1. Mentor Corporation’s Silicone Gel-Filled Breast Implants (P030053) April 13, 2005

2. Mentor P0300532 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. Mentor P0300534 Device Description High, moderate, & moderate plus profiles Smooth & textured surfaces Round Single lumen Components: shell, patch, filler, & silicone adhesive

5. Mentor P0300535 Preclinical Testing Modes and causes of rupture Fatigue testing Gel bleed Gel cohesion Shelf life

6. Mentor P0300536 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. Mentor P0300537 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. Mentor P0300538 Modes & Causes of Rupture (cont.) RUC & NAEU Failure ModesN Localized stress (presumed cause)121 Shell/patch junction23 Fold flaw20 Shell/patch delamination12 Instrument damage11 Patch internal3 Combination failures13 Total203

9. Mentor P0300539 Modes & Causes of Rupture (cont.) Supplemental Analysis of Failure Modes # (%) of Retrieved Devices 0-5 yrs6-10 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 231403

10. Mentor P03005310 Modes & Causes of Rupture (cont.)

11. Mentor P03005311 Modes & Causes of Rupture (cont.)

12. Mentor P03005312 Modes & Causes of Rupture (cont.)

13. Mentor P03005313 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.)

14. Mentor P03005314 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. Mentor P03005315 Gel Bleed Testing ASTM F703 testing Gel loss analysis Gel bleed study

16. Mentor P03005316 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/cm 2 /week ASTM F703 test method does not mimic in-vivo conditions

17. Mentor P03005317 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. Mentor P03005318 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/cm 2 /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. Mentor P03005319 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)

20. Mentor P03005320 Shelf Life Device and package testing 5-year shelf life date on package label

21. Mentor P03005321 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. Mentor P03005322 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. Mentor P03005324 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. Mentor P03005325 Degree of Crosslinking Shell: 7.90 chains/cm 3 (Sol Fraction Method) Gel:  8.81 chains/cm 3  3.0-10.0 mm (Penetrometer)

26. Mentor P03005326 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. Mentor P03005327 Extractables Gravimetric analysis Gel permeable chromatography FTIR analysis Qualitative and quantitative analysis (GC-MS Analysis)

28. Mentor P03005328 GC-MS Analysis Shell and gel LMW oligosiloxanes (up to D 10 ) present at<10ppm High MW cyclic (>D 11 ) oligosiloxanes concentrations comparable to those of saline-filled breast implants.

29. Mentor P03005329 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. Mentor P03005330 Silica Analysis Amorphous silica (X-ray diffraction) No free silica present (Raman & Photoelectron spectroscopy)

31. Mentor P03005331 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. Mentor P03005333 Five Testing Categories Pharmacokinetics Biocompatibility Immunotoxicology Reproductive and Teratogenicity Testing Genotoxicity and Carcinogenesis

34. Mentor P03005334 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. Mentor P03005335 Biocompatibility Testing Cytotoxicity Irritation and Short-Term Implantation Acute Systemic Toxicity Hemolysis Pyrogenicity

36. Mentor P03005336 Immunotoxicity Testing Sensitization Testing Other Immunotoxicity Testing Endpoints  Body, Spleen, and Thymus Weights  Hematology  Splenic T-Cells (CD 4+ and CD 8+ )  T-Cells Response to Mitogens  Mixed Lymphocyte Response  IgM Antigen Forming Cells

37. Mentor P03005337 Reproductive & Teratogenicity Testing A 1-Generation Study 100 F 0 Females – 4 groups of 25 each No Reproductive Effects in F 0 No Reproductive or Teratogenic Effects in F 1

38. Mentor P03005338 Genotoxicity & Carcinogenesis Testing Salmonella Reverse Mutation Assay Unscheduled DNA Synthesis Chromosomal Aberration Assay In Vivo Mouse Micronucleus Test Carcinogenicity Testing

39. Mentor P03005339 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. Mentor P03005341 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.

42. Mentor P03005342 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. Mentor P03005343 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. Mentor P03005344 Core Study Results

45. Mentor P03005345 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. Mentor P03005346 Core Augmentation Cohort

47. Mentor P03005347 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. Mentor P03005348 By-Patient 3-Year Cumulative KM Complication Rates - Core Aug ComplicationRate (95% CI) Reoperation15.0% (11.9%, 18.0%) Nipple Sensation Change10.8% (8.1%, 13.4%) C/C III/IV8.2% (5.9%, 10.6%) Hypertrophic Scarring6.3% (4.2%, 8.3%) Implant Removal w/ w/o replacement 5.1% (3.2%, 7.1%) Breast Mass2.4% (1.0%, 3.7%) Rupture0.5% (0.0%, 1.5%)

49. Mentor P03005349 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. Mentor P03005350 Primary Procedure for Given Reoperation ReoperationSurgical Procedure# (% of 98) Capsular contractureCapsule procedures30 (30.6%) Removal/replacement5 (5.1%) Healing relatedIncision and drainage12 (12.2%) InfectionRemoval/replacement2 (2.0%) Revision wound closure1 (1.0%) Patient requestRemoval/replacement16 (16.3%) Unsatisfactory cosmetic result Capsule procedures5 (5.1%) Removal/replacement1 (1.0%) Implant reposition1 (1.0%) Mastopexy1 (1.0%) Scar revision10 (10.2%)

51. Mentor P03005351 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. Mentor P03005352 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. Mentor P03005353 CTD Signs/Symptoms - Core Augmentation (n=494) Sign/Symptom (most commonly reported) Number with sign/symptom reported Cumulative incidence Any sign/symptom5310.3% Numbness of hands132.7% Joint pain132.7%

54. Mentor P03005354 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. Mentor P03005355 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. Mentor P03005356 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. Mentor P03005357 Core Reconstruction Cohort

58. Mentor P03005358 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. Mentor P03005359 By-Patient 3-Year Cumulative KM Complication Rates - Core Recon ComplicationRate (95% CI) Reoperation26.3% (21.7%, 31.9%) Removal/Replacement13.3% (8.8%, 17.8%) CC III/IV8.8% (4.9%, 12.7%) Ptosis6.9% (2.0%, 11.8%) Infection5.3% (2.5%, 8.1%) Breast Pain1.7% (0.0%, 0.4%) Tissue/Skin Necrosis1.2% (0.0%, 2.0%) Rupture0.8% (0.0%, 2.2%)

60. Mentor P03005360 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. Mentor P03005361 Primary Procedure for Given Reoperation ReoperationSurgical Procedure# (% of 78) Capsular contractureCapsule procedures4 (5.1%) Removal/replacement4 (5.1%) Healing relatedRemoval/replacement1 (1.3%) Incision and drainage2 (2.6%) InfectionRemoval/replacement2 (2.6%) Incision and drainage2 (2.6%) Patient requestRemoval/replacement7 (9.0%) Unsatisfactory cosmetic result Capsule procedures5 (6.4%) Removal/replacement13 (16.7%) Implant reposition6 (7.7%) Mastopexy3 (3.8%) Pocket revision1 (1.3%) Scar revision3 (3.8%)

62. Mentor P03005362 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. Mentor P03005363 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. Mentor P03005364 CTD Signs/Symptoms - Core Reconstruction (n= 221) Sign/Symptom (most commonly reported) Number with signs/symptoms reported Cumulative Incidence Any sign/symptom4421.5% Joint pain178.0% Joint swelling104.5%

65. Mentor P03005365 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. Mentor P03005366 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. Mentor P03005367 Core Revision Cohort

68. Mentor P03005368 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. Mentor P03005369 By-Patient 3-Year Cumulative KM Complication Rates - Core Revision ComplicationRate (95% CI) Reoperation26.3% (20.0%, 32.6%) CC III/IV17.2% (11.9%, 22.4%) Removal/Replacement13.3% (8.4%, 18.2%) Nipple sensation changes8.6% (4.7%, 12.6%) Scarring6.0% (2.7%, 9.3%) Breast mass5.8% (25%, 9.1%) Rupture4.8% (0.2%, 9.3%) Breast Pain2.0% (0.1%, 4.0%)

70. Mentor P03005370 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. Mentor P03005371 Primary Procedure for Given Reoperation ReoperationSurgical Procedure# (% of 71) Capsular contracture Capsule procedures13 (18.3%) Removal/replacement6 (8.5%) Healing relatedIncision and drainage7 (9.9%) Revision of wound closure1 (1.4%) Scar revision1 (1.4%) Surgical exploration1 (1.4%) InfectionRemoval/replacement1 (1.4%) Patient requestRemoval/replacement7 (9.9%) Unsatisfactory cosmetic result Capsule procedures2 (2.8%) Removal/replacement5 (7.0%) Implant reposition3 (4.2%) Scar revision2 (2.8%)

72. Mentor P03005372 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. Mentor P03005373 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. Mentor P03005374 CTD Signs/Symptoms - Core Revision (n= 226) Sign/SymptomNumber with sign/symptoms reported Cumulative incidence Any sign/symptom 3921.3% Joint pain147.3% Fatigue116.0%

75. Mentor P03005375 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. Mentor P03005376 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. Mentor P03005377 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. Mentor P03005378 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. Mentor P03005379 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. Mentor P03005380 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. Mentor P03005381 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. Mentor P03005382 Thank you

83. Rupture Overview- Mentor Silicone Breast Implants Sahar M. Dawisha, M.D., Medical Officer

84. Mentor P03005384 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. Mentor P03005385 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. Mentor P03005386 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 2 nd MRI. Non-MRI Cohort = no MRI.  Under-ascertainment of silent rupture.

87. Mentor P03005387 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. Mentor P03005388 Core Study KM Rupture Rate through 3 years in MRI Cohort: All Silent By-PatientBy-Implant Aug0.5% (0.0, 1.5) 0.2% (0.0, 0.7) Recon0.8% (0.0, 2.2) 0.5% (0.0, 1.4) Revision4.8% (0.3, 2.6) 3.9% (0.8, 1.7)

89. Mentor P03005389 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. Mentor P03005390 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).

91. Mentor P03005391 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. Mentor P03005392 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. Mentor P03005393 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. Mentor P03005394 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. Mentor P03005395 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. Mentor P03005396 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. Mentor P03005397 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.  1 st MRI 16 months later: no rupture.  2 nd MRI 1 year later: bilateral keyhole signs.  3 rd 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. Mentor P03005398 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. Mentor P03005399 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. Mentor P030053100 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. Mentor P030053101 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. Mentor P030053104 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. Mentor P030053105 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. Mentor P030053106 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.

107. Mentor P030053107 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.

108. Mentor P030053108 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

109. Mentor P030053109 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.

110. Mentor P030053110 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. Mentor P030053111 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 FDA’s Presentation

113. Panel Questions

114. Mentor P030053114 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. Mentor P030053115 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. Mentor P030053116 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.

117. Mentor P030053117 Panel Question 4 Please comment on the adequacy of Mentor’s postapproval plans to address any postapproval concerns that you may have.

118. Mentor P030053118 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. Mentor P030053119 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.