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

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

Mentor P Preclinical Testing Modes and causes of rupture Fatigue testing Gel bleed Gel cohesion Shelf life

Mentor P 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 P 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 P 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

Mentor P 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

Mentor P Modes & Causes of Rupture (cont.)

Mentor P Modes & Causes of Rupture (cont.)

Mentor P Modes & Causes of Rupture (cont.)

Mentor P 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 P Fatigue Testing lbs endurance load limit Analyzed raw data  Estimated median life of 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 P Gel Bleed Testing ASTM F703 testing Gel loss analysis Gel bleed study

Mentor P 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 – g/cm 2 /week ASTM F703 test method does not mimic in-vivo conditions

Mentor P Gel Bleed Testing (cont.) Gel Loss Analysis: 74 devices randomly selected and re-weighed to obtain post-explantation weight Calculated % implant weight  40 smooth; in-vivo years; 101% (97-107)  34 Siltex; in-vivo years; 101% (99-104) Does not identify and quantify the rate of bleed for all gel bleed constituents

Mentor P 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

Mentor P 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 P Shelf Life Device and package testing 5-year shelf life date on package label

Mentor P 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 P 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 P 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 P Degree of Crosslinking Shell: 7.90 chains/cm 3 (Sol Fraction Method) Gel:  8.81 chains/cm 3  mm (Penetrometer)

Mentor P 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 P Extractables Gravimetric analysis Gel permeable chromatography FTIR analysis Qualitative and quantitative analysis (GC-MS Analysis)

Mentor P 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.

Mentor P 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 P Silica Analysis Amorphous silica (X-ray diffraction) No free silica present (Raman & Photoelectron spectroscopy)

Mentor P 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 P Five Testing Categories Pharmacokinetics Biocompatibility Immunotoxicology Reproductive and Teratogenicity Testing Genotoxicity and Carcinogenesis

Mentor P 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 % 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 P Biocompatibility Testing Cytotoxicity Irritation and Short-Term Implantation Acute Systemic Toxicity Hemolysis Pyrogenicity

Mentor P 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

Mentor P 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

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

Mentor P 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 P Summary of Studies 1. Core Study—Started Adjunct Study—Started All open label, prospective, multicenter. Yearly F/U in Core Study. Both collected local complications.

Mentor P 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 P 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 P Core Study Results

Mentor P 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 P Core Augmentation Cohort

Mentor P 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 P 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%)

Mentor P 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 P 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%)

Mentor P 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 P 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 P 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%

Mentor P 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 P 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 P 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 P Core Reconstruction Cohort

Mentor P 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 P 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%)

Mentor P 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 P 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%)

Mentor P 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 P 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 P 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%

Mentor P 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 P 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 P Core Revision Cohort

Mentor P 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 P 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%)

Mentor P 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 P 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%)

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

Mentor P 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 P 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 P 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 P 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 P 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 P 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 P 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 P Thank you

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

Mentor P 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 P 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 P 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.

Mentor P 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 P 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)

Mentor P 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 P 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 P 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: Hölmich, et al., Arch Surg. 2003; 138:

Mentor P 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): Gaubitz, et al. Rheumatol. 2002; 41:

Mentor P 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 P 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: Hölmich, et al., Plast Recon Surg. 2004; 114:

Mentor P 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 P 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 P 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.

Mentor P 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 P 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 P 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 P 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 Statistician Division of Biostatistics

Mentor P 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 P 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 P 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 P 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 P 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 P 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 P 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 P 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.

Conclusion of FDA’s Presentation

Panel Questions

Mentor P 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 P 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 P 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.

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

Mentor P 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 P 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.