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Inamed Corporation’s McGhan Silicone-Filled Breast Implants

Inamed Corporation’s McGhan Silicone-Filled Breast Implants. October 14-15, 2003. FDA Presenters. CDR Samie Allen, USPHS Sam Arepalli, Ph.D. David Berkowitz, Ph.D., V.M.D. Sahar Dawisha, M.D. Telba Irony, Ph.D. S. Lori Brown, Ph.D., M.P.H.

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Inamed Corporation’s McGhan Silicone-Filled Breast Implants

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  1. Inamed Corporation’sMcGhan Silicone-Filled Breast Implants October 14-15, 2003

  2. FDA Presenters • CDR Samie Allen, USPHS • Sam Arepalli, Ph.D. • David Berkowitz, Ph.D., V.M.D. • Sahar Dawisha, M.D. • Telba Irony, Ph.D. • S. Lori Brown, Ph.D., M.P.H.

  3. Device Description, Mechanical Testing, Retrieval Study, & Shelf Life Overview Samie Allen

  4. Device Description • Styles 10, 20, 40, 45, 110, 120 & 153 • Round & shaped • Standard, moderate, high, & full profiles • Smooth & textured (Biocell) surfaces • Single lumen except Style 153 • Components: shell, patch, filler, & silicone adhesive

  5. Mechanical Testing • Gel Cohesion • Gel Bleed • Fatigue

  6. 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: 49.2 (39.5-56.0)

  7. Gel Bleed Testing • Gel Bleed Testing • ASTM F703 • Results: 0.0152 g/cm2 for Style 40 0.0048 g/cm2 for Style 110

  8. Fatigue Testing • Fatigue Testing of Total Device • No ASTM standard • Results: 55 lbs for Style 40 30 lbs for Style 110 • Ultimate Static Results: 1245 lbs for Style 40 1861 lbs for Style 110

  9. Retrieval Study • From 7/31/00 to 10/1/02, 339 gel explants • Physician Observations • Laboratory Observations • Mechanical Testing • Sharp-edge Analyses

  10. Retrieval Study (cont.)

  11. Shelf Life • Device and package testing • 2.5-year shelf life date on package label (2 years real + ½ year accelerated)

  12. Conclusions – Mechanical & Other • Gel Cohesion Testing • Gel Bleed Testing • Fatigue Testing • Retrieval Study • Shelf Life

  13. Chemistry Overview Sam Arepalli, Ph.D.

  14. Device Materials • Shell, middle (barrier) layer: Diphenyldimethyl-siloxane copolymer, 15 mole% diphenyl • Shell, inner/outer (base) layers: Diphenyldimethyl-siloxane copolymer, 5 mole% diphenyl • Patch, outer layer: Peroxide cure silicone elastomer • Patch, inner (barrier) layer: Dimethyl, methyl-trifluoropropylsiloxane • Silicone Gel: Two-part platinum cure gel • Silicone adhesive: Oxime cure RTV silicone

  15. Extent of Crosslinking • Shell: 3.4 crosslinked units/molecule (Sol Fraction Method) • Gel: 3.5-7.5 mm (Penetrometer)

  16. Volatiles • Shell: 1,1,1 trichloroethane (279 µg) Isopropyl alcohol (251 µg)

  17. Extractables • Gravimetric analysis • Gel permeable chromatography • FTIR analysis • Qualitative and quantitative analysis

  18. GC-MS Analysis • Cyclicoligosiloxanes up to D10 not detectable. • Higher cyclic and linear oligosiloxanes concentrations comparable to those of saline-filled breast implants.

  19. Metal Analysis • Shell: Sn (0.05 ppm); Pt (3.3 ppm) • Patch: Sn (6.6 ppm); Pt (2.6 ppm) • Gel: Sn (0.06 ppm); Pt (4 ppm)

  20. Silica Analysis • Amorphous silica (X-ray diffraction) • No free silica present (Electrospectroscopy)

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

  22. Toxicology Overview David Berkowitz, Ph.D., V.M.D.

  23. Six Testing Categories • Pharmacokinetics • Biocompatibility • Subchronic Toxicity • Reproductive and Teratogenicity • Immunotoxicology • Genotoxicity and Carcinogenesis Testing

  24. Pharmacokinetics • 30 days after implantation, only 0.06% of radiolabeled Gel left the implant site. • Lower molecular weight siloxanes (e.g., D4 and D5) diffuse out of the implants at a slow rate.

  25. Biocompatibility Testing • Cytotoxicity • Irritation and Sensitization • Acute Systemic Toxicity • Implantation Testing (Subchronic Toxicity) • Hemolysis • Pyrogenicity

  26. Reproductive & Teratogenicity - Shell Testing Results

  27. Immunotoxicity

  28. Genotoxicity • Bacterial Mutagenesis • Mammalian Cell Forward Mutation Assay • Chromosomal Aberration Assay • Mammalian Cell Transformation Assay

  29. Carcinogenicity • 2-year studies including gross and microscopic pathology. • Gel – Longer time to tumor and longer survival time than polyethylene control. • Shell – Shorter survival time than sham and control. Differences attributable to foreign body carcinogenesis.

  30. Clinical Data Overview Sahar M. Dawisha, M.D. Medical Officer

  31. Summary of Studies • Core Study—Started 1999. • Adjunct Study—Started 1998. • 1990 Study—Started 1990. • All open label, prospective, multicenter. • Yearly F/U in Core Study & 1990 Study. • All collected local complications.

  32. Core Study • Majority of Safety and Effectiveness data. • Augmentation, Reconstruction, Revision. • Yearly F/U to 10 years after implantation. • Only study with prospective MRI screening for asymptomatic rupture in 34% of 940 total patients. • Only study with QOL and CTD signs/symptoms collected.

  33. Adjunct Study • Intended to make the implants available for reconstruction and revision indications. • Collected local complications at 1, 3, and 5 years after implantation surgery. • Unlimited sample size. • Enrollment is ongoing.

  34. Majority of patients: augmentation indication. Yearly F/U to 5 years. Data from 4 of 11 styles presented. 1990 Study

  35. Core Study Results

  36. Core Study Demographics: Age

  37. Core Augmentation Cohort

  38. Patient Disposition—Core Augmentation • 494 Patients (987 devices) enrolled. • 90% of 489 expected patient F/U at 2 years. • 81% of 398 expected patient F/U at 3 years. • 1 Death • 13 Implant Removals • 76 Lost to Follow-up

  39. By-Patient 3-Year Cumulative KM Complication Rates—Core Aug

  40. Reoperation—Core Augmentation • 248 Additional procedures in 112 reoperations through 3 years in 94 of the 494 patients (19.1%). • Capsule related: 79 of 248 procedures (31.9%). • Removal with replacement: 51 of 248 procedures (20.6%).

  41. Reasons for Implant Removal through 3 Years—Core Aug

  42. Asymptomatic Implant Rupture Screening—Core Augmentation • 166 Patients (331 implants) enrolled. • At 1 year: 139 patients (87%) of expected underwent MRI screening. • At 3 years: 83 patients (64% of expected) underwent screening. • Total of 145 patients (289 implants) who had at least one MRI screening. • 3 Implants reported ruptured. • Silent rupture rate: 1.2% (0.0%, 2.6%) through 3 years, by-implant.

  43. Implant Ruptures—Core Augmentation • No MRI Screening/Symptomatic Ruptures • 2 implants (out of 698) ruptured. • 2? Additional implants reported as intact. • Unknown asymptomatic rupture rate. *Overall by-implantrupture rate: 0.6% (0.1%, 1.1%) through 3 years: •3 Asymptomatic/silent + 2 Symptomatic. •Excludes potential silent ruptures in No MRI. •Excludes 2 additional symptomatic ruptures.

  44. Other Safety Information—Core Augmentation • No increase in reports of reproductive or lactation problems. • 32 post-implant breast disease reports: 1 malignant, 29 benign, 2 unconfirmed. • 12 post-implant abnormal mammogram reports: 1 no disease; 11 benign. • 1 New CTD: Rheumatoid Arthritis.

  45. CTD Summary—Core Augmentation

  46. Effectiveness—Core Augmentation • Most patients completing 2 years of follow-up reported being satisfied, but declines in mean satisfaction over time. • Mean General QOL measures worsened over time. • Some Specific QOL measures improved (TSCS, Body Esteem--Total, Sexual Attractiveness, and Weight); while others declined over time (Rosenberg Self Esteem, Body Esteem-Physical).

  47. Core Reconstruction Cohort

  48. Patient Disposition—Core Reconstruction • 221 Patients (361 devices) enrolled. • 95% of 205 expected patient F/U at 2 years. • 91% of 116 expected patient F/U at 3 years. • 7 Deaths • 16 Implant Removals • 11 Lost to Follow-up

  49. By-Patient 3-Year Cumulative KM Complication Rates—Core Recon

  50. Reoperation—Core Reconstruction • 242 Additional procedures in 127 reoperations through 3 years in 92 of the 221 patients (41.6%). • Capsule related: 54 of 242 procedures (22.3%). • Removal with replacement: 51of 242 (21.1%). • Scar revision/wound repair: 47 of 242 (19.4%).

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