Transcript Document 7432621

Mentor Corporation’s
Silicone Gel-Filled
Breast Implants
(P030053)
April 13, 2005
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.

Mentor P030053
2
Device Description &
Preclinical Testing
Overview
Samie Allen
Device Description
High, moderate, & moderate plus profiles
 Smooth & textured surfaces
 Round
 Single lumen
 Components: shell, patch, filler, & silicone
adhesive

Mentor P030053
4
Preclinical Testing
Modes and causes of rupture
 Fatigue testing
 Gel bleed
 Gel cohesion
 Shelf life

Mentor P030053
5
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
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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
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Modes & Causes of Rupture (cont.)
RUC & NAEU Failure Modes
N
Localized stress (presumed cause)
Shell/patch junction
Fold flaw
Shell/patch delamination
Instrument damage
Patch internal
Combination failures
Total
121
23
20
12
11
3
13
203
Mentor P030053
8
Modes & Causes of Rupture (cont.)
Supplemental Analysis # (%) of Retrieved Devices
of Failure Modes
0-5 yrs
6-10 yrs
>10 yrs
112 (48%) 5 (13%) 2 (67%)
Instrument damage
81 (35%) 16 (40%) 1 (33%)
Localized stress
(presumed cause)
19 (8%)
4 (10%) 0 (0%)
Shell/patch junction
10 (4%)
10 (25%) 0 (0%)
Fold flaw
4 (10%) 0 (0%)
Shell/patch delamination 7 (3%)
2 (1%)
1 (3%)
0 (0%)
Patch internal
231
40
3
Total
Mentor P030053
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Modes & Causes of Rupture (cont.)
Distribution of Failure Modes for Retrieved
Devices at 0-5 Years (N=231)
Instrument damage
Localized shell stress
Shell/patch junction
Fold flaw
Shell/patch delamination
Patch internal
0
10 20 30 40 50 60 70
%
Mentor P030053
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Modes & Causes of Rupture (cont.)
Distribution of Failure Modes for Retrieved
Devices at 6-10 Years (N=40)
Instrument damage
Localized shell stress
Shell/patch junction
Fold flaw
Shell/patch delamination
Patch internal
0
10 20 30 40 50 60 70
%
Mentor P030053
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Modes & Causes of Rupture (cont.)
Distribution of Failure Modes for Retrieved
Devices at >10 Years (N=3)
Instrument damage
Localized shell stress
Shell/patch junction
Fold flaw
Shell/patch delamination
Patch internal
0
10 20 30 40 50 60 70
%
Mentor P030053
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Modes & Causes of Rupture (cont.)
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
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Fatigue Testing

20-30 lbs endurance load limit

Analyzed raw data
 Estimated 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
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Gel Bleed Testing

ASTM F703 testing

Gel loss analysis

Gel bleed study
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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
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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
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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
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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
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Shelf Life

Device and package testing

5-year shelf life date on package label
Mentor P030053
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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
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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
Mentor P030053
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Chemistry Overview
Sam Arepalli, Ph.D.
Device Materials

Shell, middle (barrier) layer: Diphenyldimethylsiloxane 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
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Degree of Crosslinking

Shell: 7.90 chains/cm3 (Sol Fraction
Method)

Gel:
 8.81 chains/cm3
 3.0-10.0 mm (Penetrometer)
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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
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Extractables

Gravimetric analysis

Gel permeable chromatography

FTIR analysis

Qualitative and quantitative analysis
(GC-MS Analysis)
Mentor P030053
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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
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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
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Silica Analysis

Amorphous silica (X-ray diffraction)

No free silica present (Raman &
Photoelectron spectroscopy)
Mentor P030053
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Summary - Chemistry
Shell and gel tested separately
 Degree of crosslinking
 Volatiles
 Metals
 Extractables
 Gravimetric analysis
 GPC
 FTIR
 GC-MS

Mentor P030053
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Toxicology Overview
David B. Berkowitz, Ph.D., V.M.D.
Five Testing Categories

Pharmacokinetics

Biocompatibility

Immunotoxicology

Reproductive and Teratogenicity Testing

Genotoxicity and Carcinogenesis
Mentor P030053
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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
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Biocompatibility Testing

Cytotoxicity

Irritation and Short-Term Implantation

Acute Systemic Toxicity

Hemolysis

Pyrogenicity
Mentor P030053
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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
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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
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Genotoxicity & Carcinogenesis
Testing

Salmonella Reverse Mutation Assay

Unscheduled DNA Synthesis

Chromosomal Aberration Assay

In Vivo Mouse Micronucleus Test

Carcinogenicity Testing
Mentor P030053
38
Toxicology Summary

Mentor has provided the toxicology
information recommended in the breast
implant guidance document.

No safety issues were raised by data.
Mentor P030053
39
Clinical Data
Overview
Herbert P. Lerner, M.D.
Medical Officer
Summary of Studies
1.
2.


Core Study—Started 2000.
Adjunct Study—Started 1992.
All open label, prospective, multicenter.
Yearly F/U in Core Study.
Both collected local complications.
Mentor P030053
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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
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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
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Core Study Results
Mentor P030053
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Core Study Demographics: Age
Median
Age
(range)
in years
Aug
N = 551
Recon
N = 252
Revision
N = 226
34
(18-65)
46
(18-79)
44
(20-72)
Mentor P030053
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Core Augmentation Cohort
Mentor P030053
46
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
47
By-Patient 3-Year Cumulative KM
Complication Rates - Core Aug
Complication
Reoperation
Nipple Sensation Change
C/C III/IV
Hypertrophic Scarring
Implant Removal w/ w/o
replacement
Breast Mass
Rupture
Rate
15.0%
10.8%
8.2%
6.3%
5.1%
(95% CI)
(11.9%, 18.0%)
(8.1%, 13.4%)
(5.9%, 10.6%)
(4.2%, 8.3%)
(3.2%, 7.1%)
2.4%
0.5%
(1.0%, 3.7%)
(0.0%, 1.5%)
Mentor P030053
48
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
49
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%)
Removal/replacement
1 (1.0%)
Implant reposition
1 (1.0%)
Mastopexy
1 (1.0%)
Scar revision
10 (10.2%)
Mentor P030053
50
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
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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
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CTD Signs/Symptoms - Core
Augmentation (n=494)
Sign/Symptom
(most commonly
reported)
Any sign/symptom
Numbness of hands
Joint pain
Number with
sign/symptom
reported
Cumulative
incidence
53
13
13
10.3%
2.7%
2.7%
Mentor P030053
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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
54
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
55
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.

97% of 394 patients reported being satisfied at 3
years.
Mentor P030053
56
Core Reconstruction Cohort
Mentor P030053
57
Patient Disposition - Core Recon
 252
patients (410 devices) enrolled.
 144 (57%) theoretically due at 3 years.
 95% patient follow-up rate at 3 years.
 9 deaths
 26 patients with implant
removals/replacements
 1 lost to follow-up
Mentor P030053
58
By-Patient 3-Year Cumulative KM
Complication Rates - Core Recon
Complication
Reoperation
Removal/Replacement
CC III/IV
Ptosis
Infection
Breast Pain
Tissue/Skin Necrosis
Rupture
Rate
26.3%
13.3%
8.8%
6.9%
5.3%
1.7%
1.2%
0.8%
Mentor P030053
(95% CI)
(21.7%, 31.9%)
(8.8%, 17.8%)
(4.9%, 12.7%)
(2.0%, 11.8%)
(2.5%, 8.1%)
(0.0%, 0.4%)
(0.0%, 2.0%)
(0.0%, 2.2%)
59
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
60
Primary Procedure for Given Reoperation
Reoperation
Surgical Procedure
# (% of 78)
Capsular contracture
Capsule procedures
4 (5.1%)
Removal/replacement
4 (5.1%)
Removal/replacement
1 (1.3%)
Incision and drainage
2 (2.6%)
Removal/replacement
2 (2.6%)
Incision and drainage
2 (2.6%)
Patient request
Removal/replacement
7 (9.0%)
Unsatisfactory cosmetic
result
Capsule procedures
5 (6.4%)
Removal/replacement
13 (16.7%)
Implant reposition
6 (7.7%)
Mastopexy
3 (3.8%)
Pocket revision
1 (1.3%)
Scar revision
3 (3.8%)
Healing related
Infection
Mentor P030053
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Primary Reason for Implant Removal
through 3 Years - Core Reconstruction
40 explants in 31 (25.6%) patients
 Reasons for removal

Patient request – 32.5%
 Asymmetry – 25.0%
 Capsular contracture III/IV – 10.0%
 Implant malposition/displacement – 7.5%

Mentor P030053
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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
63
CTD Signs/Symptoms - Core
Reconstruction (n= 221)
Sign/Symptom
(most commonly
reported)
Number with
Cumulative
signs/symptoms Incidence
reported
Any sign/symptom
44
21.5%
Joint pain
17
8.0%
Joint swelling
10
4.5%
Mentor P030053
64
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
65
Effectiveness - Core Reconstruction

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?”

97% of 184 patients reported being satisfied at 2
years.

98% of 121 patients reported being satisfied at 3
years.
Mentor P030053
66
Core Revision Cohort
Mentor P030053
67
Patient Disposition through 3
years - Core Revision
204 patients (386 devices) enrolled.
 158 (77%) theoretically due at 3 years.
 93% patient follow-up rate at 3 years.


0 deaths
 22 patients with implant
removals/replacements
 3 lost to follow-up
Mentor P030053
68
By-Patient 3-Year Cumulative KM
Complication Rates - Core Revision
Complication
Reoperation
CC III/IV
Rate
(95% CI)
26.3% (20.0%, 32.6%)
17.2% (11.9%, 22.4%)
Removal/Replacement
13.3% (8.4%, 18.2%)
Nipple sensation changes 8.6%
Scarring
6.0%
Breast mass
5.8%
(4.7%, 12.6%)
(2.7%, 9.3%)
(25%, 9.1%)
Rupture
Breast Pain
(0.2%, 9.3%)
(0.1%, 4.0%)
4.8%
2.0%
Mentor P030053
69
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
70
Primary Procedure for Given Reoperation
Reoperation
Surgical Procedure
# (% of 71)
Capsular
contracture
Capsule procedures
13 (18.3%)
Removal/replacement
6 (8.5%)
Healing related
Incision and drainage
7 (9.9%)
Revision of wound closure
1 (1.4%)
Scar revision
1 (1.4%)
Surgical exploration
1 (1.4%)
Infection
Removal/replacement
1 (1.4%)
Patient request
Removal/replacement
7 (9.9%)
Unsatisfactory
cosmetic result
Capsule procedures
2 (2.8%)
Removal/replacement
5 (7.0%)
Implant reposition
3 (4.2%)
Scar revision
2 (2.8%)
Mentor P030053
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Primary Reason for Implant Removal
through 3 Years - Core Revision
39 explants in 25 (17.9%) patients
 Reasons for removal

Patient choice – 35.9%
 Capsular contracture III/IV – 28.2%
 Asymmetry – 7.7%

Mentor P030053
72
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
73
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
74
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
75
Mentor P030053
Effectiveness - Core Revision

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?”

95% of 169 patients reported being satisfied at 2
years.

96% of 137 patients reported being satisfied at 3
years.
Mentor P030053
76
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
77
Summary - Core Reconstruction

Most frequent complications through 3 years:

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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.

Of patients who did not have study implant(s)
removed and who answered global satisfaction
question, 98% were satisfied at 3 years.
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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.

Of patients who did not have study implant(s)
removed and who answered global satisfaction
question, 96% were satisfied at 3 years.
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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.
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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
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Thank you
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Rupture OverviewMentor Silicone
Breast Implants
Sahar M. Dawisha, M.D.,
Medical Officer
Silicone Gel BI Rupture


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

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.
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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?

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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.
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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.
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Core Study KM Rupture Rate
through 3 years in MRI Cohort:
All Silent
Aug
Recon
Revision
By-Patient
By-Implant
0.5%
0.2%
(0.0, 1.5)
(0.0, 0.7)
0.8%
0.5%
(0.0, 2.2)
(0.0, 1.4)
4.8%
3.9%
(0.3, 2.6)
(0.8, 1.7)
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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.

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Drs. Sharpe and Collis:
MRI Case Series




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

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).
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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.
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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 study
 Several
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.
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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.
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Rupture Health Consequences:
Literature


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
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

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.
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Rupture Summary: Mentor Data
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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.
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Rupture Summary: Literature

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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)
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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.
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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.
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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.
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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
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Safety and Effectiveness
Information
Consider all complications and benefits.
 Consider augmentation and reconstruction
separately.
 Consider revision as a continuum of
augmentation or reconstruction.

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Thank You
Statistical Overview
Phyllis Silverman, M.S.
Mathematical Statistician
Division of Biostatistics
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.
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Employed Statistical Techniques


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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
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Kaplan-Meier Analyses
“Time to Event” Analyses
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.
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.
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Generalized Estimating Equations

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


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.
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Prevalence and Incidence
Point Prevalence: percentage of patients seen
at a given follow-up visit, who are experiencing a
specific adverse event (given they returned to the followup)
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
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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.
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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 crosssectional data.
Estimated rates may not apply to general
Mentor breast implant population.
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Core Study Summary

Statistical methodology mainly employed
descriptive statistics or survival techniques
 Clinical
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.
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Conclusion of FDA’s
Presentation
Panel Questions
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.
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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.
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Panel Question 3
Mentor’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.
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Panel Question 4
Please comment on the adequacy of
Mentor’s postapproval plans to address any
postapproval concerns that you may have.
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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.
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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.
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