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Mentor Corporation’s Silicone Gel-Filled Breast Implants (P030053)

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

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Mentor Corporation’s Silicone Gel-Filled Breast Implants (P030053)

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

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

  3. Device Description & Preclinical Testing Overview Samie Allen

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

  23. Chemistry Overview Sam Arepalli, Ph.D.

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

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

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

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

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

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

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

  31. Summary - Chemistry • Shell and gel tested separately • Degree of crosslinking • Volatiles • Metals • Extractables • Gravimetric analysis • GPC • FTIR • GC-MS Mentor P030053

  32. Toxicology Overview David B. Berkowitz, Ph.D., V.M.D.

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

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

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

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

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

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

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

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

  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. Mentor P030053

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

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

  44. Core Study Results Mentor P030053

  45. Core Study Demographics: Age Mentor P030053

  46. Core Augmentation Cohort Mentor P030053

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

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

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

  50. Primary Procedure for Given Reoperation Mentor P030053

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