# Presentation: 502456

## 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.

- Mentor P030053

## Device Description & Preclinical Testing Overview

- Samie Allen

## Device Description

- High, moderate, & moderate plus profiles
- Smooth & textured surfaces
- Round
- Single lumen
- Components: shell, patch, filler, & silicone adhesive

- Mentor P030053

## Preclinical Testing

- Modes and causes of rupture
- Fatigue testing
- Gel bleed
- Gel cohesion
- Shelf life

- Mentor P030053

## 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

## 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

## Modes & Causes of Rupture (cont.)

| RUC & NAEU Failure Modes | N |
| --- | --- |
| Localized stress (presumed cause) | 121  |
| Shell/patch junction  | 23  |
| Fold flaw | 20 |
| Shell/patch delamination | 12 |
| Instrument damage | 11 |
| Patch internal | 3 |
| Combination failures | 13 |
| Total | 203 |

- Mentor P030053

## Modes & Causes of Rupture (cont.)

| Supplemental Analysis of Failure Modes  | # (%) of Retrieved Devices |  |  |
| --- | --- | --- | --- |
|  | 0-5 yrs | 6-10 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  | 231  | 40 | 3 |

- Mentor P030053

## Modes & Causes of Rupture (cont.)

- Mentor P030053

## Modes & Causes of Rupture (cont.)

- Mentor P030053

## Modes & Causes of Rupture (cont.)

- Mentor P030053

## 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

- 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 P030053

## 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

## Gel Bleed Testing

- ASTM F703 testing
- Gel loss analysis
- Gel bleed study

- Mentor P030053

## 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

## 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

## 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

## 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

## Shelf Life

- Device and package testing
- 5-year shelf life date on package label

- Mentor P030053

## 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

## 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

## Chemistry Overview

- Sam Arepalli, Ph.D.

## 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

## Degree of Crosslinking

- Shell:  7.90 chains/cm3 (Sol Fraction Method)
- Gel:
- 8.81 chains/cm3
- 3.0-10.0 mm (Penetrometer)

- Mentor P030053

## 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

## Extractables

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

- Mentor P030053

## 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

## 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

## Silica Analysis

- Amorphous silica (X-ray diffraction)
- No free silica present (Raman & Photoelectron spectroscopy)

- Mentor P030053

## Summary - Chemistry

- Shell and gel tested separately
- Degree of crosslinking
- Volatiles
- Metals
- Extractables
-  Gravimetric analysis
-  GPC
-  FTIR
-  GC-MS

- Mentor P030053

## Toxicology Overview

- David B. Berkowitz, Ph.D., V.M.D.

## Five Testing Categories

- Pharmacokinetics
- Biocompatibility
- Immunotoxicology
- Reproductive and Teratogenicity Testing
- Genotoxicity and Carcinogenesis

- Mentor P030053

## 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

## Biocompatibility Testing

- Cytotoxicity
- Irritation and Short-Term Implantation
- Acute Systemic Toxicity
- Hemolysis
- Pyrogenicity

- Mentor P030053

## 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

## 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

## Genotoxicity & CarcinogenesisTesting

- Salmonella Reverse Mutation Assay
- Unscheduled DNA Synthesis
- Chromosomal Aberration Assay
- In Vivo Mouse Micronucleus Test
- Carcinogenicity Testing

- Mentor P030053

## Toxicology Summary

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

- Mentor P030053

## Clinical Data Overview

**Herbert P. Lerner, M.D.**
**Medical Officer**

## 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

## 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

## 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

## Core Study Results

- Mentor P030053

## 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 P030053

## Core Augmentation Cohort

- Mentor P030053

## 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

## By-Patient 3-Year Cumulative KM Complication Rates - Core Aug

| Complication | Rate        (95% CI) |
| --- | --- |
| Reoperation | 15.0%   (11.9%, 18.0%) |
| Nipple Sensation Change | 10.8%   (8.1%, 13.4%) |
| C/C III/IV | 8.2%     (5.9%, 10.6%) |
| Hypertrophic Scarring | 6.3%     (4.2%, 8.3%) |
| Implant Removal w/ w/o replacement | 5.1%     (3.2%, 7.1%) |
| Breast Mass | 2.4%     (1.0%, 3.7%) |
| Rupture | 0.5%     (0.0%, 1.5%) |

- Mentor P030053

## 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

## Primary Procedure for Given Reoperation 

| Reoperation | Surgical Procedure | # (% of 98) |
| --- | --- | --- |
| Capsular contracture | Capsule procedures | 30  (30.6%) |
|  | Removal/replacement | 5  (5.1%) |
| Healing related | Incision and drainage | 12  (12.2%) |
| Infection | Removal/replacement | 2  (2.0%) |
|  | Revision wound closure | 1  (1.0%) |
| Patient request | Removal/replacement | 16  (16.3%) |
| Unsatisfactory cosmetic result | Capsule procedures | 5  (5.1%) |
|  | Removal/replacement | 1  (1.0%) |
|  | Implant reposition | 1  (1.0%) |
|  | Mastopexy | 1  (1.0%) |
|  | Scar revision | 10  (10.2%) |

- Mentor P030053

## 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 P030053

## 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 P030053

## CTD Signs/Symptoms - Core Augmentation (n=494)

| Sign/Symptom
(most commonly reported) | Number with sign/symptom reported | Cumulative incidence |
| --- | --- | --- |
| Any sign/symptom | 53 | 10.3% |
| Numbness of hands | 13 | 2.7% |
| Joint pain | 13 | 2.7% |

- Mentor P030053

## 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 P030053

## 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 P030053

## 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 P030053

## Core Reconstruction Cohort

- Mentor P030053

## 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 P030053

## By-Patient 3-Year Cumulative KM Complication Rates - Core Recon

| Complication | Rate          (95%  CI) |
| --- | --- |
| Reoperation | 26.3%       (21.7%, 31.9%) |
| Removal/Replacement | 13.3%       (8.8%, 17.8%) |
| CC III/IV | 8.8%         (4.9%, 12.7%) |
| Ptosis | 6.9%         (2.0%, 11.8%) |
| Infection | 5.3%         (2.5%, 8.1%) |
| Breast Pain | 1.7%         (0.0%, 0.4%) |
| Tissue/Skin Necrosis | 1.2%         (0.0%, 2.0%) |
| Rupture | 0.8%         (0.0%, 2.2%) |

- Mentor P030053

## 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 P030053

## Primary Procedure for Given Reoperation 

| Reoperation | Surgical Procedure | # (% of 78) |
| --- | --- | --- |
| Capsular contracture | Capsule procedures | 4  (5.1%) |
|  | Removal/replacement | 4  (5.1%) |
| Healing related | Removal/replacement | 1  (1.3%) |
|  | Incision and drainage | 2  (2.6%) |
| Infection | Removal/replacement | 2  (2.6%) |
|  | Incision and drainage | 2  (2.6%) |
| Patient request | Removal/replacement | 7  (9.0%) |
| Unsatisfactory cosmetic result | Capsule procedures | 5  (6.4%) |
|  | Removal/replacement | 13  (16.7%) |
|  | Implant reposition | 6  (7.7%) |
|  | Mastopexy | 3  (3.8%) |
|  | Pocket revision | 1  (1.3%) |
|  | Scar revision | 3  (3.8%) |

- Mentor P030053

## 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 P030053

## 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 P030053

## CTD Signs/Symptoms - Core Reconstruction (n= 221)

| Sign/Symptom (most commonly reported) | Number with signs/symptoms reported | Cumulative Incidence |
| --- | --- | --- |
| Any sign/symptom | 44 | 21.5% |
| Joint pain | 17 | 8.0% |
| Joint swelling | 10  | 4.5% |

- Mentor P030053

## 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 P030053

## 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 P030053

## Core Revision Cohort

- Mentor P030053

## 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 P030053

## By-Patient 3-Year Cumulative KM Complication Rates - Core Revision

| Complication | Rate          (95% CI) |
| --- | --- |
| Reoperation | 26.3%   (20.0%, 32.6%) |
| CC III/IV | 17.2%   (11.9%, 22.4%) |
| Removal/Replacement | 13.3%   (8.4%, 18.2%) |
| Nipple sensation changes | 8.6%     (4.7%, 12.6%) |
| Scarring | 6.0%     (2.7%, 9.3%) |
| Breast mass | 5.8%     (25%, 9.1%) |
| Rupture | 4.8%     (0.2%, 9.3%) |
| Breast Pain | 2.0%     (0.1%, 4.0%) |

- Mentor P030053

## 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 P030053

## Primary Procedure for Given Reoperation 

| Reoperation | Surgical Procedure | # (% of 71) |
| --- | --- | --- |
| Capsular contracture | Capsule procedures | 13  (18.3%) |
|  | Removal/replacement | 6  (8.5%) |
| Healing related | Incision and drainage | 7  (9.9%) |
|  | Revision of wound closure | 1  (1.4%) |
|  | Scar revision | 1  (1.4%) |
|  | Surgical exploration | 1  (1.4%) |
| Infection | Removal/replacement | 1  (1.4%) |
| Patient request | Removal/replacement | 7  (9.9%) |
| Unsatisfactory cosmetic result | Capsule procedures | 2  (2.8%) |
|  | Removal/replacement | 5  (7.0%) |
|  | Implant reposition | 3  (4.2%) |
|  | Scar revision | 2  (2.8%) |

- Mentor P030053

## 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 P030053

## 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 P030053

## CTD Signs/Symptoms - Core Revision (n= 226)

| Sign/Symptom | Number with sign/symptoms reported | Cumulative incidence |
| --- | --- | --- |
| Any sign/symptom | 39 | 21.3% |
| Joint pain | 14 | 7.3% |
| Fatigue | 11 | 6.0% |

- Mentor P030053

## 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 P030053

## 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 P030053

## 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 P030053

## 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 P030053

## 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 P030053

## 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 P030053

## 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 P030053

## Thank you

- Mentor P030053

## Rupture Overview-Mentor Silicone Breast Implants

- Sahar M. Dawisha, M.D.,
- Medical Officer

## 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 P030053

## 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 P030053

## 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.

- Mentor P030053

## 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 P030053

## Core Study KM Rupture Rate through 3 years in MRI Cohort:All Silent

|  | By-Patient | By-Implant |
| --- | --- | --- |
| Aug | 0.5%
(0.0,   1.5) | 0.2%
(0.0,   0.7) |
| Recon | 0.8%
(0.0,   2.2) | 0.5%
(0.0,  1.4) |
| Revision | 4.8%
(0.3,   2.6) | 3.9%
(0.8,   1.7) |

- Mentor P030053

## 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 P030053

## 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 P030053

## 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.

- Mentor P030053

## 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; 3⁄4 recon; 1⁄4 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.

- Mentor P030053

## 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 P030053

## 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.

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## 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 P030053

## 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 P030053

## 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.

- Mentor P030053

## 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 P030053

## 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 P030053

## 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 P030053

## Safety and Effectiveness Information

- Consider all complications and benefits.
- Consider augmentation and reconstruction separately.
- Consider revision as a continuum of augmentation or reconstruction.

- Mentor P030053

## Thank You

## Statistical Overview

**Phyllis Silverman, M.S.**
**Mathematical Statistician**
**Division of Biostatistics**

## 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 P030053

## 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

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## Kaplan-Meier Analyses

- 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.

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## 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.

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## Prevalence and Incidence

**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**

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## 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 P030053

## 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 P030053

## 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.

- Mentor P030053

## Conclusion of FDA’s Presentation

## Panel Questions

## 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.

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## 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.

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## 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.

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## Panel Question 4

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

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## 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.

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## 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.

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