Inamed Corporation’sMcGhan Silicone-Filled Breast Implants

October 14-15, 2003

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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.

Device Description, Mechanical Testing, Retrieval Study, & Shelf Life OverviewSamie Allen

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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

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Mechanical Testing

Gel Cohesion

Gel Bleed

Fatigue

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Gel Cohesion Testing

Gel Cohesion Testing of Final GelASTM F703 (<4.5cm & no gel separation)Results: passed

Penetrometer Testing of In-Process GelNo standard (internal specification)Results: 49.2 (39.5-56.0)

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Gel Bleed Testing

Gel Bleed TestingASTM F703Results: 0.0152 g/cm2 for Style 40

0.0048 g/cm2 for Style 110

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Fatigue Testing

Fatigue Testing of Total DeviceNo ASTM standardResults: 55 lbs for Style 40

30 lbs for Style 110

Ultimate Static Results:1245 lbs for Style 401861 lbs for Style 110

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Retrieval Study

From 7/31/00 to 10/1/02, 339 gel explants

Physician Observations Laboratory Observations Mechanical Testing Sharp-edge Analyses

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Retrieval Study (cont.)

Observation N (339) Mode of Failure

Smooth-edge 2 Fold flaw

Sharp-edge 109 18% surgical technique

82% unknown

“Broken” device 21 Explant technique or propagation of opening

Device surface 9 Excess stress

Gel–related 40 Excess stress

“Functional” 158 N/A

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Shelf Life

Device and package testing

2.5-year shelf life date on package label

(2 years real + ½ year accelerated)

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Conclusions – Mechanical & Other

Gel Cohesion Testing Gel Bleed Testing Fatigue Testing Retrieval Study Shelf Life

Chemistry Overview

Sam Arepalli, Ph.D.

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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

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Extent of Crosslinking

Shell: 3.4 crosslinked units/molecule (Sol Fraction Method)

Gel: 3.5-7.5 mm (Penetrometer)

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Volatiles

Shell: 1,1,1 trichloroethane (279 µg)

Isopropyl alcohol (251 µg)

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Extractables

Gravimetric analysis

Gel permeable chromatography

FTIR analysis

Qualitative and quantitative analysis

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GC-MS Analysis

Cyclicoligosiloxanes up to D10 not detectable.

Higher cyclic and linear oligosiloxanes concentrations comparable to those of saline-filled breast implants.

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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)

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Silica Analysis

Amorphous silica (X-ray diffraction)

No free silica present (Electrospectroscopy)

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Conclusions - Chemistry Shell and gel tested separately Degree of crosslinking Volatiles Metals Extractables

Gravimetric analysisGPCFTIRGC-MS

Toxicology Overview

David Berkowitz, Ph.D., V.M.D.

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Six Testing Categories

Pharmacokinetics Biocompatibility Subchronic Toxicity Reproductive and Teratogenicity Immunotoxicology Genotoxicity and Carcinogenesis Testing

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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.

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Biocompatibility Testing

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

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Reproductive & TeratogenicityShell Testing Results

Test Group

# Mated

Mating Index

Fertility Index

Mean Gestation Time (days)

F0

Sham Control

35 80% 96% 21.9

Implanted 35 74% 96% 21.6

F1

Sham Control

30 80% 92% 21.6

Implanted 30 90% 96% 21.6

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Immunotoxicity

Results of Selected Immunotoxicology Tests - Gel

Test ShamControl

HighDose

CyclophosphamideControl (50mg/kg)

Spleen Weight (mg)

83 96* 54*

Lymphocytes/mm3 4412 5289 3403*

IgM AFC 884 829 0*

Mixed Leukocyte Response

59,513 53,514 17,653*

NK Cell Activity 27.0 22.6 1.2*

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Genotoxicity

Bacterial Mutagenesis

Mammalian Cell Forward Mutation Assay

Chromosomal Aberration Assay

Mammalian Cell Transformation Assay

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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.

Clinical Data Overview

Sahar M. Dawisha, M.D.

Medical Officer

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Summary of Studies

1. Core Study—Started 1999.

2. Adjunct Study—Started 1998.

3. 1990 Study—Started 1990.

All open label, prospective, multicenter. Yearly F/U in Core Study & 1990 Study. All collected local complications.

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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.

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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.

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1990 Study

Majority of patients: augmentation indication.

Yearly F/U to 5 years. Data from 4 of 11 styles presented.

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Core Study Results

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Core Study Demographics: Age

Aug

N = 494

Recon

N = 221

Revision

N = 226

Median Age

(range) in years

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(18-60)

50

(26-82)

44

(18-80)

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Core Augmentation Cohort

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Patient Disposition—Core 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 Death13 Implant Removals76 Lost to Follow-up

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By-Patient 3-Year Cumulative KM Complication Rates—Core Aug

Complication Rate (95% CI)

Reoperation 20.6% (16.8%, 24.4%)

CC III/IV 8.3% (5.8%, 10.9%)

Scarring 8.1% (5.7%, 10.6%)

Removal/Replacement 7.5% (5.0%, 10.0%)

Breast Pain 6.2% (4.0%, 8.4%)

Nipple Sensation Change 3.1% (1.6%, 4.7%)

Implant Rupture 1.2% (0.1%, 2.2%)

Infection 1.0% (0.1%, 1.9%)

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Reoperation—Core 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%).

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Reasons for Implant Removal through 3 Years—Core Aug

Primary Reason N = 60 Implants

Complication Treatment 42 (70.0%)

Rupture 2 (3.3%)

Capsular Contracture 27 (45.0%)

Extrusion/Malposition 7 (11.7%)

Asymmetry/Ptosis/Cancer 6 (10.0%)

Patient Choice 18 (30.0%)

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Asymptomatic Implant Rupture Screening—Core 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.

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Implant Ruptures—Core 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.

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Other Safety Information—Core 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: RA.

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CTD Summary—Core Augmentation Sign/Symptom Pre-Implant

N = 386

Through 2 yrs

N = 386

Muscle* 75 (19.4%) 108 (28.0%)

Joint* 50 (13.0%) 85 (22.0%)

Neurological* 158 (40.9%) 180 (46.6%)

Muscle pain 34 (8.8%) 57 (14.8%)

Joint Pain 10 (2.6%) 26 (6.7%)

AM Stiffness 39 (10.1%) 70 (18.1%)

Fatigue 33 (8.5%) 101 (26.2%)

Generalized Pain 8 (2.1%) 19 (4.9%)

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Effectiveness—Core 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).

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Core Reconstruction Cohort

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Patient Disposition—Core 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 Deaths16 Implant Removals11 Lost to Follow-up

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By-Patient 3-Year Cumulative KM Complication Rates—Core ReconComplication Rate (95% CI)

Reoperation 45.9% (36.8%, 55.1%)

Removal/Replacement 25.3% (16.9%, 33.6%)

CC III/IV 16.1% (8.7%, 23.6%)

Implant Rupture 6.3% (1.3%, 11.3%)

Tissue/Skin Necrosis 6.1% (1.1%, 11.1%)

Breast Pain 6.0% (1.2%, 10.8%)

Scarring 6.0% (1.2%, 10.8%)

Infection 2.3% (0.0%, 5.4%)

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Reoperation—Core 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%).

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Reasons for Implant Removal through 3 Years—Core ReconPrimary Reason N = 56 Implants

Complication Treatment 52 (92.9%)

Symmetry/Position/Wrinkling 26 (46.4%)

Capsular Contracture 12 (21.4%)

Rupture 5 (8.9%)

Extrusion/Pain/Hemat/Seroma 5 (8.9%)

Scarring/Cancer/Injury 4 (7.1%)

Patient Choice: Style/Size 4 (7.1%)

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Asymptomatic Implant Rupture Screening—Core 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

screening at 3 years.

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Implant Ruptures—Core Recon

No MRI Screening/Symptomatic Ruptures5 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).

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Other Safety Information—Core 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.

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CTD Signs/Symptoms—Core ReconstructionSign/Symptom Pre-Implant

N = 162

Through 2 yrs

N = 162

Skin* 20 (12.3%) 35 (21.6%)

Muscle* 56 (34.6%) 65 (40.1%)

Joint* 69 (42.6%) 94 (58.0%)

Neurological* 78 (48.1%) 97 (59.9%)

Joint Pain 17 (10.5%) 31 (19.1%)

AM Stiffness 39 (10.1%) 70 (18.1%)

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Effectiveness—Core 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)

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Core Revision Cohort

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Patient Disposition through 3 years—Core 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 Deaths10 Implant Removals32 Lost to Follow-up

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By-Patient 3-Year Cumulative KM Complication Rates—Core RevisComplication Rate (95% CI)

Reoperation 33.4% (26.9%, 39.8%)

Removal/Replacement 13.4% (8.7%, 18.1%)

CC III/IV 9.8% (5.7%, 13.9%)

Scarring 8.6% (4.7%, 12.5%)

Breast Pain 7.2% (3.7%, 10.8%)

Wrinkling/Rippling 5.0% (2.0%, 8.0%)

Implant Rupture 3.6% (1.0%, 6.3%)

Infection 2.8% (0.6%, 4.9%)

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Reoperation—Core Revision

190 Additional procedures in 100 reoperations through 3 years in 70 of the 225 patients (31.1%).

Capsule related: 23 of 190 procedures (27.9%).

Removal with replacement: 41 of 190 procedures (21.6%).

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Reasons for Implant Removal through 3 years—Core Revision

Primary Reason N = 46 Implants

Complication Treatment 33 (71.7%)

Symmetry/Position/Ptosis 15 (32.6%)

Capsular Contracture 7 (15.2%)

Rupture 6 (13.0%)

Scar/Wound/Pain/Infection 5 (10.9%)

Patient Choice: Style/Size 13 (28.3%)

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Asymptomatic Implant Rupture Screening—Core 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.

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Implant Ruptures—Core Revision

No MRI Screening/Symptomatic Ruptures4 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).

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Other Safety Information—Core Revision

No increase in reports of reproductive or lactation problems.

13 New reports of breast disease: all benign.

1 New report of CTD: Fibromyalgia.

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CTD Signs/Symptoms—Core RevisionSign/Symptom Pre-Implant

N = 386

Through 2 yrs

N = 386

Skin* 13 (8.3%) 24 (15.3%)

Muscle* 46 (29.3%) 62 (39.5%)

Joint* 41 (26.1%) 56 (35.7%)

Neurological* 59 (37.6%) 78 (49.7%)

General* 55 (35.0%) 66 (42.0%)

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Effectiveness—Core 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 measures improved (Body Esteem—Sexual Attractiveness); while all others worsened.

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Comparison to McGhan Saline Breast Implant Data

Cannot compare rupture rates. Historical control group. Confidence intervals not overlapping for

reoperation, removal, capsular contracture.

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Adjunct Study 1990 Study

Reconstruction. Revision. ~50% F/U at 1 year. ~20% F/U at 3 years. Complication rates

comparable to Core Study.

Augmentation. 70% F/U at 5 years. Complication rates at

3 years comparable to Core Study.

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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.

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Summary—Implant Rupture Implant rupture rate is under ascertained. Most implant ruptures are asymptomatic:

Asymptomatic: 15 of 26 total implant ruptures.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.

Thank You!

Statistical Overview

Telba Irony, Ph.D.Mathematical StatisticianDivision of Biostatistics

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Statistical Analyses: Core Study

• Prospective

• Multi-Center

• 10–year 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

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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 )

Core Study

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)

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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.

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Safety Endpoints - Rates

Adverse Events Implant Rupture Reoperations Implant Replacement/Removal

Employed Statistical Techniques

1. Kaplan - Meier analyses

2. “Prevalence”

3. “Incidence”

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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.

Kaplan-Meier Analyses

Independence Assumption for Censoring

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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

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Reoperation: “95% Confidence Intervals for the chance of a patient experiencing reoperation by...” (%)

4 weeks

6 months

1year

2Years

3 years*

Aug 1.9 ±1.1 6.0±2.1 11.2±2.8 17.2±3.4 20.6±3.8

Recon 4.1±2.6 23.7±5.7 32.0±6.2 37.2±6.6 45.9±9.2*

Rev 3.6±2.5 16.1±4.9 22.7±5.6 29.5±6.1 33.4±6.5

Kaplan-Meier Analyses (cont.)

** Correction by using Peto’s Formula

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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)

Other Statistical Techniques

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.

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Additional Safety InformationConnective 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.

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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.

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• 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

Additional Safety InformationConnective Tissue Disease

Signs and Symptoms

Medical Device Surveillance & Literature Overview

S. Lori Brown, Ph.D., M.P.H.Office of Surveillance and Biometrics

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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

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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

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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!

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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)

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Surveillance Reports Are

Important for providing a signal of a potential problem with a regulated medical product

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Silicone Gel Breast Implant Reports,

1/1/84 – 6/30/03Database Total Reports Inamed

Reports

DEN1/1/84-12/31/97

96,954 7,646 (8%)

MAUDE1/1/92-6/30/03

14,034 913 (6.5%)

ASR4/1/95-9/30/02

23,489 5,855 (25%)

Total 134,477 14, 414 (11%)

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Device ProblemsInamed (MAUDE Database)

Explanted Rupture Migration

35%

32%

3%

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Patient Problems Inamed (MAUDE Database)

Pain Headache Surgical procedure Capsular contracture CTD Fatigue

15%

13%

9%

7%6%

5%

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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

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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 mother’s implants but provided no details of illness

23 reports described illness in children

5 reports attributed birth defects to mother’s breast implants

9 reports described difficulty nursing

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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

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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 implantsSilicon(e) in breast milk (Semple et al, 1998)Ability to breast feed (Neifert, Hurst, Hughes,

Strom)

Limited information on these issues

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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)

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Fibromyalgia Study Findings Citation/Country

Rheumatology practice records

Fibromyalgia 0.84 (0.48-1.47)

Lai et al, 2000 Atlanta, GA

Fibromyalgia vs community controls for Silicone filled implants

Fibromyalgia, 6.06 (0.73-50.52)

Wolfe et al, 1999

Wichita, KS

Women w/breast implants vs nat’l hospitalization rates

Fibromyalgia, 1.6 (0.9-2.7)

Nyren et al, 1998 Sweden

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Fibromyalgia (cont.)

Study Findings Citation/Country

Private/public hospital implants

Unspecified Rheumatism 1.9 (1.5-2.3)

Kjøller 2001 Denmark

Women with ec silicone vs other

Fibromyalgia 2.9 (1.5-5.6)

Brown 2001 Birmingham, AL

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Cancer

Cancer Site

Study/Standardized Incidence RatioDeapen Brinton Pukkala Mellemkjae McLaughlin

All Sites 1.21 ns 1.31 ns

Brain 2.16 ns ns

Cervix ns 3.18 ns ns ns

Leukemia 2.19 ns ns

Lung 2.12 2.23 ns ns 2.7

Stomach 2.65

Vulva 5.26 2.51

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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, Meniere’s 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

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Mortality and Breast Implants

Cause of Death

Brinton, 2001 US

Koot, 2003

Sweden

Pukkala, 2003 Fin

All Causes 0.68

(0.6-0.8)

1.5

(1.2-1.8)

1.01

(0.67-1.44)

Suicide 1.54

(1.0-2.4)

2.9

(1.6-4.8)

3.19

(1.53–5.86)

Accidents 0.95

(0.6-1.4)

1.8

(0.9-3.3)

2.14

(1.17–3.58)*

Brain Malig 2.45

(1.4-4.2)

n.d. n.d.

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Resurgery and Local Complications

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

Rates for additional surgery in numerous studies reported to be about 33% of women- common reason for resurgery is capsular contracture in several studies

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Local Complications

Capsular contracture

Breast pain Infection Hematoma Implant extrusion Changes in nipple

sensation

Rashes Chest wall

skeletal changes Calcification Rupture Gel migration Etc.

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Breast Implant Rupture and Gel Migration

Breast implant rupture by MR in 344 B’ham 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)

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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

Proposed Postapproval Study & Labeling Overview

Samie Allen

109

Proposed Postapproval Study

Core Study ProtocolYearly follow-up with physician through 10

yearsMRI assessments at 1, 3, 5, 7, and 9 years

2-Phase Postapproval StudyPhase I – continued evaluations as per IDE

protocol through 5-year timepointPhase II – patient mail-in surveys for 6-10-year

timepoints (no MRI assessments)

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Proposed Labeling Directions For Use (package insert)

Patient BrochureFocus Group Study

Conclusion of FDA’s Presentation

Panel Questions

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Panel Question 1Prospective 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 Inamed’s 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.

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Panel Question 2Potential 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 Inamed’s 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.

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Panel Question 3Considering 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?

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Panel Question 4Considering 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?

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Panel Question 5To 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?

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Panel Question 6Given 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 in not currently routinely performed.

Provide your recommendations for the necessity of explantation of asymptomatic implant ruptures.

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Panel Question 7Inamed 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 patient’s 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.