1 / 118

Mentor Corporation s Silicone Gel-Filled Breast Implants P030053

Mentor P030053. 2. FDA Presenters. CDR Samie Allen, USPHS Sam Arepalli, Ph.D.David Berkowitz, Ph.D., V.M.D.Herbert P. Lerner, M.D.Sahar Dawisha, M.D.Phyllis Silverman, M.S.. Device Description

remy
Download Presentation

Mentor Corporation s Silicone Gel-Filled Breast Implants P030053

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

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

    2. Mentor P030053 2 FDA Presenters CDR Samie Allen, USPHS Sam Arepalli, Ph.D. David Berkowitz, Ph.D., V.M.D. Herbert P. Lerner, M.D. Sahar Dawisha, M.D. Phyllis Silverman, M.S.

    3. Device Description & Preclinical Testing Overview Samie Allen

    4. Mentor P030053 4 Device Description High, moderate, & moderate plus profiles Smooth & textured surfaces Round Single lumen Components: shell, patch, filler, & silicone adhesive

    5. Mentor P030053 5 Preclinical Testing Modes and causes of rupture Fatigue testing Gel bleed Gel cohesion Shelf life

    6. Mentor P030053 6 Modes & Causes of Rupture Retrieval studies of explanted devices Physical property / crosslink density testing Assessment of manufacturing processes Assessment of surgical techniques Review of literature

    7. Mentor P030053 7 Modes & Causes of Rupture (cont.) PE Database Analysis: Includes failed, retrieved devices in 3 categories Iatrogenic User Related – surgical damage Rent Unknown Cause (RUC) Not Apparent Etiology Unknown (NAEU) Focused on RUC and NAEU categories 203 available for analysis

    8. Mentor P030053 8 Modes & Causes of Rupture (cont.)

    9. Mentor P030053 9 Modes & Causes of Rupture (cont.)

    10. Mentor P030053 10 Modes & Causes of Rupture (cont.)

    11. Mentor P030053 11 Modes & Causes of Rupture (cont.)

    12. Mentor P030053 12 Modes & Causes of Rupture (cont.)

    13. Mentor P030053 13 Mentor’s Proposed Next Steps: In-vitro study to determine optimum incision size Develop inserter instrument Assess alternate texturing process Investigate patch design changes Labeling and physician training Modes & Causes of Rupture (cont.)

    14. Mentor P030053 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. Mentor P030053 15 Gel Bleed Testing ASTM F703 testing Gel loss analysis Gel bleed study

    16. Mentor P030053 16 Gel Bleed Testing (cont.) ASTM F703 Testing: Smooth Moderate Profile implants (350cc) Incubated for 15 (not 8) weeks at 110°F Ave weight gain rate – 0.0011 g/cm2/week ASTM F703 test method does not mimic in-vivo conditions

    17. Mentor P030053 17 Gel Bleed Testing (cont.) Gel Loss Analysis: 74 devices randomly selected and re-weighed to obtain post-explantation weight Calculated % implant weight 40 smooth; 0.2-15.2 in-vivo years; 101% (97-107) 34 Siltex; 0.1-9.4 in-vivo years; 101% (99-104) Does not identify and quantify the rate of bleed for all gel bleed constituents

    18. Mentor P030053 18 Gel Bleed Testing (cont.) Gel Bleed Study: 125cc implants incubated in 225ml porcine serum at 37°C Detected D4, D5, and D6. Cumulative bleed rate was 0.95 ng/cm2/day by day 30 Issues with testing: Applicability of 120 days to in-vivo conditions Implant size vs. volume of porcine serum medium Decrease in release amount for D5 and D6 after day 30 GC analysis correction due to volatility No rate of diffusion for each gel bleed constituent

    19. Mentor P030053 19 Gel Cohesion Testing Gel cohesion testing of final gel ASTM F703 (<4.5cm & no gel separation) Results: passed Penetrometer testing of in-process gel No standard (internal specification) Results: passed; 63.4 (range of 61-64)

    20. Mentor P030053 20 Shelf Life Device and package testing 5-year shelf life date on package label

    21. Mentor P030053 21 Summary – Preclinical Testing Modes and Causes of Rupture: Characterize through ?10 years Not predictive of lifetime rupture rate Proposed labeling and training to address failures related to surgical procedure Proposed several design/manufacturing changes Proposed to develop introducer instrument Fatigue Testing: Adequacy of testing and estimate lifetime cannot be validated

    22. Mentor P030053 22 Summary – Preclinical Testing (cont). Gel Bleed: Outstanding issues that should be able to be addressed by sponsor Gel Cohesion: Adequate to address issue Shelf Life: Adequate to support 5-year shelf life on label

    23. Chemistry Overview Sam Arepalli, Ph.D.

    24. Mentor P030053 24 Device Materials Shell, middle (barrier) layer: Diphenyldimethyl-siloxane copolymer, 15 mole% diphenyl Shell, inner/outer (base) layers: Dimethylsiloxane polymer Patch Assembly: Dimethylsiloxane Pt (platinum) cure polymer Silicone Gel: Two-part platinum cure gel Silicone adhesive: RTV silicone Sn (tin) cure

    25. Mentor P030053 25 Degree of Crosslinking Shell: 7.90 chains/cm3 (Sol Fraction Method) Gel: 8.81 chains/cm3 3.0-10.0 mm (Penetrometer)

    26. Mentor P030053 26 Volatiles Shell: total volatiles (11.1 ppm) IPA (1 ppm) Xylenes (0.1 ppm) Methoxymethylsilane (3 ppm) Dodecane (3 ppm) Undecane (1.3 ppm) Gel: total volatiles (2.8 ppm) D3 (0.18 ppm) D4 (0.5 ppm) D5 (1.6 ppm) Undecane (0.3 ppm)

    27. Mentor P030053 27 Extractables Gravimetric analysis Gel permeable chromatography FTIR analysis Qualitative and quantitative analysis (GC-MS Analysis)

    28. Mentor P030053 28 GC-MS Analysis Shell and gel LMW oligosiloxanes (up to D10) present at<10ppm High MW cyclic (>D11) oligosiloxanes concentrations comparable to those of saline-filled breast implants.

    29. Mentor P030053 29 Metal Analysis Extracted residue: Shell: Sn (ND); Pt (0.133 ppm) Gel: Sn (ND); Pt (0.323 ppm) Unextracted: Shell: Sn (0.03 ppm); Pt (8.8 ppm) Gel: Sn (0.01 ppm); Pt (4.8 ppm)

    30. Mentor P030053 30 Silica Analysis Amorphous silica (X-ray diffraction) No free silica present (Raman & Photoelectron spectroscopy)

    31. Mentor P030053 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. Mentor P030053 33 Five Testing Categories Pharmacokinetics Biocompatibility Immunotoxicology Reproductive and Teratogenicity Testing Genotoxicity and Carcinogenesis

    34. Mentor P030053 34 Pharmacokinetics Elastomer: Orthopedic implants in dogs and humans could be recovered after years. Gel: Long-term gel implants in rats remained at subcutaneous implantation sites for at least 450 days. 99.97% of 14-C-labeled gel remained in place in mice for at least 56 days. LMW Gel Components: Subcutaneous implants of low molecular weight cyclic siloxanes (D3-D7) were distributed to tissues over a year.

    35. Mentor P030053 35 Biocompatibility Testing Cytotoxicity Irritation and Short-Term Implantation Acute Systemic Toxicity Hemolysis Pyrogenicity

    36. Mentor P030053 36 Immunotoxicity Testing Sensitization Testing Other Immunotoxicity Testing Endpoints Body, Spleen, and Thymus Weights Hematology Splenic T-Cells (CD4+ and CD8+) T-Cells Response to Mitogens Mixed Lymphocyte Response IgM Antigen Forming Cells

    37. Mentor P030053 37 Reproductive & Teratogenicity Testing A 1-Generation Study 100 F0 Females – 4 groups of 25 each No Reproductive Effects in F0 No Reproductive or Teratogenic Effects in F1

    38. Mentor P030053 38 Genotoxicity & Carcinogenesis Testing Salmonella Reverse Mutation Assay Unscheduled DNA Synthesis Chromosomal Aberration Assay In Vivo Mouse Micronucleus Test Carcinogenicity Testing

    39. Mentor P030053 39 Toxicology Summary Mentor has provided the toxicology information recommended in the breast implant guidance document. No safety issues were raised by data.

    40. Clinical Data Overview Herbert P. Lerner, M.D. Medical Officer

    41. Mentor P030053 41 Summary of Studies Core Study—Started 2000. Adjunct Study—Started 1992. All open label, prospective, multicenter. Yearly F/U in Core Study. Both collected local complications.

    42. Mentor P030053 42 Core Study Majority of Safety and Effectiveness data. Augmentation, Reconstruction, Revision. Yearly F/U to 10 years after implantation. Study includes prospective MRI screening for silent rupture in 420 of 1007 patients. QOL and CTD signs/symptoms collected.

    43. Mentor P030053 43 Adjunct Study Intended to make the implants available for reconstruction and revision patients. Collected local complications at 1, 3, and 5 years after implantation surgery. No MRI Screening. Unlimited sample size. Enrollment is ongoing.

    44. Mentor P030053 44 Core Study Results

    45. Mentor P030053 45 Core Study Demographics: Age

    46. Mentor P030053 46 Core Augmentation Cohort

    47. Mentor P030053 47 Patient Disposition - Core Aug 551 patients (1110 devices) enrolled. 439 (80%) theoretically due at 3 years. 94% patient follow-up rate at 3 years. 0 deaths 22 patients with implant removals/replacements 9 lost to follow-up

    48. Mentor P030053 48 By-Patient 3-Year Cumulative KM Complication Rates - Core Aug

    49. Mentor P030053 49 Reoperations - Core Augmentation 160 additional surgical procedures in 98 reoperations in 79 patients. Primary reasons for reoperation: Capsular Contracture - 44% Patient Request – 32% Types of additional surgical procedures Capsule procedures - 36% Implant removal/replacement – 28%

    50. Mentor P030053 50 Primary Procedure for Given Reoperation

    51. Mentor P030053 51 Reason for Implant Removal through 3 Years - Core Augmentation 45 explants in 26 (6.4%) patients Reasons for removal Patient choice – 68.9% Capsular contracture – 11.1% Infection – 4.4% Breast pain – 4.4% Necrosis – 4.4%

    52. Mentor P030053 52 Other Safety Information - Core Augmentation No increase in reports of reproductive or lactation problems. 4 post-implant breast mass reports: 0 malignant. 6 post-implant abnormal mammogram reports: all benign. 3 Patients with New Diagnosis of CTD.

    53. Mentor P030053 53 CTD Signs/Symptoms - Core Augmentation (n=494)

    54. Mentor P030053 54 Effectiveness - Core Study QoL Tennessee Self-Concept Scale SF-36 Body Esteem Scale Rosenberg Self-Esteem Scale Functional Living Index: Cancer Patient satisfaction Chest/breast measurements

    55. Mentor P030053 55 Effectiveness - Core Augmentation TSCS – no statistically significant change in overall mean score SF-36 – statistically significant worsening in PCS and MCS BES – no statistically significant change in overall mean score Rosenberg – statistically significant improvement in overall mean score

    56. Mentor P030053 56 Effectiveness - Core Augmentation Global satisfaction assessed by patients who did not have study implant(s) removed by answering the following question – “Would you have the surgery over again?” 99% of 495 patients reported being satisfied at 2 years. 97% of 394 patients reported being satisfied at 3 years.

    57. Mentor P030053 57 Core Reconstruction Cohort

    58. Mentor P030053 58 Patient Disposition - Core Recon 252 patients (410 devices) enrolled. 144 (57%) theoretically due at 3 years. 95% patient follow-up rate at 3 years. 9 deaths 26 patients with implant removals/replacements 1 lost to follow-up

    59. Mentor P030053 59 By-Patient 3-Year Cumulative KM Complication Rates - Core Recon

    60. Mentor P030053 60 Reoperations - Core Reconstruction 139 additional surgical procedures in 78 reoperations in 64 patients Primary reasons for reoperation Asymmetry - 26% Patient request - 17% Implant malposition/displacement - 14% Capsular contracture III/IV - 13% Types of additional surgical procedures Implant removal/replacement - 29% Capsule procedures - 19%

    61. Mentor P030053 61 Primary Procedure for Given Reoperation

    62. Mentor P030053 62 Primary Reason for Implant Removal through 3 Years - Core Reconstruction 40 explants in 31 (25.6%) patients Reasons for removal Patient request – 32.5% Asymmetry – 25.0% Capsular contracture III/IV – 10.0% Implant malposition/displacement – 7.5%

    63. Mentor P030053 63 Other Safety Information - Core Reconstruction No increase in reports of reproductive or lactation problems. 0 New reports of breast malignancy: recurrence or metastasis. 1 New report of CTD: Fibromyalgia.

    64. Mentor P030053 64 CTD Signs/Symptoms - Core Reconstruction (n= 221)

    65. Mentor P030053 65 Effectiveness - Core Reconstruction TSCS – no statistically significant change in overall mean score SF-36 – no statistically significant change in PCS and MCS BES – no statistically significant change in overall mean score Rosenberg – no statistically significant change in overall mean score FLIC – statistically significant improvement for delayed post-mastectomy recon patients

    66. Mentor P030053 66 Effectiveness - Core Reconstruction Global satisfaction assessed by patients who did not have study implant(s) removed by answering the following question – “Would you have the surgery over again?” 97% of 184 patients reported being satisfied at 2 years. 98% of 121 patients reported being satisfied at 3 years.

    67. Mentor P030053 67 Core Revision Cohort

    68. Mentor P030053 68 Patient Disposition through 3 years - Core Revision 204 patients (386 devices) enrolled. 158 (77%) theoretically due at 3 years. 93% patient follow-up rate at 3 years. 0 deaths 22 patients with implant removals/replacements 3 lost to follow-up

    69. Mentor P030053 69 By-Patient 3-Year Cumulative KM Complication Rates - Core Revision

    70. Mentor P030053 70 Reoperation - Core Revision 141 additional surgical procedures in 71 reoperations in 51 patients Primary reasons for reoperation: Capsular contracture III/IV – 39% Patient request – 20% Types of additional surgical procedures: Capsular procedures – 29% Implant removal/replacement – 28%

    71. Mentor P030053 71 Primary Procedure for Given Reoperation

    72. Mentor P030053 72 Primary Reason for Implant Removal through 3 Years - Core Revision 39 explants in 25 (17.9%) patients Reasons for removal Patient choice – 35.9% Capsular contracture III/IV – 28.2% Asymmetry – 7.7%

    73. Mentor P030053 73 Other Safety Information - Core Revision No increase in reports of reproductive or lactation problems. 1 new case of breast cancer reported 2 New report of CTD: Fibromyalgia and Pyoderma gangrenosa w/ IBD.

    74. Mentor P030053 74 CTD Signs/Symptoms - Core Revision (n= 226)

    75. Mentor P030053 75 Effectiveness - Core Revision TSCS – statistically significant worsening in overall mean score SF-36 – statistically significant worsening in PCS and MCS BES – statistically significant worsening in overall mean score Rosenberg – no statistically significant change in overall mean score FLIC – statistically significant improvement for revision patients with reconstruction and history of cancer

    76. Mentor P030053 76 Effectiveness - Core Revision Global satisfaction assessed by patients who did not have study implant(s) removed by answering the following question – “Would you have the surgery over again?” 95% of 169 patients reported being satisfied at 2 years. 96% of 137 patients reported being satisfied at 3 years.

    77. Mentor P030053 77 Summary - Core Augmentation Most frequent complications through 3 years: Reoperation Nipple sensation changes Capsular contracture III/IV Hypertrophic scarring Most frequent reason for reoperation and medical reason for implant removal through 3 years was CC III/IV. Of patients who did not have study implant(s) removed and who answered global satisfaction question, 97% were satisfied at 3 years.

    78. Mentor P030053 78 Summary - Core Reconstruction Most frequent complications through 3 years: Reoperation Implant removal with or without replacement Capsular contracture III/IV Ptosis Most frequent medical reason for reoperation and implant removal through 3 years was asymmetry. Of patients who did not have study implant(s) removed and who answered global satisfaction question, 98% were satisfied at 3 years.

    79. Mentor P030053 79 Summary - Core Revision Most frequent complications through 3 years: Reoperation Capsular contracture III/IV Implant removal with or without replacement Nipple sensation changes Most frequent medical reason for reoperation and implant removal through 3 years was CC III/IV. Of patients who did not have study implant(s) removed and who answered global satisfaction question, 96% were satisfied at 3 years.

    80. Mentor P030053 80 QOL - Literature Review Difficult to assess benefits of implants for augmentation in a literature review. Studies had numerous weaknesses, including: Short duration of follow-up Lack of controls Selective exclusion criteria Variable assessment tools “Anecdotal” reports Use of unvalidated instruments. Diagnosis of cancer makes QOL assessments difficult in reconstruction patients.

    81. Mentor P030053 81 Adjunct Study Through 11/02, 44,951 patients (87,106 devices) have been enrolled. For the reconstruction and revision cohorts respectively, follow-up rates have been: Year 1: 34%, 35% Year 3: 19%, 18% Year 5: 11%, 10% No MRI cohort

    82. Mentor P030053 82 Thank you

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

    84. Mentor P030053 84 Silicone Gel BI Rupture Silent rupture = asymptomatic to the patient and physician. MRI to detect silent rupture. Symptomatic rupture = a/w symptoms (i.e. implant flattening, lumps, silicone extrusion). Intracapsular rupture = within fibrous capsule. Extracapsular rupture = outside the fibrous capsule.

    85. Mentor P030053 85 Implant Rupture Questions: What is the implant rupture rate over the expected device lifetime? How often and when do intracapsular vs. extracapsular rupture occur? What is the rate at which intracapsular rupture becomes extracapsular? What are the local health consequences of implant rupture?

    86. Mentor P030053 86 Core Study: Silent Rupture MRI Cohort = screening for silent rupture at years 1, 2, 4, 6, 8, and 10 via MRI. 80% follow-up compliance at 1st MRI. 90% follow-up compliance at 2nd MRI. Mean implantation duration = 2 years at 2nd MRI. Non-MRI Cohort = no MRI. Under-ascertainment of silent rupture.

    87. Mentor P030053 87 Core Study: Rupture No symptomatic ruptures reported. No silent ruptures in Non-MRI Cohort. All ruptures are silent. All ruptures are in MRI Cohort. Follow-up at 3 years is partial. ~ 26% of patients not yet due for 3 year visit. MRI scheduled at years 1 and 2.

    88. Mentor P030053 88 Core Study KM Rupture Rate through 3 years in MRI Cohort: All Silent

    89. Mentor P030053 89 Core Study: Rupture Details 8 implants (in 6 patients) suspected ruptured through 3 years, all in MRI Cohort. Of these, 2 implants (in 1 rev-aug patient) confirmed ruptured via explant: 1 intracapsular and 1 extracapsular. Intracapsular rupture: 4 implants via MRI. Extracapsular gel: 4 implants via MRI. 1 implant with intra ? extracapsular rupture. 3 of 6 patients had both year 1 and 2 MRI.

    90. Mentor P030053 90 Drs. Sharpe and Collis: MRI Case Series Augmentation patients from Dr. Sharpe’s practice. ~ 200 women eligible; ~100 women had 1 MRI. Protocol excludes women with implant removal, Capsular Contracture Grade III/IV, surgical interventions, or clinical evidence of rupture. All textured Mentor implants, all subglandular. 1 MRI examination » » » point prevalence of rupture rather than rupture rate over time. 11 of 204 implants had intracapsular rupture via explant. By-implant point prevalence of silent rupture = 5% (median implant duration 8.8 years; range 4-12 years).

    91. Mentor P030053 91 Rupture Rate: Danish Literature Scandinavian MRI studies of silent rupture Several manufacturers; Augmentation only. Excludes implants removed in first 3 years. Median implant duration: 12 yrs (3-25 years). Rupture prevalence = 32% of implants. ~25% of ruptures extracapsular. Rupture incidence = 8.9 per 100 implants/yr. 56 ruptures: 48 via MRI; 8 at reoperation.

    92. Mentor P030053 92 Rupture Rate: Other Literature FDA MRI rupture study Several manufacturers; Augmentation only. Excludes implants removed in first 6 years. Median implant duration: 16 yrs (6-28 years). Prevalence = 55% of implants; 12% extracap. Gaubitz MRI study Several Manufacturers; ľ recon; Ľ aug. Mean implant duration 9 yrs (1- 26 years). Prevalence = 24% of women; 12% extracap.

    93. Mentor P030053 93 Rupture Health Consequences: Mentor Implants Complications and satisfaction from Core Study: 1 patient with confirmed rupture: no complications reported; patient satisfied at re-implantation. Number of patients with rupture too small to compare with non-ruptured. Rheum eval from Sharpe/Collis case series: 1 patient with myalgic encephalitis and rupture. No comparison group.

    94. Mentor P030053 94 Rupture Health Consequences: Literature Case reports of local and distant silicone granulomas. Silicone in liver via MRS; higher with rupture. No statistically significant differences for autoantibodies and self-reported diseases and symptoms 1 year before rupture in Danish women. Extracapsular rupture: 6x ? breast hardness. Implant rupture: 2x ? pain or change in shape. Intracap ? extracap: 9% of implants over 2 years. Extracap progression: 14% of implants over 2 years.

    95. Mentor P030053 95 Rupture Summary: Mentor Data 2-3 years of comprehensive rupture data. All ruptures silent, diagnosed via MRI. Half of ruptures are intracapsular via MRI. 1 implant: intra ? extracapsular progression. Data limited to address lifetime rupture rate. Data limited to address intra ? extracapsular rupture and silent ? symptomatic rupture. Data limited to rupture address health consequences.

    96. Mentor P030053 96 Rupture Summary: Literature Serial silent rupture data over 2 years. Most ruptures are silent, diagnosed via MRI. Most ruptures are intracapsular: 25% extracapsular via MRI. 9% intra ? extracapsular rupture; half a/w trauma. 14% extracap ? progressive silicone seepage. Breast pain and hardness a/w rupture. Evidence of silicone outside the breast area. Rupture incidence = 9 ruptures/100 implants/year » » » 22,500 augmentation implant ruptures per year in U.S. (2004 rate)

    97. Mentor P030053 97 Silent Extracapsular Rupture: Patient History 31 Year Old Bilateral Augmentation 6 years later entered Core Study as revision patient: severe CC and rupture on R. 1st MRI 16 months later: no rupture. 2nd MRI 1 year later: bilateral keyhole signs. 3rd MRI 10 months later: bilateral intracapsular rupture with extracapsular silicone on R. Ruptured implants removed and replaced. Large tear in one implant; large hole in other. No complications reported.

    98. Mentor P030053 98 Rupture Issues to Consider Whether the data are adequate to characterize rupture rate over time and health consequences of rupture. Whether the existing rupture data provide reasonable assurance of safety. What to recommend for silent rupture screening method and frequency.

    99. Mentor P030053 99 Labeling Issues Method and frequency of silent rupture screening. Annual or biannual examination; method not specified. MRI considered if clinical suspicion of rupture. Silent rupture not addressed. Clinical management of rupture. Removal of ruptured implant recommended; no mention of whether to remove silent ruptured implant. Health consequences of extracapsular gel. Monitor for lumps or change in breast shape; addresses symptomatic rather than silent rupture.

    100. Mentor P030053 100 Post-approval Issues Continue Core Study. MRI discontinuation issues Use existing ASPS/PSEF National Breast Implant Registry. Voluntary Collects short-term complications and reoperation No planned follow-up visits No specific rupture information collected Physician education/training program. Certification required for product access Rupture screening method and frequency not included

    101. Mentor P030053 101 Safety and Effectiveness Information Consider all complications and benefits. Consider augmentation and reconstruction separately. Consider revision as a continuum of augmentation or reconstruction.

    102. Thank You

    103. Statistical Overview Phyllis Silverman, M.S. Mathematical Statistician Division of Biostatistics

    104. Mentor P030053 104 Descriptive Nature of Studies There were no claims, targets, or formal control groups in this study. Statistical techniques: means, confidence intervals, rate estimation from survival analyses Sample size: Reflected in the width (i.e. precision) of the confidence interval. Acceptability of rates and adequacy of precision must be assessed by weighing the risks and benefits of implants.

    105. Mentor P030053 105 Employed Statistical Techniques Means/proportions with confidence intervals Safety and effectiveness data Kaplan - Meier Analyses Adverse Events including Rupture Cox Regression Covariate analysis Generalize Estimating equations CTD Analyses Prevalence and Incidence Rupture rate estimation

    106. Mentor P030053 106

    107. Mentor P030053 107 Generalized Estimating Equations A longitudinal analysis which can adjust for a covariate Sponsor analyzed Signs/Symptoms of CTD’s adjusted for age of patient Several significant results in Aug and Rev cohorts (e.g. fatigue, exhaustion, joint pain) Increases in certain S/S are beyond what would be due to aging alone Some associations could be spurious due to sheer number of comparisons; best to look for consistencies across cohorts.

    108. Mentor P030053 108

    109. Mentor P030053 109 Prevalence and Incidence (cont’d) Incidence: percentage of patients seen at a given follow-up visit who are experiencing the adverse event not experienced at earlier visits (i.e., the new cases) Disadvantages: Subject to biases from patients who did not return for follow-up; may not be consistent from one time interval to the next.

    110. Mentor P030053 110 Sharpe and Collis Data FDA clinical reviewer has pointed out differences in indication, surface type, and device placement. Sponsor calculated point prevalence based on single MRI exam. Sponsor used statistical techniques to estimate cumulative incidence from cross-sectional data. Estimated rates may not apply to general Mentor breast implant population.

    111. Mentor P030053 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 FDA’s Presentation

    113. Panel Questions

    114. Mentor P030053 114 Panel Question 1 Considering the rupture information in their submission, and given that majority of ruptures for silicone gel-filled breast implants are silent, please discuss whether Mentor has adequately characterized the rupture rate and how this rate changes over the expected lifetime of their device.

    115. Mentor P030053 115 Panel Question 2 Please discuss whether Mentor has adequately characterized the consequences of rupture for their device with regard to: freq of observed intracapsular gel, extracapsular gel, & migrated gel; destination of migrated gel the local health consequences silent ruptures ? symptomatic ruptures intracapsular ? extracapsular ruptures.

    116. Mentor P030053 116 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 P030053 117 Panel Question 4 Please comment on the adequacy of Mentor’s postapproval plans to address any postapproval concerns that you may have.

    118. Mentor P030053 118 Panel Question 5 Please discuss whether you believe that there is reasonable assurance that this device is safe over its expected lifetime for the proposed indications of breast augmentation, reconstruction, and revision.

    119. Mentor P030053 119 Panel Question 6 Please discuss whether you believe that there is a reasonable assurance that their device is effective for the proposed indications of breast augmentation, reconstruction, and revision.

More Related