mentor corporation’s silicone gel-filled breast implants (p030053) april 13, 2005

Mentor Corporation’sSilicone Gel-Filled Breast Implants (P030053)April 13, 2005

Mentor P030053 2

FDA Presenters

CDR Samie Allen, USPHS Sam Arepalli, Ph.D. David Berkowitz, Ph.D., V.M.D. Herbert P. Lerner, M.D. Sahar Dawisha, M.D. Phyllis Silverman, M.S.

Device Description & Preclinical Testing Overview

Samie Allen

Mentor P030053 4

Device Description

High, moderate, & moderate plus profiles Smooth & textured surfaces Round Single lumen Components: shell, patch, filler, & silicone

adhesive

Mentor P030053 5

Preclinical Testing

Modes and causes of rupture Fatigue testing Gel bleed Gel cohesion Shelf life

Mentor P030053 6

Modes & Causes of Rupture

Retrieval studies of explanted devices Physical property / crosslink density testing Assessment of manufacturing processes Assessment of surgical techniques Review of literature

Mentor P030053 7

Modes & Causes of Rupture (cont.)

PE Database Analysis:

Includes failed, retrieved devices in 3 categories Iatrogenic User Related – surgical damage Rent Unknown Cause (RUC) Not Apparent Etiology Unknown (NAEU)

Focused on RUC and NAEU categories

203 available for analysis

Mentor P030053 8


RUC & NAEU Failure Modes N

Localized stress (presumed cause) 121

Shell/patch junction 23

Fold flaw 20

Shell/patch delamination 12

Instrument damage 11

Patch internal 3

Combination failures 13

Total 203

Mentor P030053 9


Supplemental Analysis of Failure Modes

# (%) of Retrieved Devices0-5 yrs 6-10 yrs >10 yrs

Instrument damage 112 (48%) 5 (13%) 2 (67%)

Localized stress (presumed cause)

81 (35%) 16 (40%) 1 (33%)

Shell/patch junction 19 (8%) 4 (10%) 0 (0%)

Fold flaw 10 (4%) 10 (25%) 0 (0%)

Shell/patch delamination 7 (3%) 4 (10%) 0 (0%)

Patch internal 2 (1%) 1 (3%) 0 (0%)

Total 231 40 3

Mentor P030053 10


Distribution of Failure Modes for Retrieved Devices at 0-5 Years (N=231)

0 10 20 30 40 50 60 70

Patch internalShell/patch delamination

Fold flawShell/patch junction

Localized shell stressInstrument damage

%

Mentor P030053 11


Distribution of Failure Modes for Retrieved Devices at 6-10 Years (N=40)

0 10 20 30 40 50 60 70




%

Mentor P030053 12


Distribution of Failure Modes for Retrieved Devices at >10 Years (N=3)

0 10 20 30 40 50 60 70




%

Mentor P030053 13

Mentor’s Proposed Next Steps:

In-vitro study to determine optimum incision size

Develop inserter instrument

Assess alternate texturing process

Investigate patch design changes

Labeling and physician training


Mentor P030053 14

Fatigue Testing

20-30 lbs endurance load limit

Analyzed raw dataEstimated median life of 25-47 years

Appropriateness of test set-up and accuracy of estimate unknown based on lack of pure cyclic failures observed in modes and causes of rupture studies

Mentor P030053 15

Gel Bleed Testing

ASTM F703 testing

Gel loss analysis

Gel bleed study

Mentor P030053 16

Gel Bleed Testing (cont.)

ASTM F703 Testing:

Smooth Moderate Profile implants (350cc)

Incubated for 15 (not 8) weeks at 110°F

Ave weight gain rate – 0.0011 g/cm2/week

ASTM F703 test method does not mimic in-vivo conditions

Mentor P030053 17

Gel Bleed Testing (cont.)Gel Loss Analysis:

74 devices randomly selected and re-weighed to obtain post-explantation weight

Calculated % implant weight 40 smooth; 0.2-15.2 in-vivo years; 101% (97-107) 34 Siltex; 0.1-9.4 in-vivo years; 101% (99-104)

Does not identify and quantify the rate of bleed for all gel bleed constituents

Mentor P030053 18

Gel Bleed Testing (cont.)Gel Bleed Study:

125cc implants incubated in 225ml porcine serum at 37°C

Detected D4, D5, and D6. Cumulative bleed rate was 0.95 ng/cm2/day by day 30

Issues with testing: Applicability of 120 days to in-vivo conditions Implant size vs. volume of porcine serum medium Decrease in release amount for D5 and D6 after day 30 GC analysis correction due to volatility No rate of diffusion for each gel bleed constituent

Mentor P030053 19

Gel Cohesion Testing

Gel cohesion testing of final gel ASTM F703 (<4.5cm & no gel separation) Results: passed

Penetrometer testing of in-process gel No standard (internal specification) Results: passed; 63.4 (range of 61-64)

Mentor P030053 20

Shelf Life

Device and package testing

5-year shelf life date on package label

Mentor P030053 21

Summary – Preclinical Testing Modes and Causes of Rupture:

Characterize through 10 years Not predictive of lifetime rupture rate Proposed labeling and training to address

failures related to surgical procedure Proposed several design/manufacturing

changes Proposed to develop introducer instrument

Fatigue Testing: Adequacy of testing and estimate lifetime

cannot be validated

Mentor P030053 22

Summary – Preclinical Testing (cont). Gel Bleed:

Outstanding issues that should be able to be addressed by sponsor

Gel Cohesion: Adequate to address issue

Shelf Life: Adequate to support 5-year shelf life on label

Chemistry Overview

Sam Arepalli, Ph.D.

Mentor P030053 24

Device Materials Shell, middle (barrier) layer: Diphenyldimethyl-

siloxane copolymer, 15 mole% diphenyl

Shell, inner/outer (base) layers: Dimethylsiloxane polymer

Patch Assembly: Dimethylsiloxane Pt (platinum) cure polymer

Silicone Gel: Two-part platinum cure gel

Silicone adhesive: RTV silicone Sn (tin) cure

Mentor P030053 25

Degree of Crosslinking

Shell: 7.90 chains/cm3 (Sol Fraction Method)

Gel: 8.81 chains/cm3

3.0-10.0 mm (Penetrometer)

Mentor P030053 26

Volatiles Shell: total volatiles (11.1 ppm)

IPA (1 ppm) Xylenes (0.1 ppm) Methoxymethylsilane (3 ppm) Dodecane (3 ppm) Undecane (1.3 ppm)

Gel: total volatiles (2.8 ppm) D3 (0.18 ppm) D4 (0.5 ppm) D5 (1.6 ppm) Undecane (0.3 ppm)

Mentor P030053 27

Extractables

Gravimetric analysis

Gel permeable chromatography

FTIR analysis

Qualitative and quantitative analysis (GC-MS Analysis)

Mentor P030053 28

GC-MS Analysis

Shell and gel

LMW oligosiloxanes (up to D10) present at<10ppm

High MW cyclic (>D11) oligosiloxanes concentrations comparable to those of saline-filled breast implants.

Mentor P030053 29

Metal Analysis

Extracted residue: Shell: Sn (ND); Pt (0.133 ppm) Gel: Sn (ND); Pt (0.323 ppm)

Unextracted: Shell: Sn (0.03 ppm); Pt (8.8 ppm) Gel: Sn (0.01 ppm); Pt (4.8 ppm)

Mentor P030053 30

Silica Analysis

Amorphous silica (X-ray diffraction)

No free silica present (Raman & Photoelectron spectroscopy)

Mentor P030053 31

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

Gravimetric analysis GPC FTIR GC-MS

Toxicology Overview

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

Mentor P030053 33

Five Testing Categories

Pharmacokinetics

Biocompatibility

Immunotoxicology

Reproductive and Teratogenicity Testing

Genotoxicity and Carcinogenesis

Mentor P030053 34

Pharmacokinetics Elastomer: Orthopedic implants in dogs and

humans could be recovered after years.

Gel: Long-term gel implants in rats remained at subcutaneous implantation sites for at least 450 days.

99.97% of 14-C-labeled gel remained in place in mice for at least 56 days.

LMW Gel Components: Subcutaneous implants of low molecular weight cyclic siloxanes (D3-D7) were distributed to tissues over a year.

Mentor P030053 35

Biocompatibility Testing

Cytotoxicity

Irritation and Short-Term Implantation

Acute Systemic Toxicity

Hemolysis

Pyrogenicity

Mentor P030053 36

Immunotoxicity Testing

Sensitization Testing Other Immunotoxicity Testing Endpoints

Body, Spleen, and Thymus Weights

Hematology

Splenic T-Cells (CD4+ and CD8+)

T-Cells Response to Mitogens

Mixed Lymphocyte Response

IgM Antigen Forming Cells

Mentor P030053 37

Reproductive & Teratogenicity Testing

A 1-Generation Study

100 F0 Females – 4 groups of 25 each

No Reproductive Effects in F0

No Reproductive or Teratogenic Effects in F1

Mentor P030053 38

Genotoxicity & CarcinogenesisTesting

Salmonella Reverse Mutation Assay

Unscheduled DNA Synthesis

Chromosomal Aberration Assay

In Vivo Mouse Micronucleus Test

Carcinogenicity Testing

Mentor P030053 39

Toxicology Summary

Mentor has provided the toxicology information recommended in the breast implant guidance document.

No safety issues were raised by data.

Clinical Data Overview

Herbert P. Lerner, M.D.Medical Officer

Mentor P030053 41

Summary of Studies

1. Core Study—Started 2000.

2. Adjunct Study—Started 1992.

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

Mentor P030053 42

Core Study

Majority of Safety and Effectiveness data. Augmentation, Reconstruction, Revision. Yearly F/U to 10 years after implantation. Study includes prospective MRI screening

for silent rupture in 420 of 1007 patients. QOL and CTD signs/symptoms collected.

Mentor P030053 43

Adjunct Study

Intended to make the implants available for reconstruction and revision patients.

Collected local complications at 1, 3, and 5 years after implantation surgery.

No MRI Screening. Unlimited sample size. Enrollment is ongoing.

Mentor P030053 44

Core Study Results

Mentor P030053 45

Core Study Demographics: Age

Aug

N = 551

Recon

N = 252

Revision

N = 226

Median Age

(range) in years

34

(18-65)

46

(18-79)

44

(20-72)

Mentor P030053 46

Core Augmentation Cohort

Mentor P030053 47

Patient Disposition - Core Aug

551 patients (1110 devices) enrolled. 439 (80%) theoretically due at 3 years. 94% patient follow-up rate at 3 years.

0 deaths 22 patients with implant

removals/replacements 9 lost to follow-up

Mentor P030053 48

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

Complication Rate (95% CI)

Reoperation 15.0% (11.9%, 18.0%)

Nipple Sensation Change 10.8% (8.1%, 13.4%)

C/C III/IV 8.2% (5.9%, 10.6%)

Hypertrophic Scarring 6.3% (4.2%, 8.3%)

Implant Removal w/ w/o replacement

5.1% (3.2%, 7.1%)

Breast Mass 2.4% (1.0%, 3.7%)

Rupture 0.5% (0.0%, 1.5%)

Mentor P030053 49

Reoperations - Core Augmentation

160 additional surgical procedures in 98 reoperations in 79 patients.

Primary reasons for reoperation: Capsular Contracture - 44% Patient Request – 32%

Types of additional surgical procedures Capsule procedures - 36% Implant removal/replacement – 28%

Mentor P030053 50

Primary Procedure for Given Reoperation

Reoperation Surgical Procedure # (% of 98)

Capsular contracture Capsule procedures 30 (30.6%)

Removal/replacement 5 (5.1%)

Healing related Incision and drainage 12 (12.2%)

Infection Removal/replacement 2 (2.0%)

Revision wound closure 1 (1.0%)

Patient request Removal/replacement 16 (16.3%)

Unsatisfactory cosmetic result

Capsule procedures 5 (5.1%)


Implant reposition 1 (1.0%)

Mastopexy 1 (1.0%)

Scar revision 10 (10.2%)

Mentor P030053 51

Reason for Implant Removal through 3 Years - Core Augmentation

45 explants in 26 (6.4%) patients Reasons for removal

Patient choice – 68.9% Capsular contracture – 11.1% Infection – 4.4% Breast pain – 4.4% Necrosis – 4.4%

Mentor P030053 52

Other Safety Information - Core Augmentation No increase in reports of reproductive or

lactation problems. 4 post-implant breast mass reports: 0

malignant. 6 post-implant abnormal mammogram

reports: all benign. 3 Patients with New Diagnosis of CTD.

Mentor P030053 53

CTD Signs/Symptoms - Core Augmentation (n=494)

Sign/Symptom

(most commonly reported)

Number with sign/symptom reported

Cumulative incidence

Any sign/symptom 53 10.3%

Numbness of hands 13 2.7%

Joint pain 13 2.7%

Mentor P030053 54

Effectiveness - Core Study QoL

Tennessee Self-Concept Scale SF-36 Body Esteem Scale Rosenberg Self-Esteem Scale Functional Living Index: Cancer

Patient satisfaction Chest/breast measurements

Mentor P030053 55

Effectiveness - Core Augmentation

TSCS – no statistically significant change in overall mean score

SF-36 – statistically significant worsening in PCS and MCS

BES – no statistically significant change in overall mean score

Rosenberg – statistically significant improvement in overall mean score

Mentor P030053 56

Effectiveness - Core Augmentation

Global satisfaction assessed by patients who did not have study implant(s) removed by answering the following question –

“Would you have the surgery over again?”

99% of 495 patients reported being satisfied at 2 years.


Mentor P030053 57

Core Reconstruction Cohort

Mentor P030053 58

Patient Disposition - Core Recon




Mentor P030053 59

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

Reoperation 26.3% (21.7%, 31.9%)

Removal/Replacement 13.3% (8.8%, 17.8%)

CC III/IV 8.8% (4.9%, 12.7%)

Ptosis 6.9% (2.0%, 11.8%)

Infection 5.3% (2.5%, 8.1%)

Breast Pain 1.7% (0.0%, 0.4%)

Tissue/Skin Necrosis 1.2% (0.0%, 2.0%)

Rupture 0.8% (0.0%, 2.2%)

Mentor P030053 60

Reoperations - Core Reconstruction

139 additional surgical procedures in 78 reoperations in 64 patients

Primary reasons for reoperation Asymmetry - 26% Patient request - 17% Implant malposition/displacement - 14% Capsular contracture III/IV - 13%

Types of additional surgical procedures Implant removal/replacement - 29% Capsule procedures - 19%

Mentor P030053 61

Primary Procedure for Given Reoperation Reoperation Surgical Procedure # (% of 78)

Capsular contracture Capsule procedures 4 (5.1%)


Healing related Removal/replacement 1 (1.3%)

Incision and drainage 2 (2.6%)


Incision and drainage 2 (2.6%)






Mastopexy 3 (3.8%)

Pocket revision 1 (1.3%)


Mentor P030053 62

Primary Reason for Implant Removal through 3 Years - Core Reconstruction


Patient request – 32.5% Asymmetry – 25.0% Capsular contracture III/IV – 10.0% Implant malposition/displacement – 7.5%

Mentor P030053 63

Other Safety Information - Core Reconstruction

No increase in reports of reproductive or lactation problems.

0 New reports of breast malignancy: recurrence or metastasis.

1 New report of CTD: Fibromyalgia.

Mentor P030053 64

CTD Signs/Symptoms - Core Reconstruction (n= 221)

Sign/Symptom (most commonly reported)

Number with signs/symptoms reported

Cumulative Incidence

Any sign/symptom 44 21.5%

Joint pain 17 8.0%

Joint swelling 10 4.5%

Mentor P030053 65

Effectiveness - Core Reconstruction TSCS – no statistically significant change in

overall mean score

SF-36 – no statistically significant change in PCS and MCS

BES – no statistically significant change in overall mean score

Rosenberg – no statistically significant change in overall mean score

FLIC – statistically significant improvement for delayed post-mastectomy recon patients

Mentor P030053 66

Effectiveness - Core Reconstruction

Global satisfaction assessed by patients who did not have study implant(s) removed by answering the following question –




Mentor P030053 67

Core Revision Cohort

Mentor P030053 68

Patient Disposition through 3 years - Core Revision




Mentor P030053 69

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

Reoperation 26.3% (20.0%, 32.6%)

CC III/IV 17.2% (11.9%, 22.4%)

Removal/Replacement 13.3% (8.4%, 18.2%)

Nipple sensation changes 8.6% (4.7%, 12.6%)

Scarring 6.0% (2.7%, 9.3%)

Breast mass 5.8% (25%, 9.1%)

Rupture 4.8% (0.2%, 9.3%)

Breast Pain 2.0% (0.1%, 4.0%)

Mentor P030053 70

Reoperation - Core Revision

141 additional surgical procedures in 71 reoperations in 51 patients

Primary reasons for reoperation: Capsular contracture III/IV – 39% Patient request – 20%

Types of additional surgical procedures: Capsular procedures – 29% Implant removal/replacement – 28%

Mentor P030053 71

Primary Procedure for Given Reoperation Reoperation Surgical Procedure # (% of 71)

Capsular contracture



Healing related Incision and drainage 7 (9.9%)

Revision of wound closure 1 (1.4%)


Surgical exploration 1 (1.4%)








Mentor P030053 72

Primary Reason for Implant Removal through 3 Years - Core Revision


Patient choice – 35.9% Capsular contracture III/IV – 28.2% Asymmetry – 7.7%

Mentor P030053 73

Other Safety Information - Core Revision

No increase in reports of reproductive or lactation problems.

1 new case of breast cancer reported 2 New report of CTD: Fibromyalgia and

Pyoderma gangrenosa w/ IBD.

Mentor P030053 74

CTD Signs/Symptoms - Core Revision (n= 226)

Sign/Symptom Number with sign/symptoms reported

Cumulative incidence

Any sign/symptom

39 21.3%

Joint pain 14 7.3%

Fatigue 11 6.0%

Mentor P030053 75

Effectiveness - Core Revision TSCS – statistically significant worsening in

overall mean score

SF-36 – statistically significant worsening in PCS and MCS

BES – statistically significant worsening in overall mean score

Rosenberg – no statistically significant change in overall mean score

FLIC – statistically significant improvement for revision patients with reconstruction and history of cancer

Mentor P030053 76

Effectiveness - Core Revision Global satisfaction assessed by patients who did

not have study implant(s) removed by answering the following question –




Mentor P030053 77

Summary - Core Augmentation Most frequent complications through 3 years:

Reoperation Nipple sensation changes Capsular contracture III/IV Hypertrophic scarring

Most frequent reason for reoperation and medical reason for implant removal through 3 years was CC III/IV.

Of patients who did not have study implant(s) removed and who answered global satisfaction question, 97% were satisfied at 3 years.

Mentor P030053 78

Summary - Core Reconstruction Most frequent complications through 3 years:

Reoperation Implant removal with or without replacement Capsular contracture III/IV Ptosis

Most frequent medical reason for reoperation and implant removal through 3 years was asymmetry.


Mentor P030053 79

Summary - Core Revision

Most frequent complications through 3 years: Reoperation Capsular contracture III/IV Implant removal with or without replacement Nipple sensation changes

Most frequent medical reason for reoperation and implant removal through 3 years was CC III/IV.


Mentor P030053 80

QOL - Literature Review Difficult to assess benefits of implants for

augmentation in a literature review.

Studies had numerous weaknesses, including: Short duration of follow-up Lack of controls Selective exclusion criteria Variable assessment tools “Anecdotal” reports Use of unvalidated instruments.

Diagnosis of cancer makes QOL assessments difficult in reconstruction patients.

Mentor P030053 81

Adjunct Study

Through 11/02, 44,951 patients (87,106 devices) have been enrolled.

For the reconstruction and revision cohorts respectively, follow-up rates have been: Year 1: 34%, 35% Year 3: 19%, 18% Year 5: 11%, 10%

No MRI cohort

Mentor P030053 82

Thank you

Rupture Overview-Mentor Silicone Breast Implants

Sahar M. Dawisha, M.D.,

Medical Officer

Mentor P030053 84

Silicone Gel BI Rupture

Silent rupture = asymptomatic to the patient and physician.

MRI to detect silent rupture. Symptomatic rupture = a/w symptoms (i.e.

implant flattening, lumps, silicone extrusion). Intracapsular rupture = within fibrous capsule. Extracapsular rupture = outside the fibrous

capsule.

Mentor P030053 85

Implant Rupture Questions:

What is the implant rupture rate over the expected device lifetime?

How often and when do intracapsular vs. extracapsular rupture occur?

What is the rate at which intracapsular rupture becomes extracapsular?

What are the local health consequences of implant rupture?

Mentor P030053 86

Core Study: Silent Rupture

MRI Cohort = screening for silent rupture at years 1, 2, 4, 6, 8, and 10 via MRI.80% follow-up compliance at 1st MRI.90% follow-up compliance at 2nd MRI.Mean implantation duration = 2 years at 2nd

MRI.

Non-MRI Cohort = no MRI.Under-ascertainment of silent rupture.

Mentor P030053 87

Core Study: Rupture

No symptomatic ruptures reported. No silent ruptures in Non-MRI Cohort. All ruptures are silent. All ruptures are in MRI Cohort. Follow-up at 3 years is partial.

~ 26% of patients not yet due for 3 year visit.MRI scheduled at years 1 and 2.

Mentor P030053 88

Core Study KM Rupture Rate through 3 years in MRI Cohort:

All SilentBy-Patient By-Implant

Aug 0.5%(0.0, 1.5)

0.2%(0.0, 0.7)

Recon 0.8%(0.0, 2.2)

0.5%(0.0, 1.4)

Revision 4.8%(0.3, 2.6)

3.9%(0.8, 1.7)

Mentor P030053 89

Core Study: Rupture Details 8 implants (in 6 patients) suspected ruptured

through 3 years, all in MRI Cohort.Of these, 2 implants (in 1 rev-aug patient) confirmed

ruptured via explant: 1 intracapsular and 1 extracapsular.

Intracapsular rupture: 4 implants via MRI. Extracapsular gel: 4 implants via MRI. 1 implant with intra → extracapsular rupture. 3 of 6 patients had both year 1 and 2 MRI.

Mentor P030053 90

Drs. Sharpe and Collis:MRI Case Series

Augmentation patients from Dr. Sharpe’s practice. ~ 200 women eligible; ~100 women had 1 MRI. Protocol excludes women with implant removal, Capsular

Contracture Grade III/IV, surgical interventions, or clinical evidence of rupture.

All textured Mentor implants, all subglandular. 1 MRI examination » » » point prevalence of rupture rather

than rupture rate over time. 11 of 204 implants had intracapsular rupture via explant. By-implant point prevalence of silent rupture = 5% (median

implant duration 8.8 years; range 4-12 years).

Mentor P030053 91

Rupture Rate: Danish Literature Scandinavian MRI studies of silent rupture

Several manufacturers; Augmentation only.Excludes implants removed in first 3 years.Median implant duration: 12 yrs (3-25 years).Rupture prevalence = 32% of implants.~25% of ruptures extracapsular.Rupture incidence = 8.9 per 100 implants/yr.56 ruptures: 48 via MRI; 8 at reoperation.

Hölmich, et al., Plast Recon Surg. 2001; 108: 848-858.Hölmich, et al., Arch Surg. 2003; 138: 801-806.

Mentor P030053 92

Rupture Rate: Other Literature FDA MRI rupture study

Several manufacturers; Augmentation only. Excludes implants removed in first 6 years. Median implant duration: 16 yrs (6-28 years).Prevalence = 55% of implants; 12% extracap.

Gaubitz MRI studySeveral Manufacturers; ¾ recon; ¼ aug.Mean implant duration 9 yrs (1- 26 years).Prevalence = 24% of women; 12% extracap.

Brown, et al., Am J Roent. 2000; 175(4): 1057-1064.Gaubitz, et al. Rheumatol. 2002; 41: 129-135.

Mentor P030053 93

Rupture Health Consequences: Mentor Implants

Complications and satisfaction from Core Study: 1 patient with confirmed rupture: no complications

reported; patient satisfied at re-implantation.Number of patients with rupture too small to

compare with non-ruptured. Rheum eval from Sharpe/Collis case series:

1 patient with myalgic encephalitis and rupture.No comparison group.

Mentor P030053 94

Rupture Health Consequences: Literature

Case reports of local and distant silicone granulomas. Silicone in liver via MRS; higher with rupture. No statistically significant differences for

autoantibodies and self-reported diseases and symptoms 1 year before rupture in Danish women.

Extracapsular rupture: 6x breast hardness. Implant rupture: 2x pain or change in shape. Intracap → extracap: 9% of implants over 2 years. Extracap progression: 14% of implants over 2 years.Hölmich, et al., Plast Recon Surg. 2003; 111: 723-732.Hölmich, et al., Plast Recon Surg. 2004; 114: 204-214.

Mentor P030053 95

Rupture Summary: Mentor Data

2-3 years of comprehensive rupture data. All ruptures silent, diagnosed via MRI. Half of ruptures are intracapsular via MRI. 1 implant: intra → extracapsular progression. Data limited to address lifetime rupture rate. Data limited to address intra → extracapsular rupture

and silent → symptomatic rupture. Data limited to rupture address health

consequences.

Mentor P030053 96

Rupture Summary: Literature Serial silent rupture data over 2 years. Most ruptures are silent, diagnosed via MRI. Most ruptures are intracapsular: 25% extracapsular

via MRI. 9% intra → extracapsular rupture; half a/w trauma. 14% extracap → progressive silicone seepage. Breast pain and hardness a/w rupture. Evidence of silicone outside the breast area. Rupture incidence = 9 ruptures/100 implants/year » »

» 22,500 augmentation implant ruptures per year in U.S. (2004 rate)

Mentor P030053 97

Silent Extracapsular Rupture:Patient History

31 Year Old Bilateral Augmentation 6 years later entered Core Study as revision patient:

severe CC and rupture on R. 1st MRI 16 months later: no rupture. 2nd MRI 1 year later: bilateral keyhole signs. 3rd MRI 10 months later: bilateral intracapsular rupture with

extracapsular silicone on R. Ruptured implants removed and replaced. Large tear in one implant; large hole in other. No complications reported.

Mentor P030053 98

Rupture Issues to Consider

Whether the data are adequate to characterize rupture rate over time and health consequences of rupture.

Whether the existing rupture data provide reasonable assurance of safety.

What to recommend for silent rupture screening method and frequency.

Mentor P030053 99

Labeling Issues Method and frequency of silent rupture screening.

Annual or biannual examination; method not specified. MRI considered if clinical suspicion of rupture. Silent rupture not addressed.

Clinical management of rupture. Removal of ruptured implant recommended; no mention

of whether to remove silent ruptured implant. Health consequences of extracapsular gel.

Monitor for lumps or change in breast shape; addresses symptomatic rather than silent rupture.

Mentor P030053 100

Post-approval Issues

Continue Core Study. MRI discontinuation issues

Use existing ASPS/PSEF National Breast Implant Registry. Voluntary Collects short-term complications and reoperation No planned follow-up visits No specific rupture information collected

Physician education/training program. Certification required for product access Rupture screening method and frequency not included

Mentor P030053 101

Safety and Effectiveness Information

Consider all complications and benefits. Consider augmentation and reconstruction

separately. Consider revision as a continuum of

augmentation or reconstruction.

Thank You

Statistical Overview

Phyllis Silverman, M.S.Mathematical StatisticianDivision of Biostatistics

Mentor P030053 104

Descriptive Nature of Studies There were no claims, targets, or formal control

groups in this study.

Statistical techniques: means, confidence intervals, rate estimation from survival analyses

Sample size: Reflected in the width (i.e. precision) of the confidence interval.

Acceptability of rates and adequacy of precision must be assessed by weighing the risks and benefits of implants.

Mentor P030053 105

Employed Statistical Techniques

Means/proportions with confidence intervals Safety and effectiveness data

Kaplan - Meier Analyses Adverse Events including Rupture

Cox Regression Covariate analysis

Generalize Estimating equations CTD Analyses

Prevalence and Incidence Rupture rate estimation

Mentor P030053 106

Kaplan-Meier analyses were conducted on the time to first occurrence of each adverse event.

Advantage: Patients who were lost or not due for follow-up provide information for the time they were followed.

Kaplan-Meier Analyses“Time to Event” Analyses

Assumption: reasons for not being followed (i.e., censoring) are unrelated to the event in question.

Biases: Exact time of onset of event may not be known; correlations between adverse events not taken into account; competing risks.

Mentor P030053 107

Generalized Estimating Equations A longitudinal analysis which can adjust for a

covariate Sponsor analyzed Signs/Symptoms of CTD’s

adjusted for age of patient Several significant results in Aug and Rev

cohorts (e.g. fatigue, exhaustion, joint pain) Increases in certain S/S are beyond what would

be due to aging alone Some associations could be spurious due to

sheer number of comparisons; best to look for consistencies across cohorts.

Mentor P030053 108

Point 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)

May be thought of as a “snapshot in time”

Disadvantage: Persons experiencing a complication that was resolved, or a rupture that was explanted before the “snapshot” will not be captured; Does not distinguish between new and existing cases

Prevalence and Incidence

Mentor P030053 109

Prevalence and Incidence (cont’d)

Incidence: percentage of patients seen at a given follow-up visit who are experiencing the adverse event not experienced at earlier visits (i.e., the new cases)

Disadvantages: Subject to biases from patients who did not return for follow-up; may not be consistent from one time interval to the next.

Mentor P030053 110

Sharpe and Collis Data FDA clinical reviewer has pointed out

differences in indication, surface type, and device placement.

Sponsor calculated point prevalence based on single MRI exam.

Sponsor used statistical techniques to estimate cumulative incidence from cross-sectional data.

Estimated rates may not apply to general Mentor breast implant population.

Mentor P030053 111

Core Study Summary Statistical methodology mainly employed

descriptive statistics or survival techniquesClinical assessment is necessary

Minimal bias from loss to follow-up

Sharpe and Collis data limited in its ability to characterize the long term rupture rate for Mentor Core Study patients.

Conclusion of FDA’s Presentation

Panel Questions

Mentor P030053 114

Panel Question 1

Considering the rupture information in their submission, and given that majority of ruptures for silicone gel-filled breast implants are silent, please discuss whether Mentor has adequately characterized the rupture rate and how this rate changes over the expected lifetime of their device.

Mentor P030053 115

Panel Question 2

Please discuss whether Mentor has adequately characterized the consequences of rupture for their device with regard to:

freq of observed intracapsular gel, extracapsular gel, & migrated gel; destination of migrated gel

the local health consequences silent ruptures → symptomatic ruptures intracapsular → extracapsular ruptures.

Mentor P030053 116

Panel Question 3Mentor’s proposed labeling includes recommendations for: (1) the method and frequency of screening for silent rupture; (2) clinical management of suspicious and confirmed intracapsular and extracapsular rupture; and (3) potential health consequences of extracapsular and migrated gel.

Please discuss the appropriateness of these recommendations and the extent to which the proposed labeling is supported by the available information.

Mentor P030053 117

Panel Question 4

Please comment on the adequacy of Mentor’s postapproval plans to address any postapproval concerns that you may have.

Mentor P030053 118

Panel Question 5

Please discuss whether you believe that there is reasonable assurance that this device is safe over its expected lifetime for the proposed indications of breast augmentation, reconstruction, and revision.

Mentor P030053 119

Panel Question 6

Please discuss whether you believe that there is a reasonable assurance that their device is effective for the proposed indications of breast augmentation, reconstruction, and revision.

mentor corporation’s silicone gel-filled breast implants (p030053) april 13, 2005

Documents