NATRELLE HIGHLY COHESIVE SILICONE-FILLED BREAST IMPLANTS

P040046 · Allergan · FTR · Feb 20, 2013 · General, Plastic Surgery

Device Facts

• Record ID: P040046
• Device Name: NATRELLE HIGHLY COHESIVE SILICONE-FILLED BREAST IMPLANTS
• Applicant: Allergan
• Product Code: FTR · General, Plastic Surgery
• Decision Date: Feb 20, 2013
• Decision: APPR
• Regulation: 21 CFR 878.3540
• Device Class: Class 3
• Attributes: Therapeutic

Intended Use

Natrelle® 410 Highly Cohesive Anatomically Shaped Silicone-Filled Breast Implants are indicated for women for the following uses (procedures): Breast Augmentation for women at least 22 years old. Breast augmentation includes primary breast augmentation to increase the breast size, as well as revision surgery to correct or improve the result of a primary breast augmentation surgery. Breast Reconstruction. Breast reconstruction includes primary reconstruction to replace breast tissue that has been removed due to cancer or trauma or that has failed to develop properly due to a severe breast abnormality. Breast reconstruction also includes revision surgery to correct or improve the result of a primary breast reconstruction surgery.

Device Story

Natrelle® 410 is a single-lumen, anatomically shaped, BIOCELL® textured silicone elastomer shell implant filled with highly cohesive silicone gel. Designed for breast augmentation and reconstruction; implanted by surgeons in clinical settings. Features orientation marks (silicone elastomer dots) on anterior/posterior surfaces to assist vertical alignment in the pocket. Distinguishable from previous Natrelle designs by more cohesive gel, specific anatomical shapes, and orientation marks. Implanted via surgical pocket; provides volume and shape correction. Benefits include aesthetic improvement and tissue replacement. Safety monitored via clinical studies tracking complications (e.g., rupture, capsular contracture, reoperation). MRI used for rupture detection; gel fracture distinguished from rupture via imaging. Device provided dry-heat sterilized.

Clinical Evidence

Prospective, 10-year, multicenter, single-arm observational study (Core Study) of 941 women. 7-year follow-up data reported. Primary endpoints: local complication rates, reoperation, implant removal, and patient satisfaction. 7-year cumulative complication rates: 31% (primary augmentation), 47.7% (revision-augmentation), 53% (primary reconstruction), 57.2% (revision-reconstruction). MRI sub-study evaluated rupture detection sensitivity/specificity. No clinical data on ALCL in pivotal study; two global cases reported post-market. Bench testing included fatigue, gel bleed, gel cohesion, and toxicology (mutagenicity, reproductive, chronic toxicity).

Technological Characteristics

Single-lumen, anatomically shaped, BIOCELL® textured silicone elastomer shell. Materials: Dimethyl/Diphenyl Silicone Elastomer (shell/patch), Dimethyl Silicone Gel (fill). Shell thickness: 0.018-0.060 inches. Orientation marks: circular silicone elastomer dots. Sterilization: dry-heat. Connectivity: N/A. No software/algorithm.

Indications for Use

Indicated for women >=22 years old for primary breast augmentation, revision breast augmentation, primary breast reconstruction (post-cancer/trauma/abnormality), and revision breast reconstruction. Contraindicated in women with active infection, existing breast cancer/pre-cancer without adequate treatment, or those currently pregnant or nursing.

Regulatory Classification

Identification

(1) Single-lumen silicone gel-filled breast prosthesis. A single-lumen silicone gel-filled breast prosthesis is a silicone rubber shell made of polysiloxane(s), such as polydimethylsiloxane and polydiphenylsiloxane. The shell either contains a fixed amount cross-linked polymerized silicone gel, filler, and stabilizers or is filled to the desired size with injectable silicone gel at time of implantation. The device is intended to be implanted to augment or reconstruct the female breast.(2) Double-lumen silicone gel-filled breast prosthesis. A double lumen silicone gel-filled breast prosthesis is a silicone rubber inner shell and a silicone rubber outer shell, both shells made of polysiloxane(s), such as polydimethylsiloxane and polydiphenylsiloxane. The inner shell contains fixed amounts of cross-linked polymerized silicone gel, fillers, and stabilizers. The outer shell is inflated to the desired size with sterile isotonic saline before or after implantation. The device is intended to be implanted to augment or reconstruct the female breast.(3) Polyurethane covered silicone gel-filled breast prosthesis. A polyurethane covered silicone gel-filled breast prosthesis is an inner silicone rubber shell made of polysiloxane(s), such as polydimethylsiloxane and polydiphenylsiloxane, with an outer silicone adhesive layer and an outer covering of polyurethane; contained within the inner shell is a fixed amount of cross-linked polymerized silicone gel, fillers, and stabilizers and an inert support structure compartmentalizing the silicone gel. The device is intended to be implanted to augment or reconstruct the female breast.

Reference Devices

• Natrelle Silicone-Filled Breast Implants (P020056)

Submission Summary (Full Text)

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SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)

I. GENERAL INFORMATION

Device Generic Name: Gel-Filled Mammary Prosthesis
Device Trade Name: Natrelle® 410 Highly Cohesive Anatomically Shaped Silicone-Filled Breast Implants
Device Procode: FTR
Applicant’s Name and Address: Allergan, Inc. 71 South Los Carneros Road Goleta, California 93117
Date(s) of Panel Recommendation: Not Applicable
Premarket Approval Application (PMA) Number: P040046
Date of FDA Notice of Approval: February 20, 2013
Expedited: Not Applicable

II. INDICATIONS FOR USE

Natrelle® 410 Highly Cohesive Anatomically Shaped Silicone-Filled Breast Implants are indicated for women for the following uses (procedures):

- Breast Augmentation for women at least 22 years old. Breast augmentation includes primary breast augmentation to increase the breast size, as well as revision surgery to correct or improve the result of a primary breast augmentation surgery.
- Breast Reconstruction. Breast reconstruction includes primary reconstruction to replace breast tissue that has been removed due to cancer or trauma or that has failed to develop properly due to a severe breast abnormality. Breast reconstruction also includes revision surgery to correct or improve the result of a primary breast reconstruction surgery.

III. CONTRAINDICATIONS

Breast implant surgery should not be performed in:

- Women with active infection anywhere in the body.
- Women with existing cancer or pre-cancer of their breast who have not received adequate treatment for those conditions

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- Women who are currently pregnant or nursing

## IV. WARNINGS AND PRECAUTIONS

The warnings and precautions can be found in the Natrelle® 410 Highly Cohesive Anatomically Shaped Silicone-Filled Breast Implants labeling.

## V. DEVICE DESCRIPTION

Each Natrelle® 410 Highly Cohesive Anatomically Shaped Silicone-Filled Breast Implant consists of a single-lumen, shaped, textured (BIOCELL®) elastomer surface shell, with a patch positioned on the posterior side and filled with a highly cohesive silicone gel. Orientation marks are attached to the implant shell. The implants are provided dry-heat sterilized with a 5-year shelf life from the date of sterilization. Figure 1 shows a diagram of the implant.

Figure 1: Natrelle® 410 Highly Cohesive Anatomically Shaped Silicone-Filled Breast Implant

The orientation marks are circular silicone elastomer dots located on the anterior and posterior surfaces of the implant to assist in aligning the implant vertically in the pocket. There are 2 orientation marks present on the anterior side of the implant in the lower pole. Depending on the style, there are either 3 or 4 orientation marks on the posterior surface of the implant. (The smaller and/or shorter styles may only have the 3 marks). An illustration of the orientation marks are shown in Figure 2 below.

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Figure 2: General Orientation Mark Locations

The principal features distinguishing this style from Allergan's previously approved Natrelle Silicone-Filled Breast Implants (P020056) are the:

More cohesive silicone gel fill
Device shape (Figure 3)
Range of shapes and sizes (Table 1)
- Presence of orientation marks (Figure 2)

Figure 3 shows the device shapes and the profiles of the implants.
Figure 3: Profiles Available for Natrelle® 410 Highly Cohesive Anatomically Shaped Silicone-Filled Breast Implants

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A = Width
B = Height
C = Projection

Table 1 below shows the Allergan styles that are approved. All approved implants are shaped and BIOCELL® textured, with shell thicknesses of 0.018-0.060 inches. Table 2 shows the general device materials for the shell, patch, and gel components.

Table 1: Approved Natrelle® 410 Highly Cohesive Anatomically Shaped Silicone-Filled Breast Implants

| Style Number | Profiles | | Volume (cc) | Number of Sizes |
| --- | --- | --- | --- | --- |
| | Height | Projection | | |
| 410FM | Full | Moderate | 205-670 | 11 |
| 410FF | Full | Full | 185-740 | 12 |
| 410MM | Moderate | Moderate | 160-450 | 9 |
| 410MF | Moderate | Full | 140-640 | 13 |

Table 2: Device Materials

| Component | Material |
| --- | --- |
| Shell, inner/outer layers | Dimethyl/Diphenyl Silicone Elastomer |
| Shell, barrier layer | Dimethyl/Diphenyl Silicone Elastomer |
| Shell, textured layer | Dimethyl/Diphenyl Silicone Elastomer |
| Patch assembly | Dimethyl Silicone Elastomer and Dimethyl/Diphenyl Silicone Elastomer |
| Silicone adhesive | Dimethyl Silicone Elastomer |
| Gel | Dimethyl Silicone Gel: Base and Crosslinker; Platinum Cure (78% silicone oil by weight extractable by hexane) |

# VI. ALTERNATIVE PRACTICES AND PROCEDURES

There are several other alternatives for augmentation or reconstruction of the breast with silicone-filled breast implants. Alternative procedures include undergoing no treatment, wearing an external prosthesis inside the woman's brassiere, transferring tissue from other parts of the body (autologous tissue transfer procedure or flap procedure), or placement of saline-filled breast implants. Each alternative has its own advantages and

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disadvantages. A patient should fully discuss these alternatives with his/her physician to select the method that best meets expectations and lifestyle.

## VII. MARKETING HISTORY

Silicone-filled breast implants are pre-amendment devices that have been used since 1963. The Natrelle® 410 Highly Cohesive Anatomically Shaped Silicone-Filled Breast Implants are similar to the pre-amendment silicone-filled breast implants with the major difference being that the Natrelle® Highly Cohesive devices are shaped devices filled with a more cohesive gel. Over 600,000 of the current Natrelle® 410 design have been produced and sold outside the United States in 24 countries since 1993. Allergan’s Natrelle® 410 Highly Cohesive Anatomically Shaped Silicone-Filled Breast Implants have not been withdrawn from any foreign market for any reason relating to the safety and effectiveness of the device.

On September 8, 2000, Allergan received approval to begin the Natrelle® 410 Highly Cohesive Anatomically Shaped Silicone-Filled Breast Implant Pivotal clinical study (referred to as the Pivotal or Core study below). The Pivotal Study is the primary clinical data set in this PMA. Two additional clinical studies, Continued Access and Continued Access Reconstruction/Revision (CARE), provided further access and information in the U.S.

## VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH

Below is a list of the potential adverse effects (e.g., complications) associated with the use of the device.

- Reoperation (additional surgeries)
- Implant Removal with or without Replacement
- Implant Rupture
- Capsular Contracture
- Swelling
- Implant Malposition or Displacement
- Breast Pain
- Ptosis
- Infection including toxic shock syndrome
- Breast/Skin Sensation Changes
- Nipple Complications
- Seroma/Fluid Accumulation
- Delayed Wound Healing
- Hematoma
- Hypertrophic Scarring
- Asymmetry
- Redness
- Wrinkling/Rippling

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- Skin Rash
- Bruising
- Extrusion of Implant
- Implant Palpability/Visibility
- Gel Fracture
- Irritation
- Tissue/Skin Necrosis
- Upper Pole Fullness
- Capsule Calcification
- Lymphadenopathy
- Lymphedema
- Palpable Orientation mark
- Pneumothorax
- Scarring
- Breastfeeding difficulties
- Calcium deposits
- Breast tissue atrophy/chest wall deformity
- Connective Tissue Disease (CTD)
- CTD signs and symptoms
- Neurological Disease
- Neurological Signs and Symptoms
- Cancer
- Lymphoma
- Suicide
- Potential Effects on Offspring

For the specific adverse events that occurred in the clinical studies, please see Section X below.

## IX. SUMMARY OF PRECLINICAL CLINICAL STUDIES

The preclinical studies are divided into 6 sections: chemistry, toxicology, mechanical testing, modes and causes of device failure, magnetic resonance imaging phantom study, and shelf life.

## A. Chemistry Data

### 1. Extent of Crosslinking

Shell and Patch Materials - The physical strength (tensile strength) and elasticity (elongation at failure) of the shell and patch materials are results of the extent of crosslinking achieved during the vulcanization process. The physical properties of cured samples of all elastomer lots used for breast implant shells and

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patches are measured to ensure they meet or exceed pre-established material specifications prior to being released for use in the manufacture of the devices.

This testing demonstrated the extent of crosslinking of the elastomers used in the device shell is sufficient to assure all shells meet a specification of a minimum 3.0 lb break force and 380% elongation.

**Gel Materials** - Using penetrometer testing, every lot of gel received by Allergan is tested to ensure that the extent of crosslink density conforms to predetermined specifications prior to being released for use in the manufacture of breast implants. In addition, every batch of mixed gel is penetrometer tested to ensure that the penetration conforms to predetermined specifications.

The penetrometer testing on mixed gel lots occurs during the manufacture of every lot of Natrelle® 410 Highly Cohesive Anatomically Shaped Silicone-Filled Breast Implants produced by Allergan. Penetrometer samples are obtained from the same batch that is used to fill the implants. The uniformity of the crosslink density across all lots of gel used is thus ensured by conducting penetrometer testing on every batch of mixed gel prior to filling the devices, for each breast implant lot produced. All lots of gel used in the implants have an extent of crosslinking sufficient to achieve the internal penetrometer specification.

## 2. Extractables

Finished sterilized devices were analyzed for extractables. Table 3 provides the amounts of various low molecular weight components present in the subject device. The techniques used to detect these components include solvent extraction followed by gas chromatography, using both a mass spectrometer (GC-MS) and a flame ionization detector (GC-FID), and by gel permeation chromatography.

The highest level of extracts was isolated using n-hexane as the extracting solvent. Table 3 also lists the concentration of the various oligosiloxanes quantified from hexane extract. Polydimethyl cyclic siloxanes (PDMS) from cyclic dimethyl oligo siloxanes (D₄–D₂₁) were detected and analyzed from extracts of both the shell and gel; polydimethyl linear oligosiloxanes from L₅ to L₁₈ were detected in hexane extracts of the gel and shell that had been exposed to gel. Identification of the various low molecular weight components was performed by matching the elution time of the component of the extract with analytical standards, or in some cases extrapolation of the data obtained from these standards. Standards for linear and cyclic polydimethyl siloxanes are commercially available; however, because there are no commercially available standards for diphenyl oligosiloxanes (diphenyl siloxanes or mixed dimethyl diphenyl siloxanes), it is not possible to determine the level of these compounds in the extracts.

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Table 3: Concentrations of Low Molecular Weight Silicone Components Detected (in ppm by component weight)

| Identification | Molecular Weight (amu) | Gel (ppm) | Implant Shell & Patch (ppm) |
| --- | --- | --- | --- |
| D3 | 222 | ND<10 | ND<0.1 |
| D4 | 296 | 10 | ND<0.1 |
| D5 | 370 | 8 | 2 |
| D6 | 444 | 46 | 2 |
| D7 | 518 | 35 | 4 |
| D8 | 592 | 23 | 3 |
| D9 | 666 | 17 | 3 |
| D10 | 740 | 63 | 43 |
| D11 | 814 | 88 | 66 |
| D12 | 888 | 52 | 41 |
| D13 | 962 | 59 | 11 |
| D14 | 1036 | 90 | 16 |
| D15 | 1110 | 130 | 21 |
| D16 | 1184 | 127 | 25 |
| D17 | 1258 | 193 | 25 |
| D18 | 1332 | 207 | 27 |
| D19 | 1406 | 240 | 30 |
| D20 | 1480 | 267 | 34 |
| D21 | 1554 | 283 | 33 |
| L1 | 236 | ND<10 | ND<0.1 |
| L2 | 310 | ND<10 | ND<0.1 |
| L3 | 384 | ND<10 | ND<0.1 |
| L4 | 458 | ND<10 | ND<0.1 |
| L5 | 532 | TR<1 | ND<0.1 |
| L6 | 606 | 2 | ND<0.1 |
| L7 | 680 | 13 | 0 |
| L8 | 754 | 3 | 0 |
| L9 | 828 | 4 | 1 |
| L10 | 902 | 8 | 3 |
| L11 | 976 | 43 | 25 |
| L12 | 1050 | 15 | 6 |
| L13 | 1124 | 5 | 8 |
| L14 | 1198 | 26 | 10 |
| L15 | 1272 | 30 | 14 |
| L16 | 1346 | 28 | 61 |
| L17 | 1420 | 100 | 70 |
| L18 | 1494 | 97 | 64 |

ND = Not Detected (at limit indicated); TR = Trace (at limit indicated)

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The extractables testing results are comparable to results seen in previously approved breast implant devices.

# 3. Volatiles

Analysis for volatiles present in the shell and patch material showed that the maximum exposure possible from implant residuals for isopropyl alcohol to be $201.1\mu \mathrm{g}$ and for xylene to be $337.2\mu \mathrm{g}$ . Analysis for volatiles present in gel was not necessary because the gel materials do not contain any organic solvents. The volatiles testing results are comparable to results seen in previously approved breast implant devices.

# 4. Heavy Metals

Complete metal analyses were provided on the individual components of the device. The metal concentrations obtained from the atomic absorption of digested device materials are shown in Table 4 below.

Table 4: Concentrations of Metal Contents Detected (in ppm)

| Metal | Atomic Weight (amu) | Gel | Shell (Inner and Outer Layers) | Shell (Barrier Layer) | Patch |
| --- | --- | --- | --- | --- | --- |
| Antimony | 121.76 | ND (<0.1) | ND (<0.1) | ND (<0.1) | ND (<0.1) |
| Arsenic | 74.92 | ND (<0.1) | ND (<0.1) | ND (<0.1) | ND (<0.1) |
| Barium | 137.33 | 1 | 1 | 1 | 2 |
| Beryllium | 9.01 | ND (<0.1) | ND (<0.1) | ND (<0.1) | ND (<0.1) |
| Cadmium | 112.41 | ND (<0.1) | ND (<0.1) | ND (<0.1) | ND (<0.1) |
| Calcium | 40.08 | ND (<10) | ND (<10) | ND (<10) | ND (<10) |
| Chromium | 52.00 | 0.2 | 0.3 | 0.4 | 1.8 |
| Cobalt | 58.93 | ND (<0.2) | ND (<0.2) | ND (<0.2) | ND (<0.2) |
| Copper | 63.55 | ND (<0.1) | ND (<0.1) | ND (<0.1) | ND (<0.1) |
| Iron | 55.84 | 1.2 | ND (<0.1) | 0.2 | 8.7 |
| Lead | 207.19 | 0.3 | ND (<0.2) | ND (<0.2) | ND (<0.2) |
| Magnesium | 24.30 | ND (<10) | ND (<10) | ND (<10) | ND (<10) |
| Manganese | 54.94 | ND (<0.05) | ND (<0.05) | ND (<0.05) | 0.15 |
| Mercury | 200.59 | ND (<1) | ND (<1) | ND (<1) | ND (<1) |
| Molybdenum | 95.94 | ND (<0.5) | ND (<0.5) | ND (<0.5) | ND (<0.5) |
| Nickel | 58.69 | ND (<0.2) | ND (<0.2) | 1 | 0.7 |
| Potassium | 39.10 | ND (<1) | ND (<1) | 8 | 1 |
| Selenium | 78.96 | ND (<0.1) | ND (<0.1) | ND (<0.1) | ND (<0.1) |
| Silver | 107.87 | ND (<0.1) | ND (<0.1) | 0.2 | ND (<0.1) |
| Sodium | 22.99 | ND (<10) | ND (<10) | ND (<10) | ND (<10) |
| Thallium | 204.38 | ND (<1) | ND (<1) | ND (<1) | ND (<1) |
| Vanadium | 50.94 | ND (<0.4) | ND (<0.4) | ND (<0.4) | ND (<0.4) |
| Zinc | 63.40 | 0.22 | 0.12 | ND (<0.05) | 3.9 |

ND = Not Detected (at limit indicated)

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In addition, complete catalyst metal analyses were provided on the individual components of the device. The metal concentrations obtained from the atomic absorption of digested device materials are shown in Table 5 below.

Table 5: Concentrations of Catalyst Metals Detected (in ppm by component weight)

| Identification | Atomic Weight (amu) | PQL (ppm) | Gel (ppm) | Implant Shell (ppm) | Patch (ppm) | Total (ppm) |
| --- | --- | --- | --- | --- | --- | --- |
| Tin | 118.71 | 0.01 | 0.06 | 0.05 | 6.60 | 0.077 |
| Platinum | 195.08 | 0.01 | 4.00 | 3.30 | 2.60 | 3.95 |

The heavy metal analysis results are comparable to results seen in previously approved breast implant devices.

As a note, platinum is a metal used as a catalyst in the manufacture of the shell and gel components of silicone breast implants. The small amounts of platinum remaining in the product following manufacturing may enter the body, either by diffusing through the intact shell (i.e., through gel bleed) or through an implant rupture. Based on a review of the gel bleed testing, the published literature on this topic, as well as the biocompatibility testing and clinical data on the device, FDA concluded that the platinum contained in breast implants is in the zero oxidation state, which has the lowest toxicity and, thus, does not pose a significant risk to women with silicone breast implants. FDA has posted a Backgrounder on its website, which provides a brief summary of some of the key scientific studies on platinum and silicone gel-filled breast implants (http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/ImplantsandProsthetics/BreastImplants/UCM064040)

5. Silicone Filler (Silica)

X-ray diffraction studies on the elastomer shell confirmed that the silica used as reinforcing filler material is in the amorphous form, not in crystalline form.

B. Toxicology Data

Allergan provided toxicology data, including pharmacokinetic analysis information, immunotoxicity determinations, reproductive toxicology/teratology and carcinogenicity data regarding the breast implant device. Style 410 Silicone-Filled Breast Implant, the subject of this PMA, was subjected to toxicological risk assessment and concluded to be chemically identical to breast implant Styles 10, 20, 40, 45, 110, and 120 devices which were approved for marketing via P020056. As the Style 410 device gel is constructed from the same silicone materials and uses the same manufacturing methods as the devices that are the subject of P020056, all biocompatibility testing completed for Style 10, 20, 40, 45, 110, and 120 devices was also considered to be applicable to the Style 410 device.

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1. Pharmacokinetic Studies

A literature review was completed regarding the pharmacokinetics of silicone elastomers, gel, fluids, and low molecular weight compounds. The reviewed literature included 63 published journal articles and publicly available Dow Corning studies. These studies examined aspects of the Absorption, Distribution, Metabolism or Elimination (ADME) of silicone fluid and low molecular weight silicones. Pharmacokinetic studies of silicone were also reviewed as part of the evaluation performed by the Committee on the Safety of Silicone Breast Implants, Institute of Medicine (IOM). The literature indicates that silicone materials appear to have low mobility, typically remaining where implanted, and eliciting only a local response. The IOM concurs with this perspective stating that the depots of gel, whether free or in implants, remain predominantly where they are implanted.

To independently assess the potential for distribution of silicone post-implantation, a pharmacokinetics study of the silicone gel used in Allergan's Silicone-Filled Breast Implants was performed. The study design consisted of 3 Fischer F-344 female rats that were subcutaneously implanted with approximately 3.4 grams of C¹⁴ radiolabeled silicone gel for 30 days. After dosing, the rats were housed in individual glass metabolism chambers, which allowed separate collection of carbon dioxide, potential expired volatile chemicals, feces and urine. Blood was drawn throughout the study period. Low amounts of the radiolabel were collected in blood (0.0190% of dose), or were measured cumulatively in expired air (0.0004% of dose), feces (0.0186% of dose) and urine (0.0005% of dose). In regard to individual tissues, the liver, muscle and skin had the highest counts (0.0122%, 0.0055% and 0.0020% of the implanted dose, respectively). The vast majority of the gel remained at the implantation site (~100% of dose), thus demonstrating that the gel was encapsulated, with minimal movement away from the site of implantation. The data are similar to the observations reported in the published scientific literature. The results are comparable to results seen in previously approved breast implant devices.

2. General Toxicity Evaluations

Cytotoxicity

Cytotoxicity testing using mouse L929 cells in the ISO agarose overlay method was conducted in parallel on silicone gel from the previously approved Style 110 breast implant and the current Style 410 breast implant device. Concurrent control groups included a negative control (HDPE) and a positive control (latex). For the acceptance criteria, the negative control must have been a grade of 0 (reactivity none), the positive control must have produced a zone of lysis (reactivity moderate, to severe), and the three monolayers exposed to the test article showed no greater than a grade of 2 (reactivity mild). In the agarose overlay assessment, the negative and positive control groups performed as anticipated, validating the tests. Both products were found to be non-cytotoxic in that neither device showed evidence of causing cell lysis or toxicity.

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Minimum essential medium (MEM) extracts of test articles representative of the silicone elastomers and gel materials used in the Style 410 device were also evaluated for cytotoxic effects on mouse L929 fibroblast cells. Shells were extracted at 120 cm²/20-mL extraction medium, while all other remaining components were extracted at 4 g/20-mL extraction medium. Samples were extracted at 37°C for 24-hours. Cultures containing test material extract medium were incubated at 37°C for 48-hours. Cells were examined for lysis and changes in cell morphology or cell death following 24- and 48-hours exposure. The results showed that the test articles consisting of the silicone gel filling, shell (also referred to as barrier), patch, adhesive, and orientation marks (same material as patch) met the acceptance criterion of being non-cytotoxic.

## 3. Irritation

Saline, sesame seed oil, polyethylene glycol (PEG), and alcohol in saline (1:10) extracts of test articles representative of the silicone elastomers and gel materials used in the Style 410 gel-filled device were evaluated for irritation in rabbits. Test articles were extracted at the USP-specified ratio of 60 cm²/20-mL extract solution. Resulting test article extracts composed of the silicone gel filling, shell, patch, adhesive and orientation marks (same material as patch) were injected subcutaneously (individually or as composite samples) at the USP-specified volume and observed for erythema and edema. For the acceptance criterion, the mean macroscopic scores for test implants were compared to mean scores of the control sites. The requirements of the test were met if the difference between test and control score means (macroscopic) was not greater than 1.0. The results showed that none of the test article extracts were irritants.

## 4. Acute Systemic Toxicity

Saline, sesame seed oil, PEG, and alcohol in saline (1:10) extracts of test articles representative of the silicone elastomers and gel materials used in the Style 410 gel-filled devices were evaluated for acute systemic toxicity in mice. Test articles were extracted at the USP-specified ratio of 60 cm²/20-mL extract solution. Resulting test article extracts composed of the silicone gel fill, shell, patch, adhesive and orientation marks (same material as patch) were then injected intravenously or intraperitoneally into mice (individually or as composite samples) at the USP-specified volumes. Animals were observed for abnormal clinical signs and mortality. If during the observation period, none of the mice treated with the individual test extract exhibited a significantly greater reaction than the corresponding control mice, the test extract met the test requirements. The results showed that none of the test article extracts were toxic.

## 5. Hemocompatibility

Test article (2 g) representative of the silicone elastomers and gel materials used in the Style 410 gel-filled devices was added to 10 mL 0.9% sodium chloride USP solution (SC) to determine whether direct contact with the test article would cause hemolysis in vitro. For the acceptance criteria, an average hemolytic index of the triplicate test samples was compared to the negative control. A hemolytic index of

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2% or less was considered to be nonhemolytic. Whole rabbit blood (0.2 mL) was added to the test article in SC. A negative control (SC) and USP Purified Water (PW) positive control were similarly prepared but without the test article. Samples examined spectrophotometrically at 545 nm showed a hemolysis value of 0% indicating that the test article was not hemolytic. In a second study, test article (13 g) representative of the silicone elastomers and gel materials used in the Style 410 gel-filled devices was extracted with 65 mL SC at 121°C for 1 hour to determine whether indirect contact with leachables from the test article would cause hemolysis in vitro. Whole rabbit blood (0.2 mL) was added to 10 mL of the test article SC extract. A negative control (SC) and PW positive control were similarly prepared but without the test article. Samples examined spectrophotometrically at 545 nm showed a hemolysis value of 0% indicating that the test article was not hemolytic.

## 6. Pyrogenicity

Test article (39.4 g) representative of the silicone elastomers and gel material used in the Style 410 gel-filled devices was extracted with 197 mL of SC at 121°C for 1 hour, and then allowed to cool to 37°C. Three rabbits each received a single intravenous injection of the test extract via the marginal ear vein at 10 mL/kg body weight. Rectal temperatures were measured and recorded at 30-minute intervals between 1 and 3 hours after injection. The test article met the USP criteria because no single animal showed an increase of 0.5°C or more above its baseline temperature. The test article was determined to be non-pyrogenic.

## 7. Immunology

Test articles representative of the silicone elastomers and gel material used in the Style 410 gel-filled devices were evaluated for immunotoxicity and dermal sensitization.

- Immunotoxicity – In 5 separate studies, female B6C3F1 mice were subcutaneously implanted for 28-days with 1) 1, 2, or 3 cc silicone gel, 2) 56.52 mm², 113.04 mm², or 226.08 mm² silicone shell, 3) 56.52 mm², 113.04 mm², or 226.08 mm² leaf valve and overlay assembly materials, 4) 56.52 mm², 113.04 mm², or 226.08 mm² patch and overlay assembly material, or 5) 150.8 mm², 301.6 mm², or 452.4 mm² diaphragm valve and plug assembly materials. The immunological parameters evaluated at sacrifice on study Day 29 included: absolute body weight and body weight gain, absolute and relative spleen and thymus weights, thymus histopathology, hematological measurements (e.g., RBC, hemoglobin, hematocrit, MCV, MCH, MCHC, platelet number, WBC, WBC differential), spleen IgM antibody response to the T-dependent antigen, T cell and T cell subsets and B cell enumeration, mixed leukocyte response (MLR) to allogeneic spleen cells, and natural killer (NK) cell activity. For the acceptance criteria, animals were assessed for signs of toxicity.

In the silicone gel evaluation, there were no statistically significant differences between the test article and control groups for the immunologic assays.

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Exposure to the silicone shell also did not affect the immunological functions of the study animals. Although there was a statistically significant increase in the antibody-forming response observed between groups in the study, this was considered related to the historically low response of the control group, as compared to an actual change in activity due to test article exposure.

In the leaf valve and overlay assembly evaluation, the functional ability of the immune system was also not affected, with the possible exception of the percentage of eosinophils, which increased in the low dose group. It was considered, however, that the increase was related to a low percentage of eosinophils in the sham control animals, and no significant increase was seen in the absolute number of eosinophils.

In the diaphragm valve and plug assembly evaluation, the functional ability of the immune system was also not affected, with the possible exception of natural killer cells (NK), which decreased in the low and middle dose groups and increased in the high dose group. It was considered, however, that the physical size and number of implants employed may have contributed to the effects observed in NK activity.

In the patch and overlay evaluation, although some changes were observed in spleen cell number and spleen cell populations, exposure to the test article was concluded to not have adversely affected the functional ability of the immune system.

In conclusion, the data indicate that the test articles did not adversely affect the immune system.

- Sensitization – Saline and sesame seed oil extracts of the silicone shell (60 cm²/20 mL extraction solution) were used to evaluate the sensitization potential in Hartley Albino guinea pigs by the Magnusson and Kligman method. Positive and negative controls included DNCB and ethanol, respectively. Scoring grades of 1 or greater in the test group generally indicated sensitization, provided that grades of less than 1 were observed on the control animals. The results following induction and challenge showed that the test articles were not irritants or sensitizers.

In a second study, a complete device was subdivided to expose both inner and outer surfaces and then extracted in cottonseed oil or saline at 121°C for 1-hour. Other experimental conditions were as described above. The results following induction and challenge showed that the test article (composite sample) was not an irritant or sensitizer.

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# 8. Mutagenicity

Test articles representative of the silicone elastomers and gel material used in the Style 410 gel-filled devices were evaluated for mutagenicity using several standard mutagenicity and genotoxicity assays.

- Bacterial Mutagenicity (Ames Test) – Saline, ethanol, and/or DMSO extracts of silicone elastomer shell, gel, and leaf valve assemblies were evaluated for bacterial mutagenicity in the presence and absence of metabolic activation. Bacterial tester strains included TA98, TA100, TA1535, TA1537, and TA1538.

For DMSO extract of the test articles (as individually submitted materials), 6 doses were tested, from 2.50 µL to 100 µL per plate. The results showed that the test articles did not cause a positive increase in the number of histidine revertants per plate in any of the tester strains either in the presence or absence of microsomal enzymes prepared from Arochlor-induced rat liver homogenate.

For ethanol extracts a complete device was apportioned and then tested. Shell test material was extracted at 70°C for 24 hours at a ratio of 120 cm²/20 mL ethanol, while gel and leaf valve assembly test materials were extracted at a ratio of 4 g/20 mL ethanol. Other experimental conditions were as described above. The results showed that the test articles did not cause a positive increase in the number of histidine revertants per plate in any of the tester strains either in the presence or absence of microsomal enzymes prepared from Arochlor-induced rat liver homogenate.

Additional testing of a complete device (slit open to expose inner and outer surfaces) was completed using saline and DMSO and an extraction ratio of 4 g/20 mL extract. Other experimental conditions were as described above. Under the conditions of this study, both saline and DMSO extracts of the test article (complete device) were concluded to be negative in the Salmonella Ames test for mutagenicity.

- CHO/HGPRT Forward Mutation Assay – Ethanol extracts of elastomer and gel test articles were evaluated for mutagenicity with the CHO/HGPRT Forward Mutation Assay in the presence and absence of metabolic activation. The extracts were prepared by extracting the elastomer shell, gel, and leaf valve assembly in ethanol at 70°C for 24 hours. The shell test materials were extracted at a ratio of 120 cm²/20 mL ethanol, while the gel and leaf valve assembly were extracted at a ratio of 4 g/20 mL ethanol. Equal volumes of the individual extracts were combined and reduced to 20% of the initial composite volume by evaporation. Mutation assays were performed with and without S9 metabolic activation. In each assay, 5 dose levels were used that included 1.0, 2.5, 5.0, 7.5, and 10.0 µL/mL. The test material was not toxic in either mutation assay at any concentration tested. The mutant frequencies of

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treated cultures varied randomly with dose within the range acceptable for background mutant frequencies, i.e., 0-15 x 10⁻⁶. The results showed that the test articles were negative for inducing forward mutations at the HGPRT locus in CHO cells with and without S9 metabolic activation.

- In Vitro Cytogenetic Assay Measuring Chromosomal Aberration Frequencies in CHO Cells – Ethanol extracts of elastomer and gel test articles were evaluated for mutagenicity in the presence and absence of metabolic activation. The extracts from silicone shell, gel and leaf valve assembly were prepared individually from the test articles in ethanol and were mixed in equal amounts. Replicate cultures of CHO cells were incubated with 1.25 to 5.00 μL/mL of the combined extracts in a 10-hour aberrations assay, with 5.00 to 10.0 μL/mL in a 20-hour aberrations assay under non-activation conditions, and with 1.25 to 10.0 μL/mL in a 10-hour aberrations assay with metabolic activation. No significant increase in cells with chromosomal aberrations was observed at the concentrations analyzed; thus the test articles (shell, gel, and leaf valve assembly) were considered negative for inducing chromosomal aberrations in CHO under both non-activation and activation conditions.

- Mouse Lymphoma Mutagenicity Assay – Saline and DMSO extracts of a complete device were tested in the L5178Y/TK⁺/⁻ Mouse Lymphoma Mutagenesis Assay in the presence and absence of metabolic activation. The test article was slit open to expose the inner and outer surfaces and extracted at a ratio of 4 g/20 mL extraction medium. The dose levels for mutagenesis ranged from 6.3 to 100 μL/mL for the saline test article and 0.63 to 10 μL/mL for the DMSO test article in both the non-activated and metabolically activated cultures. Under the conditions of this study, saline and DMSO extracts of the test articles were concluded to be negative for mutagenesis.

- Unscheduled DNA Synthesis Assay – Saline and DMSO extracts of a complete device were tested in the Unscheduled DNA Synthesis Assay using primary cultures of rat hepatocytes. The test article was slit open to expose the inner and outer surfaces and extracted at a ratio of 4 g/20 mL extraction medium. The test articles extracts were tested and fully evaluated at 5 dose levels ranging from 6.3 to 100 μL/mL for the saline extract and 0.63 to 10 μL/mL for the DMSO extract. The results of the UDS assay indicate that under the test conditions, neither the saline nor the DMSO extracts of the test article induced a significant increase in the mean number of net nuclear grain counts, i.e., indication of DNA synthetic activity, at any dose level in isolated rat hepatocytes, and therefore, the test article was considered to be negative in this study.

- Cell Transformation Assay – Saline and DMSO extracts of a complete device were tested in the BALB/3T3 cell transformation assay in the presence and absence of metabolic activation. The test article was slit open to expose the inner and outer surfaces and extracted at a ratio of 4 g/20 mL extraction

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medium. The assays were conducted with a 3 day exposure in the non-activated test system and with a 4-hour exposure in the metabolically activated system. The dose levels evaluated were 12.5, 25, 50 and 100 μL for the saline test article extract and 1.25, 2.5, 5 and 10 μL for the DMSO extract. No increases in transformation frequency were observed relative to the negative controls in either the activated or non-activated test systems with either extract.

## 9. Muscle Implantation

Test articles representative of the silicone elastomers used in the shell, patch and overlay system, and diaphragm valve and plug assembly used in the Style 410 gel-filled devices were evaluated for irritation in 90 day muscle implantation studies conducted in New Zealand White rabbits. Test article implantation sites were macroscopically and microscopically assessed, with comparison to a low-density polyethylene control. The gross observations were classified as either non-reactive or slightly reactive, and the microscopic observations were given an overall toxicity rating of zero for each test article. For the acceptance criterion, the mean macroscopic scores for test implants were compared to mean scores of the control sites. The requirements of the test were met if the difference between test and control score means (macroscopic) was not greater than 1.0. The results showed that the test articles were non-toxic.

## 10. Subchronic Toxicity

Test articles representative of the silicone elastomers used in the shell, patch and overlay system, leaf valve and overlay system, diaphragm valve and plug assembly, and gel material used in the Style 410 gel-filled devices were evaluated in 90 day toxicity studies. Female Fischer 344 rats were evaluated for mortality, body weight, clinical chemistry, hematology, organ weights, organ/body weight or brain weight ratios, and tissue histopathology. For the acceptance criterion, the animals were assessed for toxicity. The histopathological findings at the implant site were those typically associated with the implantation of test article and included fibrous encapsulation. The histological findings in non-implant, distant site tissues were considered typical for the animals at their age and occurred in similar frequency and severity among the control and implanted groups. The results demonstrated that the test articles did not produce subchronic toxicity in rats.

## 11. Chronic Toxicity and Carcinogenicity

Test articles representative of the silicone elastomers used in the shell, patch and overlay system, leaf valve and overlay system, diaphragm valve and plug assembly, and gel material used in the Style 410 gel-filled devices were subcutaneously implanted in female Fisher 344 rats. The elastomers were pulverized prior to implantation. For the acceptance criterion, the animals were assessed for toxicity. No evidence of systemic toxicity or carcinogenicity, other than solid state tumorigenicity, was observed in association with the test articles. The incidence and type of histologic findings other than those related to the presence of a foreign body reaction were typical of Fischer 344 rats and were not considered test article related. Encapsulation of pulverized low-density polyethylene control or elastomer test article varied somewhat from that of the gel due to their differing physical characteristics.

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Whereas the connective tissue septa penetrated between separate pulverized polyethylene or elastomeric particles, the connective tissue septa surrounded but did not penetrate the gel. As previously stated, solid state tumorigenicity was observed in the studies. This is a typical finding for this type of study, as it is a known rodent-specific response to the implantation of materials.

With respect to solid state tumorigenicity, important discussion may be found in ISO 10993-3, Annex C (informative) – Role of implantation carcinogenicity studies, §C.1 a-f, §C.2 – The process and rationale of decision, and §C.3 – Carcinogenicity studies performed as implantation tests. Importantly, in §C.2 it is noted that representatives from European, Japanese, and U.S regulatory bodies agreed that no decision on carcinogenic risk has been made on the basis of solid state carcinogenesis alone. In the few examples known, where decisions on carcinogenic risk were made using solid state carcinogenesis results, there had always been supporting data, such as mutagenicity data. Noteworthy, the current test articles were negative for mutagenicity testing (Salmonella Reverse Mutation Assay (Ames test), CHO/HGPRT Forward Mutation Assay, Chromosome Aberration Frequencies in CHO cells, Mouse Lymphoma Mutagenicity Assay, Unscheduled DNA Synthesis Assay, and a Cell Transformation Assay, all with and without microsomal activation), and the US FDA has previously determined that bacterial mutagenesis, mammalian mutagenesis, and DNA damage had been adequately addressed. Such foreign body reactions resulting in solid state tumorigenicity have long been documented in the literature (cf. Oppenheimer BS, Oppenheimer ET Stout AP (1948) Sarcomas induced in rats by implanting cellophane. Proc. Soc. Exp. Biol. Med., 67 (33); Bischoff F, Bryson G (1964) Carcinogenesis through solid state surfaces. Prog. Exp. Tumor Res. 5: 85-133; and, Brand KG, Johnson KH, Buoen LC, Golberg L (1976) Foreign body tumorigenesis. Critical Reviews in Toxicology, 4(4): 353-394) and are discussed extensively in IARC Monographs Volume 74, Surgical implants and other foreign body reactions, §4B.22.1 and 5B.4.1.

## 12. Reproductive Toxicology

A literature review was completed regarding reproductive and developmental toxicity studies on silicone elastomers, gel, fluids, and low molecular weight compounds. The reviewed literature included 33 published journal articles and publicly available Dow Corning studies. The literature indicated that the silicone materials are neither reproductive nor developmental toxins.

In addition, a 2-generation reproductive toxicology study was performed evaluating the elastomer materials used in gel-filled devices. The test article, gel-exposed patched shells, was pulverized and subcutaneously implanted in F₀ generation female Sprague-Dawley rats of the test article group at a dose of 2 g/kg. The control female animals underwent a sham control surgery. F₀ generation female rats were then mated and allowed to deliver their litters (F₁ generation pups). F₁ generation offspring were evaluated during the lactation period. At the time of weaning, sufficient numbers of F₁ generation male and female rats in both the

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control and test article groups were selected to continue on in the study. Those animals not selected were sacrificed.

Subsequently, the female F₁ generation animals in the test article group were implanted with the test article at a dose of 2 g/kg and the female control animals underwent a sham surgery. Upon reaching maturity, some F₁ generation male and female adult animals were sacrificed to evaluate reproductive organs and selected endocrine tissues. The majority of the F₁ generation male and female rats were mated. The F₁ generation females were allowed to deliver their litters (F₂ generation pups). F₂ generation offspring were evaluated throughout the lactation period, and then the dams and pups were sacrificed.

The resulting mating indices demonstrated that the F₀ generation and F₁ generation animals in both the test article and the sham control groups were capable of successful mating and subsequent delivery of live pups. Furthermore, there were no significant histological differences observed between the test article and sham control groups with respect to the reproductive organs and selected endocrine tissues of male and female F₁ generation rats. Overall, there were no biologically significant differences observed between the control and implanted groups in any of the adult F₀ generation and F₁ generation parental parameters or F₁ generation and F₂ generation offspring parameters evaluated as part of this 2 consecutive generation reproductive toxicity study.

## 13. Developmental Toxicity (Teratology)

Test articles representative of the silicone elastomers used in the Style 410 device were evaluated in 3 separate studies. In the first, the gel material was subcutaneously implanted between the scapula of female CD Sprague-Dawley rats. The animals were exposed to either 0.62, 7.28 or 14.79 g/kg test article. In a second study, 2 g of pulverized complete device materials representative of the Style 410 device (0.3 to 1.0 mm particle size) were implanted subcutaneously in the dorsal area of the back. In a third study, 2 g of pulverized test materials representative of the patch materials used in the Style 410 device were also implanted subcutaneously in the dorsal area of the back. Treated females were mated, and litters were evaluated between Days 20 and 25 (depending on study) of gestation. For all studies, there were no biologically significant differences observed between the controls and the implanted groups for the maternal dam and fetal pup parameters evaluated, including pregnancy rates, dam organ weights, and fetal survival, weight, sex and morphological development. The results showed that the gel and pulverized patch/gel/shell material did not produce developmental effects.

## C. Mechanical Data

This section includes a summary of the fatigue, gel bleed, and gel cohesion testing that Allergan provided in support of establishing the safety of their product.

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1. Fatigue Rupture

Implants (125 cc) with the LF profile (Style 410LF) were chosen for fatigue testing as representative of Allergan’s Highly Cohesive product line. Although the LF profile is not proposed in this application, the surface area of the 125 cc implants with the LF profile is less than the surface areas of the implants proposed in this PMA; therefore, the 125 cc implants with the LF profile represent a worst case for fatigue testing. All implants tested were final, sterilized versions with the minimum allowable radial shell thickness. The test set-up consisted of a uniaxial test fixture of parallel plates. Testing was performed under ambient laboratory conditions in air. The applied cyclic loads ranged from 10 to 55 lbs. Testing was performed at 1 Hz for all applied loads. A minimum of 3 implants for each style was tested for each load level. Runout was defined as 6.5 million cycles. The resulting endurance load level was 10 lbs. As expected, based on the test set-up, all fatigue failure modes were radial tears. FDA believes that these data demonstrated that the Allergan product can withstand physiological static loading and in-vivo cyclic loading. In addition, the results are comparable to the results seen in approved breast implants.

2. Gel Bleed

Allergan provided testing to identify the gel bleed constituents (including the platinum species [or other catalysts]), the rate that the gel constituents bleed out, and how that rate changes over time. Allergan’s test method, which was designed to mimic in-vivo exposure to silicone gel-filled breast implants, involved the incubation of smooth implants in bovine serum at 37°C. At specific timepoints, samples of the solution were withdrawn for analysis for low molecular weight (LMW) silicones and platinum. The results indicated that the diffusion of measured constituents essentially ceased by 90 days and that measurable amounts of silicones from D4 to D21 and from MD2M to MD19M diffused into the serum over that period.

Through 90 days immersion of the Style 410 devices (125 gm size) in bovine serum, the cumulative amount of LMW observed silicone release was 470 µg and the observed rate of total LMW silicone gel bleed leveled off at approximately 13 ng/cm²/day. This suggests that the total cumulative LMW silicones released through 10 years for even the largest of Allergan’s Natrelle® 410 Highly Cohesive Anatomically Shaped Silicone-Filled Breast Implants (775 gm) would be less than 23.7 mg in this physiologically relevant model. This represents less than 0.003% of the total weight of the silicone in the implant, indicating that over 99% of the LMW silicones and platinum stayed in the implant.

With regard to the health consequences of gel bleed, the literature has reported small quantities of LMW silicone compounds, as well as platinum (in zero oxidation state), have been found to diffuse (“bleed”) through an intact implant shell. The evidence is mixed as to whether there are any clinical consequences

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associated with gel bleed. For instance, studies on implants implanted for a long duration have suggested that such bleed may be a contributing factor in the development of capsular contracture$^{ii}$ and lymphadenopathy.$^{iii}$ However, evidence against gel bleed being a significant contributing factor to capsular contracture and other local complications is provided by the fact that there are similar or lower complication rates for silicone gel-filled breast implants than for saline-filled breast implants. Saline-filled breast implants do not contain silicone gel and, therefore, gel bleed is not an issue for those products. Furthermore, toxicology testing has indicated that the silicone material used in the Allergan implants does not cause toxic reactions in test animals. It should also be noted that studies reported in the literature have demonstrated that the low concentration of platinum contained in breast implants is in the zero oxidation (most biocompatible) state.$^{iv,v,vi,vii}$ The overall body of available evidence supports that the low level of gel bleed for Allergan’s product is of no clinical consequence. In addition, the results are comparable to the results seen in approved breast implants.

## 3. Gel Cohesivity

Gel cohesivity and penetration testing assess the cohesive and cure characteristics of silicone gel, respectively. Gel cohesivity testing was performed as per ASTM F703 (cone/pendant method) using gel from final finished product. Of the 289 samples tested, the average pendant length was 0.0 cm (range of 0.0-0.8cm), which meets the ASTM F703 specification of &lt;4.5cm. Gel penetration testing was performed as per an Allergan test method involving measurement of the penetration of a plunger into in-process gel in a jar. All samples passed Allergan’s internal penetration specification.

## D. Modes and Causes of Device Failure

### Rupture

Allergan provided numerous test reports and other information to characterize modes and causes of failure of their device for a range of in-vivo times, such as failure analyses of retrieved devices (i.e., retrieval study), physical property testing, assessment of manufacturing processes and surgical techniques that may impact rupture, and a review of the explant literature.

The primary set of modes and causes of rupture data was a retrieval study that involved 2,390 explanted Style 410 devices (IDE and Worldwide returns) that were returned to the Allergan Device Analysis Laboratory. Of the devices returned, 512 were categorized as failed devices. The samples analyzed were explanted anywhere from time 0 (damaged during the implantation procedure and, thus, not implanted) to over 10 years after implantation. For these 512 explants, the failure modes were surgical instrument damage (n=267); unidentified openings (n=208); surgical impact (n=16); manufacturing (n=14); and fold flaw (n=7). FDA determined that these data

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are adequate to characterize the modes and causes of rupture through approximately 10 years. See Section XI below for more details.

## Gel Fracture

Gel fracture, or a fissure, or crack, in the gel, has been reported in the Natrelle 410 Highly Cohesive Anatomically Shaped Silicone-Filled Breast Implants. About 16.2% (n=386) of the 2,390 explanted Style 410 devices (IDE and Worldwide returns) that were returned to the Allergan Device Analysis Laboratory implants showed signs of gel fracture. Manipulation during explantation may have caused additional fractures. The occurrence of gel fracture was low, and it was noted that the rupture rate did not increase with the reported gel fractures. While there were no clinical consequences of gel fractures seen in the study, any clinical consequences of gel fracture will be investigated further in the post-approval studies.

## E. Magnetic Resonance Imaging (MRI) Phantom Study

### 1. MRI Use for Rupture Detection

Allergan provided data showing that MRI remained a definitive tool for diagnosing the rupture/intact status of their highly cohesive implants.

Allergan performed an in vitro phantom MRI study using both Natrelle® Silicone-Filled Breast Implants (P020056) and their implant with a more cohesive gel, Natrelle® 410 Highly Cohesive Anatomically Shaped Silicone-Filled Breast implants. This in vitro study was designed to determine if there were significant differences in rupture detection based on the differences in the two gel types used in the two different styles of implants.

The comparative study was conducted on 40 implants (20 style 410 and 20 round approved silicone implants) of differing sizes. Fine-line ruptures were created at specific points using a scalpel. Ruptures were not opened or manipulated further. Two implants were randomly suspended in each container in agar and subjected to MRI. Each implant contained 0 to 4 ruptures of 2 cm size on the anterior region (front of the implant) and 0 to 4 ruptures on the peripheral edge placed in specified quadrants of the implant according to a SAS randomization table. Images were collected, stored on CD, and read in a blinded fashion by two MRI expert physician reviewers. The presence or absence of a rupture in each quadrant on the anterior or peripheral region of the implant was determined and declared to be positive if at least 1 of the 2 reviewers identified it. Sensitivity was determined by the number of positively identified quadrants with ruptures per total with each style of implant. Specificity was determined by the number of quadrants without ruptures correctly identified per total negative quadrants. Data collected on both types of implants was compared and is summarized in the Table 6 below.

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Table 6 : Comparative Study Results For Rupture Diagnosis

| | Number of Correctly identified quadrants with or without a rupture per total (%) | |
| --- | --- | --- |
| | Style 410 | Approved Round |
| Sensitivity* | 40/82 (49%) | 47/82 (57%) |
| Specificity** | 54/78 (69%) | 52/78 (66%) |

* Number or percent of correctly identified ruptures per total quadrants with ruptures; 95% confidence interval for 410 = 37.6 to 68.2 and for Approved Round= 45.9 to 68.2
** Number or percent of correctly identified quadrants without rupture per total quadrants without rupture; 95% confidence interval for 410= 57.8 to 79.2 and for Approved Round= 55.1 to 76.9

Allergan concluded that no significant difference was observed in the sensitivity or specificity of MRI detection of fine-line ruptures in this study and that this in vitro study indicates that the detection of fine line ruptures in the 410 device with a more cohesive silicone gel is comparable to that for the approved silicone implants

## 2. MRI Use for Gel Fracture Detection With and Without Implant Rupture

Allergan clarified that gel fracture and implant rupture can be distinguished on MRI, using either 1.5T or 3.0T, and that gel fracture will not mask rupture. Testing showed that although air voids and/or shell deformation can be identified at both 1.5T and 3.0T, when a rupture to the shell is introduced, the air in the void dissipates through the rupture and the fracture is no longer visible under either setting. The only imaging signature present is that of a distinguishable shell rupture.

In the clinical study, gel fracture was seen within the intact shell due to excessive compressive forces, where, upon release of the force, the gel sections may not immediately return to their original position. In vitro, gel fracture results in a fissure with an air void with or without a distortion in the shape of the implant. Imaging via MRI identified this gel fracture and air void as dark shaded areas within the implant. Conversely, imaging of shell rupture by MRI are recognized as an inverted loop, subcapsular line, linguini sign, or extracapsular silicone without intracapsular sign.

## F. Shelf Life Data

Allergan’s shelf life testing was performed on representative devices (gel cohesion, tension set, shell/patch joint strength, ultimate elongation, and break force) and the package (thermoform dye penetration and peel seal strength). Validated accelerated test results were the primary set of data used to establish the shelf life of the Allergan product. All device and package testing met the acceptance criteria set in the protocol. Accordingly, the data supported a 5-year shelf life for the Allergan product.

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# X. SUMMARY OF THE ALLERGAN STYLE 410 CORE STUDY

Allergan performed a clinical pivotal study to establish a reasonable assurance of safety and effectiveness of the Natrelle® Style 410 Highly Cohesive Anatomically Shaped Silicone-Filled Breast Implants for breast augmentation, reconstruction and/or revision in the US under IDE # G000201. Data from this clinical study were the basis for the PMA approval decision. A summary of the clinical study is presented below.

## A. Study Design

Patients were implanted between February 5, 2001 and February 28, 2002. The database for this PMA reflected data collected through September 8, 2009.

The Allergan Style 410 Core Study is a prospective, 10-year, multicenter, single arm observational clinical study conducted across 47 investigational sites in 941 women undergoing breast augmentation, reconstruction and revision operations. Patients are serially followed at 4 weeks, 6 months, 1 year, and annually thereafter through 10 years. A subset of patients was consented to receive MRIs at years 1, 3, 5, 7, and 10 years to screen for silent breast implant rupture. There were originally 2 patient cohorts—those screened for silent rupture by MRI and those who were not screened for silent rupture by MRI. On May 27, 2008, the study protocol was revised to include MRI evaluations for those patients not originally consented to receive periodic scheduled MRIs (known as non-MRI patients) who are MRI-eligible and consent to undergo MRI at Years 7 and 10. The results through 7-year patient follow-up are reported, and the study remains ongoing.

Key aspects of the protocol are as follows:

### 1. Clinical Inclusion and Exclusion Criteria

Enrollment in the Core study was limited to patients who met the following inclusion criteria:

- Female, age 18 years or older
- Patient presents with one or more of the following conditions:

i. Primary breast augmentation (i.e., no previous breast implant surgery) indicated for the following:

- Patient dissatisfaction with size or shape of breast (e.g., mammary hypoplasia)
- Asymmetry
- Ptosis
- Aplasia

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ii. Primary breast reconstruction (i.e., no previous breast implant surgery other than implantation of tissue expanders or contralateral augmentation for asymmetry) indicated for the following:

- For affected breast(s):
- Mastectomy for cancer
- Prophylactic mastectomy
- Breast trauma (resulting in mastectomy)

- For the unaffected (contralateral) breast
- Contralateral asymmetry (may be performed on the date of the mastectomy or the date when permanent implants are placed in the reconstructed breast)

iii. Breast implant revision surgery (i.e., removal and replacement of breast implants) indicated for the following:

- Previous augmentation or reconstruction with silicone-filled or saline-filled breast implants

- Adequate tissue available to cover implants
- Patients at MRI designated sites must be willing to undergo MRI at their 1, 3, 5, 7, and 10-year follow-up visits (serial MRI). The patient must be eligible for MRI (for example, no implanted metal or metal devices and no history of severe claustrophobia that may make her ineligible for MRI).
- Patient is willing to follow all study requirements, including agreeing to attend all required follow-up visits, and accepts the risks involved as indicated by signing and dating (at the same time as the signature) the study Patient Informed Consent prior to surgery

Patients were not permitted to enroll in the Core study if they met any of the following exclusion criteria:

- Advanced fibrocystic disease considered to be premalignant without accompanying subcutaneous mastectomy
- Existing carcinoma of the breast, without mastectomy
- Abscess or infection in the body at the time of enrollment
- Pregnant or nursing
- Have any disease, including uncontrolled diabetes (e.g., Hb A1c &gt; 8%), that is clinically known to impact wound healing ability
- Show tissue characteristics that are clinically incompatible with mammoplasty, such as tissue damage resulting from radiation, inadequate tissue, compromised vascularity or ulceration
- Have, or under treatment for, any condition that may constitute an unwarranted surgical risk (e.g., unstable cardiac or pulmonary problems)
- Show psychological characteristics that may be incompatible with the surgical procedure and the prosthesis, such as inappropriate attitude or motivation (e.g., body dysmorphic disorder)
- Are not willing to undergo further surgery for revision, if medically required

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# 2. Follow-up Schedule

All patients were scheduled to return for follow-up examinations at 4 weeks, 6 months, 1 year, and annually through 10 years. Patient medical histories and baseline clinical data were collected preoperatively. Rupture is assessed for patients who have scheduled MRIs serially throughout the study. The follow-up schedule is shown in Table 7 below:

Table 7: Follow-up Schedule of Core Clinical Study

| Data CollectedA | Enrollment | Prior to Explant | 0-4 wks | 6 mo | 1 yr | 2 yr | 3 yr | 4 yr | 5 yr | 6 yr | 7 yr | 8 yr | 9 yr | 10 yr |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Eligibility/Screening | X | | | | | | | | | | | | | |
| Scheduled Visit | | | X | X | X | X | X | X | X | X | X | X | X | X |
| Quality of Life Questionnaire | X | | | | X | X | | | | | | | | |
| Activities and Lifestyle Index | X | | | | X | X | | X | | X | | X | | X |
| MRI Central Reviewer ReadingB | | X | | | X | | X | | X | | X | | | X |
| MRI Investigational Site ReadingB | | X | | | X | | X | | X | | X | | | X |
| Documentation Photographs | X | | | | X | | | | | | | | | |

A Complications/treatment, secondary procedures, explants, connective tissue diseases, breast cancer diagnoses, unanticipated adverse events, and discontinuation information were collected any time throughout the study as applicable.
B Originally there were two cohorts, an MRI cohort that underwent serial MRI at 1, 3, 5, 7, and 9 years, and a non-MRI cohort that did not undergo serial MRIs. On May 27, 2008, FDA approved a protocol revision so that non-MRI patients who were MRI-eligible and consented would also receive MRI evaluations at the 7 and 10 year follow-up time points.

# 3. Clinical Endpoints

Safety assessments include local complication rates (e.g., infection, capsular contracture), implant-related complications (e.g., wrinkling, asymmetry), device failure (e.g., implant rupture, gel fracture), and reasons for reoperation and implant removal. A qualitative analysis is performed on patients who experience a systemic condition (e.g., connective tissue disease), breast cancer, or other adverse event.

Effectiveness assessments include change in breast size (augmentation patients only), patient and physician satisfaction with outcome (augmentation,

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reconstruction and revision patients), and quality of life (QoL) (augmentation and reconstruction patients). QoL is comprised of measures of self-esteem, body image and general health outcome.

## 4. Prespecified Analysis Plan

All statistical methods were established prior to conducting the analyses. All patients implanted with the study device contributed to the analyses. Descriptive statistics, appropriate to the type of variable and scale of measurement, were provided. All analyses were performed separately for each indication cohort, except where noted below.

All safety outcomes were summarized descriptively, separately by cohort. For key outcomes, Kaplan-Meier product limit survival analyses were performed and the cumulative risk of first occurrence reported. For each reported follow-up timepoint, the complication rate estimate is provided along with the associated 95% confidence interval. Effectiveness and survey-based outcomes were summarized descriptively, separately by cohort. An analysis of potential risk factors that are related to key safety outcomes was performed using multiple logistic regression.

If a primary study implant for augmentation or reconstruction is removed and replaced with another device ("secondary implant"), data continue to be gathered on the secondary study implant, adhering to the patient's same ongoing study schedule as for the primary implant. However data collected on these secondary implants are not included in the primary analysis with the exception of patient quality of life and satisfaction. Outcomes following replacement surgery are presented in the Revision cohorts identified as Revision-Augmentation and Revision-Reconstruction. For patients having all study implants removed without replacement, the patient is followed by telephone follow-up on the same follow-up schedule to track development and/or duration of adverse events.

For patients enrolled into the study for one side only (i.e. unilaterally) who later receive a study device on the contralateral side, all by-patient analyses are performed based on the surgery date for the patient's first implant. All by-implant analyses are based on the separate implant surgery dates for each device.

The rate of rupture in the MRI cohort was calculated as a Kaplan-Meier rate with censoring at the time of last MRI. If a patient had no MRI assessments, she was considered censored immediately after implantation. The numerator for this Kaplan-Meier calculation included both explant-confirmed ruptures and unconfirmed but suspected ruptures (suspected due to imaging or physical exam). In addition, if a patient had a symptomatic rupture, this patient was included in the numerator and the implant was considered ruptured at the time of the symptomatic rupture. For the non-MRI cohort in the Core Study, the rupture rate was calculated using the same methodology at the timepoints when MRI screening was performed.

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B. Accountability of PMA Cohort

At the time of database lock, of 941 patients enrolled in the PMA study, 656 patients are available for analysis at the 7-year follow-up timepoint. Taking into account patients who died or had all study devices removed without replacement with other study devices, follow-up compliance was 76.4%.

1. Augmentation, Reconstruction and Revision Cohorts

The study consists of 941 patients of which data are available through 7 years. The study is divided into four cohorts including 492 primary augmentation patients, 156 revision-augmentation patients, 225 primary reconstruction patients and 68 revision-reconstruction patients. The 7-year follow-up rates by cohort are 74.9% (356) for augmentation, 81.3% (152) for reconstruction, 73.8% (104) for revision augmentation, and 77.2% (44) for revision reconstruction. Tables 8 through 11 below provide a tabulation of patient compliance with study visits.

To assess the representativeness of the responder results to those patients who did not provide data, additional analyses were performed for cohorts having less than an 80% rate of patient follow-up at 7 years. These analyses are described in section c.

Table 8: Patient Accountability for the Augmentation Cohort

| | 0-4 weeks | 6 months | 1 year | 2 years | 3 years | 4 years | 5 years | 6 years | 7 years |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Theoretically Due | 492 | 492 | 492 | 492 | 492 | 492 | 492 | 492 | 492 |
| Deaths | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Explant-Related Discontinuations | 0 | 1 | 2 | 6 | 7 | 9 | 10 | 13 | 17 |
| Replacement with non-study device | 0 | 0 | 1 | 5 | 5 | 7 | 8 | 11 | 13 |
| Unknown replacement status | 0 | 1 | 1 | 1 | 2 | 2 | 2 | 2 | 4 |
| Expected | 492 | 491 | 490 | 486 | 485 | 483 | 482 | 479 | 475 |
| Actual Evaluated | 492 | 473 | 466 | 436 | 422 | 409 | 390 | 350 | 356 |
| Lost-to-Follow-Up | 0 | 18 | 24 | 50 | 63 | 74 | 92 | 129 | 119 |
| % Follow-Up | 100% | 96.3% | 95.1% | 89.7% | 87.0% | 84.7% | 80.9% | 73.1% | 74.9% |

Table 9: Patient Accountability for the Reconstruction Cohort

| | 0-4 weeks | 6 months | 1 year | 2 years | 3 years | 4 years | 5 years | 6 years | 7 years |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Theoretically Due | 225 | 225 | 225 | 225 | 225 | 225 | 225 | 225 | 225 |
| Deaths | 0 | 0 | 0 | 2 | 6 | 10 | 13 | 15 | 15 |
| Explant-Related Discontinuations | 0 | 4 | 5 | 5 | 9 | 14 | 17 | 22 | 23 |
| Replacement with non-study device | 0 | 4 | 4 | 4 | 7 | 12 | 15 | 20 | 21 |
| Unknown replacement status | 0 | 0 | 1 | 1 | 2 | 2 | 2 | 2 | 2 |
| Expected | 225 | 221 | 220 | 218 | 210 | 201 | 195 | 188 | 187 |
| Actual Evaluated | 225 | 209 | 215 | 200 | 191 | 181 | 175 | 156 | 152 |
| Lost-to-Follow-Up | 0 | 12 | 5 | 18 | 19 | 20 | 20 | 32 | 35 |

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Table 10: Patient Accountability for the Revision-Augmentation Cohort

| | 0-4 weeks | 6 months | 1 year | 2 years | 3 years | 4 years | 5 years | 6 years | 7 years |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Theoretically Due | 156 | 156 | 156 | 156 | 156 | 156 | 156 | 156 | 156 |
| Deaths | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Explant-Related Discontinuations | 0 | 1 | 4 | 6 | 9 | 11 | 11 | 13 | 15 |
| Replacement with non-study device | 0 | 1 | 4 | 6 | 9 | 11 | 11 | 13 | 14 |
| Unknown replacement status | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Expected | 156 | 155 | 152 | 150 | 147 | 145 | 145 | 143 | 141 |
| Actual Evaluated | 156 | 146 | 145 | 137 | 127 | 117 | 117 | 108 | 104 |
| Lost-to-Follow-Up | 0 | 9 | 7 | 13 | 20 | 28 | 28 | 35 | 37 |
| % Follow-Up | 100% | 94.2% | 95.4% | 91.3% | 86.4% | 80.7% | 80.7% | 75.5% | 73.8% |

Table 11: Patient Accountability for the Revision-Reconstruction Cohort

| | 0-4 weeks | 6 months | 1 year | 2 years | 3 years | 4 years | 5 years | 6 years | 7 years |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Theoretically Due | 68 | 68 | 68 | 68 | 68 | 68 | 68 | 68 | 68 |
| Deaths | 0 | 0 | 0 | 1 | 1 | 1 | 2 | 2 | 2 |
| Explant-Related Discontinuations | 0 | 0 | 0 | 2 | 4 | 6 | 7 | 8 | 9 |
| Replacement with non-study device | 0 | 0 | 0 | 2 | 3 | 4 | 4 | 5 | 6 |
| Unknown replacement status | 0 | 0 | 0 | 0 | 1 | 2 | 3 | 3 | 3 |
| Expected | 68 | 68 | 68 | 65 | 63 | 61 | 59 | 58 | 57 |
| Actual Evaluated | 68 | 64 | 64 | 59 | 59 | 54 | 52 | 48 | 44 |
| Lost-to-Follow-Up | 0 | 4 | 4 | 6 | 4 | 7 | 7 | 10 | 13 |
| % Follow-Up | 100% | 94.1% | 94.1% | 90.8% | 93.7% | 88.5% | 88.1% | 82.8% | 77.2% |

# 2. MRI Cohorts

A total of 316 patients were originally enrolled in the MRI sub-study of the Core study to screen for silent breast implant rupture. This includes 150 primary augmentation patients, 45 revision augmentation patients, 96 primary reconstruction patients and 25 revision-reconstruction patients. As previously stated, FDA approved a protocol revision on May 27, 2008 so that all enrolled patients—both the MRI and non-MRI cohorts—who were MRI-eligible and consented would undergo MRI evaluations at the 7-year and 10-year follow-up time points. Therefore, the number of patients theoretically due at the 7-year timepoint was changed to 317 primary augmentation patients, 88 revision-augmentation patients, 146 primary reconstruction patients and 39 revision-reconstruction patients. The 7-year MRI compliance rate in the MRI cohort was $69.6\%$ for the augmentation cohort, $81.6\%$ for the revision augmentation cohort, $67.2\%$ for the reconstruction cohort and $83.3\%$ for the revision reconstruction cohort. Tables 12 through 15 below present patient accounting for the MRI cohort.

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Table 12: Patient Accountability for MRI Evaluations – Augmentation

| | 1 year | 3 years | 5 years | 7 years (MRI cohort) | 7 years (Non-MRI cohort) |
| --- | --- | --- | --- | --- | --- |
| Theoretically Due | 150 | 150 | 150 | 150 | 167 |
| Deaths | 0 | 0 | 0 | 0 | 0 |
| Discontinued Due to Claustrophobia/ Metal-Implanted Devices | 0 | 0 | 1 | 2 | 0 |
| Explant-Related Discontinuations | 0 | 2 | 5 | 13 | 3 |
| Expected | 150 | 148 | 144 | 135 | 164 |
| Actual Evaluated | 124 | 127 | 119 | 94 | 120 |
| Lost-to-Follow-Up | 26 | 21 | 25 | 41 | 44 |
| % Follow-Up | 82.7% | 85.8% | 82.6% | 69.6% | 73.2% |

Table 13: Patient Accountability for MRI Evaluations – Revision-Augmentation

| | 1 year | 3 years | 5 years | 7 years | 7 years (Non-MRI cohort) |
| --- | --- | --- | --- | --- | --- |
| Theoretically Due | 45 | 45 | 45 | 45 | 43 |
| Deaths | 0 | 0 | 0 | 0 | 0 |
| Discontinued Due to Claustrophobia/ Metal-Implanted Devices | 0 | 2 | 2 | 2 | 0 |
| Explant-Related Discontinuations | 0 | 3 | 4 | 5 | 2 |
| Expected | 45 | 40 | 39 | 38 | 41 |
| Actual Evaluated | 37 | 33 | 31 | 31 | 30 |
| Lost-to-Follow-Up | 8 | 7 | 8 | 7 | 11 |
| % Follow-Up | 82.2% | 82.5% | 79.5% | 81.6% | 73.2% |

Table 14: Patient Accountability for MRI Evaluations – Reconstruction

| | 1 year | 3 years | 5 years | 7 years | 7 years (Non-MRI cohort) |
| --- | --- | --- | --- | --- | --- |
| Theoretically Due | 96 | 96 | 96 | 96 | 50 |
| Deaths | 0 | 4 | 6 | 6 | 0 |
| Discontinued Due to Claustrophobia/ Metal-Implanted Devices | 0 | 3 | 4 | 3 | 0 |
| Explant-Related Discontinuations | 8 | 16 | 22 | 29 | 0 |
| Expected | 88 | 73 | 64 | 58 | 50 |
| Actual Evaluated | 80 | 64 | 56 | 39 | 37 |
| Lost-to-Follow-Up | 8 | 9 | 8 | 19 | 13 |
| % Follow-Up | 90.9% | 87.7% | 87.5% | 67.2% | 74.0% |

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Table 15: Patient Accountability for MRI Evaluations – Revision-Reconstruction

| | 1 year | 3 years | 5 years | 7 years | 7 years (Non-MRI cohort) |
| --- | --- | --- | --- | --- | --- |
| Theoretically Due | 25 | 25 | 25 | 25 | 14 |
| Deaths | 0 | 0 | 0 | 0 | 0 |
| Discontinued Due to Claustrophobia/ Metal-Implanted Devices | 0 | 0 | 0 | 0 | 0 |
| Explant-Related Discontinuations | 1 | 2 | 4 | 7 | 2 |
| Expected | 24 | 23 | 21 | 18 | 12 |
| Actual Evaluated | 23 | 23 | 19 | 15 | 4 |
| Lost-to-Follow-Up | 1 | 0 | 2 | 3 | 8 |
| % Follow-Up | 95.8% | 100% | 90.5% | 83.3% | 33.3% |

## C. Study Population Demographics and Baseline Parameters

Demographic information for the Core Study with regard to race is as follows: 92% were Caucasian, 3% were Hispanic, 2% were Asian, 2% were African American, and 1% were other. The median age at surgery was 36 years for primary augmentation patients, 44 years for revision-augmentation patients, 48 years for primary reconstruction patients, and 52 years for revision-reconstruction patients. Approximately 65% of the Pivotal Study patients were married, and approximately 82% had some college education. Table 16 below presents the study population demographics at baseline by cohort.

Table 16: Patient Demographics by Cohort

| | All Cohorts | Augmentation (n = 492) | Reconstruction (n = 225) | Revision-Augmentation (n = 156) | Revision-Reconstruction (n = 68) | MRI (n=316) | Non-MRI (n=625) |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Race: | | | | | | | |
| Caucasian | 91.5% | 90.5% | 90.7% | 94.9% | 94.1% | 92.1% | 91.2% |
| Hispanic | 3.0% | 4.0% | 0.4% | 2.6% | 4.4% | 0.9% | 4.0% |
| Asian | 2.3% | 3.0% | 3.1% | 0.0% | 0.0% | 2.8% | 2.1% |
| African American | 1.5% | 0.8% | 4.0% | 0.6% | 0.0% | 1.6% | 1.4% |
| Other | 1.3% | 1.6% | 0.9% | 0.6% | 1.5% | 1.3% | 1.3% |
| Not Provided | 0.4% | 0.0% | 0.9% | 1.3% | 0.0% | 1.3% | 0 |
| Median Age^{A} | 40 | 36 | 48 | 44 | 52 | 42 | 40 |
| Median BMI (Range) | 21.1 (15.8-42.8) | 20.6 (15.8 - 33.3) | 22.6 (17.1 - 41.6) | 21.0 (16.0 - 36.4) | 22.4 (18.1 - 42.8) | 21.3 (16.0-36.4) | 21.1 (15.8-42.8) |
| Married | 65.1% | 59.8% | 71.6% | 69.2% | 73.5% | 69.0% | 63.2% |
| College Education^{B} | 81.8% | 81.7% | 81.8% | 80.8% | 85.3% | 82.6% | 81.4% |

A at time of surgery
B includes some college education, college graduates, post college education

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With respect to surgical baseline factors in the Core study, for primary augmentation patients, the most frequently used devices were full height with moderate projection (49.3%), the most common incision site was inframammary (86.8%), and the most frequent site of placement was submuscular (84.3%). The majority of patients (79.1%) enrolled for augmentation and the remaining patients enrolled for cosmetic augmentation with accompanying conditions as follows: 10.6% asymmetry, 6.7% ptosis, and 3.7% aplasia.

For revision-augmentation patients, the most frequently used devices were full height with full projection (37.1%), the most common incision site was inframammary (76%), and the most frequent site of placement was submuscular (71.6%).

For primary reconstruction patients, the most frequently used devices were full height with full projection (40.1%), the most common incision site was the mastectomy scar (75%), and the most frequent site of placement was submuscular (87.6%).

For revision-reconstruction patients, the most frequently used devices were full height with full projection (62.5%), the most common incision site was mastectomy scar (54%), and the most frequent site of placement was submuscular (91.9%).

Table 17: Surgical Baseline Factors by Cohort

| | All Cohorts | Augmentation (n = 983) | Reconstruction (n = 354) | Revision-Augmentation (n = 310) | Revision-Reconstruction (n = 112) |
| --- | --- | --- | --- | --- | --- |
| Style Number | | | | | |
| 410FM | 38.3% | 49.3% | 23.4% | 31.3% | 8.9% |
| 410FF | 30.8% | 21.9% | 40.1% | 37.1% | 62.5% |
| 410MM | 19.9% | 21.9% | 14.7% | 22.9% | 10.7% |
| 410MF | 10.9%…