Mentor Corporation

1
Mentor CorporationsSilicone Gel-Filled Breast
Implants (P030053)

• April 13, 2005

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.

3
Device Description Preclinical Testing Overview

• Samie Allen

4
Device Description

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

5
Preclinical Testing

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

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

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

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
9
Modes Causes of Rupture (cont.)
Supplemental Analysis of Failure Modes () of Retrieved Devices () of Retrieved Devices () of Retrieved Devices
Supplemental Analysis of Failure Modes 0-5 yrs 6-10 yrs gt10 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
10
Modes Causes of Rupture (cont.)
11
Modes Causes of Rupture (cont.)
12
Modes Causes of Rupture (cont.)
13
Modes Causes of Rupture (cont.)

• Mentors 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

14
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

15
Gel Bleed Testing

• ASTM F703 testing
• Gel loss analysis
• Gel bleed study

16
Gel Bleed Testing (cont.)

• ASTM F703 Testing
• Smooth Moderate Profile implants (350cc)
• Incubated for 15 (not 8) weeks at 110F
• Ave weight gain rate 0.0011 g/cm2/week
• ASTM F703 test method does not mimic in-vivo
  conditions

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

18
Gel Bleed Testing (cont.)

• Gel Bleed Study
• 125cc implants incubated in 225ml porcine serum
  at 37C
• 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

19
Gel Cohesion Testing

• Gel cohesion testing of final gel
• ASTM F703 (lt4.5cm no gel separation)
• Results passed
• Penetrometer testing of in-process gel
• No standard (internal specification)
• Results passed 63.4 (range of 61-64)

20
Shelf Life

• Device and package testing
• 5-year shelf life date on package label

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

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

23
Chemistry Overview

• Sam Arepalli, Ph.D.

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

25
Degree of Crosslinking

• Shell 7.90 chains/cm3 (Sol Fraction Method)
• Gel
• 8.81 chains/cm3
• 3.0-10.0 mm (Penetrometer)

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)

27
Extractables

• Gravimetric analysis
• Gel permeable chromatography
• FTIR analysis
• Qualitative and quantitative analysis (GC-MS
  Analysis)

28
GC-MS Analysis

• Shell and gel
• LMW oligosiloxanes (up to D10) present atlt10ppm
• High MW cyclic (gtD11) oligosiloxanes
  concentrations comparable to those of
  saline-filled breast implants.

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)

30
Silica Analysis

• Amorphous silica (X-ray diffraction)
• No free silica present (Raman Photoelectron
  spectroscopy)

31
Summary - Chemistry

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

32
Toxicology Overview

• David B. Berkowitz, Ph.D., V.M.D.

33
Five Testing Categories

• Pharmacokinetics
• Biocompatibility
• Immunotoxicology
• Reproductive and Teratogenicity Testing
• Genotoxicity and Carcinogenesis

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.

35
Biocompatibility Testing

• Cytotoxicity
• Irritation and Short-Term Implantation
• Acute Systemic Toxicity
• Hemolysis
• Pyrogenicity

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

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

38
Genotoxicity CarcinogenesisTesting

• Salmonella Reverse Mutation Assay
• Unscheduled DNA Synthesis
• Chromosomal Aberration Assay
• In Vivo Mouse Micronucleus Test
• Carcinogenicity Testing

39
Toxicology Summary

• Mentor has provided the toxicology information
  recommended in the breast implant guidance
  document.
• No safety issues were raised by data.

40
Clinical Data Overview

• Herbert P. Lerner, M.D.
• Medical Officer

41
Summary of Studies

• Core StudyStarted 2000.
• Adjunct StudyStarted 1992.
• All open label, prospective, multicenter.
• Yearly F/U in Core Study.
• Both collected local complications.

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.

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.

44
Core Study Results
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)
46
Core Augmentation Cohort
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

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)
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

50
Primary Procedure for Given Reoperation
Reoperation Surgical Procedure ( of 98)
Capsular contracture Capsule procedures 30 (30.6)
Capsular contracture Removal/replacement 5 (5.1)
Healing related Incision and drainage 12 (12.2)
Infection Removal/replacement 2 (2.0)
Infection Revision wound closure 1 (1.0)
Patient request Removal/replacement 16 (16.3)
Unsatisfactory cosmetic result Capsule procedures 5 (5.1)
Unsatisfactory cosmetic result Removal/replacement 1 (1.0)
Unsatisfactory cosmetic result Implant reposition 1 (1.0)
Unsatisfactory cosmetic result Mastopexy 1 (1.0)
Unsatisfactory cosmetic result Scar revision 10 (10.2)
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

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.

53
CTD Signs/Symptoms - Core Augmentation (n494)
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
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

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

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.

57
Core Reconstruction Cohort
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

59
By-Patient 3-Year Cumulative KM Complication
Rates - Core Recon
Complication 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)
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

61
Primary Procedure for Given Reoperation
Reoperation Surgical Procedure ( of 78)
Capsular contracture Capsule procedures 4 (5.1)
Capsular contracture Removal/replacement 4 (5.1)
Healing related Removal/replacement 1 (1.3)
Healing related Incision and drainage 2 (2.6)
Infection Removal/replacement 2 (2.6)
Infection Incision and drainage 2 (2.6)
Patient request Removal/replacement 7 (9.0)
Unsatisfactory cosmetic result Capsule procedures 5 (6.4)
Unsatisfactory cosmetic result Removal/replacement 13 (16.7)
Unsatisfactory cosmetic result Implant reposition 6 (7.7)
Unsatisfactory cosmetic result Mastopexy 3 (3.8)
Unsatisfactory cosmetic result Pocket revision 1 (1.3)
Unsatisfactory cosmetic result Scar revision 3 (3.8)
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

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.

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
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

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.

67
Core Revision Cohort
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

69
By-Patient 3-Year Cumulative KM Complication
Rates - Core Revision
Complication 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)
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

71
Primary Procedure for Given Reoperation
Reoperation Surgical Procedure ( of 71)
Capsular contracture Capsule procedures 13 (18.3)
Capsular contracture Removal/replacement 6 (8.5)
Healing related Incision and drainage 7 (9.9)
Healing related Revision of wound closure 1 (1.4)
Healing related Scar revision 1 (1.4)
Healing related 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)
Unsatisfactory cosmetic result Removal/replacement 5 (7.0)
Unsatisfactory cosmetic result Implant reposition 3 (4.2)
Unsatisfactory cosmetic result Scar revision 2 (2.8)
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

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.

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
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

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.

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.

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.

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.

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.

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

82

• Thank you

83
Rupture Overview-Mentor Silicone Breast Implants

• Sahar M. Dawisha, M.D.,
• Medical Officer

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.

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?

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.

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.

88
Core Study KM Rupture Rate through 3 years in MRI
CohortAll Silent
By-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)
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.

90
Drs. Sharpe and CollisMRI Case Series

• Augmentation patients from Dr. Sharpes 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).

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.
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 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.
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.

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.
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.

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)

97
Silent Extracapsular RupturePatient 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.

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.

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.

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

101
Safety and Effectiveness Information

• Consider all complications and benefits.
• Consider augmentation and reconstruction
  separately.
• Consider revision as a continuum of augmentation
  or reconstruction.

102
Thank You
103
Statistical Overview

• Phyllis Silverman, M.S.
• Mathematical Statistician
• Division of Biostatistics

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.

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

106
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.
107
Generalized Estimating Equations

• A longitudinal analysis which can adjust for a
  covariate
• Sponsor analyzed Signs/Symptoms of CTDs 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.

108
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 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
109
Prevalence and Incidence (contd)

• 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.

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.

111
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.

112
Conclusion of FDAs Presentation
113
Panel Questions
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.

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.

116
Panel Question 3

• Mentors 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.

117
Panel Question 4

• Please comment on the adequacy of Mentors
  postapproval plans to address any postapproval
  concerns that you may have.

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.

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.