# Presentation: 037910

## 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.

## Device Description, Mechanical Testing, Retrieval Study, & Shelf Life Overview

- Samie Allen

## 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

## Mechanical Testing

- Gel Cohesion
- Gel Bleed
- Fatigue

## 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)

## Gel Bleed Testing

- ASTM F703
- Results:  0.0152 g/cm2 for Style 40
- 	0.0048 g/cm2 for Style 110

## 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

## Retrieval Study

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

## Retrieval Study (cont.)

| Observation | N (339) | Mode of Failure |
| --- | --- | --- |
| Smooth-edge | 2 | Fold flaw |
| Sharp-edge | 109 | 18% surgical technique
82% unknown |
| “Broken” device | 21 | Explant technique or propagation of opening |
| Device surface | 9 | Excess stress |
| Gel–related | 40 | Excess stress |
| “Functional” | 158 | N/A |

## Shelf Life

- Device and package testing
- 2.5-year shelf life date on package label
- 	(2 years real + 1⁄2 year accelerated)

## Conclusions – Mechanical & Other

- Gel Cohesion Testing
- Gel Bleed Testing
- Fatigue Testing
- Retrieval Study
- Shelf Life

## Chemistry Overview

- Sam Arepalli, Ph.D.

## 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

## Extent of Crosslinking

- Shell: 3.4 crosslinked units/molecule (Sol Fraction Method)
- Gel: 3.5-7.5 mm (Penetrometer)

## Volatiles

- Shell:	1,1,1 trichloroethane (279 μg)
-               	Isopropyl alcohol (251 μg)

## Extractables

- Gravimetric analysis
- Gel permeable chromatography
- FTIR analysis
- Qualitative and quantitative analysis

## GC-MS Analysis

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

## 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)

## Silica Analysis

- Amorphous silica (X-ray diffraction)
- No free silica present (Electrospectroscopy)

## Conclusions - Chemistry

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

## Toxicology Overview

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

## Six Testing Categories

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

## 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.

## Biocompatibility Testing

- Cytotoxicity
- Irritation and Sensitization
- Acute Systemic Toxicity
- Implantation Testing (Subchronic Toxicity)
- Hemolysis
- Pyrogenicity

## Reproductive & TeratogenicityShell Testing Results

| Test Group | # Mated | Mating Index |  | Fertility Index | Mean Gestation Time (days) |
| --- | --- | --- | --- | --- | --- |
| F0 |  |  |  |  |  |
| Sham Control |   35 | 80% | 96% |  | 21.9 |
| Implanted |   35 | 74% | 96% |  | 21.6 |
| F1 |  |  |  |  |  |
| Sham Control |   30 | 80% | 92% |  | 21.6 |
| Implanted |   30 | 90% | 96% |  | 21.6 |

## Immunotoxicity

| Results of Selected Immunotoxicology Tests - Gel |  |  |  |
| --- | --- | --- | --- |
| Test | Sham
Control | High
Dose | Cyclophosphamide
Control (50mg/kg) |
| Spleen Weight (mg) | 83 | 96* | 54* |
| Lymphocytes/mm3 | 4412 |   5289 | 3403* |
| IgM AFC  | 884 | 829 | 0* |
| Mixed Leukocyte Response | 59,513 | 53,514 | 17,653* |
| NK Cell Activity | 27.0 | 22.6 | 1.2* |

## Genotoxicity

- Bacterial Mutagenesis
- Mammalian Cell Forward Mutation Assay
- Chromosomal Aberration Assay
- Mammalian Cell Transformation Assay

## 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.

## Clinical Data Overview

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

## 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.

## 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.

## 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.

## 1990 Study

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

## Core Study Results

## Core Study Demographics: Age

|  | 
Aug
N = 494 | 
Recon
N = 221 | 
Revision
N = 226 |
| --- | --- | --- | --- |
| Median Age
(range) in years | 
34
(18-60) | 
50
(26-82) | 
44
(18-80) |

## Core Augmentation Cohort

## 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

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

| Complication | Rate        (95% CI) |
| --- | --- |
| Reoperation | 20.6%   (16.8%, 24.4%) |
| CC III/IV | 8.3%     (5.8%,   10.9%) |
| Scarring | 8.1%     (5.7%,   10.6%) |
| Removal/Replacement | 7.5%     (5.0%,   10.0%) |
| Breast Pain | 6.2%     (4.0%,     8.4%) |
| Nipple Sensation Change | 3.1%     (1.6%,     4.7%) |
| Implant Rupture | 1.2%     (0.1%,     2.2%) |
| Infection | 1.0%     (0.1%,     1.9%) |

## 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%).

## Reasons for Implant Removal through 3 Years—Core Aug

| Primary Reason | N = 60 Implants |
| --- | --- |
| Complication Treatment | 42    (70.0%) |
|      Rupture |      2     (3.3%)    |
|      Capsular Contracture |      27   (45.0%) |
|      Extrusion/Malposition |      7     (11.7%) |
|      Asymmetry/Ptosis/Cancer |      6     (10.0%) |
| Patient Choice | 18     (30.0%)    |

## 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.

## 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-implant** **rupture 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.

## 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: RA.

## CTD Summary—Core Augmentation 

| Sign/Symptom | Pre-Implant
N = 386 | Through 2 yrs
N = 386 |
| --- | --- | --- |
| Muscle* | 75    (19.4%) | 108  (28.0%) |
| Joint* | 50    (13.0%) | 85    (22.0%) |
| Neurological* | 158  (40.9%) | 180  (46.6%) |
| Muscle pain | 34    (8.8%) | 57    (14.8%) |
| Joint Pain | 10    (2.6%) | 26    (6.7%) |
| AM Stiffness | 39    (10.1%) | 70    (18.1%) |
| Fatigue | 33    (8.5%) | 101  (26.2%) |
| Generalized Pain | 8      (2.1%) | 19    (4.9%) |

## 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).

## Core Reconstruction Cohort

## 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

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

| Complication | Rate               (95%  CI) |
| --- | --- |
| Reoperation | 45.9%       (36.8%,     55.1%) |
| Removal/Replacement | 25.3%       (16.9%,     33.6%) |
| CC III/IV | 16.1%       (8.7%,       23.6%) |
| Implant Rupture | 6.3%         (1.3%,       11.3%) |
| Tissue/Skin Necrosis | 6.1%         (1.1%,       11.1%) |
| Breast Pain | 6.0%         (1.2%,       10.8%) |
| Scarring | 6.0%         (1.2%,       10.8%) |
| Infection | 2.3%         (0.0%,         5.4%) |

## 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%).

## Reasons for Implant Removal through 3 Years—Core Recon

| Primary Reason | N = 56 Implants |
| --- | --- |
| Complication Treatment | 52     (92.9%) |
|    Symmetry/Position/Wrinkling |      26     (46.4%) |
|    Capsular Contracture |      12     (21.4%) |
|    Rupture |       5      (8.9%) |
|    Extrusion/Pain/Hemat/Seroma |       5      (8.9%) |
|    Scarring/Cancer/Injury |       4      (7.1%) |
| Patient Choice: Style/Size  | 4      (7.1%) |

## Asymptomatic Implant Rupture Screening—Core Reconstruction

- 108 Patients (184 implants) enrolled.
- Total of 101 patients (170 implants) at least one MRI screening (93.5% of expected).
- 8 implants ruptured.
- Silent rupture rate: 4.7%  (1.5%,  7.9%) by-implant through 3 years.
- Only 2 patients (2 implants) with 2nd screening at 3 years.

## Implant Ruptures—Core Recon

- No MRI Screening/Symptomatic Ruptures
- 5 implants (out of 191) ruptured.
- Unknown asymptomatic rupture rate.
***Overall by-implant rupture rate: 4.2% ** (2.0%,    6.5%) through 3 years:
- 	•8 Asymptomatic/silent + 5 Symptomatic.
- 	•Excludes potential silent ruptures in No MRI Group (53% of Core Reconstruction implants).

## Other Safety Information—Core Reconstruction 

- No increase in reports of reproductive or lactation problems.
- 5 New reports of breast malignancy:  recurrence or metastasis.
- 1 New report of CTD: Scleroderma.

## CTD Signs/Symptoms—Core Reconstruction

| Sign/Symptom | Pre-Implant
N = 162 | Through 2 yrs
N = 162 |
| --- | --- | --- |
| Skin* | 20   (12.3%) | 35   (21.6%) |
| Muscle* | 56   (34.6%) | 65   (40.1%) |
| Joint* | 69   (42.6%) | 94   (58.0%) |
| Neurological* | 78   (48.1%) | 97   (59.9%) |
| Joint Pain | 17   (10.5%) | 31   (19.1%) |
| AM Stiffness | 39   (10.1%) | 70   (18.1%) |

## Effectiveness—Core Reconstruction

- Most patients completing 2 years of follow-up reported being satisfied, but declines in mean satisfaction over time.
- Mean General QOL measures improved over time.
- Some specific QOL measures improved (Semantic Differential, Body Esteem-Sexual Attractiveness); while others worsened (TSCS, Rosenberg Self Esteem, Body Esteem-Total)

## Core Revision Cohort

## Patient Disposition through 3 years—Core Revision

- 225 Patients (432 devices) enrolled.
- 87% of 216 expected patient F/U at 2 years.
- 83% of 192 expected patient F/U at 3 years.
- 4 Deaths
- 10 Implant Removals
- 32 Lost to Follow-up

## By-Patient 3-Year Cumulative KM Complication Rates—Core Revis

| Complication | Rate          (95%  CI) |
| --- | --- |
| Reoperation | 33.4%   (26.9%,   39.8%) |
| Removal/Replacement | 13.4%   (8.7%,     18.1%) |
| CC III/IV | 9.8%     (5.7%,     13.9%) |
| Scarring | 8.6%     (4.7%,     12.5%) |
| Breast Pain | 7.2%     (3.7%,     10.8%) |
| Wrinkling/Rippling | 5.0%     (2.0%,       8.0%) |
| Implant Rupture | 3.6%     (1.0%,       6.3%) |
| Infection | 2.8%     (0.6%,       4.9%) |

## Reoperation—Core Revision

- 190 Additional procedures in 100 reoperations through 3 years in 70 of the 225 patients (31.1%).
- Capsule related: 23 of 190 procedures (27.9%).
- Removal with replacement: 41 of 190 procedures (21.6%).

## Reasons for Implant Removal through 3 years—Core Revision

| Primary Reason | N = 46 Implants |
| --- | --- |
| Complication Treatment | 33     (71.7%) |
|   Symmetry/Position/Ptosis |    15   (32.6%) |
|   Capsular Contracture |     7    (15.2%) |
|   Rupture |     6    (13.0%) |
|   Scar/Wound/Pain/Infection |     5    (10.9%) |
| Patient Choice: Style/Size | 13     (28.3%) |

## Asymptomatic Implant Rupture Screening—Core Revision

- 77 Patients (148 implants) enrolled.
- Total of 72 patients (138 implants) at least 1 MRI screening (93.5% of expected).
- 4 implants ruptured.
- Silent rupture rate: 2.9%  (0.1%,  5.7%) by-implant through 3 years.
- Only 1 patient (2 implants) with 2nd MRI screening at 3 years.

## Implant Ruptures—Core Revision

- No MRI Screening/Symptomatic Ruptures
- 4 implants (out of 294) ruptured.
- Unknown asymptomatic rupture rate.
- ***Overall by-implant rupture rate: 2.2%**  (0.7%,   3.7%) through 3 years:
- 	• 4 Asymptomatic/silent + 4 Symptomatic.
- 	•Excludes potential silent ruptures from No MRI Group (68% of Core Revision Implants).

## Other Safety Information—Core Revision

- No increase in reports of reproductive or lactation problems.
- 13 New reports of breast disease: all benign.
- 1 New report of CTD: Fibromyalgia.

## CTD Signs/Symptoms—Core Revision

| Sign/Symptom | Pre-Implant
N = 386 | Through 2 yrs
N = 386 |
| --- | --- | --- |
| Skin* | 13   (8.3%) | 24   (15.3%) |
| Muscle* | 46   (29.3%) | 62   (39.5%) |
| Joint* | 41   (26.1%) | 56   (35.7%) |
| Neurological* | 59   (37.6%) | 78   (49.7%) |
| General* | 55   (35.0%) | 66   (42.0%) |

## Effectiveness—Core Revision

- 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 measures improved (Body Esteem—Sexual Attractiveness); while all others worsened.

## Comparison to McGhan Saline Breast Implant Data

- Cannot compare rupture rates.
- Historical control group.
- Confidence intervals not overlapping for reoperation, removal, capsular contracture.

## Adjunct Study           1990 Study

- Reconstruction.
- Revision.
- ~50% F/U at 1 year.
- ~20% F/U at 3 years.
- Complication rates comparable to Core Study.

- Augmentation.
- 70% F/U at 5 years.
- Complication rates at 3 years comparable to Core Study.

## Summary

- Reoperation most frequent complication.
- Capsular contracture reoperation most common procedure.
- Most implants removed to treat a complication.
- CTD signs/symptoms increase over time.
- Patient satisfaction high but decreases over time; General QOL measures improved for reconstruction; Body Esteem-Sexual Attractiveness only specific measure consistently improved.

## Summary—Implant Rupture

- Implant rupture rate is under ascertained.
- Most implant ruptures are asymptomatic:
- Asymptomatic: 15 of 26 total implant ruptures.
**Asymptomatic** **rupture rate** (MRI) based on 34% of implants and 1 year data.
**Overall rupture rate** excludes asymptomatic ruptures in 66% of implants.
- Almost all asymptomatic ruptures were intracapsular.

## Thank You!

## Statistical Overview

**Telba Irony, Ph.D.**
**Mathematical Statistician**
**Division of Biostatistics**

## Statistical Analyses: Core Study

**Prospective**
**Multi-Center**
**10–year study **
**Reported follow-up time points: **
** ****4 weeks, 6 months, 1, 2, 3 years**
**All patients traversed the 2-year window**
**A large fraction of patients traversed the 3-year window**

## Core Study

- 494 patients and 83% traversed the 3-year visit.
- 398 patients were expected at 3 years.
- Actual # of patients at 3 years: 322 (19% lost to follow-up)

**Reconstruction**
- 221 patients and 58% traversed the 3-year visit.
- 116 patients were expected at 3 years.
- Actual # of patients at 3 years: 105 (9% lost to follow-up )

**Core Study**

**Revision**
- 225 patients and 91% traversed the 3-year visit.
- 192 patients were expected at 3 years.
- Actual # of patients at 3 years: 160 (17% lost to follow-up)

## Descriptive Nature of Studies

**There were no claims, targets, or control groups in this study. **
**Descriptive statistics:  No hypothesis tests.**
**Sample size:  Reflected in the width (i.e. precision) of the confidence interval. **
**Decision makers should assess the adequacy of the precision of the results when weighing the risks and benefits of the implants.**

## Safety Endpoints - Rates

**Adverse Events**
**Implant Rupture**
**Reoperations**
**Implant Replacement/Removal**

**Employed Statistical Techniques**

**  ****Kaplan - Meier analyses**
**  “****Prevalence”**
**  “****Incidence”**

## Kaplan-Meier Analyses

**Result:****  Estimated probability that a patient will experience the adverse event from the time of implant up to the considered time point.**

**Advantage:**** ****Patients who were lost to follow-up provide information up to the time they left the study.**

**Kaplan-Meier Analyses**

**Independence**** Assumption for Censoring**

## Kaplan-Meier Analyses (cont.)

**Days were used as units of time for the computation of the rates (alleviates interval censoring bias).**** ****Assumption:**** ****reporting is accurate to the date**
**Correlation among adverse events:  not taken into account**
**Competing Risks Problem:**** ****To solve it, all patients that experienced a complication were returned to the “pool” of patients who could experience another complication.****  ****Exception****:**** ****Implant Removal**

## Kaplan-Meier Analyses (cont.)

|  | 4 
weeks | 6 months | 1
year | 2
Years | 3 
years* |
| --- | --- | --- | --- | --- | --- |
| Aug | 1.9 ±1.1 | 6.0±2.1 | 11.2±2.8 | 17.2±3.4 | 20.6±3.8 |
| Recon | 4.1±2.6 | 23.7±5.7 | 32.0±6.2 | 37.2±6.6 | 45.9±9.2* |
| Rev | 3.6±2.5 | 16.1±4.9 | 22.7±5.6 | 29.5±6.1 | 33.4±6.5 |

**Kaplan-Meier Analyses (cont.)**

- * Correction by using Peto’s Formula

## Other Statistical Techniques

**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)

**Other Statistical Techniques**

**Incidence**:  percentage of patients _seen_ at a given follow-up visit who are experiencing the adverse event not experienced at earlier visits (given they returned to the follow-up).

**Disadvantage**: Both measures are _very__ _sensitive to biases generated by losses  to follow up.

## Additional Safety Information

**Connective Tissue Disease **
**Signs and Symptoms**

**The frequencies of patients reporting 8 categories of signs and symptoms of CTD before implantation was compared to the frequencies 2 years after implantation. **
**For**** all ****cohorts,**** all 8**** frequencies increased after implantation. The only exception was the urinary symptom: the frequency remained the same in the Reconstruction group.**

## Additional Safety InformationConnective Tissue Disease Signs and Symptoms

**To assess the statistical significance of the increases in the frequencies, the  sponsor used a Bonferroni correction that was too conservative for this case. It did not take into account possible correlations among signs and symptoms.**
**Consequence:  It was difficult to detect statistical significance.**

## Additional Safety InformationConnective Tissue Disease Signs and Symptoms

**Despite the  conservative statistical analysis, the increase in the frequency of some signs and symptoms was statistically significant.**
**However, the clinical interpretation is problematic: no control group**

**Additional Safety Information****Connective Tissue Disease ****Signs and Symptoms**

## Medical Device Surveillance & Literature Overview

- S. Lori Brown, Ph.D., M.P.H.Office of Surveillance and Biometrics

## Medical Device Reporting

**What is Medical Device Reporting (MDR)?**
- MDR is the mechanism for the Food and Drug Administration to receive significant medical device adverse events from manufacturers, importers, and user facilities

## CDRH Surveillance Databases

- Manufacturer And User Facility Device Experience (_MAUDE_) database - MDR and MedWatch reports are entered into database - 1992-present
- Alternative Summary Reporting (_ASR_) –1995-present
- Device Experience Network (_DEN_) – 1984-1996

## Surveillance is NOT the equivalent of a clinical study:

- Rates cannot be calculated because of under-reporting of adverse events
- Number of individuals at risk (denominator) is unknown.  It is not appropriate to use the number of devices sold as the denominator!

## Surveillance does not always establish causality:

- Accuracy and completeness not verified
- Cannot always establish a causal link between a death or injury and the listed device(s)

## Surveillance Reports Are

- Important for providing a _**signal**_ of a potential problem with a regulated medical product

## Slide 90

| Silicone Gel Breast Implant Reports, 
1/1/84 – 6/30/03 |  |  |
| --- | --- | --- |
| Database | Total Reports | Inamed Reports |
| DEN
1/1/84-12/31/97 | 96,954 | 7,646 (8%) |
| MAUDE
1/1/92-6/30/03 | 14,034 | 913 (6.5%) |
| ASR
4/1/95-9/30/02 | 23,489 | 5,855 (25%) |
| Total | 134,477 | 14, 414 (11%) |

## Device ProblemsInamed (MAUDE Database)

- Explanted
- Rupture
- Migration

- 35%
- 32%
- 3%

## Patient Problems Inamed (MAUDE Database)

-   Pain
-   Headache
-   Surgical procedure
-   Capsular contracture
-   CTD
-   Fatigue

- 15%
- 13%
- 9%
- 7%
- 6%
- 5%

## MAUDE Analysis:  Breast Implant Rupture During Mammography

- Between 1992 and 2002, FDA received 33 adverse event reports describing breast implant rupture during mammography
- An additional 8 reports described mammography as possible cause of subsequently detected ruptures

## MAUDE Analysis: Reproductive/2nd Generation Issues

- 130 reports from MAUDE that described injury or illness in mothers or their children attributed to breast implants
- 89 of these reports asserted that children were ill due to mother’s implants but provided no details of illness
- 23 reports described illness in children
- 5 reports attributed birth defects to mother’s breast implants
- 9 reports described difficulty nursing

## Literature Review

- Reproductive/second generation issues
- Connective tissue disease
- Fibromyalgia
- Cancer
- Mammography
- Neurologic disease
- Breast implants and mortality
- Resurgery and local complications
- Rupture and gel migration

## Literature on Reproductive/2nd Generation Issues

- Illness in children of mothers with implants (Levine, Teuber, Signorello, Kjøller)
- Birth defects (Signorello, Kjøller)
- Breast feeding by mothers with implants
- Silicon(e) in breast milk (Semple et al, 1998)
- Ability to breast feed (Neifert, Hurst, Hughes, Strom)
- Limited information on these issues

## Connective Tissue Disease

- Meta-analyses of relation between silicone breast implants and risk of connective-tissue disease (Janowski et al, 2000)
- Institute of Medicine review of safety of silicone breast implants concluded that “[these studies] do not support an association between connective tissue disease, combined or individually, for these diseases in women with silicone breast implants...” (1999)

## Fibromyalgia 

| Study  | Findings | Citation/Country |
| --- | --- | --- |
| Rheumatology practice records | Fibromyalgia 0.84 (0.48-1.47) | Lai et al, 2000 Atlanta, GA |
| Fibromyalgia vs community controls for Silicone filled implants | Fibromyalgia, 6.06 (0.73-50.52) | Wolfe et al, 1999 
Wichita, KS |
| Women w/breast implants vs nat’l  hospitalization rates  | Fibromyalgia, 1.6 (0.9-2.7) | Nyren et al, 1998 Sweden |

## Fibromyalgia (cont.)

| Study | Findings | Citation/Country |
| --- | --- | --- |
| Private/public hospital implants  | Unspecified Rheumatism 1.9 (1.5-2.3) | Kjøller 2001 Denmark |
| Women with ec silicone vs other | Fibromyalgia 2.9 (1.5-5.6) | Brown 2001  Birmingham, AL |

## Cancer

| Cancer Site | Study/Standardized Incidence Ratio |  |  |  |  |
| --- | --- | --- | --- | --- | --- |
|  | Deapen | Brinton | Pukkala | Mellemkjae | McLaughlin |
| All Sites |  | 1.21 | ns | 1.31 | ns |
| Brain |  | 2.16 |  | ns | ns |
| Cervix | ns | 3.18 | ns | ns | ns |
| Leukemia |  | 2.19 | ns |  | ns |
| Lung | 2.12 | 2.23 | ns | ns | 2.7 |
| Stomach |  | 2.65 |  |  |  |
| Vulva | 5.26 | 2.51 |  |  |  |

## Mammography

- Implant rupture during mammography
- Implants obscure 22-83% of breast tissue (Hayes et al, 1988)
- Modified techniques needed (Ecklund et al, 1988)
- Breast cancer detection delayed but no difference in mortality (Brinton et al, 2000)
- Tumor size, lymph node involvement, histopathology similar (Cahan et al, 1995)

## Neurologic Disease

- Swedish population based cohort found no increase in MS, ALS, Meniere’s syndrome, but significant increase in neurological disease in general (1.7, 1.1-2.6) (Nyren et al, 1998)
- Danish study found no increase in specific neurologic diagnoses;  neurologic disease in general slightly increased but not statistically significant (1.7, 0.9-2.9) (Winther et al, 1998)
- Similar findings in breast reduction comparison groups in both studies
- Both studies based on hospitalization

## Mortality and Breast Implants

| Cause of Death | Brinton,  2001 US | Koot, 2003
Sweden | Pukkala, 2003 Fin |
| --- | --- | --- | --- |
| All Causes | 0.68 
(0.6-0.8) | 1.5 
(1.2-1.8) | 1.01 
(0.67-1.44) |
| Suicide | 1.54 
(1.0-2.4) | 2.9 
(1.6-4.8) | 3.19 
(1.53–5.86) |
| Accidents | 0.95 
(0.6-1.4) | 1.8 
(0.9-3.3) | 2.14 
(1.17–3.58)* |
| Brain Malig | 2.45 
(1.4-4.2) | n.d. | n.d. |

## Resurgery and Local Complications

- Gabriel, 1997
- Gutowski, 1997
- Brown, 2001

- 28% of 749 fu 8 yr
- 21% of 504 fu 6 yr
- 33% of 907 mt 11.5 yr

- Rates for additional surgery in numerous studies reported to be about 33% of women- common reason for resurgery is capsular contracture in several studies

## Local Complications

- Capsular contracture
- Breast pain
- Infection
- Hematoma
- Implant extrusion
- Changes in nipple sensation

- Rashes
- Chest wall skeletal changes
- Calcification
- Rupture
- Gel migration
- Etc.

## Breast Implant Rupture and Gel Migration

- Breast implant rupture by MR in 344 B’ham women found _55%_ of implants ruptured affecting _68%_ of women, _22%_ ruptures extracapsular, _17_ yr median (Brown et al, 2000)
- Breast implant rupture by MR in 271 Danish women found _26%_ of implants ruptured affecting _36%_ of women, _22%_ ruptures extracapsular, _10_ yr median (Holmich et al, 2001)

## Breast Implant Rupture and Gel Migration (cont.)

- Extracapsular spread of silicone gel reported in 11-23% of ruptured implants across several series
- Frequency or severity of distant migration not known
- Migration may result in gel/oil in lymph nodes,  intraductal extension of gel, granuloma formation, transcutaneous leakage of gel, ulceration, tissue destruction, scarring
- Silicone in tissues confirmed by imaging, microscopic examination of granulomatous response

## Proposed Postapproval Study & Labeling Overview

- Samie Allen

## Proposed Postapproval Study 

- Core Study Protocol
- Yearly follow-up with physician through 10 years
- MRI assessments at 1, 3, 5, 7, and 9 years
- 2-Phase Postapproval Study
- Phase I – continued evaluations as per IDE protocol through 5-year timepoint
- Phase II – patient mail-in surveys for 6-10-year timepoints (no MRI assessments)

## Proposed Labeling

- Directions For Use (package insert)
- Patient Brochure
- Focus Group Study

## Conclusion of FDA’s Presentation

## Panel Questions

## Panel Question 1

- Prospective MRI screening for asymptomatic rupture was conducted in a subset of Core Study participants (approximately 34%).  Complete MRI screening data are available for the 1-year post-operative timepoint for each indication and partial 3-year data are available for the augmentation indication at the time of database closure.  Continued MRI screening of this Core Study subset is planned for at years 3, 5, 7, and 9 after implantation.
- Of the 15 implant ruptures that Inamed reports as confirmed at the time of database closure, the majority--9 implants (60%)--were initially detected by MRI screening and were asymptomatic:  Core Augmentation, 0 of 3 ruptures; Core Reconstruction, 6 of 8 ruptures; and Core Revision, 3 of 5 ruptures.
- Additionally, published literature on silicone gel implant rupture, although not specific to Inamed’s implants, indicates that rupture rate increases significantly with implant age and that depending on implant type, manufacturer, and age, between 26% (median implant age 12 years) and 55% (median implant age 16.4 years) of implants assessed by MRI had MRI evidence of rupture.
**Please discuss the adequacy of the information to determine the safety of this product with respect to asymptomatic rupture. **

## Panel Question 2

- Potential long-term and general health effect issues for these implants include the risk of cancer(s), connective tissue disorders (typical and atypical), gel migration, interference of implant on ability of mammography to detect tumors in implanted breasts, interference with breast feeding, reproductive/teratogenic effects, and the later effects on offspring from women with implants.  To address these issues, Inamed utilized historical published literature, which is not specific to Inamed’s implants, as well as animal studies on their product.  **Please discuss the adequacy of the literature and preclinical testing to determine the safety of this product with respect to long-term and general health effects.**

## Panel Question 3

- Considering the safety data reported for the augmentation group:
- local complications reported in Core Study, Adjunct Study, and AR90 Study
- asymptomatic/silent rupture information based on approximately 30% of the patients in the Core Study with only the first of 5 prospective serial screenings with complete data
- published historical literature and animal data to address long term and general health effects.
**Given these data, and that the augmentation patient generally has breast implant surgery at a younger age which includes childbearing years compared to the other indications, is there reasonable assurance that the device is safe for augmentation patients?**

## Panel Question 4

- Considering the safety data reported for the reconstruction and revision groups:
- local complications reported in Core Study, Adjunct Study, and AR90 Study
- asymptomatic/silent rupture information based on approximately 30% of the patients in the Core Study with only the first of 5 prospective serial screenings with complete data
- published historical literature and animal data to address long term and general health effects.
**Given these data, and that reconstruction and revision patients generally undergo breast implantation at an older age than augmentation patients, is there reasonable assurance that the device is safe for reconstruction and revision patients?**

## Panel Question 5

- To evaluate device effectiveness, Inamed collected data on patient satisfaction and health status/quality of life (e.g., SF-36, MOS-20, Body Esteem Scale, etc.).  **Based on these data, has Inamed adequately demonstrated reasonable assurance of effectiveness of the implants for each of the augmentation, reconstruction, and revision indications?**

## Panel Question 6

- Given the information in question 1 and if you recommend approval of the PMA, please address the following with respect to labeling for the device:
**Provide your recommendations for the frequency and method of screening for asymptomatic rupture, given that prospective screening for asymptomatic rupture in not currently routinely performed.**
**Provide your recommendations for the necessity of explantation of asymptomatic implant ruptures.**

## Panel Question 7

- Inamed provided a brief description of their postapproval study plan.  The Core Study protocol, as well as informed consent, currently requires yearly follow-up with a physician.  Inamed is now proposing a change to the study requirements as follows.  More specifically, Inamed is proposing a 2-phase postapproval study.  Phase I involves continued physician evaluation as per the IDE protocol through a patient’s 5-year follow-up timepoint.  Phase II involves mail-in surveys completed by the patient from their 6 to 10-year follow-up timepoints.  In the proposed Phase II protocol, for example, MRI screening for asymptomatic rupture would not be captured.  Given this proposal and if you recommend approval of the PMA:
**Please comment on the method of data collection (mailed survey) from the 6-10-year timepoints, given that the Core Study protocol as well as informed consent currently calls for prospective yearly follow-up.  **
**In addition, please describe any other specific endpoints that should be captured as part of their postapproval study.  For example, in the proposed protocol, silent rupture would not be captured. **