mentor corporation’s silicone gel-filled breast implants (p030053) april 13, 2005
TRANSCRIPT
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
Modes & Causes of Rupture (cont.)
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
Modes & Causes of Rupture (cont.)
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
Modes & Causes of Rupture (cont.)
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
Modes & Causes of Rupture (cont.)
Distribution of Failure Modes for Retrieved Devices at 6-10 Years (N=40)
0 10 20 30 40 50 60 70
Patch internalShell/patch delamination
Fold flawShell/patch junction
Localized shell stressInstrument damage
%
Mentor P030053 12
Modes & Causes of Rupture (cont.)
Distribution of Failure Modes for Retrieved Devices at >10 Years (N=3)
0 10 20 30 40 50 60 70
Patch internalShell/patch delamination
Fold flawShell/patch junction
Localized shell stressInstrument damage
%
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
Modes & Causes of Rupture (cont.)
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%)
Removal/replacement 1 (1.0%)
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.
97% of 394 patients reported being satisfied at 3 years.
Mentor P030053 57
Core Reconstruction Cohort
Mentor P030053 58
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 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%)
Removal/replacement 4 (5.1%)
Healing related Removal/replacement 1 (1.3%)
Incision and drainage 2 (2.6%)
Infection 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%)
Mentor P030053 62
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 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 –
“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 67
Core Revision Cohort
Mentor P030053 68
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 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
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 72
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 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 –
“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 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.
Of patients who did not have study implant(s) removed and who answered global satisfaction question, 98% were satisfied at 3 years.
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.
Of patients who did not have study implant(s) removed and who answered global satisfaction question, 96% were satisfied at 3 years.
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.