 221 Patients (361 devices) enrolled.
  • 95 of 205 expected patient F/U at 2 years.
  • 91 of 116 expected patient F/U at 3 years.
  • 7 Deaths
  • 16 Implant Removals
  • 11 Lost to Follow-up

49
By-Patient 3-Year Cumulative KM Complication
RatesCore Recon
50
ReoperationCore Reconstruction
  • 242 Additional procedures in 127 reoperations
    through 3 years in 92 of the 221 patients
    (41.6).
  • Capsule related 54 of 242 procedures (22.3).
  • Removal with replacement 51of 242 (21.1).
  • Scar revision/wound repair 47 of 242 (19.4).

51
Reasons for Implant Removal through 3 YearsCore
Recon
52
Asymptomatic Implant Rupture ScreeningCore
Reconstruction
  • 108 Patients (184 implants) enrolled.
  • Total of 101 patients (170 implants) at least one
    MRI screening (93.5 of expected).
  • 8 implants ruptured.
  • Silent rupture rate 4.7 (1.5, 7.9)
    by-implant through 3 years.
  • Only 2 patients (2 implants) with 2nd MRI
    screening at 3 years.

53
Implant RupturesCore Recon
  • No MRI Screening/Symptomatic Ruptures
  • 5 implants (out of 191) ruptured.
  • Unknown asymptomatic rupture rate.
  • Overall by-implant rupture rate 4.2 (2.0,
    6.5) through 3 years
  • 8 Asymptomatic/silent 5 Symptomatic.
  • Excludes potential silent ruptures in No MRI
    Group (53 of Core Reconstruction Implants).

54
Other Safety InformationCore Reconstruction
  • No increase in reports of reproductive or
    lactation problems.
  • 5 New reports of breast malignancy recurrence
    or metastasis.
  • 1 New report of CTD Scleroderma.

55
CTD Signs/SymptomsCore Reconstruction
56
EffectivenessCore Reconstruction
  • Most patients completing 2 years of follow-up
    reported being satisfied, but declines in mean
    satisfaction over time.
  • Mean General QOL measures improved over time.
  • Some Specific QOL measures improved (Semantic
    Differential, Body Esteem-Sexual Attractiveness)
    while others worsened (TSCS, Rosenberg Self
    Esteem, Body Esteem-Total)

57
Core Revision Cohort
58
Patient Disposition through 3 yearsCore Revision
  • 225 Patients (432 devices) enrolled.
  • 87 of 216 expected patient F/U at 2 years.
  • 83 of 192 expected patient F/U at 3 years.
  • 4 Deaths
  • 10 Implant Removals
  • 32 Lost to Follow-up

59
By-Patient 3-Year Cumulative KM Complication
RatesCore Revision
60
ReoperationCore Revision
  • 190 Additional procedures in 100 reoperations
    through 3 years in 70 of the 225 patients
    (31.1).
  • Capsule related 53 of 190 procedures (27.9).
  • Removal with replacement 41 of 190 procedures
    (21.6).

61
Reasons for Implant Removal through 3 yearsCore
Revision
62
Asymptomatic Implant Rupture ScreeningCore
Revision
  • 77 Patients (148 implants) enrolled.
  • Total of 72 patients (138 implants) at least 1
    MRI screening (93.5 of expected).
  • 4 implants ruptured.
  • Silent rupture rate 2.9 (0.1, 5.7)
    by-implant through 3 years.
  • Only 1 patient (2 implants) with 2nd MRI
    screening at 3 years.

63
Implant RupturesCore Revision
  • No MRI Screening/Symptomatic Ruptures
  • 4 implants (out of 294) ruptured.
  • Unknown asymptomatic rupture rate.
  • Overall by-implant rupture rate 2.2 (0.7,
    3.7) through 3 years
  • 4 Asymptomatic/silent 4 Symptomatic.
  • Excludes potential silent ruptures from No MRI
    Group (68 of Core Revision Implants).

64
Other Safety InformationCore Revision
  • No increase in reports of reproductive or
    lactation problems.
  • 13 New reports of breast disease all benign.
  • 1 New report of CTD Fibromyalgia.

65
CTD Signs/SymptomsCore Revision
66
EffectivenessCore Revision
  • Most patients completing 2 years of follow-up
    reported being satisfied, but declines in mean
    satisfaction over time.
  • Mean General QOL measures worsened over time.
  • Some Specific QOL measures improved (Body
    EsteemSexual Attractiveness) while all others
    worsened.

67
Comparison to McGhan Saline-Filled Breast Implant
Data
  • Cannot compare rupture rates.
  • Historical control group.
  • Confidence intervals not overlapping for
    reoperation, removal, capsular contracture.

68
Adjunct Study 1990 Study
  • Reconstruction.
  • Revision.
  • 50 F/U at 1 year.
  • 20 F/U at 3 years.
  • Complication rates at 3 years comparable to Core
    Study.
  • Augmentation.
  • 70 F/U at 5 years.
  • Complication rates at 3 years comparable to Core
    Study.

69
Summary
  • Reoperation most frequent complication.
  • Capsular contracture reoperation most common
    procedure.
  • Most implants removed to treat a complication.
  • CTD signs/symptoms increase over time.
  • Patient satisfaction high but decreases over
    time General QOL measures improved for
    reconstruction Body Esteem-Sexual Attractiveness
    only specific measure consistently improved.

70
SummaryImplant Rupture
  • Implant rupture rate is under ascertained.
  • Most implant ruptures are asymptomatic
  • Asymptomatic 15 of 26 total implant ruptures
    (57.7).
  • Asymptomatic rupture rate (MRI) based on 34 of
    implants and 1 year data.
  • Overall rupture rate excludes asymptomatic
    ruptures in 66 of implants.
  • Almost all asymptomatic ruptures were
    intracapsular.

71
Thank You!
72
Statistical Overview
  • Telba Irony, Ph.D.
  • Mathematical Statistician
  • Division of Biostatistics

73
Statistical Analyses Core Study
  • Prospective
  • Multi-Center
  • 10year study
  • Reported follow-up time points
  • 4 weeks, 6 months, 1, 2, 3 years
  • All patients traversed the 2-year window
  • A large fraction of patients traversed the 3-year
    window

74
Core Study
  • Augmentation
  • 494 patients and 83 traversed the 3-year visit.
  • 398 patients were expected at 3 years.
  • Actual of patients at 3 years 322 (19 lost to
    follow-up)
  • Reconstruction
  • 221 patients and 58 traversed the 3-year visit.
  • 116 patients were expected at 3 years.
  • Actual of patients at 3 years 105 (9 lost to
    follow-up )
  • Revision
  • 225 patients and 91 traversed the 3-year visit.
  • 192 patients were expected at 3 years.
  • Actual of patients at 3 years 160 (17 lost to
    follow-up)

75
Descriptive Nature of Studies
  • There were no claims, targets, or control groups
    in this study.
  • Descriptive statistics No hypothesis tests.
  • Sample size Reflected in the width (i.e.
    precision) of the confidence interval.
  • Decision makers should assess the adequacy of the
    precision of the results when weighing the risks
    and benefits of the implants.

76
Safety Endpoints - Rates
  • Adverse Events
  • Implant Rupture
  • Reoperations
  • Implant Replacement/Removal

Employed Statistical Techniques
  • Kaplan - Meier analyses
  • Prevalence
  • Incidence

77
Kaplan-Meier Analyses
Kaplan-Meier analyses were conducted on the time
to first occurrence of each adverse event.
Result Estimated probability that a patient
will experience the adverse event from the time
of implant up to the considered time point.
Advantage Patients who were lost to follow-up
provide information up to the time they left the
study.
Independence Assumption for Censoring
78
Kaplan-Meier Analyses (cont.)
  • Days were used as units of time for the
    computation of the rates (alleviates interval
    censoring bias). Assumption reporting is
    accurate to the date
  • Correlation among adverse events not taken into
    account
  • Competing Risks Problem To solve it, all
    patients that experienced a complication were
    returned to the pool of patients who could
    experience another complication. Exception
    Implant Removal

79
Kaplan-Meier Analyses (cont.)
Reoperation 95 Confidence Intervals for the
chance of a patient experiencing reoperation
by... ()
Correction by using Petos Formula
80
Other Statistical Techniques
Prevalence percentage of patients seen at a
given follow-up visit, who are experiencing a
specific adverse event. (given they returned to
the follow-up)
Incidence percentage of patients seen at a
given follow-up visit who are experiencing the
adverse event not experienced at earlier visits
(given they returned to the follow-up).
Disadvantage Both measures are very sensitive to
biases generated by losses to follow up.
81
Additional Safety Information Connective Tissue
Disease Signs and Symptoms
  • The frequencies of patients reporting 8
    categories of signs and symptoms of CTD before
    implantation was compared to the frequencies 2
    years after implantation.
  • For all cohorts, all 8 frequencies increased
    after implantation. The only exception was the
    urinary symptom the frequency remained the same
    in the Reconstruction group.

82
Additional Safety InformationConnective Tissue
Disease Signs and Symptoms
  • To assess the statistical significance of the
    increases in the frequencies, the sponsor used a
    Bonferroni correction that was too conservative
    for this case. It did not take into account
    possible correlations among signs and symptoms.
  • Consequence It was difficult to detect
    statistical significance.

83
Additional Safety InformationConnective Tissue
Disease Signs and Symptoms
  • Despite the conservative statistical analysis,
    the increase in the frequency of some signs and
    symptoms was statistically significant.
  • However, the clinical interpretation is
    problematic no control group

84
Medical Device Surveillance Literature Overview
  • S. Lori Brown, Ph.D., M.P.H.Office of
    Surveillance and Biometrics

85
Medical Device Reporting
  • What is Medical Device Reporting (MDR)?
  • MDR is the mechanism for the Food and Drug
    Administration to receive significant medical
    device adverse events from manufacturers,
    importers, and user facilities

86
CDRH Surveillance Databases
  • Manufacturer And User Facility Device Experience
    (MAUDE) database - MDR and MedWatch reports are
    entered into database - 1992-present
  • Alternative Summary Reporting (ASR) 1995-present
  • Device Experience Network (DEN) 1984-1996

87
Surveillance is NOT the equivalent of a clinical
study
  • Rates cannot be calculated because of
    under-reporting of adverse events
  • Number of individuals at risk (denominator) is
    unknown. It is not appropriate to use the number
    of devices sold as the denominator!

88
Surveillance does not always establish causality
  • Accuracy and completeness not verified
  • Cannot always establish a causal link between a
    death or injury and the listed device(s)

89
Surveillance Reports Are
  • Important for providing a signal of a potential
    problem with a regulated medical product

90
(No Transcript)
91
Device ProblemsInamed (MAUDE Database)
  • Explanted
  • Rupture
  • Migration
  • 35
  • 32
  • 3

92
Patient Problems Inamed (MAUDE Database)
  • Pain
  • Headache
  • Surgical procedure
  • Capsular contracture
  • CTD
  • Fatigue
  • 15
  • 13
  • 9
  • 7
  • 6
  • 5

93
MAUDE Analysis Breast Implant Rupture During
Mammography
  • Between 1992 and 2002, FDA received 33 adverse
    event reports describing breast implant rupture
    during mammography
  • An additional 8 reports described mammography as
    possible cause of subsequently detected ruptures

94
MAUDE Analysis Reproductive/2nd Generation
Issues
  • 130 reports from MAUDE that described injury or
    illness in mothers or their children attributed
    to breast implants
  • 89 of these reports asserted that children were
    ill due to mothers implants but provided no
    details of illness
  • 23 reports described illness in children
  • 5 reports attributed birth defects to mothers
    breast implants
  • 9 reports described difficulty nursing

95
Literature Review
  • Reproductive/second generation issues
  • Connective tissue disease
  • Fibromyalgia
  • Cancer
  • Mammography
  • Neurologic disease
  • Breast implants and mortality
  • Resurgery and local complications
  • Rupture and gel migration

96
Literature on Reproductive/2nd Generation Issues
  • Illness in children of mothers with implants
    (Levine, Teuber, Signorello, Kjøller)
  • Birth defects (Signorello, Kjøller)
  • Breast feeding by mothers with implants
  • Silicon(e) in breast milk (Semple et al, 1998)
  • Ability to breast feed (Neifert, Hurst, Hughes,
    Strom)
  • Limited information on these issues

97
Connective Tissue Disease
  • Meta-analyses of relation between silicone breast
    implants and risk of connective-tissue disease
    (Janowski et al, 2000)
  • Institute of Medicine review of safety of
    silicone breast implants concluded that these
    studies do not support an association between
    connective tissue disease, combined or
    individually, for these diseases in women with
    silicone breast implants (1999)

98
Fibromyalgia
99
Fibromyalgia (cont.)
100
Cancer
101
Mammography
  • Implant rupture during mammography
  • Implants obscure 22-83 of breast tissue (Hayes
    et al, 1988)
  • Modified techniques needed (Ecklund et al, 1988)
  • Breast cancer detection delayed but no difference
    in mortality (Brinton et al, 2000)
  • Tumor size, lymph node involvement,
    histopathology similar (Cahan et al, 1995)

102
Neurologic Disease
  • Swedish population based cohort found no increase
    in MS, ALS, Menieres syndrome, but significant
    increase in neurological disease in general (1.7,
    1.1-2.6) (Nyren et al, 1998)
  • Danish study found no increase in specific
    neurologic diagnoses neurologic disease in
    general slightly increased but not statistically
    significant (1.7, 0.9-2.9) (Winther et al, 1998)
  • Similar findings in breast reduction comparison
    groups in both studies
  • Both studies based on hospitalization

103
Mortality and Breast Implants
104
Resurgery and Local Complications
Rates for additional surgery in numerous studies
reported to be about 33 of women- common reason
for resurgery is capsular contracture in several
studies
  • Gabriel, 1997
  • Gutowski, 1997
  • Brown, 2001
  • 28 of 749 fu 8 yr
  • 21 of 504 fu 6 yr
  • 33 of 907 mt 11.5 yr

105
Local Complications
  • Capsular contracture
  • Breast pain
  • Infection
  • Hematoma
  • Implant extrusion
  • Changes in nipple sensation
  • Rashes
  • Chest wall skeletal changes
  • Calcification
  • Rupture
  • Gel migration
  • Etc.

106
Breast Implant Rupture and Gel Migration
  • Breast implant rupture by MR in 344 Bham women
    found 55 of implants ruptured affecting 68 of
    women, 22 ruptures extracapsular, 17 yr median
    (Brown et al, 2000)
  • Breast implant rupture by MR in 271 Danish women
    found 26 of implants ruptured affecting 36 of
    women, 22 ruptures extracapsular, 10 yr median
    (Holmich et al, 2001)

107
Breast Implant Rupture and Gel Migration (cont.)
  • Extracapsular spread of silicone gel reported in
    11-23 of ruptured implants across several series
  • Frequency or severity of distant migration not
    known
  • Migration may result in gel/oil in lymph nodes,
    intraductal extension of gel, granuloma
    formation, transcutaneous leakage of gel,
    ulceration, tissue destruction, scarring
  • Silicone in tissues confirmed by imaging,
    microscopic examination of granulomatous response

108
Proposed Postapproval Study Labeling Overview
  • Samie Allen

109
Proposed Postapproval Study
  • Core Study Protocol
  • Yearly follow-up with physician through 10 years
  • MRI assessments at 1, 3, 5, 7, and 9 years
  • 2-Phase Postapproval Study
  • Phase I continued evaluations as per IDE
    protocol through 5-year timepoint
  • Phase II patient mail-in surveys for 6-10-year
    timepoints (no MRI assessments)

110
Proposed Labeling
  • Directions For Use (package insert)
  • Patient Brochure
  • Focus Group Study

111
Conclusion of FDAs Presentation
112
Panel Questions
113
Panel Question 1
  • Prospective MRI screening for asymptomatic
    rupture was conducted in a subset of Core Study
    participants (approximately 34). Complete MRI
    screening data are available for the 1-year
    post-operative timepoint for each indication and
    partial 3-year data are available for the
    augmentation indication at the time of database
    closure. Continued MRI screening of this Core
    Study subset is planned for at years 3, 5, 7, and
    9 after implantation.
  • Of the 15 implant ruptures that Inamed reports as
    confirmed at the time of database closure, the
    majority--9 implants (60)--were initially
    detected by MRI screening and were asymptomatic
    Core Augmentation, 0 of 3 ruptures Core
    Reconstruction, 6 of 8 ruptures and Core
    Revision, 3 of 5 ruptures.
  • Additionally, published literature on silicone
    gel implant rupture, although not specific to
    Inameds implants, indicates that rupture rate
    increases significantly with implant age and that
    depending on implant type, manufacturer, and age,
    between 26 (median implant age 12 years) and 55
    (median implant age 16.4 years) of implants
    assessed by MRI had MRI evidence of rupture.
  • Please discuss the adequacy of the information to
    determine the safety of this product with respect
    to asymptomatic rupture.

114
Panel Question 2
  • Potential long-term and general health effect
    issues for these implants include the risk of
    cancer(s), connective tissue disorders (typical
    and atypical), gel migration, interference of
    implant on ability of mammography to detect
    tumors in implanted breasts, interference with
    breast feeding, reproductive/teratogenic effects,
    and the later effects on offspring from women
    with implants. To address these issues, Inamed
    utilized historical published literature, which
    is not specific to Inameds implants, as well as
    animal studies on their product. Please discuss
    the adequacy of the literature and preclinical
    testing to determine the safety of this product
    with respect to long-term and general health
    effects.

115
Panel Question 3
  • Considering the safety data reported for the
    augmentation group
  • local complications reported in Core Study,
    Adjunct Study, and AR90 Study
  • asymptomatic/silent rupture information based on
    approximately 30 of the patients in the Core
    Study with only the first of 5 prospective serial
    screenings with complete data
  • published historical literature and animal data
    to address long term and general health effects.
  • Given these data, and that the augmentation
    patient generally has breast implant surgery at a
    younger age which includes childbearing years
    compared to the other indications, is there
    reasonable assurance that the device is safe for
    augmentation patients?

116
Panel Question 4
  • Considering the safety data reported for the
    reconstruction and revision groups
  • local complications reported in Core Study,
    Adjunct Study, and AR90 Study
  • asymptomatic/silent rupture information based on
    approximately 30 of the patients in the Core
    Study with only the first of 5 prospective serial
    screenings with complete data
  • published historical literature and animal data
    to address long term and general health effects.
  • Given these data, and that reconstruction and
    revision patients generally undergo breast
    implantation at an older age than augmentation
    patients, is there reasonable assurance that the
    device is safe for reconstruction and revision
    patients?

117
Panel Question 5
  • To evaluate device effectiveness, Inamed
    collected data on patient satisfaction and health
    status/quality of life (e.g., SF-36, MOS-20, Body
    Esteem Scale, etc.). Based on these data, has
    Inamed adequately demonstrated reasonable
    assurance of effectiveness of the implants for
    each of the augmentation, reconstruction, and
    revision indications?

118
Panel Question 6
  • Given the information in question 1 and if you
    recommend approval of the PMA, please address the
    following with respect to labeling for the
    device
  • Provide your recommendations for the frequency
    and method of screening for asymptomatic rupture,
    given that prospective screening for asymptomatic
    rupture is not currently routinely performed.
  • Provide your recommendations for the necessity of
    explantation of asymptomatic implant ruptures.

119
Panel Question 7
  • Inamed provided a brief description of their
    postapproval study plan. The Core Study
    protocol, as well as informed consent, currently
    requires yearly follow-up with a physician.
    Inamed is now proposing a change to the study
    requirements as follows. More specifically,
    Inamed is proposing a 2-phase postapproval study.
    Phase I involves continued physician evaluation
    as per the IDE protocol through a patients
    5-year follow-up timepoint. Phase II involves
    mail-in surveys completed by the patient from
    their 6 to 10-year follow-up timepoints. In the
    proposed Phase II protocol, for example, MRI
    screening for asymptomatic rupture would not be
    captured. Given this proposal and if you
    recommend approval of the PMA
  • Please comment on the method of data collection
    (mailed survey) from the 6-10-year timepoints,
    given that the Core Study protocol as well as
    informed consent currently calls for prospective
    yearly follow-up.
  • In addition, please describe any other specific
    endpoints that should be captured as part of
    their postapproval study. For example, in the
    proposed protocol, silent rupture would not be
    captured.
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