# Presentation: 681474

## Inamed Corporation’sSilicone-Filled Breast Implants (P020056)

- April 12, 2005

- Inamed P020056

## FDA Presenters

- CDR Samie Allen, USPHS
- Sahar Dawisha, M.D.
- Pablo Bonangelino, Ph.D.

- Inamed P020056

## Background, Device Description, &Preclinical Testing Overview

- Samie Allen

- Inamed P020056

## Background	

- Dec 2002 – Inamed submitted PMA P020056
- Oct 2003 – PMA presented to Panel
- 494 aug, 221 recon, and 225 rev
- Physician – complete 2-year; partial 3-year
- MRI data – complete 1-year; partial 3-year
- 9 to 6 Panel vote for approvable w/conditions
- Jan 2004 – FDA issued not-approvable letter
- Rupture rate over the lifetime of the device
- Health consequences of implant rupture
- Modes and causes of rupture

- Inamed P020056

## Background	 (cont.)

- Aug 2004 – Inamed submitted response
- April 2005 – return to Panel
- Physician – complete 3-year; partial 4-year
- MRI  data –
- Complete 1 and 3-year for aug
- Complete 1-year and partial 3-year for recon and rev

- Inamed P020056

## Device Description

- Styles 10, 15, 20, 40, 45, 110, 115, 120 & 153
- Round & shaped
- Range of profiles
- Smooth & textured surfaces
- Single lumen except Style 153
- Components: shell, patch, filler, & silicone adhesive

- Inamed P020056

## Preclinical Testing

- Modes and causes of rupture
- Gel bleed
- Shelf life

- Inamed P020056

## 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

- Inamed P020056

## Inamed’s Retrieval Program Analysis: 

Explanted devices received through 3/31/04

442 devices:  40 Core Study and 402 Adjunct Study devices

287 devices intact, 20 excluded

135 available for analysis

- Explanted devices received through 3/31/04
- 442 devices:  40 Core Study and 402 Adjunct Study devices
- 287 devices intact, 20 excluded
- 135 available for analysis

- Modes & Causes of Rupture (cont.)

- Inamed P020056

## Modes & Causes of Rupture (cont.)

| Failure Modes | N |
| --- | --- |
| Surgical damage | 63 |
| Style 153 posterior opening | 48 |
| Sharp edge opening (cause unknown) | 12 |
| Surgical impact | 5 |
| Manufacturing | 4 |
| Style 153 bladder separation | 2 |
| Fold flaw | 1 |
| Total | 135 |

- Inamed P020056

## Modes & Causes of Rupture (cont.)

| Supplemental Analysis of Failure Modes | # (%) of Retrieved Device |  |  |
| --- | --- | --- | --- |
|  | 0-5 yrs | 6-10 yrs |  >10 yrs |
| Instrument damage  | 68 (46%) | 4 (15%) | 0 (0%) |
| Style 153 post. opening | 54 (36%) | 11 (41%) | 0 (0%) |
| Sharp edge opening
(cause unknown) | 17 (11%) | 7 (26%) | 6 (67%) |
| Manufacturing | 4 (3%) | 4 (15%) | 1 (11%) |
| Fold flaw | 1 (1%) | 1 (4%) | 2 (22%) |
| Surgical impact | 4 (3%) | 0 (0%) | 0 (0%) |
| Total  | 148 | 27 | 9  |

- Inamed P020056

## Modes & Causes of Rupture (cont.)

- Inamed P020056

## Modes & Causes of Rupture (cont.)

- Inamed P020056

## Modes & Causes of Rupture (cont.)

- Inamed P020056

## Inamed’s Proposed Next Steps: 

Investigate sharp edge openings

Modify Style 153 design to reinforce patch area

Research if correlation between surgical factors and device rupture

Labeling and physician training

- Investigate sharp edge openings
- Modify Style 153 design to reinforce patch area
- Research if correlation between surgical factors and device rupture
- Labeling and physician training

- Modes & Causes of Rupture (cont.)

- Inamed P020056

## Gel Bleed Testing

- 80cc Style 40 implants incubated on 3M silica disks for 8 weeks at 110°F
- Detected cyclic species D8 to D21 and linear species MD6M to MD18M at 8 weeks.  Cum. bleed rate was 0.0003 gm/cm2/wk by week 8
- Issues with testing:
- No extrapolation of methodology to in-vivo condition
- Control disk saturation impacts all silicone values
- No information on binding capacity of 3M disks
- No analysis for high MW silicone polymers
- No rate of diffusion for each gel bleed constituent

- Inamed P020056

## Shelf Life

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

- Inamed P020056

## 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 Style 153 design changes
- Investigate sharp edge openings
- _Gel Bleed_:
- Issues with methodology that may warrant new testing
- _Shelf Life_:
- Adequate but should continue studies

- Inamed P020056

## Rupture Overview-Inamed Silicone Breast Implants

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

- Inamed P020056

## 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.

- Inamed P020056

## 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?

- Inamed P020056

## Core Study: Silent Rupture 

- _MRI Cohort_ = screening for silent rupture at years 1, 3, 5, 7, and 9 via MRI.
- 90% follow-up compliance at 1st MRI.
- 85% follow-up compliance at 2nd MRI.
- MRI data at 2nd MRI is partial for recon & rev.
- _Non-MRI Cohort_ = no MRI.
- Under-ascertainment of silent rupture.

- Inamed P020056

## Core Study KM Rupture Rate through 4 years : By-Patient

|  | 
MRI | 
Non-MRI |
| --- | --- | --- |
| Aug | 3.4%  (0.5,  6.3)
N = 166 | 1.1%  (0.0,  2.2)
N = 320 |
| Recon | 20.5%  (11.3, 29.2)
N = 107 | 4.9%  (0.2,  9.6)
N = 113 |
| Revision
 | 10.9%  (3.8,  18.1)
N = 78 | 1.7%  (0.0,  4.1)
N = 138 |

- Inamed P020056

## Core Study Rupture Rate through 4 Years: By-Implant

|  | MRI 
N = 663 implants |  | Non-MRI 
N = 1119 implants |  |
| --- | --- | --- | --- | --- |
|  | Silent | Sympt | Silent | Sympt |
| Aug | 5  (0.8%) | 1  (0.2%) | 2  (0.2%) | 3  (0.3%) |
| Recon | 17 (2.6%) | 1  (0.2%) | 4  (0.4%) | 0   |
| Rev | 8  (1.2%) | 0 | 1  (0.1%) | 1  (0.1%) |

- Inamed P020056

## Core Study: Rupture Details

- 25 implants (in 25 patients) confirmed ruptured at explant through 4 years.
- 16 of these silent from MRI Cohort; 7 silent from Non-MRI Cohort » » » 23/25 (92%) silent ruptures.
- 23 intracapsular.
- 1 extracapsular (aug patient from MRI Cohort).
- 1 detachment of Style 153 lumens (recon pt; MRI).
- No obvious cases of migrated gel: no sampling.
- No cases of intra → extracapsular gel: all removed.

- Inamed P020056

## Inamed 10-year Rupture Rate Estimation: Assumptions

- Appropriate to estimate silent rupture rate in Non-MRI using data from MRI group.
- Appropriate to reduce this estimated rate by excluding unconfirmed false positives.
- Appropriate to pool indications.
- Assume rupture rate will remain constant, resulting in straight line for shape of rupture curve.

- Inamed P020056

## Rupture Rate: Other Sources

- Adjunct Study data.
- No assessment of silent rupture.
- Low follow-up.
- Saline-filled breast implant data.
- Deflation is symptomatic rather than silent.
- Differing materials and design.
- Differing implantation techniques.
- Complaint database.
- Voluntary.
- Denominator based on number sold.
- Danish Breast Implant Registry.
- No rupture but also no MRI screening.

- Inamed P020056

## Adjunct Study: Rupture Details

- 99 implants in 99 patients confirmed ruptured at explant.
- 93 intracapsular.
- 6 extracapsular.
- 3 with silicone gel leaking from incision wound (all recon pts).
- 3 with migrated silicone gel in axilla: (1 revision aug, 1 contralateral aug, 1 recon—all after 3 years).

- Inamed P020056

## 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.

- Inamed P020056

## 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.

- Inamed P020056

## Rupture Health Consequences: 				Core Study

- Local Complications, CTD Signs and Symptoms, Patient Satisfaction.
- N = 25 confirmed ruptured.
- N = 131 confirmed intact.
- Combined indications.
- 30-60% without F/U after explant.

- Inamed P020056

## Rupture Health Consequences: Adjunct Study

- Local complications.
- N = 99 confirmed ruptured.
- Complications reported at explant: CC, asymmetry, palpability.
- N = 77 implants replaced.
- Follow-up of 63 patients; 21 w/ complication.
- Complication after rupture: reoperation.
- Removal with replacement
- Capsule procedure

- Inamed P020056

## 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.

- Inamed P020056

## Rupture Summary: Inamed Data

- 3-4 years of comprehensive rupture data.
- Most ruptures are silent, diagnosed via MRI.
- Most ruptures are intracapsular: 4-6% extracapsular; 3% migrated silicone gel.
- Data at 3-4 years extrapolated to 10 years.
- Data limited to address intra → extracapsular rupture and silent → symptomatic rupture.
- No statistical associations between rupture and local complications, satisfaction, CTD S/S:  lack of statistical power.

- Inamed P020056

## 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)

- Inamed P020056

## Silent Extracapsular Rupture:Patient History

- 36 Year Old Bilateral Augmentation.
- Capsulectomy at 10 months in right implant.
- 1st MRI 4 months later: no rupture.
- 2nd MRI at 3 years: rupture in left implant
- Exploratory surgery in left implant 2 weeks later shows free gel in pocket.
- Silicone extruding through left incision 2 months later.
- Bilateral implant removal without replacement.
- No complications reported.

- Inamed P020056

## 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.

- Inamed P020056

## Labeling Issues

- Method and frequency of silent rupture screening.
- Low sensitivity and specificity of MRI.
- Frequency of MRI screening every 1-2 years or as recommended by surgeon.
- Most ruptures as silent not addressed.
- Clinical management of rupture.
- Recommendation on whether to remove silent ruptured implant is not clear.
- Health consequences of extracapsular gel.
- No evidence that extracapsular gel causes any symptoms is inconsistent with Danish literature.

- Inamed P020056

## Post-approval Issues

- Continue Core Study.
- MRI discontinuation issues
- Link voluntary registry to rupture warranty program.
- no clinical postop data collected
- Additional data from Danish Registry or 3rd party (e.g., NIH).
- 3rd party data source not specified
- types of analyses not specified
- Physician education/training program.
- No certification required for product access
- Rupture screening method and frequency not included

- Inamed P020056

## Safety and Effectiveness Information

- Complications other than rupture and benefits as described in Tab 5 of Panel Pack—database closure one year earlier.
- Consider augmentation and reconstruction separately.
- Consider revision as a continuum of augmentation or reconstruction.

- Inamed P020056

## Thank You

- Inamed P020056

## Difficulties in Predicting Long-Term Probability of Rupture

- Pablo Bonangelino, Ph.D.

- Inamed P020056

## Sponsor’s Approach

- Based on extrapolating an average percent ruptures per year of 1.4%.
- Simply computed 1.4% x 10 yrs to obtain a probability of rupture by year 10 of approximately 14%.
- 1.4% ruptures/year can be questioned.
- The underlying assumption is a constant percentage of ruptures per year out to 10 years.

- Inamed P020056

## The Issue: Difficulty in Predicting Long-Term Effects

- Difficulty demonstrated by considering  various models for the rate of occurrence of rupture (percentage of ruptures/year).
- Consider three possibilities (out of many):
- Constant percentage of ruptures per year
- Linearly increasing percentage of ruptures per year
- Quadratically increasing percentage of ruptures per year.

- Inamed P020056

- These three models for the percentage of ruptures per year correspond to three survival models.
- It is not known whether any of these models represent the true situation.
- Models give an example of variability.

- Inamed P020056

## Available Data

- Kaplan-Meier rates of symptomatic rupture through year 3.
- Kaplan-Meier rates of silent rupture based on MRI data from year 1 and year 3.

- Inamed P020056

## We attempted to fit our models only for the MRI Cohort, as these were the only patients who had active ascertainment of implant rupture. 

Note that for silent rupture in the MRI cohort, we really only have two data points, at the year-1 and year-3 MRI.  Thus there are only two points on the following graphs to represent the data.

The example which follows consists of data from the augmentation MRI cohort.

- Note that for silent rupture in the MRI cohort, we really only have two data points, at the year-1 and year-3 MRI.  Thus there are only two points on the following graphs to represent the data.
- The example which follows consists of data from the augmentation MRI cohort.

- Inamed P020056

## Assumption 1: Constant % of ruptures/year

- Inamed P020056

## Assumption 2:  Linearly increasing % of ruptures/year

- Inamed P020056

## Assumption 3:  Quadratically increasing % of ruptures/yr

- Inamed P020056

- All three of our selected models appear plausible.
- With limited data points, any number of models will approximately fit.

- Inamed P020056

## Methods

- We used the three models selected for the percentage of ruptures per year to illustrate the corresponding cumulative probability of implant rupture by year 10.
- Predictions are given for the MRI cohort for augmentation, reconstruction, revision and all indications combined.

- Inamed P020056

## Illustration of the Variability in Cumulative Probability of Implant Rupture by Year 10

| MRI Cohort- All Ruptures (Silent and Symptomatic) |  |  |  |
| --- | --- | --- | --- |
| Model: | Constant hazard | Linearly increasing
hazard | Quadratically increasing
Hazard |
| Augmentation | 5%  
(0%, 10%)  | 12%  
(0%, 22%)                           | 29%  
(0%, 46%) |
| Reconstruction | 39%  
(22%, 54%) | 70%  
(46%, 83%) | 95%  
(82%, 99%) |
| Revision | 18%  
(6%, 28%) | 38%  
(15%, 55%) | 70%  
(39%, 84%) |
| Indications combined | 21% 
(13%, 28%) | 43%  
(29%, 54%) | 77%  
(61%, 86%)  |

- Inamed P020056

## Graphical Illustration of Variability in Probability of being Rupture-free for Three Models:

- Inamed P020056

## Summary

- It is difficult to reasonably predict the probability of rupture by year 10 with the available data.

- Inamed P020056

## Conclusion of FDA’s Presentation

- Inamed P020056

## Panel Questions

- Inamed P020056

## Panel Question 1

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

- Inamed P020056

## Panel Question 2

- Please discuss whether Inamed 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.

- Inamed P020056

## Panel Question 3

- Inamed’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.

- Inamed P020056

## Panel Question 4

- Please discuss whether the plans are adequate to address the issues previously noted by the Panel or any other postapproval concerns that you might have.

- Inamed P020056

## 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.

- Inamed P020056