Contains Nonbinding Recommendations 
Saline, Silicone Gel, and 
Alternative Breast Implants 
 
Guidance for Industry and 
Food and Drug Administration Staff 
 
Document issued on September 29, 2020. 
 
Document originally issued on November 17, 2006.  
 
 
 
 
 
 
 
 
 
 
For questions about this document, contact OHT4: Office of Surgical and Infection Control 
Devices/DHT4B: Division of Infection Control and Plastic Surgery Devices at 301-796-6970.  
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Devices and Radiological Health 
 
    Contains Nonbinding Recommendations 
 
Preface 
 
 
Public Comment 
 
 
You may submit electronic comments and suggestions at any time for Agency consideration to 
https://www.regulations.gov. Submit written comments to the Dockets Management Staff, Food 
and Drug Administration, 5630 Fishers Lane, Room 1061, (HFA-305), Rockville, MD 20852.   
Identify all comments with the docket number FDA-2004-D-0124. Comments may not be acted 
upon by the Agency until the document is next revised or updated. 
 
 
Additional Copies 
 
 
Additional copies are available from the Internet. You may also send an e-mail request to 
CDRH-Guidance@fda.hhs.gov to receive a copy of the guidance. Please include the document 
number 1239 and complete title of the guidance in the request. 
    Contains Nonbinding Recommendations 
 
Table of Contents 
 
I.  Introduction ............................................................................................................................. 1 
 
II.  Background ............................................................................................................................. 2 
A.  Saline-Filled Breast Implant ............................................................................................. 2 
B.  Silicone Gel-Filled Breast Implant ................................................................................... 3 
C.  Alternative Breast Implant ............................................................................................... 3 
III.  Device Description ............................................................................................................... 4 
IV.  Chemistry Data .................................................................................................................... 5 
A.  General Information ......................................................................................................... 5 
B.  Extent of Crosslinking ...................................................................................................... 5 
C.  Extractables ...................................................................................................................... 6 
D.  Volatiles ........................................................................................................................... 7 
E.  Heavy Metals .................................................................................................................... 7 
F.  Saline Filler .......................................................................................................................... 7 
G.  Silicone Gel Filler ............................................................................................................ 8 
H.  Alternative Filler  Polymer ............................................................................................. 8 
I.  Alternative Filler  Non-Polymer ........................................................................................ 8 
V.  Toxicology Data...................................................................................................................... 9 
A.  General Information ......................................................................................................... 9 
B.  Pharmacokinetic Studies .................................................................................................. 9 
C.  Toxicological Testing ..................................................................................................... 10 
VI.  Mechanical Data ................................................................................................................ 11 
A.  General Information ....................................................................................................... 11 
B.  Fatigue Rupture Testing of Total Device ....................................................................... 12 
C.  Valve Competency Testing ............................................................................................ 13 
D.  Cohesivity Testing.......................................................................................................... 13 
E.  Bleed Testing .................................................................................................................. 14 
F.  Stability Testing of Alternative Breast Implants ............................................................... 15 
G.  Shelf Life Testing ........................................................................................................... 15 
VII.  Device Explant Analyses ................................................................................................... 17 
A.  Retrieval Study ............................................................................................................... 17 
B.  Supplemental Information to Characterize Device Failure ............................................ 18  Contains Nonbinding Recommendations 
 
VIII.  Core Study Clinical Data................................................................................................ 19 
A.  General Information ....................................................................................................... 19 
B.  Patient Accounting ......................................................................................................... 22 
C.  Demographics and Baseline Characteristics .................................................................. 23 
D.  Safety Assessment  Complications .............................................................................. 24 
E.  Safety Assessment  Rupture ......................................................................................... 27 
F.  Safety Assessment  Connective Tissue Diseases (CTDs) ................................................ 29 
G.  Safety Assessment  Mammography Data ..................................................................... 32 
H.  Effectiveness Assessment .............................................................................................. 32 
I.  Other Statistical Analysis ................................................................................................... 34 
IX.  Other Clinical Data ............................................................................................................ 35 
A.  Supplemental Clinical Information to Address Rupture ................................................ 35 
B.  Supplemental Literature Information ............................................................................. 36 
X.  Labeling ................................................................................................................................ 37 
A.  General Information ....................................................................................................... 37 
B.  Physician Labeling ......................................................................................................... 37 
C.  Patient Labeling .............................................................................................................. 39 
XI.  Postapproval Requirements ............................................................................................... 40 
 
 
  Contains Nonbinding Recommendations 
 
 
 
Saline, Silicone Gel, and 
Alternative Breast Implants 
 
 
Guidance for Industry and 
Food and Drug Administration Staff 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or 
Agency) on this topic.  It does not establish any rights for any person and is not binding on FDA or 
the public.  You can use an alternative approach if it satisfies the requirements of the applicable 
statutes and regulations.  To discuss an alternative approach, contact the FDA staff or Office 
responsible for this guidance as listed on the title page.  
 
 
I.  Introduction 
This guidance document identifies the device description, non-clinical, clinical, and 
labeling information we recommend you present in a premarket approval application 
(PMA) for a breast implant. This guidance document may also be useful in preparing an 
application for an investigational device exemption (IDE). This document addresses 
breast implants filled with saline, silicone gel, or alternative filler intended for breast 
augmentation or breast reconstruction. This guidance document does not address tissue 
expanders, which are reviewed under the premarket notification (510(k)) process. 
 
This guidance document supplements other FDA publications on PMA and IDE 
applications and should not be construed as a replacement for these documents. For 
general information about these applications, please refer to the following resources: 
 
  PMAs (21 CFR Part 814), https://www.fda.gov/medical-devices/premarket-
submissions/premarket-approval-pma  
  IDEs (21 CFR Part 812), https://www.fda.gov/medical-devices/how-study-and-market-your-
device/investigational-device-exemption-ide.  
 
Sponsors are responsible for developing clinical protocols and providing reasonable 
assurance of the safety and effectiveness of their devices. 
 
1 
 
 
  Contains Nonbinding Recommendations 
 
 
 
For the current edition of the FDA-recognized standard(s) referenced in this document, see 
the FDA Recognized Consensus Standards Database.1  For more information regarding use 
of consensus standards in regulatory submissions, please refer to the FDA guidance titled 
Appropriate Use of Voluntary Consensus Standards in Premarket Submissions for Medical 
Devices.2   
 
FDA's guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidances describe the Agencys current thinking on a topic and 
should be viewed only as recommendations, unless specific regulatory or statutory 
requirements are cited.  The use of the word should in Agency guidance means that 
something is suggested or recommended, but not required.   
 
II.  Background 
Saline-filled, silicone gel-filled, and alternative breast implants may be indicated for breast 
augmentation and/or breast reconstruction, which are defined as follows: 
 
  Breast augmentation. Breast augmentation includes primary breast augmentation to 
increase the breast size, as well as revision surgery to correct or improve the result of 
an original primary breast augmentation surgery (i.e., revision-augmentation). 
 
  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 an original primary breast 
reconstruction surgery (i.e., revision-reconstruction). 
 
However, as discussed later in this document, we recommend you collect clinical data for 
each of the individual indication subgroups of primary augmentation, revision-
augmentation, primary reconstruction, and revision-reconstruction. 
 
A.  Saline-Filled Breast Implant  
A saline-filled breast implant has a silicone rubber shell made of polysiloxane(s), such as 
polydimethylsiloxane and polydiphenylsiloxane, which is inflated to the desired size with 
sterile isotonic saline. Saline-filled breast implants may vary in shell surface, shape, profile, 
volume, and shell thickness. The sterile saline used as a filler material should follow United 
States Pharmacopeia (USP) standards for Normal Physiological Saline (injection grade), 
which has a concentration of 0.15M and a pH of 7.2-7.4. 
 
                                                 
1 Available at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfStandards/search.cfm. 
2 Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/appropriate-use-
voluntary-consensus-standards-premarket-submissions-medical-devices.  
2 
 
 
  Contains Nonbinding Recommendations 
 
 
 
Currently, the approved designs for saline-filled breast implants include:  
 
  a fixed volume implant with a single lumen that is intraoperatively filled with the 
entire volume of saline via a valve  
  an adjustable volume implant with multiple lumens that is intraoperatively filled with 
the entire volume of saline via a valve. 
 
In the Federal Register of June 24, 1988 (53 FR 23856), FDA issued a final rule classifying 
the silicone inflatable (saline-filled) breast prosthesis into class III (21 CFR  878.3530).  
On January 6, 1989 (54 FR 550), FDA published a notice of intent to require submission of 
PMAs for these devices. On January 8, 1993 (58 FR 3436), FDA issued a proposed rule to 
require submission of PMAs or completion of product development protocols (PDPs). On 
August 19, 1999 (64 FR 45155), FDA issued a final rule requiring PMAs for these devices 
to be filed with FDA, or PDPs to be completed, within 90 days. Thus, an approved PMA or 
PDP is now required to market a saline-filled breast implant. 
 
B.  Silicone Gel-Filled Breast Implant 
A silicone gel-filled breast implant has a silicone rubber shell made of polysiloxane(s), such 
as polydimethylsiloxane and polydiphenylsiloxane, which is filled with a fixed amount of 
silicone gel. Silicone gel-filled breast implants may vary in shell surface, shape, profile, 
volume, and shell thickness. 
 
Currently, the approved design for silicone gel-filled breast implants is a fixed volume 
implant with a single lumen containing a fixed amount of silicone gel that may be shaped or 
round, textured or smooth, and filled with silicone gel of more or less viscosity. 
 
In the Federal Register of June 24, 1988 (53 FR 23856), FDA issued a final rule classifying the 
silicone gel-filled breast prosthesis into class III (21 CFR  878.3540). On January 6, 1989 (54 
FR 550), FDA published a notice of intent to require submission of PMAs for these devices. On 
May 17, 1990 (55 FR 20568), FDA issued a proposed rule to require submission of PMAs 
or completion of PDPs. On April 10, 1991 (56 FR 14620), FDA issued a final rule requiring 
PMAs for these devices to be filed with FDA, or PDPs to be completed, within 90 days. Thus, 
an approved PMA or PDP is now required to market a silicone gel-filled breast implant. 
 
C.  Alternative Breast Implant  
An alternative breast implant is not a saline-filled breast implant or a silicone gel-filled 
breast  implant, as defined above. Instead, an alternative breast implant typically has a 
silicone rubber shell with a filler other than saline or silicone gel. The filler material 
may or may not be a gel. However, an alternative breast implant may also have an 
alternative shell made from a material other than silicone rubber. We may recommend 
3 
 
 
  Contains Nonbinding Recommendations 
 
 
 
different or additional evaluations of alternative breast implants depending on their 
design, materials, and performance characteristics. 
 
All alternative breast implants are class III post-amendment devices that require an 
approved PMA or PDP for marketing (Federal Food, Drug, and Cosmetic Act 
(FDCA)  513(f) and 515(a) (21 U.S.C.  360c(f) & 360e(a))). 
 
III.  Device Description  
The Background section above (Section II) provides a very basic device description 
for each of the three types of breast implants. This section recommends the type of 
device description information you should include in your application. However, 
depending on the particular design of your device, additional information may be 
appropriate. 
 
We recommend you provide the following device description information (as applicable): 
 
  the type of implant, as described in the Background section (e.g., a fixed volume, 
single lumen silicone gel-filled breast implant) 
  a written description of each component that comprises the device (e.g., 
shell, gel, patch, textured surface, valve) 
  the specific materials (with suppliers) used to manufacture each component 
  a description of any connector systems, fill tubes, and injection domes, 
including materials and a magnified sketch depicting their 
placement/use 
  a description of when the device is filled by the surgeon if it is not a 
prefilled device (i.e., intraoperatively and/or postoperatively) 
  a description of any overexpansion/overfill of the filler material, even if on a 
temporary basis (e.g., a range of saline filler allowed for a given size implant) 
  a description of the method used to sterilize the device 
  a summary table of all device styles under review in the submission, with the 
following information identified for each style: 
  shell surface  
o
  shape  
o
  profile  
o
  volume 
o
  width 
o
  height 
o
  projection 
o
  shell thickness  
o
 
4 
 
 
  Contains Nonbinding Recommendations 
 
 
 
Depending on the specific design features of your device, we may recommend you include 
additional information and/or columns in your summary table. 
 
IV.  Chemistry Data 
A.  General Information 
For the chemicals and materials used in the manufacture of your breast implant, we 
recommend you provide the: 
 
  common names and trade names of each chemical/material (including additives, 
plasticizers, and antioxidants) 
  specific role of each chemical and material in the manufacturing process and/or in 
the final device 
  location of the material within the device (e.g., shell, filler, valve, adhesive) 
  chemical name, the mean molecular weight, and a measure of the polydispersity for 
each polymeric component 
  material safety data sheets for each chemical 
  Master File (MAF) numbers for each material, including specific volume and page 
number references, as well as a signed letter from the MAF owner granting you 
permission to use its data, if applicable. 
 
We also recommend you state whether the silica used in the elastomer shell dispersion is in 
the amorphous form or the crystalline form. 
 
Sections IV.B through IV.E of this document describe chemical analyses of the elastomer 
shell (including the patch and valve) that we recommend you include in your submission. 
Sections IV.F through IV.I describe chemical analyses of the filler material. Additional 
analyses may be appropriate depending upon the design features of your device, such as 
texturing, variations in device components (such as patches or valves), or the sterility 
methods used. 
 
B.  Extent of Crosslinking 
The manufacture of the shell involves curing of polymeric components of silicones by 
chemical crosslinking. We recommend you provide the extent of crosslinking from at least 
three different manufacturing lots to confirm the uniformity of the degree of crosslinking 
across lots. Suggested methods to determine the extent of crosslinking include: 
 
  measurement of Youngs modulus at low strain (this is approximately proportional 
to crosslink density) 
  measurement of equilibrium swelling of the polymeric component by an 
5 
 
 
  Contains Nonbinding Recommendations 
 
 
 
appropriate solvent similar to that used for the extractable analyses 
  determination of the amount of unreacted crosslinker from the total extractables. 
 
We recommend you also perform an analysis on the cured polymer to confirm the presence of 
silicone functional groups. One recommended method is Fourier Transform Infrared 
Spectroscopy (FTIR). 
 
C.  Extractables 
We recommend you conduct an analysis of the extractables or releasable chemicals obtained 
by exhaustive solvent extraction to identify potentially toxic chemicals and estimate the 
upper limits of the chemicals that could be released into the patient. Soxhlet extraction is 
one recommended method. Below is a general description of a protocol for attaining 
exhaustive extraction of extractables or releasable chemicals. 
 
Perform the extraction of the shell for chemical analyses with at least one polar solvent 
(e.g., ethanol or a mixture of ethanol-water) and two non-polar solvents (e.g., 
dichloromethane and n-hexane) at 37C. To determine the duration of the exhaustive 
extractions, you should conduct a series of successive extractions by exposing the 
sample to the solvent for a period of time, analyzing the solvent for extractables, 
replacing with fresh solvent, exposing the sample again for a period of time, 
analyzing, and repeating the process. 
 
When the level of the analyte for the extraction is one-tenth (0.1) the level in the 
previous extraction, the extraction is deemed complete so that a 10% correction to the 
total extractable material can be applied. In cases where this condition may not occur 
because of extremely slow migration of the higher molecular weight material, you 
should apply the test to the contents of the extract with molecular weights of 1500 
Daltons because these are the compounds of greatest clinical interest. You should add 
all separate analyte levels to calculate the cumulative value and, via the sample/solvent 
ratio, the sample and device levels. You should use the total extraction from the polar 
solvent and the extraction from one of the non-polar solvents that yields the higher 
amounts of extractables for both quantitative and qualitative analyses. For extracts 
that may contain oligomeric or polymeric species, you should provide the molecular 
weight distribution, along with the number and weight average molecular weights and 
the polydispersity. You should perform an FTIR analysis on the extractable residuals. 
 
We recommend you provide the following information from your analyses of the 
extractables: 
 
  identification and quantification of all compounds with molecular weights of 1500 
Daltons after exhaustive extraction of the final sterilized shell. These should include, 
but need not be limited to: 
6 
 
 
  Contains Nonbinding Recommendations 
 
 
 
  residual monomers, cyclic and linear oligo-siloxanes 
o
  known toxic residues such as polychlorinated biphenyls (PCBs), if 
o
peroxide curing process is involved 
  aromatic amines, if polyurethanes are used 
o
  the percent recovery, especially for the polydimethylsiloxanes (up to D20) 
  evidence that shows that exhaustive extraction has been achieved with one of the 
solvents 
  identification of all experimental methodology3 
  raw data (including instrument reports) with all chromatograms, spectrograms, etc. 
You should also provide the practical quantitative limit when the analyte of interest 
is not detected.4 
 
D.  Volatiles 
We recommend you analyze the elastomer shell for volatile components using a headspace 
detector. 
 
E.  Heavy Metals 
We recommend you provide qualitative and quantitative analyses for heavy metals on the 
final finished shell. The heavy metal analyses should include, but need not be limited to, 
analyses of the following metals: antimony, arsenic, barium, beryllium, cadmium, 
chromium, cobalt, copper, lead, magnesium, mercury, molybdenum, nickel, platinum, 
selenium, silver, tin, titanium, vanadium, and zinc. In addition, for the metal used as the 
catalyst in the curing reaction, we recommend you provide the valence state and the amount 
of residue of the catalyst. 
 
In lieu of providing a complete heavy metal analysis on the finished shell, you may provide 
the purity of the catalyst (with trace elements) used in the raw shell material, along with an 
analysis of the finished shell for just the catalyst metal used. 
 
F.  Saline Filler 
Normal physiological sterile saline has a long history of use in breast implants and is 
standardized by the USP. As stated above, the sterile saline used with your device should 
follow USP standards for Normal Physiological Saline (injection grade), which has a 
concentration of 0.15M and a pH of 7.2-7.4. If your breast implant is to be filled with any 
other saline, we recommend you provide a complete chemical analysis of that saline. 
                                                 
3 For example: Gel Permeable Chromatography (GPC), Gas Liquid Chromatography (GLC), Mass Spectrometry 
(MS), Atomic Emission Detector (AED), and FTIR. 
4 Keith, L. Compilation of EPA's Sampling and Analysis Methods. Lewis Publishers, 1992.  
 
7 
 
 
  Contains Nonbinding Recommendations 
 
 
 
G.  Silicone Gel Filler  
The analyses of the silicone gel should be very similar to those for the elastomer shell. For 
the final sterilized gel, we recommend you provide the: 
 
  qualitative and quantitative analyses for extractables (such as cyclic polysiloxanes), 
including: 
  characterization of the polymers present 
o
  molecular weight averages and polydispersities of the polymers 
o
  identification and quantification of all compounds present with 
o
molecular weights 1500 Daltons 
  qualitative and quantitative analyses for volatiles 
  qualitative and quantitative analyses for heavy metal contents 
  physical properties of the gel, including viscosity, cohesivity, and approximate 
crosslink density (if possible) 
  percentage of silicone oil and its chemical and physical properties (e.g., molecular 
weight, viscosity). 
 
H.  Alternative Filler  Polymer  
For the final sterilized, alternative polymer filler, we recommend you provide the: 
 
  rationale for the use of the specific alternative filler material 
  list of components used in the synthesis and the method of synthesis of any 
polymer used in the preparation of filler (if a synthetic polymer) or the source and 
isolation procedure of the polymer (if a natural polymer) 
  quantitative analyses of monomers (if a synthetic polymer) and their safety profiles 
  method of purification of the polymer 
  complete physical and chemical characteristics of the polymer (e.g., viscosity, 
molecular weight) 
  formulation of the polymer (the ratio of polymer should be specified if the filler 
material is a mixture of more than one component) 
  structural analyses of the polymer, including molecular weight distribution 
  quantification and identification of all chemicals with molecular weights 1500 
Daltons and their characterization 
  trace metal/heavy metal analysis and the valence state if metals were used as 
catalysts in the polymerization reaction 
  crosslink density (if a synthetic and cured material). 
 
I.  Alternative Filler  Non-Polymer 
For the final sterilized, alternative non-polymer filler, we recommend you provide the: 
 
8 
 
 
  Contains Nonbinding Recommendations 
 
 
 
  rationale for the use of the specific alternative filler material 
  composition of the non-polymer, including characterization of smaller molecular 
weight components 
  method of purification of the non-polymer 
  complete physical and chemical characteristics of the non-polymer (e.g., viscosity, 
molecular weight) 
  source and isolation procedure of the non-polymer 
  structural analyses of the non-polymer, including molecular weight distribution. 
 
V.  Toxicology Data 
A.  General Information  
We recommend you provide a toxicological assessment because breast implants contain not 
only the major polymeric materials (e.g., polymerized polydimethylsiloxane), but also low 
molecular weight components (e.g., D ) from the manufacturing or sterilization processes 
4
that may leach out into the patients body. In addition to the chemical composition 
information (Section IV.A above), the toxicological safety assessment should include 
information from pharmacokinetic studies and toxicological testing, as described below. 
 
B.  Pharmacokinetic Studies 
Knowledge of the pharmacokinetic behavior of potentially toxic chemicals is a scientific 
assessment of the potential of the chemicals to accumulate in the body at concentrations that 
cause human health risks. Your pharmacokinetic study design should address the worst case 
assumption (i.e., all of the material in the device is absorbed into the body at once). If this 
assumption, with the addition of safety factors, results in toxic levels of exposure, 
demonstrations of slow diffusion of substances from the device into the body, or rapid 
metabolism or excretion of the substances by the patient, may negate the worst case 
assumption. The pharmacokinetic testing of toxicants of concern should determine the rates 
of absorption into and clearance from the blood, the distribution in the body, and the rates of 
metabolism and/or excretion. If radiolabeling is used, we recommend you label the device to 
reflect the fates of all of the components of interest. For additional information about 
pharmacokinetics, refer to ISO 10993-16.5 
 
 
 
 
                                                 
5ISO 10993-16: Biological evaluation of medical devices  Part 16: Toxicokinetic study design for 
degradation products and leachables. 
 
9 
 
 
  Contains Nonbinding Recommendations 
 
 
 
C.  Toxicological Testing 
Toxicological testing is used to detect unidentified toxicants and to quantify the exposure to 
known toxic compounds. We recommend you perform the following toxicological tests 
separately on both the final sterilized shell and filler: 
 
  cytotoxicity 
  acute systemic toxicity 
  hemocompatibility 
  immunotoxicity 
  reproductive toxicity 
  teratogenicity 
  genotoxicity 
  carcinogenicity 
  implantation testing. 
 
 
Refer to ISO 10993-16 and the CDRH guidance document, Use of International Standard 
ISO 10993-1, Biological evaluation of medical devices  Part 1: Evaluation and testing within a 
risk management process,7 for more details about the toxicological tests above. We have 
included additional special considerations for some of these tests below. 
 
Acute Systemic Toxicity 
For the pyrogenicity element of the acute systemic toxicity testing, we recommend that you 
perform both the rabbit pyrogen and the Limulus Amebocyte Lysate (LAL) tests. For 
routine batch monitoring, the LAL test should be sufficient. 
 
Immunotoxicity Testing 
For immunotoxicity testing, we recommend you assess the level of immunotoxicity of the 
shell and any leachable compounds from the shell and the gel (if applicable). For more 
information, you should refer to the CDRH Immunotoxicity Testing Guidance.8  
 
Reproductive and Teratogenicity Testing 
For reproductive and teratogenicity testing, you should measure the rates of conception, 
maturation, and cycling abnormalities, as well as the number of fetal deaths and 
malformations. Obvious malformations are rare; therefore, we recommend extensive 
examinations to adequately assess the malformation rates. The studies should include at least 
                                                 
6 ISO 10993-1: Biological evaluation of medical devices  Part 1: Evaluation and testing within a risk 
management process. 
7 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/use-international-standard-iso-
10993-1-biological-evaluation-medical-devices-part-1-evaluation-and.  
8 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/immunotoxicity-testing-
guidance.  
10 
 
 
  Contains Nonbinding Recommendations 
 
 
 
two generations. You should test individual compounds at the highest possible exposure that 
does not produce non-reproductive systemic toxicity. 
 
Genotoxicity Testing 
For genotoxicity testing, you should address the potential of leachable compounds and/or 
degradation products of your device to cause cancer. The short-term genotoxicity testing 
should consist of: 
 
  a bacterial mutagenicity test (including point mutations and frameshift mutations) 
  a mammalian forward mutation assay (e.g., a mouse lymphoma test) 
  an in-vivo rodent micronucleus test. 
 
Genotoxicity testing may be sufficient in lieu of 2-year carcinogenicity testing, if all of the 
short-term genotoxicity testing is negative. However, even if the short-term genotoxicity 
testing is negative, FDA may still recommend 2-year carcinogenicity testing if your device 
consists of other materials than those typically present in polydimethylsiloxane-based breast 
implants or material compounds (e.g., D ) at higher than expected levels. 
4
 
Implantation Testing 
We recommend you provide acute, subchronic, and chronic implantation testing because 
some implant components may elicit immediate tissue reactions, while others may diffuse 
out of the device slowly and/or undergo chemical changes that affect the surrounding 
tissues long after implantation. You should implant samples of shell and gel, as well as a 
standard control (e.g., polyethylene), subcutaneously or submuscularly. We do not 
recommend that you use extracts. You should report the gross and histological 
observations of the effects of implantation. We recommend that the chronic implantation 
testing be extended for 2 years, roughly the lifetime of the rat. 
 
If the short-term genetic toxicology testing is negative and the clinical carcinogenic 
experience with the materials continues to support safety, it may be appropriate to complete 
the carcinogenicity testing and/or chronic implantation testing concurrently with an ongoing 
clinical study. 
 
VI.  Mechanical Data  
A.  General Information  
We recommend you provide mechanical testing on the final finished product or individual 
components of it (e.g., shell, valve). These tests are described in Sections VI.B through VI.G 
below. Whenever possible (and applicable), testing should mimic in-vivo conditions. If your 
device is sterilized by different methods (e.g., ethylene oxide, gamma radiation), you should 
perform the testing on samples sterilized by the different methods, or provide an adequate 
rationale why the change in sterilization method does not negatively impact the mechanical 
characteristics. You should also provide complete reports for all testing, including 
11 
 
 
  Contains Nonbinding Recommendations 
 
 
 
identification of the devices tested and a description of the test set-up and methods, including 
sketches or photographs. 
 
B.  Fatigue Rupture Testing of Total Device 
Most materials have a finite fatigue life when repeatedly stressed in-vivo. Repeated 
stressing of the device may eventually weaken the shell and lead to failure. While FDA 
recommends a test method that mimics in-vivo conditions, FDA recognizes that a test 
method cannot be adequately validated until in-vivo rupture from cyclic fatigue has been 
analyzed and characterized. Currently available data on retrieved devices implanted for 
approximately 10 years suggest that the devices may be failing due to reasons such as fold 
flaw, localized shell stress, and instrument damage, rather than shell rupture due to pure 
cyclic loading. Nevertheless, FDA believes that cyclic testing provides useful information 
about the fatigue characteristics of the device. 
 
Therefore, we recommend you provide a complete test report of fatigue testing on the worst 
case, final, sterilized device(s) with the thinnest shells allowed by the design release criteria 
using a test set-up with particular focus on the loading direction(s) on the device, the shape 
of the loading apparatus that contacts the device, and the testing medium, etc., that best 
mimics expected in-vivo loading. The common test methodology, in which flat plates 
compress the device, may or may not be predictive of clinical failure for your device. 
 
We recommend you perform fatigue testing in a constant load or a constant displacement 
mode. However, you should perform constant displacement testing only if you measure the 
actual applied loads continuously or at frequent points during the testing and the variation of 
the actual applied load is minimal. You should use the minimal load applied during constant 
displacement testing to establish the endurance load level. 
 
You should cyclically load the samples at varying loads or displacements to generate an 
applied force versus number of cycles to failure (AF/N) curve for each style of device tested. 
You should test a minimum of 3 samples from a typical production run at a given load or 
displacement because of the general variance seen in elastomer testing. We recommend the 
endurance load (or the load at which the samples do not fail under cyclic loading) be 
established at a minimum of 6.5 million cycles runout. The AF/N curves may be generated 
by best-fit approach or by averaging the number of samples tested at each load. There 
should be a tight range (e.g., 10%) of points around and at the endurance load level for an 
optimal estimate of fatigue strength. 
 
We recommend you provide the following results for each style of device tested: 
 
  the resulting endurance load level 
  the clinical relevance for the resulting endurance load level 
  the AF/N curve 
12 
 
 
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  the raw data (e.g., applied loads, applied displacements for displacement control 
test, number of cycles to failure, sample thicknesses). 
 
In addition to the fatigue testing described above, we recommend you perform an analysis of 
the cyclic raw data to estimate a pure cyclic fatigue lifetime of your device. However, FDA 
believes that this will remain unvalidated until you have analyzed and duplicated clinical 
failures from pure cyclic fatigue in bench testing. 
 
C.  Valve Competency Testing  
This testing pertains only to breast implants with valves. Valve competence tests are 
performed to demonstrate that valve integrity is maintained at in-vivo loads. Devices can be 
subjected to hydrostatic forces that tend to force fluid out of the device, causing a deflation 
and change in size and shape. The most likely source for increased pressure inside the 
devices would be from patients reclining with various body parts (e.g., head, arm, trunk) 
pressing on their devices. 
 
 
ASTM standard F20519 states that there shall be no leakage observable after a normally 
closed valve is subjected to a retrograde pressure equivalent to 30cm H2O for 5 minutes 
and then to a retrograde pressure equivalent to 3cm H2O for 5 minutes. FDA does not 
believe that the ASTM F2051 methodology is clinically relevant with respect to the load 
levels. However, this methodology may provide useful information about the valves 
response to shifts in pressure. Therefore, we recommend you provide a complete report of 
valve competency testing, as described in ASTM F2051 or an equivalent method, with 
pass/fail results for leakage. 
 
In addition to the testing above, you should provide a complete report of destructive testing 
to address in-vivo loading conditions. You should gradually load the samples until valve 
failure occurs to define a maximum pressure for the device. We recommend you provide 
the: 
 
  burst pressures 
  failure modes (including whether the failed test valves reseal upon removal of the 
excess failure-inducing pressures) 
  rationale why the resulting burst pressures are clinically relevant. 
 
D.  Cohesivity Testing 
This testing pertains only to silicone gel-filled and, possibly, alternative breast implants. 
 
                                                 
9 ASTM F2051: Standard Specification for Implantable Saline Filled Breast Prosthesis. 
13 
 
 
  Contains Nonbinding Recommendations 
 
 
 
Cohesivity of Silicone Gel-Filled Breast Implants 
We recommend you quantify the cohesivity of the silicone gel. Although the two methods 
described in ASTM F70310 were not developed to address gels with high cohesivities, we 
believe the results provide useful device characterization information. We recommend you 
provide complete reports of the following testing to address gel cohesivity: 
  gel cohesion testing on the final gel as described in the cone/pendant method in 
ASTM F703 and provide the pass/fail results 
  penetration testing (an indirect measure of gel cohesivity) on the in-process gel and 
provide a complete description of the penetration test method, the acceptance 
criteria, and the results. 
 
Cohesivity of Alternative Breast Implants 
Depending on the filler used in your alternative breast implant, FDA may recommend a 
different method to assess cohesivity than described above for silicone gel-filled breast 
implants. 
 
E.  Bleed Testing 
This testing pertains only to silicone gel-filled and alternative breast implants. 
 
Bleed of Silicone Gel-Filled Breast Implants 
Silicone gel bleed is the diffusion of gel constituents through an intact shell. It is important 
to assess gel bleed for your silicone gel-filled breast implants in order to have information 
accurately characterizing the gel bleed of your product, which can be included in your 
labeling. 
 
The ASTM F703 test is one method to evaluate the extent of gel bleed. However, the results 
from this testing have limited clinical correlation because the ASTM F703 test method was 
established for the purpose of allowing comparison between device models rather than 
quantifying in-vivo gel bleed. In addition, the ASTM F703 test method was not established 
to identify and quantify gel bleed constituents. Thus, FDA does not believe that this test 
methodology provides adequate data to address gel bleed for the purposes of a PMA. 
 
Accordingly, we recommend you provide a complete report of gel bleed bench testing based 
on a protocol that mimics in-vivo conditions. That is, you should incubate (immerse) the 
breast implants in a medium that simulates the known composition of human interstitial 
fluid.11  Animal serum that approximates this composition or any artificial medium with a 
composition similar to interstitial fluid may be acceptable. Because the in-vivo environment 
is dynamic, you should allow for transfer of new medium to prevent saturation. The testing 
                                                 
10 ASTM F703: Standard Specification for Implantable Breast Prostheses. 
11 Fogh-Andersen, N, BM Altura, BT Altura, and OS Siggaard-Andersen: Composition of Interstitial Fluid, Clin 
Chem (41/10), 1522-1525 (1995).  
14 
 
 
  Contains Nonbinding Recommendations 
 
 
 
should continue until the change in gel bleed rate of the detectable gel constituents has 
leveled off. We recommend you identify the gel bleed constituents (including silicones and 
platinum species (or other catalysts)), the rate that these gel constituents bleed out, and how 
that rate changes over time. 
 
FDA understands the limitations of this gel bleed bench testing in mimicking the in-vivo 
environment, as well as the limitations of how these data correlate with clinical use. 
Nevertheless, we believe this testing is a step closer to more accurately characterizing gel 
bleed than the existing ASTM F703 test methodology. If you believe that you have an 
alternative method (e.g., animal study) or clinical data that identifies and quantifies the gel 
bleed constituents over time, we recommend you contact FDA. 
 
Bleed of Alternative Breast Implants 
For devices with alternative fillers, FDA is concerned about potential changes in the 
composition of the alternative filler resulting from long-term chronic bleed. Therefore, in 
addition to performing the testing described above for a silicone gel-filled breast implant, 
we recommend you provide the results of a chemical analysis of the material remaining in 
the device, over time, when evaluated in a test that mimics in-vivo conditions. 
 
F.  Stability Testing of Alternative Breast Implants 
Whereas silicone polymers (e.g., silicone gel) are considered to be highly stable, the stability 
characteristics of an alternative polymer or non-polymer filler may be unknown. Therefore, 
for a breast implant with an alternative polymer or non-polymer filler, we recommend you 
provide a complete report of stability/aging testing to demonstrate the effects of time and 
temperature (physiological temperature (37C) and elevated temperature (60C)) on the 
physical properties and chemical composition of the device as a whole and of the filler 
material. You should measure key physical parameters of the filler, such as viscosity and 
cohesivity, at each timepoint. If there are mechanical changes, you should conduct complete 
chemical analyses to explain the physical changes. 
 
G.  Shelf Life Testing 
We recommend you provide both real-time mechanical testing and packaging testing to 
establish the shelf life (i.e., expiration date) for the device. Accelerated shelf life testing 
may be appropriate if it has been validated by real-time data. 
 
Mechanical Testing 
We recommend you perform mechanical testing on representative aged samples at time 
zero and at various intervals throughout the shelf life. The mechanical tests should include, 
but need not be limited to: 
 
  ultimate elongation 
15 
 
 
  Contains Nonbinding Recommendations 
 
 
 
  joint 
  tensile set 
  break force 
  valve competency (if applicable) 
  gel cohesivity (if applicable). 
 
Packaging Testing 
With regard to packaging testing, we recommend you test the final finished package for 
initial integrity and maintenance of integrity after selecting the appropriate materials and 
qualifying the package configuration. You should use test methods that are either validated 
or standardized. Below is a more detailed description of what we recommend you provide 
to address initial package integrity and maintenance of package integrity. 
 
Initial Package Integrity 
We recommend you test the integrity of the seal and the whole package at time zero. This 
includes both seal and whole package testing. You should test the seals of the package for 
seal integrity and seal strength. Seal integrity may be established by demonstrating that the 
seal is impermeable and continuous. There are several standardized methods that may be 
used to determine seal integrity. For example, ASTM F192912 is a dye penetration method 
for detecting seal leaks. Seal strength should demonstrate that the fiber shedding, splitting, 
and tearing of the package is within your specifications. 
 
For whole package testing, you may use physical or microbiological test methods. Examples 
of whole package integrity tests are internal pressure test, dye penetration, gas sensing test, or 
vacuum leak test. Currently, there are only a few standardized physical whole package test 
methods. ASTM D307813 is an example of a test method by bubble emission. Alternatively, a 
microbial challenge test may be appropriate. 
 
Maintenance of Package Integrity 
We recommend you evaluate the ability of the package to maintain its integrity over time by 
the same functional tests used for integrity testing. You should expose the package, with the 
device in it, to the environmental stresses imposed by manufacturing, sterilization processes, 
distribution, handling, vibration, and the storage environment. You should perform the seal 
integrity and whole package testing after stressing and at various intervals throughout the 
shelf life of the package. The data obtained during this time period should remain within the 
validated limits of the performance specification. 
 
 
                                                 
12 ASTM F1929: Standard Test Method for Detecting Seal Leaks in Porous Medical Packaging by Dye 
Penetration. 
13ASTM D3078: Standard Test Method for Determination of Leaks in Flexible Packaging by Bubble Emission. 
16 
 
 
  Contains Nonbinding Recommendations 
 
 
 
VII. Device Explant Analyses 
You should provide device explant analyses with the goal of characterizing modes and 
causes of device failure and potentially minimizing the identified failures. In order to 
provide as large a sample as possible, we recommend that the analyses include any 
available explanted devices, such as those from the European market, as long as they are 
the same devices for which you are seeking PMA approval. 
 
A.  Retrieval Study  
We recommend that you perform a retrieval study as the primary means of evaluating all 
available explanted devices. A standard retrieval study should involve: 
 
  data collection at the time of explantation by the surgeon or appropriate 
healthcare provider 
  laboratory analysis/testing of the explanted devices by you or a third party. 
 
If the retrieval study involves explants from the Core Study (i.e., the primary IDE study used 
to support PMA approval), FDA may also request that you provide some Core Study 
clinical data, such as complication and MRI data, that correspond to the patients with 
explants to better understand the results of the laboratory analyses. 
 
Data at Time of Explantation 
We recommend the following observations be recorded on a field report form by the 
explanting surgeon or appropriate healthcare provider at the explant site: 
 
  reason(s) for the device explantation 
  relevant device observations at explantation, for example: 
  presence of any shell defects, such as a hole or tear 
o
  presence and extent of implant rupture (intracapsular gel, extracapsular gel, 
o
or migrated gel) 
  the condition of the valves and/or patches 
o
  any discoloration of the filler 
o
  fungal or bacterial contamination in shell or within filler 
o
  if applicable, whether implant rupture is believed to have occurred before or during 
explantation. 
 
You should implement a standardized method of sterilization for the explanted devices to 
minimize the factors that may impact device mechanical properties. 
 
Laboratory Analyses/Testing 
We recommend you provide laboratory analyses/testing on all available explanted devices, 
whether or not the explanted device is identified by the explanting party as being ruptured, 
17 
 
 
  Contains Nonbinding Recommendations 
 
 
 
in order to characterize the modes and causes of failure from the available explanted 
devices. While rupture (or shell opening) is one example of a failure, any undesirable 
change to the device should also be characterized as a failure (e.g., gel fracture of the more- 
cohesive silicone gel-filled breast implants). 
 
As part of the laboratory analyses/testing, FDA recommends you provide thorough visual 
and microscopic examination findings of all available explanted devices and physical 
property testing to assess trends, to address retrieval study findings, etc. 
 
FDA recommends you consider the article by Brandon, et al.14 for a description of the type 
of analyses/testing that may be appropriate for your retrieval study (e.g., control group of 
unimplanted devices, detailed chemical analyses of materials, detailed mechanical testing, 
scanning electron microscopy, and analysis of local tissue/capsule). 
 
You should also consider the impact of the following factors when characterizing the modes 
and causes of failure of your device: 
 
  device type/model, lot number, size, shell thickness, surface type (smooth or 
textured) 
  implantation duration 
  device handling prior to insertion 
  device position (subglandular or submuscular) 
  incision size 
  observations recorded at the time of explantation (section above) 
  surgical damage during implantation (scalpel nicks, suture punctures, surgeons 
finger imprints, clamp grip marks) 
  in-vivo trauma (accident, mammography) 
  procedures performed while device is in-situ (biopsies, cyst aspirations) 
  explantation technique 
  in-vivo material property and chemistry changes or degradation. 
 
B.  Supplemental Information to Characterize Device 
Failure 
To further characterize the modes and causes of failure of your device, we recommend you 
provide: 
 
  an assessment of your manufacturing processes related to release specifications of 
your shell to determine whether any allowances for imperfections, such as bubbles 
and contaminants, may be related to device failure 
                                                 
14Brandon, et. al, Protocol for Retrieval and Analysis of Breast Implants, Journal of Long-Term Effects of 
Medical Implants, 13(1): 49-61. 2003.  
18 
 
 
  Contains Nonbinding Recommendations 
 
 
 
  an assessment of the surgical techniques that may increase the risk of rupture 
  a comprehensive literature review of durability studies based on explanted devices 
  any additional appropriate studies to assess the modes and causes of device failure. 
 
FDA believes that this information may be used to design non-clinical tests that are more 
predictive of the long-term rupture rate. We recommend that you also use the results to 
design improved devices and establish new manufacturing acceptance criteria. 
 
VIII.  Core Study Clinical Data 
A.  General Information 
Indications 
We recommend that the Core Study (i.e., the primary IDE study used to support PMA 
approval) include separate patient cohorts of: 
 
  primary augmentation 
  primary reconstruction 
  revision-augmentation 
  revision-reconstruction. 
 
Because these studies are complicated by the fact that an individual patient may receive two 
devices for two different reasons (e.g., a woman may receive one device for reconstruction 
and one for augmentation), we recommend you record and analyze the data for both on a per 
patient and a per device basis. 
 
We recommend you classify the patient and device by the initial indication at study entry as 
follows: 
 
  If a reconstruction patient undergoes contralateral augmentation, you should 
classify that patient as reconstruction. The device should be classified as 
one reconstruction and one augmentation. 
  If a revision-augmentation patient (i.e., the patient entered the study due to 
replacement of an existing device, regardless of the type or manufacturer of the 
existing device), undergoes contralateral augmentation, you should classify that 
patient as a revision-augmentation patient. The device should be classified as 
one revision-augmentation and one augmentation. 
  Even if the device is removed and replaced during the study (i.e., after 
initial implantation), you should classify the patient and device under the 
original indication (i.e., primary augmentation, primary reconstruction, or 
revision- augmentation or revision-reconstruction). 
 
19 
 
 
  Contains Nonbinding Recommendations 
 
 
 
Core Study Duration 
FDA recommends that the Core Study involve 10 years or more of prospective patient 
follow-up, including some premarket and some postmarket follow-up. The premarket 
duration of the Core Study will depend on the device design and all of the available safety 
and effectiveness data, including, but not limited to, the Core Study data. As a whole, the 
premarket data (clinical and non-clinical) should be sufficient to characterize complication 
rates over time, potential health consequences of those complications, and any other specific 
safety concern for your device, whether it is a saline-filled, silicone gel-filled, or alternative 
breast implant. 
 
Section IX of this document describes how additional information to address issues 
associated with silicone gel-filled breast implants may be addressed by clinical data other 
than the Core Study. In addition, Section IX describes how literature may provide 
supplemental information to address specific breast implant topics. 
 
At this time, a minimum of three years of premarket Core Study data have been submitted to 
support approval of standard silicone gel breast implants, and a minimum of two years of 
premarket Core Study data have been submitted to support approval of standard saline-filled 
breast implants. However, the appropriate length of time for collection of premarket Core 
Study data will be determined on a case-by-case basis for each implant after careful 
consideration of all available clinical and non-clinical data. 
 
Evaluation Timepoints 
FDA recommends that you conduct regularly scheduled evaluations of complications, with 
follow-up intervals of 6-10 weeks, 1 year, and annually through 10 years. We recommend 
you perform annual evaluations to minimize the number of patients lost-to-follow-up. 
 
For MRIs to screen for asymptomatic (silent) rupture (see Section VIII.E), connective 
tissue diseases evaluations (see Section VIII.F), and patient reported outcome evaluations 
(Section VIII.H), we recommend biennial follow-up evaluations. 
 
Follow-up after Device Removal  
For patients who undergo device removal and replacement with your device or removal 
without replacement, you should continue to collect safety data on these patients as 
described in your protocol. 
 
Control Group 
If you choose to incorporate a concurrent control group, we recommend that you select an 
approved breast implant. If you choose not to incorporate a concurrent control group, we 
recommend that you use historical controls and provide the rationale for not using a 
concurrent control group. 
 
20 
 
 
  Contains Nonbinding Recommendations 
 
 
 
Sample Size 
We recommend you base sample size estimates on the precision of safety and effectiveness 
outcomes or the detection of a clinically meaningful difference from baseline or from a 
control group, taking into account the lost-to-follow-up rates estimated for 10 years of 
follow-up. If sample size estimates are based on the precision with which complication 
rates can be estimated, then the sample size should be large enough to ensure this precision 
is within a pre-specified number of percentage points based on 95% confidence intervals. 
 
For example, for sufficient numbers of patients with primary augmentation or primary 
reconstruction (i.e., assuming 75% primary augmentation and 25% primary reconstruction) 
to determine the rupture rate with a precision as follows, data on 500 patients would be 
needed at 10 years post-implantation. If you estimate a hypothetical 40% drop out rate at 10 
years, then you should enroll at least 850 patients to achieve 10-year data on 500 patients. 
This sample size will provide a worst case precision of +/-4%, given a rupture rate of 50%. 
The precision will improve as the rate moves away from 50%, with a +/-1.9% precision at a 
rupture rate of 5% or 95%. Pooling of primary augmentation and primary reconstruction 
cohorts represents the overall best case (i.e. lowest) precision. However, FDA recommends 
you provide the precision (i.e., confidence intervals) separately for each patient cohort. 
 
Because both safety and effectiveness data from patients presenting for revision may be 
significantly different from data from primary implantation patients, you should include a 
proportion of patients presenting for revision. For example, if you estimate approximately 
20% of patients present for breast implants due to revision, you should increase the sample 
size by 20%. Therefore, if you need 850 primary implantation patients, you should enroll 
approximately 170 revision patients, with the majority of these patients being revision- 
augmentation patients. This leads to an overall sample size of approximately 1020 patients. 
 
You should support all marketing claims of equivalence or superiority to existing implants 
or therapies with statistically justified numbers of patients, clinically relevant endpoints, 
and direct comparisons made to an appropriate control group. 
 
Although the sample size example above is based on a worst-case assumption of 40% lost- 
to-follow-up at 10 years, FDA believes you should provide a minimum of 80% follow-up 
at each timepoint per patient cohort to have meaningful data to evaluate the safety and 
effectiveness of your device. 
 
Lost-to-Follow-Up Analyses 
High lost-to-follow-up rates may affect FDA's ability to evaluate your PMA. Therefore, we 
recommend you include a comparison of baseline characteristics between those subjects 
with complete data and those without to ascertain the presence of any non-respondent bias.       
We recommend you contact patients who are lost-to-follow-up at the end of the study to 
determine whether the outcomes for these patients are the same as those for the patients who 
were compliant with follow-up. Failure to do this may delay filing or approval of the PMA 
because additional clinical data may be necessary. 
21 
 
 
  Contains Nonbinding Recommendations 
 
 
 
Data Presentations 
The sections below describe the types of safety and effectiveness data that we recommend 
you provide regarding your Core Study in a breast implant PMA. We encourage you to 
provide your own data presentations, as well as those described below. While most of these 
presentations apply to all types of breast implants, some data presentations, such as silent 
rupture (i.e., asymptomatic rupture) information, are not applicable to saline-filled breast 
implants. 
 
The majority of the data described below should be reported for the separate patient 
cohorts of primary augmentation, primary reconstruction, revision-augmentation, and 
revision-reconstruction (i.e., the patient status/indication at study entry). Furthermore, you 
should provide the data on both per patient and per device bases for most of the items below. 
 
B.  Patient Accounting 
We recommend you provide complete patient accounting on a per patient basis for each 
cohort. You should include the number of patients theoretically due, discontinued because 
of death or device removal, expected for follow-up, and actually evaluated at each 
evaluation timepoint. Table 1 below is an example of cumulative patient accounting. 
 
Table 1 - Cumulative Patient Accounting 
  Periop  1 yr  2 yr  n yr 
Theoretically dueA  100  85  50   
Deaths  0  1  1   
Patients with all devices removed without  0  2  2   
replacement 
Patients with all devices removed and  0  1  3   
replaced with other manufacturers devices 
Patients with all devices removed and  0  4  6   
replaced with your devices 
ExpectedB  100  81  44   
Actual (Patients with complete follow-up)  100  68  39   
Lost-to-follow-up  0  13  5   
Percent Follow-up (Actual/Expected)  100/100  68/81  39/44   
(100%)  (84%)  (89%) 
APatients who would have been examined according to date of implantation and follow-up 
schedules. 
BPatients who are theoretically due minus the sum of the deaths, removals without 
replacement, and removals with replacement with different manufacturers devices. 
 
 
 
22 
 
 
  Contains Nonbinding Recommendations 
 
 
 
We also recommend you include the reasons for: 
 
  patients lost to follow-up, as well as any measures to minimize such future events 
  patient and physician-initiated discontinuations 
  any deaths, including reports from post-mortem examinations. 
 
To limit the potential bias in the safety and effectiveness data, we recommend you 
provide at least 80% follow-up at each timepoint. 
 
C.  Demographics and Baseline Characteristics 
We recommend you provide the information below regarding demographics and baseline 
characteristics for each cohort. 
 
Patient Demographics (per patient basis) 
 
  patient age, height, weight, and race 
  menstrual status (i.e., last menstrual period (LMP)) 
 
Patient Baseline Characteristics (per patient basis) 
 
  indication for use (i.e., augmentation, reconstruction, revision-augmentation, or 
revision-reconstruction) 
 
Device Baseline Characteristics (per device basis) 
 
  device surface type (e.g., smooth, textured) 
  device type (i.e., single or multi-lumen) 
  device style and size 
  valve type (e.g., leaf, diaphragm), if applicable 
 
Surgical Baseline Characteristics (per device basis) 
 
  surgical incision site (e.g., periareolar, inframammary fold, axillary) 
  incision size 
  device placement (e.g., retromuscular, subglandular) 
  timing of reconstruction (i.e., immediate or delayed) 
  use and type of surgical pocket irrigation 
  use and type of intraluminal agents, if applicable. 
 
 
 
23 
 
 
  Contains Nonbinding Recommendations 
 
 
 
D.  Safety Assessment  Complications 
Complications 
The information described below is important in determining the safety of breast implants.15 
Regardless of whether or not the complications may be related to the device, we recommend 
you provide: 
 
  the incidence, timing, and resolution of all complications, such as rupture, capsular 
contracture (include Baker Grade), infection, calcification, malposition, extrusion, 
skin erosion, necrosis, lymphadenopathy, delayed wound healing, 
breast/chest/axillary mass formation, hematoma, seroma, pain, wrinkling, 
asymmetry, scar formation, palpability/visibility of the device, iatrogenic injury, etc. 
 
  the incidence, timing, and severity of alterations in nipple or breast sensation 
 
  the incidence, timing, and severity of interference and/or difficulties with lactation, 
as well as the frequency of attempted lactation without success 
 
  the incidence, timing, and nature of difficulties with pregnancy 
 
  the incidence, timing, and cause of patient deaths (the causes of death should be 
taken from post-mortem examinations) 
 
  the incidence, timing, and type of new breast cancer diagnosis post-implantation, 
including any mammographic difficulties/interference caused by the device 
 
  the incidence, timing, and extent of new connective tissue disease (CTD) diagnoses, 
signs, and symptoms. 
 
Cumulative Incidence of Complications 
We recommend you provide the cumulative incidence of each complication at each 
timepoint on both per patient and per device bases for each cohort. This data set should 
include reoperation and removal with or without replacement. 
 
You should provide the numerator and denominator used and describe how these values 
were obtained. The denominator should be the number of patients or devices at that 
timepoint. 
 
If the same complication is reported in the same patient or breast more than once, it should 
be counted once in the numerator if that same complication did not resolve during the entire 
follow-up period. If a complication occurs in a patient or breast, resolves, and then recurs at 
                                                 
15Safety of Silicone Breast Implants. Institute of Medicine National Academy Press, Washington, D.C. 2000. 
[IOM Report] Safety of Silicone Breast Implants.  
24 
 
 
  Contains Nonbinding Recommendations 
 
 
 
a subsequent timepoint in the same patient or breast, it should be counted twice in the 
numerator. 
 
If more than one different or new complication occurs in the same patient or breast 
cumulatively, it should be counted each time in the numerator and once in the denominator 
for per patient and per device reporting for the total (overall) data presentation. 
 
Each capsular contracture grade should be considered a new or different complication and a 
new (after implantation) diagnosis of breast cancer should be considered a new 
complication. 
 
Kaplan-Meier Analyses of Complications 
We recommend you provide Kaplan-Meier analyses (i.e., 1 minus the complication-free 
survival rate over time) on both per patient and per device bases for each cohort for each 
complication, whether or not the complications may be related to the device. The Kaplan- 
Meier analyses should include reoperation and removal with or without replacement. For 
capsular contracture, you should present capsular contracture grades II, III, and IV 
separately, as well as capsular contracture grades III and IV together. For rupture of silicone 
gel-filled breast implants, see Section VIII.E below for more details. 
 
To avoid the problem of competing risks, a patient who experiences one complication 
should still be considered a candidate to experience any other potential complication. 
 
Summary Table of Reoperations, Additional Surgical Procedures, Patients, and Implants  
We recommend you provide a table that summarizes the number of reoperations and 
corresponding number of additional surgical procedures, patients, and implants, per 
indication, for the Core Study. See the sample table below. 
 
Indication  Number of 
Reoperations  Additional  Patients  Implants 
Surgical Procedures 
Augmentation         
Reconstruction         
Revision-Augmentation         
Revision-Reconstruction         
 
 
Primary Reasons for Reoperation 
A reoperation is defined as a single surgery performed on a patient at a given timepoint, 
irrespective of whether one or two implants are involved. If a patient undergoes another 
surgery at a later timepoint, it should be counted as a separate reoperation. One or more 
reasons for a single reoperation may be reported by a surgeon. 
 
25 
 
 
  Contains Nonbinding Recommendations 
 
 
 
If more than one reason for a single reoperation is reported, FDA recommends you 
determine the primary reason using the following hierarchy: 
 
  rupture/deflation 
  infection 
  capsular contracture 
  necrosis/extrusion 
  hematoma/seroma 
  delayed wound healing 
  breast pain 
  implant malposition 
  wrinkling 
  palpability/visibility 
  asymmetry 
  ptosis 
  scarring 
  nipple complications 
  device injury/iatrogenic 
  breast cancer mass 
  biopsy 
  patient request for style/size change. 
 
We recommend you provide the cumulative primary reasons for reoperation for each cohort 
at each timepoint. The denominator should be the total number of reoperations since the 
initial implantation until that timepoint. Because you are providing primary reasons, the 
sum of the numerators should equal the denominator. 
 
Primary Reasons for Device Removal 
We recommend you provide the cumulative reasons for device removal for each cohort at 
each timepoint. The denominator should be the total number of devices removed since the 
initial implantation until that timepoint. If more than one reason for a single removal is 
reported by the surgeon, then FDA recommends you determine the primary reason using the 
same hierarchy above used to determine the primary reason for a reoperation. Because you 
are providing primary reasons, the sum of the numerators should equal the denominator. 
 
Types of Additional Surgical Procedures 
Multiple surgical procedures can be performed in a given reoperation. Examples of types of 
additional surgical procedures include capsulotomy, capsulectomy, device removal followed 
by replacement, device removal without replacement, saline volume adjustment, reposition 
of device, drainage of abscess/hematoma/seroma, excision of masses/lymph nodes in 
ipsilateral axilla or arm of implanted breast, and biopsy/cyst removal. 
 
26 
 
 
  Contains Nonbinding Recommendations 
 
 
 
We recommend you provide the cumulative types of additional surgical procedures for each 
cohort at each timepoint. The denominator should be the total number of additional surgical 
procedures since the initial implantation until that timepoint. If more than one type of 
procedure is reported for a reoperation, you should report all procedures performed. 
 
Cumulative Incidence of Complications after Removal of Study Device With Replacement  
As stated above, we recommend you continue to follow patients who have undergone device 
removal with study device replacement. We recommend you provide the cumulative 
incidence of individual complications at each timepoint on both per patient and per device 
bases for each cohort. You should provide the numerator and denominator used and 
describe how these values were obtained. The denominator should be the number of                 
patients or devices at that timepoint. See the Cumulative Incidence of Complications 
section above for more details. 
 
Cumulative Incidence of Complications after Removal of Study Device Without 
Replacement 
As stated above, we recommend you continue to follow patients who have undergone device 
removal without replacement in order to assess complications that may occur after removal, 
particularly for those patients who had their device(s) removed due to rupture. We 
recommend you provide the cumulative incidence of individual complications at each 
timepoint on both per patient and per device bases for each cohort. You should provide the 
numerator and denominator used and describe how these values were obtained. The 
denominator should be the number of patients or devices at that timepoint. See the 
Cumulative Incidence of Complications section above for more details. 
 
E.  Safety Assessment  Rupture 
Rupture of Silicone Gel-Filled Breast Implants 
FDA believes device rupture is one of the primary safety concerns presented by gel-filled 
breast implants. When a silicone gel-filled breast implant ruptures, the patient and the 
physician are often unaware of it (i.e., silent rupture or asymptomatic rupture). The rupture 
may be intracapsular (when the gel remains within the scar tissue capsule surrounding the 
implant), extracapsular (when the gel moves outside the capsule but remains within the 
breast tissue), or involve migrated gel (when the gel moves beyond the breast). 
 
Please note that the recommendations below are for safety assessments of rupture of 
silicone gel-filled breast implants for patients undergoing the 10-year Core Study.  For 
current recommendations concerning rupture screening for patients with approved 
silicone-gel breast implants, please refer to the Rupture Screening Recommendations 
Update section of FDAs guidance, Breast Implants - Certain Labeling Recommendations 
to Improve Patient Communication16 (Breast Implant Labeling Guidance). 
                                                 
16 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/breast-implants-certain-labeling-
recommendations-improve-patient-communication. 
27 
 
 
  Contains Nonbinding Recommendations 
 
 
 
FDA recommends magnetic resonance imaging (MRI) as the current method of choice for 
detecting silent rupture of silicone gel-filled breast implants. In fact, the sensitivity of 
physical examination to detect silicone breast implant rupture is 30%17 compared to 89% for 
MRI.18  MRI of the breast should be performed with a dedicated breast coil, with a magnet of 
at least 1.5 Tesla, and preferably in centers experienced in performing and interpreting this 
type of examination. The MRI films should be read by both the local radiologist at the 
center performing the exam and by a radiologist experienced in reading breast implant MRIs 
(i.e., qualified MRI assessor). The radiologists should be masked to the investigators 
judgment of a possible rupture (if applicable) and should each perform an independent 
assessment of each MRI and rate the presence or absence of rupture as definitive, 
suspicious/indeterminate, or none/intact. 
 
For devices that are explanted, the final rupture determination should be made at the time of 
explantation. If explantation is not performed for devices reported as definitive or 
indeterminate for rupture via MRI, the determination of rupture should be based on the 
worst case reading by either the qualified MRI assessor or the local radiologist. 
 
FDA recommends that all patients receiving silicone gel-filled breast implants in the Core 
Study undergo MRI evaluations at 1, 2, 4, 6, 8, and 10 years to assure that patients are 
adequately monitored for silent rupture consistent with the recommended method and 
frequency that is included in the labeling for the approved silicone gel-filled breast 
implants. In addition, this allows you to determine a single rupture rate, for each cohort, 
for the purposes of patient labeling.19  
 
If, because of the mechanical or chemical properties of your device, rupture cannot be 
visualized using MRI, we recommend you develop an alternative validated method with 
sensitivity and specificity comparable to that of MRI. 
 
To characterize rupture, we recommend you provide: 
 
  the rupture rate over the duration of the Core Study via prospective, sequential 
screening of the study population using diagnostic radiographic or other techniques 
of comparable sensitivity and specificity (some of the Core Study data may be 
premarket and some may be postapproval) 
 
  the frequency of observed intracapsular gel, extracapsular gel, and migrated gel, as 
well as the destination of the migrated gel for all patients with symptomatic or silent 
ruptured devices 
                                                 
17 Holmich, L.R., et al. 2005a. The diagnosis of silicone breast implant rupture. Clinical findings compared to 
findings at MRI. Ann Plast Surg 54 (6): 583-9. 
18 Holmich, L.R., et al. 2005b. The diagnosis of breast implant rupture: MRI findings compared to findings at 
explantation. 2005. Eur J. Radiol. 53: 213-25.  
19  This is not the case with past Core Study designs that involved MRI and non-MRI cohorts because FDA 
believed those cohorts should not be statistically combined. 
28 
 
 
  Contains Nonbinding Recommendations 
 
 
 
  a detailed description of the local and systemic health consequences for all patients 
with symptomatic or silent ruptured devices, including the severity of these health 
consequences and the clinical course of these patients. Systemic health 
consequences can include the results of connective tissue disease (CTD) screening. 
 
In addition, we recommend you provide the incidence, prevalence, and Kaplan-Meier rates for 
each of the following rupture events: 
 
  MRI diagnosis of definitive or indeterminate rupture, regardless of confirmation with 
removal. If there is disagreement between the MRI readings of the qualified MRI 
assessor and the local radiologist, then the worst case reading from either should be 
utilized in the silent rupture rate 
 
  rupture noted at removal, regardless of MRI diagnosis 
 
  rupture noted during the retrieval study, if performed and applicable 
 
  overall rupture rate based on rupture data from any of the sources from the 3 bullets 
above. 
 
For each device suspected of rupture or reported as ruptured, we recommend you provide a 
summary of the dates and results of all diagnostic procedures performed related to rupture.  
We also recommend you provide the actual reports of these diagnostic procedures (e.g., MRI 
reports, mammogram reports) and provide the surgical explant reports for devices removed 
with or without replacement. In addition, we recommend you provide the final status of each 
device suspected of rupture or where rupture is confirmed. 
 
Rupture of Alternative Breast Implants 
Depending on the filler of your alternative breast implants, FDA may recommend you 
provide rupture information similar to that described above for silicone gel-filled breast 
implants. 
 
F.  Safety Assessment  Connective Tissue Diseases 
(CTDs)  
FDA recognizes that much has been learned over the last few decades about CTDs, 
including data and analysis from the 1999 Institute of Medicine (IOM) Report on the Safety 
of Silicone Breast Implants.20  In addition, we recognize that the Core Study is not designed 
to examine a potential association between breast implants and the development of CTDs. 
We do recommend, however, that you collect CTD information as part of the overall safety 
                                                 
20Safety of Silicone Breast Implants. Institute of Medicine National Academy Press, Washington, D.C. 2000. 
[IOM Report].  
29 
 
 
  Contains Nonbinding Recommendations 
 
 
 
assessment on your device, as well as to provide complete information to patients who may 
consider getting breast implants. 
 
FDA recommends you conduct the CTD evaluations on all patients at the preoperative 
timepoint and at the 1, 2, 4, 6, 8, and 10-year postoperative timepoints. If indicated, patients 
should have a follow-up evaluation(s) by a rheumatologist or other appropriate specialist 
with collection of serological information (e.g., anti-nuclear antibody (ANA), rheumatoid 
factor (RF), erythrocyte sedimentation rate (ESR), immunoglobulin levels, c-reactive protein 
(CRP), anticardiolipin antibodies (both IgG and IgM), evaluation for monoclonal proteins, 
complement levels). 
 
Because you should refer patients reporting signs and symptoms that were not present at 
baseline to the appropriate specialist for evaluation, please provide the criteria (i.e., number 
and types of responses) for referral to a rheumatologist or other specialist. You should also 
report the proportion of patients who were referred to specialists based on these evaluations. 
 
CTD Diagnoses 
CTD diagnoses include: 
 
  rheumatic diseases  such as rheumatoid arthritis, systemic lupus erythematosus, 
discoid lupus, scleroderma, vasculitis, polymyositis, and dermatomyositis 
 
  rheumatic syndromes  such as Raynauds phenomenon, Sjogrens syndrome, 
CREST syndrome, morphea, carpal tunnel syndrome, multiple sclerosis-like 
syndrome, multiple myeloma-like syndrome, chronic fatigue syndrome, and 
fibromyalgia. 
 
We recommend you provide the following on a per patient basis for each cohort: 
 
  Kaplan-Meier analyses (e.g., 1 minus the Systemic Lupus Erythematosus-free 
survival rate over time) for each CTD diagnosis separately and for having one or 
more CTD diagnosis 
 
  the cumulative incidence of CTD diagnoses at each timepoint for each CTD diagnosis 
separately and for having one or more CTD diagnosis. You should provide the 
numerator and denominator used and describe how these values were obtained. The 
denominator should be the number of patients at that timepoint. 
 
CTD Sign/Symptom Categories 
A sign/symptom category is an anatomical or body function area (e.g., skin, muscle, joint, 
gastrointestinal, respiratory, neurological, general). For example: 
 
  skin includes alopecia, facial rash, pruritis, and echymoses 
 
30 
 
 
  Contains Nonbinding Recommendations 
 
 
 
  muscle includes myalgias, muscle weakness, and elevated CRP 
 
  joint includes arthralgia, arthritis, and morning stiffness 
 
  neurological includes cognitive dysfunction, memory problems, peripheral 
neuropathy, and multiple sclerosis-like symptoms 
 
  general includes fatigue, generalized pain, fever, and depression. 
 
We recommend you provide the following data on a per patient basis for each cohort: 
 
  Kaplan-Meier analysis for each symptom category 
 
  Kaplan-Meier analysis describing patients who are free from one or more positive 
symptoms 
 
  the cumulative incidence of at least one CTD sign/symptom category at each 
timepoint. You should provide the numerator and denominator used and describe 
how these values were obtained. The denominator should be the number of patients 
at that timepoint. 
 
Individual CTD Signs and Symptoms 
Examples of individual CTD signs and symptoms include hair loss, facial rash, 
photosensitivity, dry eyes, dry mouth, arthralgias, myalgias, neuralgias, difficulty 
swallowing, morning stiffness that lasts more than 30 minutes, ocular 
inflammation/retinitis/optic neuritis, muscle weakness, joint swelling for more than 6 weeks, 
pleurisy, respiratory difficulty, skin rash, lymphadenopathy, cognitive dysfunction, fatigue, 
paresthesia, dizziness, abnormal bruising or bleeding, purpura, unexplained fever, urticaria, 
telangiectasia, and petechiae. 
 
We recommend you provide the following data on a per patient basis for each cohort: 
 
  the cumulative incidence of each individual CTD sign and symptom at each 
timepoint. You should provide the numerator and denominator used and describe 
how these values were obtained. The denominator should be the number of 
patients at that timepoint 
 
  the status of device rupture, reported complications, and patient satisfaction for 
patients reporting CTD signs and symptoms that were not present before breast 
implantation 
 
  a comparison of the incidence and types of new CTD signs and symptoms reported 
with information from the published literature or other comparable sources (e.g., data 
from patients with other types of devices, data from patients seeking other types of 
31 
 
 
  Contains Nonbinding Recommendations 
 
 
 
cosmetic surgery). 
 
G.  Safety Assessment  Mammography Data 
For patients who undergo screening mammography during the study, we recommend you 
provide separate analyses for mammographic suspicion for tumor: 
 
  regardless of biopsy results 
  with a biopsy positive for malignant tumor 
  with a biopsy negative for malignant tumor. 
 
The analyses for each event should include: 
 
  the non-cumulative point prevalence at each timepoint on both per patient and per 
device bases for each cohort. You should provide the numerator and denominator 
used and describe how these values were obtained. The denominator should be the 
number of patients or devices at that timepoint 
 
  the cumulative incidence at each timepoint on both per patient and per device bases 
for each cohort. You should provide the numerator and denominator used and 
describe how these values were obtained. The denominator should be the number of 
patients or devices at that timepoint 
 
  a comparison of the data to that reported in the literature for aged-matched cohorts. 
 
H.  Effectiveness Assessment 
Patient Reported Outcomes (PROs) 
We recommend you provide the results from PRO assessments to assess the beneficial 
impact of the device. These are the same assessments that were previously referred to by 
FDA as health related quality of life assessments. These assessments should include, but 
need not be limited to: 
 
  a measure of self esteem (e.g., Rosenberg Self Esteem Scale21 or Tennessee Self- 
Concept Scale22) 
  a measure of body image (e.g., Body Esteem Scale23) 
                                                 
21 Rosenberg, M. 1989. Society and the Adolescent Self-Image. Revised edition. Middletown, CT: Wesleyan 
University Press.  
22 Fitts, W. Tennessee Self-Concept Scale: Manual. Western Psychological Services, Los Angeles, CA, July 
1989.  
23 Franzoi, S and Shields, S. (1984). The Body-Esteem Scale: Multidimensional structure and sex differences in 
a college population. Journal of Personality Assessment, 48, 173-178. 
32 
 
 
  Contains Nonbinding Recommendations 
 
 
 
  a measure of general health outcome (e.g., SF-36 Status Survey,24 Medical Outcomes 
Study (MOS) 20-Item Health Survey25). 
 
FDA recommends you conduct PRO assessments on all patients at the preoperative 
timepoint and at the 1, 2, 4, 6, 8, and 10-year postoperative timepoints. For reconstruction 
patients, you should describe the timing of administration of these instruments (delayed or 
immediately following reconstruction). 
 
We recommend you provide the mean ( standard deviation) change in each validated PRO 
measure (preoperative to each visit). You should report these results on a per patient basis 
for each cohort. The denominator should be the number of patients evaluated at each visit 
interval. FDA also recommends that you compare your results to published normative data 
for those PROs for which these data exist (e.g., SF-36). 
 
Satisfaction 
We also recommend you provide data on patient satisfaction. Patient-reported satisfaction 
measures should incorporate satisfaction based on: 
 
  preoperative expectations 
  the initial surgical procedure 
  any adjunctive surgical and medical procedures 
  any complications 
  device removal, regardless of whether the device was replaced 
  whether the expected benefits of the devices have been met 
  whether the patient would have the surgery over again. 
 
For those patients reporting dissatisfaction following breast implantation, we recommend 
you provide the following information: 
 
  detailed reason for dissatisfaction 
  presence, severity, status (i.e., resolved or not resolved), and method of resolution of 
any complications 
  reports of CTD diagnoses, signs, and symptoms. 
 
Anatomical Effect 
We recommend you provide data on the anatomical effect of the device for augmentation 
and augmentation-revision cohorts. This may be accomplished by comparing matched 
analyses of before and after bra and cup sizes, chest circumference, symmetry, or other 
                                                 
24 Ware J, et al. SF-36 Health Survey Manual and Interpretation Guide. The Health Institute, New England 
Medical Center, Boston, MA 1993. 
25 Stewart A., et al. The MOS Short-Form General Health Survey: Reliability and validity in a patient 
population. Medical Care 1988; 26: 724-735. 
33 
 
 
  Contains Nonbinding Recommendations 
 
 
 
standardized measurements. For example, we recommend you provide the following on a 
per patient basis: 
 
  frequency distribution of bra cup size at baseline, end of study, and change from 
baseline 
  mean ( standard deviation) chest circumferences at baseline, end of the study, and 
change from baseline. 
 
I.  Other Statistical Analysis 
Sample Size Rationale 
We recommend you provide the statistical rationale for why the sample size is adequate to 
evaluate the device. This should include: 
 
  identification of effect criteria (i.e., clinically significant difference in the response 
variables to be detected) 
  statistical error tolerances of alpha and beta (as applicable) 
  desired precision for rate estimates (e.g., defined as 12 width of confidence interval) 
  anticipated variances of response variables (if known) 
  any assumptions or statistical formulas with a list of references used 
  reasonable estimations of lost-to-follow-up rates 
  all calculations used. 
 
Pooling Analyses 
We recommend you provide the statistical rationale for pooling across: 
 
  investigational sites 
  demographic and baseline characteristics. 
 
Logistic Regression Analyses of Each Safety and Effectiveness Outcome 
To determine which variables are associated with each safety and effectiveness outcome, we 
recommend you provide logistic regression analyses, where appropriate, on a per device 
basis for each cohort using, but not necessarily limited to, the following static covariates: 
 
  patient age 
  indication for use (i.e., augmentation, reconstruction, revision-augmentation, or 
revision-reconstruction) 
  device surface type (i.e., smooth or textured) 
  device type (i.e., single or multi-lumen) 
  device size 
  valve type (e.g., leaf, diaphragm) 
  surgical incision site (e.g., periareolar, inframammary fold, axillary) 
34 
 
 
  Contains Nonbinding Recommendations 
 
 
 
  incision size 
  device placement (e.g., retromuscular, subglandular) 
  timing of reconstruction (i.e., immediate or delayed) 
  use and type of surgical pocket irrigation 
  use and type of intraluminal agents. 
 
Cox Proportional Hazards Regression Analyses of Rupture/Deflation 
To determine which variables are associated with rupture/deflation, we recommend you 
provide Cox regression analyses of rupture/deflation on a per patient basis for each cohort 
using the static covariates above, as well as time-dependent covariates (e.g., infection, 
capsular contracture). The coefficient estimates should be the relative risks (hazard ratios) 
of rupture/deflation based on transition to a complication. An advantage of this approach is 
that rupture/deflation is clearly defined and multiple complications can be easily handled as 
separate time-dependent covariates for each type of event. This also addresses the problem 
of competing risks. 
 
Generalized Estimating Equations (GEE) Analyses of CTDs 
To analyze whether any increases in the signs and symptoms of CTDs were due to the 
implant or due to the increased age of the patient, we recommend that you provide GEE 
analyses on a per patient basis for each cohort, using age as a covariate. 
 
IX.  Other Clinical Data 
A.  Supplemental Clinical Information to Address Rupture 
This section pertains only to silicone gel-filled and alternative breast implants. 
 
Silicone Gel-Filled Breast Implants 
Because of its limited sample size, we believe the Core Study may not fully address 
concerns about device rupture. Using other sources of information, such as other U.S. or 
European retrospective or prospective studies or the literature, we recommend you provide 
the following additional clinical information on your device: 
 
  any available long-term rupture rate data, ideally collected via prospective, sequential 
screening of the study population using diagnostic radiographic or other techniques of 
comparable sensitivity and specificity 
  the frequency of observed intracapsular gel, extracapsular gel, and migrated gel, as 
well as the destination of the migrated gel 
  a detailed description of the local and systemic health consequences for all patients 
with ruptured devices (both symptomatic and silent rupture patients), including the 
severity of the local health consequences and the clinical course of these patients 
  the incidence, prevalence, and timing of silent ruptures that progress to symptomatic 
ruptures 
35 
 
 
  Contains Nonbinding Recommendations 
 
 
 
  the incidence, prevalence, and timing of intracapsular ruptures that progress to 
extracapsular ruptures. 
 
Alternative Breast Implants 
Depending on the design or materials of your alternative breast implant, FDA may 
recommend supplemental clinical information similar to that described above for silicone 
gel-filled breast implants. 
 
B.  Supplemental Literature Information 
Because of the limited sample size of the Core Study, we recommend you provide a current 
review of the literature on breast implants for the topics below. The topics include: 
 
  cancer (both breast and non-breast) 
  benign breast disease 
  CTD diagnoses, signs, and symptoms, including fibromyalgia 
  interference of device with mammographic detection of tumors or rupture 
  neurological disease 
  ability to lactate 
  offspring issues (safety of milk for breastfeeding and 2nd generation effects) 
  potential systemic health consequences of extracapsular and migrated gel rupture 
  potential health consequences of gel bleed 
  depression, anxiety, and suicide. 
 
We recommend you provide a thorough search of current medical literature on breast 
implants to address the range of clinical experience with each of the topics bulleted above as 
they relate to the specific type of device (i.e., silicone gel-filled, saline-filled, or alternative), 
as well as the criteria and method for selecting the literature. We recommend you provide 
copies of the literature references and develop a table that summarizes the information. 
 
We recommend you provide literature information specific to the subject breast implant 
type. However, if no device type-specific information is available, you should provide 
pooled data (e.g., silicone gel and saline data) from the literature. 
 
For alternative breast implants for which the alternative material is used in another type of 
medical device, we recommend you provide a summary of the literature involving clinical 
experience with that material. 
 
 
 
 
 
36 
 
 
  Contains Nonbinding Recommendations 
 
 
 
X.  Labeling 
A.  General Information 
General labeling requirements for medical devices are described in 21 CFR Part 801. 
Additional labeling requirements for IDE submissions are found in 21 CFR  812.5 and 
812.20(b)(10). Additional labeling requirements for PMA submissions are found in 21 CFR  
814.20(b)(10). The IDE and PMA regulations require that you provide copies of all labeling 
for your device(s).  
 
Below is a description of the physician labeling, patient labeling, and patient device card, which 
we recommend that you provide for your device, when submitting an IDE or a PMA for           
a breast implant.  The labeling recommendations provided below are based on labeling 
recommendations for saline and silicone-gel filled breast implants.  While FDA believes that 
these labeling recommendations are also generally applicable to alternative breast implants, 
FDA notes that certain recommendations may not apply or that FDA may recommend different 
or additional labeling for alternative breast implants depending on their design, materials and 
performance characteristics.  We encourage manufacturers of other breast implants to engage 
with CDRH through the pre-submission process to obtain more detailed feedback regarding their 
specific device.  For more information on pre-submissions, please see FDAs guidance, 
Requests for Feedback and Meetings for Medical Device Submissions: The Q-Submission 
Program.26  
 
Please refer to FDAs Guidance, Breast Implants - Certain Labeling Recommendations to 
Improve Patient Communication27 (Breast Implant Labeling Guidance) for additional 
recommendations concerning the content and format for certain labeling information for saline 
and silicone gel-filled breast implants, including incorporation of a boxed warning and a patient 
checklist into the labeling for these devices, updates to the silicone gel-filled breast implant 
rupture screening recommendations, inclusion of an easy-to-find description of materials, and 
provision of patient device cards.  These labeling recommendations are intended to enhance, 
but not replace, the physician-patient discussion of the benefits and risks of breast implants 
that uniquely pertain to individual patients. 
 
B.  Physician Labeling 
We recommend you provide physician labeling (i.e., package insert) for a breast implant 
PMA that includes the following types of information: 
 
  device name, style(s), and brief device description 
                                                 
26 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/requests-feedback-and-
meetings-medical-device-submissions-q-submission-program.  
27 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/breast-implants-certain-labeling-
recommendations-improve-patient-communication. 
37 
 
 
  Contains Nonbinding Recommendations 
 
 
 
  name and address of manufacturer, packer, or distributor 
  Sterile, Do not resterilize, and Single use only notations (or similar wording) 
  indications for use 
  any relevant contraindications (including surgical procedures which are 
contraindicated due to interference with device integrity or performance) 
  boxed warning, as described in the Boxed Warning section of the Breast 
Implant Labeling Guidance  
  any additional relevant warnings, including, but not necessarily limited to: 
  a warning against closed capsulotomy because it has been shown to 
o
potentially result in device rupture 
  a warning against the addition of substances into the filler (i.e., betadine, 
o
steroids, and antibiotics) other than those recommended because the 
substance may potentiate and/or accelerate delamination of the shell 
  any relevant precautions 
  list of potential complications 
  preoperative patient procedures (e.g., prophylactic antibiotics), operating room 
procedures (e.g., what supplies should be on hand), and troubleshooting procedures 
  instructions for implantation, including surgical approach and device specific 
information (depends on type of breast implant) 
  intraoperative test procedures to ensure device integrity and proper placement (if 
necessary) 
  instructions for postoperative patient care, including how to monitor device 
integrity and placement 
  instruction on how to minimize failure related to surgical procedure based on 
modes/causes of rupture studies 
  appropriate clinical study safety and effectiveness results 
  appropriate non-clinical study results, including modes/causes of rupture and gel 
bleed results 
  literature information as per Section IX.B above 
  for silicone gel-filled breast implants, recommendations for method(s) and frequency 
of screening for rupture as outlined in the Rupture Screening Recommendations 
Update section of the Breast Implant Labeling Guidance  
  clinical management of suspicious and confirmed rupture 
  recommendation for implant removal if rupture is detected. 
 
The IDE physician labeling should include all elements identified in the bullets above except 
for those involving specific clinical results. In addition, the labeling must include the 
following statement, CAUTION - Investigational Device. Limited by Federal (or United 
States) law to investigational use. (21 CFR  812.5). 
 
38 
 
 
  Contains Nonbinding Recommendations 
 
 
 
You should make the physician labeling available to the patient before the surgery, upon 
request, whether the request comes directly from the patient or through the physician or 
surgeon. 
 
C.  Patient Labeling 
The purpose of the patient labeling is to provide a patient with sufficient information (e.g., 
realistic expectations of the benefits and risks) so that the patient may make an informed 
decision about the benefits and risks of breast implants. 
 
The patient booklet/brochure and the patient device card are all part of the patient labeling 
for breast implants.  FDA recommends that the patient booklet/brochure include a boxed 
warning, patient decision checklist, rupture screening recommendations, and materials/device 
description (as described in the Breast Implant Labeling Guidance) as well as other patient 
information (as described in this guidance).  For those patients who decide to have breast 
implants, a patient device card should also be provided to patients after surgery.  
     
Patient labeling and the informed consent document for an IDE should not exceed the 
reading comprehension level that is easily understood and usable by most readers in the 
United States. For additional information, we recommend you refer to FDAs Guidance 
on Medical Device Patient Labeling28  and information regarding plain language at 
http://www.plainlanguage.gov. 
 
Patient Information Booklet/Brochure 
We recommend the patient information booklet/brochure include the following types of 
information: 
 
  device name, styles, and brief device description 
  indications for use 
  boxed warning, as described in the Breast Implant Labeling Guidance  
  relevant contraindications, warnings, and precautions 
  potential complications, including possible methods of resolving them 
  postoperative care instructions (e.g., what to expect after surgery, symptoms to tell 
doctor about immediately, length of recovery, physical limitations, how to monitor 
her breast) 
  factors to consider in deciding whether or not to get breast implants (e.g., may not be 
lifetime device or one-time surgery, many of the changes to breasts following 
implantation are irreversible, breast implants may affect the ability to breast feed, 
routine screening mammography may be more difficult, there may be health insurance 
coverage issues) 
                                                 
28 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/guidance-medical-device-
patient-labeling.  
39 
 
 
  Contains Nonbinding Recommendations 
 
 
 
  other factors to consider (e.g., choosing a surgeon, device size and shape, surface 
texturing, palpability, device placement, incision sites) 
  detailed device description of the materials of construction of the breast implant 
shell and filling, as described in the Materials/Device Descriptions section of 
the Breast Implant Labeling Guidance  
  warranty information 
  toll-free number for questions/information 
  appropriate clinical study safety and effectiveness results 
  appropriate non-clinical study results, including gel bleed results 
  literature information as per Section IX.B above 
  for silicone gel-filled breast implants, recommendations for method(s) and frequency 
of  rupture screening as outlined in the Rupture Screening Recommendations 
Update section of the Breast Implant Labeling Guidance  
  clinical management of suspicious and confirmed rupture 
  recommendation for implant removal if rupture is detected 
  Patient Decision Checklist, as described in the Patient Decision Checklist section of 
the Breast Implant Labeling Guidance.  
 
For an IDE study, informed consent must be documented (21 CFR  50.27). The basic 
elements of informed consent are described in 21 CFR  50.25, and include some of the 
information in the bullets above. 
 
Note that the informed consent document required for a patient to participate in an IDE 
study should not be confused with a standard surgical consent form that a hospital requires 
to be signed by any surgical patient. 
 
Patient Device Card  
We recommend you provide patient device card(s) as part of the informed consent process 
for your IDE study and as part of the patient labeling for your PMA approved device. This 
piece of labeling has been referred to in different ways by manufacturers, such as 
manufacturer device card, patient identification card, or patient information card.  Regardless 
of the name used, its purpose is to provide the patient with specific information about their 
device(s).  
 
Refer to the Patient Device Card section of the Breast Implant Labeling Guidance for 
information to include in the patient device card.  
 
XI.  Postapproval Requirements 
As a condition of approval of your PMA, or in connection with the approval, FDA may require 
you to conduct postapproval studies, to track your device, or to comply with restrictions 
relating to the sale, distribution, or use of your device (FDCA  515(d)(1)(B)(ii), 519(e), 
520(e), and 522 (21 USC  360e(d)(1)(B)(ii), 360i(e), 360j(e), & 360l), and 21 CFR Part 814, 
40 
 
 
  Contains Nonbinding Recommendations 
 
 
 
Subpart E). Specific postapproval commitments for your PMA will be determined at the time 
of PMA approval; however, these requirements could include: 
 
  continued follow-up of your Core Study patients. In determining whether to require 
annual mail-in questionnaires or annual physician follow-up visits, FDA will consider 
the specific device and the available premarket data 
  a patient registry or additional postapproval study (other than postapproval Core 
Study above) to collect additional postapproval data 
  additional studies to address the modes and causes of failure 
  an education and certification program to train physicians and surgeons with 
regard to proper surgical technique, patient selection, patient monitoring, and 
management of complications to obtain access to your device 
  focus group study to improve the patient labeling 
  a formal informed decision process that assures that the patient has been provided the 
patient labeling with adequate time to read it prior to surgery and that documents that 
the patient has an adequate understanding of the risks and follow-up 
recommendations associated with your device 
  labeling updates on a regular interval to reflect any appropriate findings from 
postapproval studies. 
 
FDA also intends to require mandatory tracking upon approval of a silicone gel-filled breast 
implant PMA. Mandatory tracking is not specified as a condition of PMA approval under 
the PMA regulations. Instead, FDA issues tracking orders pursuant to FDCA  519(e) (21 
U.S.C.  360i) and 21 CFR Part 821. 
 
 
 
41