FDA Publications.

Date: Tue, 14 Sep 1999 16:03:28 -0500 (CDT)

Guidance for Industry and/or FDA Reviewers/Staff

Guidance on Preclinical and Clinical Data and Labeling for Breast Prostheses Draft Guidance - Not for Implementation This guidance document is being distributed for comment purposes only. Draft released for comment on [release date as stated in FR Notice] This document supersedes Draft Guidance for Preparation of FDA Submissions of Silicone Gel-Filled Breast Prostheses - 5/11/92; Draft Guidance for Preparation of PMA Applications for Silicone Inflatable (Saline) Breast Prostheses - 1/18/95; and Draft Guidance for Testing of Alternative Breast Prostheses (non-silicone gel-filled) - 9/1/94 U.S. Department of Health and Human Services Food and Drug Administration Center for Devices and Radiological Health Plastic and Reconstructive Surgery Devices Branch Division of General and Restorative Devices Office of Device Evaluation

Preface

Public Comment:

For 90 days following the date of publication in the Federal Register of the notice announcing the availability of this guidance, comments and suggestions regarding this document should be submitted to the Docket No. assigned to that notice, Dockets Management Branch, Division of Management Systems and Policy, Office of Human Resources and Management Services, Food and Drug Administration, 5630 Fishers Lane, Room 1061, (HFA-305), Rockville,

MD 20852.

Additional Copies:

World Wide Web/CDRH home page at http://www.fda.gov/cdrh/ode/1354.pdf or

CDRH Facts on Demand at 1-800-899-0381 or 301-827-0111, specify number 1354 when prompted for the document shelf number.

This document is intended to provide guidance. It represents the Agency's current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statute, regulations, or both. page 1 Guidance 1 on Preclinical and Clinical Data and Labeling for Breast Prostheses

REGULATORY BACKGROUND 4

DEVICE DESCRIPTION 4

MANUFACTURING / STERILIZATION 5

PRECLINICAL DATA 6

1. Preclinical Data – Chemistry 6

1.1 General Information 6

1.2 Chemical Analysis of Elastomer Shell including Patch and Valve 6

1.3 Chemical Analysis of Filler Materials 7

1.3.1 Saline 7

1.3.2 Silicone Gel 7

1.3.3 Alternative Filler – Polymer 7

1.3.4 Alternative Filler - Non-Polymer 8

1.4 Bleed Tests 8

1.4.1 Bleed Rates of Silicone Gel and Alternative Filler 8

1.4.2 Bleed Material Analysis of Alternative Filler 9

2. Preclinical Data – Toxicology 9

2.1 General Information 9

2.2 Pharmacokinetic Studies 10

2.3 Biocompatibility Testing 10

2.4 Special Considerations 10

3. Preclinical Data - Mechanical Properties 11

3.1 General Information 11

3.2 Tensile Strength and Ultimate Elongation 12

3.3 Tear Resistance 12

3.4 Integrity of Fused or Adhered Joints 12

3.5 Fold Flaw 12

3.6 Abrasion 13

3.7 Static Rupture Testing of Total Device 13

3.8 Fatigue Rupture Testing of Total Device 13

3.9 Static Impact Testing of Total Device 14

3.10 Valve Competence 14

3.11 Cohesivity of Silicone Gel or Alternative

Filler 14

CLINICAL DATA 15

4.1 General Information 15

4.2 Study Design / Statistical Issues 15

4.3 Safety Assessment 17

4.4 Effectiveness Assessment 19

4.5 Explant Information 19

4.6 Patient / Physician Information 20

4.7 Special Considerations 20

This document is intended to provide guidance. It represents the Agency's current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statute, regulations, or both.

4.8 Special Considerations for Alternative Breast Implants 20

4.9 Supplemental Information 21

4.10 Additional Postapproval Study Considerations 21

LABELING 22

5.1 General Information 22

5.2 Package Labels 22

5.3 Package Insert 23

5.4 Patient Labeling 23

Appendix I - Breast Implant Clinical Data Presentation 25

INTRODUCTION

The purpose of this document is to provide guidance to sponsors of breast implant prostheses on important preclinical, clinical, and labeling information that should be presented in an investigational device exemptions (IDE), a premarket approval (PMA), or a product development protocol (PDP) application. It may also be useful in the preparation of reclassification petitions and master files. This guidance document is based upon the scientific review and analysis by the FDA of published studies and discussions and correspondence between the Plastic and Reconstructive Surgery Devices Branch (PRSB) and sponsors of breast implant applications. This guidance document should be viewed as a "living" document. As new results are obtained and scientific techniques are improved, the Center for Devices and Radiological Health (CDRH) will periodically revise the document. This guidance document discusses information relevant to breast prostheses filled with silicone gel, saline, and alternative filler intended for breast augmentation, breast reconstruction following mastectomy, and revision of a failed prosthesis. This guidance does not address tissue expanders, which are unclassified devices for temporary use. Additionally, this guidance does not address alternative shell materials for use in breast implants. This guidance document is intended to combine and replace the following three individual guidances that were previously developed for silicone gel, saline, and alternative breast prostheses:

??Draft Guidance for Preparation of FDA Submissions of Silicone Gel-Filled Breast Prostheses - 5/11/92;

??Draft Guidance for Preparation of PMA Applications for Silicone Inflatable (Saline) Breast Prostheses -1/18/95; and

??Draft Guidance for Testing of Alternative Breast Prostheses (non-silicone gel-filled) - 9/1/94.

This guidance document provides a framework to assist in developing preclinical and clinical studies for an IDE, PMA, or PDP (which is submitted in lieu of an IDE and PMA). This guidance document serves as a supplement to other FDA publications on IDE, PMA, and PDP applications and should not be construed as a replacement for these documents. For general IDE information, a sponsor should refer to 21 CFR 812 or to the Investigational Device Exemptions Manual, which can be obtained at

For general PMA information, a sponsor should refer to 21 CFR 814 or to the PremarketApproval Manual, which can be obtained at

Any sponsor considering the PDP option should refer to the Guidance for Industry: Contents of a Product Development Protocol for specific input regarding PDP applications; this guidance can be obtained at

Although use of this document to prepare preclinical and clinical protocols will not ensure IDE, PMA, or PDP approval, following this guidance should reduce unnecessary work by sponsors and should allow for a more efficient review by FDA.

All FDA publications referred to in this guidance document, as well as additional IDE, PMA, and PDP information, can be obtained by contacting the Division of Small Manufacturers Assistance (DSMA) at 800-638- 2041 (toll free) or 301-443-6597. Some publications can be obtained via DSMA's Internet site at

Specific questions and clarification regarding this guidance document should be directed to PRSB at 301-594-3090.

REGULATORY BACKGROUND

Silicone inflatable (saline-filled) breast prosthesis

In the FEDERAL REGISTER of June 24, 1988 (53 FR 23856), FDA issued a final ruling classifying silicone inflatable (saline-filled) breast prosthesis into Class III (21 CFR 878.3530). In the FEDERAL REGISTER of January 6, 1989, (54 FR 550), FDA published a notice of intent to require premarket approval and in the FEDERAL REGISTER of January 8, 1993 (58 FR 3436), FDA issued a proposed rule requiring a PMA. Silicone gel-filled breast prosthesis In the FEDERAL REGISTER of June 24, 1988 (53 FR 23863), FDA issued a final rule classifying silicone gel-filled breast prosthesis into class III (21 CFR 878.3540). In the FEDERAL REGISTER of January 6, 1989, (54 FR 550), FDA published a notice of intent to require premarket approval. On April 10, 1991 (56 FR 14620), FDA required a PMA for these devices be filed with the Agency within 90 days.

Alternative breast prosthesis

All alternative breast prostheses are class III postamendment devices that require approved PMAs or product development protocol (PDP)s for marketing.

DEVICE DESCRIPTION

There are 3 types of breast implants, all of which are intended for breast augmentation, breast reconstruction following mastectomy, and/or revision of a failed prosthesis.

Silicone inflatable (saline-filled) breast prosthesis

A silicone inflatable (saline-filled) breast prosthesis has a silicone rubber shell made of polysiloxane(s), such as polydimethylsiloxane and polydiphenylsiloxane that is inflated to the desired size with sterile isotonic saline before or after implantation. Most of these prostheses are single lumen devices with a valve that is sealable by the surgeon or self- sealing for the purposes of filling the prosthesis. The implants have a patch that covers the manufacturing port of the prosthesis. There are two types of saline-filled prostheses. One type is a fixed volume prosthesis, which is filled with the entire volume of saline at implantation. Another type is an adjustable volume prosthesis, which is filled intraoperatively and has the potential for further postoperative adjustment. Although not provided by the sponsor, the sterile saline to be used with the implant should be provided as part of the device description. The sterile saline used as a filler material should conform to United States Pharmacopeia (USP) standards of Normal Physiological Saline (injection grade) which has a concentration of 0.15M and a pH of 7.2-7.4. Otherwise, the sponsor should provide a complete device description of the saline to be used with their breast prosthesis.

Silicone gel-filled breast prosthesis

Silicone gel-filled breast prostheses are sub-classified by their number of lumens. Each implant has a patch that covers the manufacturing port of the prosthesis. A single-lumen silicone gel-filled breast prosthesis has a silicone rubber shell made of polysiloxane(s), such

The shell contains a fixed amount of silicone gel. A double lumen silicone gel-filled breast prosthesis is a silicone rubber inner shell and a silicone rubber outer shell, both shells made of polysiloxanes(s), such polydimethylsiloxane and polydiphenylsiloxane. The inner shell contains a fixed amount of silicone gel. There is either a valve on the outer shell for inflating with saline at implantation or a valve on the outer shell that allows for intraoperative filling and postoperative volume adjustments.

A tri-lumen silicone gel-filled breast prosthesis incorporates a separate gel-filled core within a gel-filled lumen, both surrounded by an outer shell designed to be filled, generally, with physiological saline.

Alternative breast prosthesis

Typically, an alternative breast prosthesis has a silicone rubber shell whose filler contains any material 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 other than that made from silicone rubber. The sponsor should keep in mind that the additional information other than that described below may be necessary for alternative shell breast implants.

MANUFACTURING / STERILIZATION

The Office of Device Evaluation (ODE) focuses on the manufacturing information as it relates to the safety and effectiveness of the design of the device. The Office of Compliance (OC) is primarily responsible for the review of the manufacturing information and its compliance with the Quality System Regulation (21 CFR 820). 21 CFR 812.20(b)(3) states that a description of the methods, facilities and controls used for the manufacture, processing, packaging, storage and, where appropriate, installation of the device, in sufficient detail so that a person generally familiar with good manufacturing practices can make a knowledgeable judgment about the quality control used in the manufacture of the device should be provided. However, this summarized wording is not sufficient to capture the detailed information that is necessary under 21 CFR 820. Therefore, it is strongly suggested a sponsor contact OC with any questions regarding what information is necessary to address 21 CFR 820. In addition to the information needed for purposes of manufacturing review, a sponsor should provide the following information for review by ODE: ??basic manufacturing information that addresses device design issues (e.g., application of patch and valve); and ??sterilization information. This information includes the sterilization method(s) used, all parameters of the sterilization cycle, the validation method, the resulting sterility assurance level, a description of the packaging, and data supporting any pyrogenicity claims. For gamma radiation sterilization, the sponsor should provide the radiation dose. For EtO sterilization, the sponsor should provide the maximum residual levels of ethylene oxide, ethylene chlorohydrin and ethylene glycol met and a rationale why the residual levels are acceptable. Resterilization of breast implants are not recommended. However, if a sponsor plans to allow for resterilization, then supporting data that the resterilization method does not impact the chemical and mechanical properties of the implant should be provided.

PRECLINICAL DATA

All preclinical testing (chemical, toxicology, or mechanical) should be performed on the final sterilized product or components thereof. The type of information below should be provided for an IDE, PMA, or PDP unless an adequate rationale is provided.

1. Preclinical Data - Chemistry

1.1 General Information

A complete list of all of the chemicals used in the manufacture of the breast prosthesis should be provided. The list should include the common names and trade names of each chemical component, the specific role of each chemical in the manufacturing process and/or in the final device. The location of the chemical within the device, e.g., in the shell, the inner or outer layers of the shell, in the filler, valve, or adhesive, should also be provided. Polymeric components should be described by chemical name, mean molecular weight, and a measure of the polydispersity. Material safety data sheets (MSDS) should be provided for each chemical.

1.2 Chemical Analysis of Elastomer Shell including Patch and Valve

Chemical analyses of the elastomer shell, including the patch and valve, should be provided.

The elastomer should be cryoground and analyzed separately from the filler.

The cryoground elastomer shell should be analyzed for volatile components; using a headspace detector is one method. Changes in design features, such as texturing, variations of device components such as patches or valves, or changes in sterilization, may necessitate additional analyses to detect variations in chemical composition.

An analysis of the extractable or releasable chemicals of an implant is necessary for the assessment of the safety of the device. The identification and quantification of releasable chemicals should be provided to identify potentially toxic chemicals and estimate the upper limits of the chemicals that could be released to the patient.

The following is one suggested method to address this issue. The extraction of the shell for chemical analysis can be performed with at least one polar solvent (i.e., ethanol or a mixture of ethanol-water) and two non-polar solvents (i.e., dichloromethane and hexane). To determine the duration of the exhaustive extractions, a series of successive extractions can then be conducted by exposing the sample to the solvent for a period of time, analyzing the solvent for extractables, replacing with fresh solvent, again exposing the sample 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, the test can be applied to the contents of the extract with molecular weights below 1500 because these are the compounds of greatest interest. All the separate analyte levels are then added together to calculate the cumulative value and, via the sample/solvent ratio, the sample and device levels. The total extraction from the polar solvent and the extraction from one of the non-polar solvents that yields the higher amounts of extractables should be used for both quantitative and qualitative analyses. Extracts that may contain oligomeric or polymeric species should have the molecular weight distribution provided, along with the number and weight average molecular weights and the polydisdpersity. Experimental evidence should be provided to show that exhaustive extraction has been achieved with one of the solvents. The percent recovery, especially for the polydimethylsiloxanes (D3 Or D4), should be reported.

All chemicals below a molecular weight of 1500 should be quantified and identified after exhaustive extraction of the final sterilized device. These include, but are not limited to, residual monomers, cyclics, and oligomers; known toxic residues such as polychlorinated biphenyls (PCBs) if dichlorobenzoyl peroxides are used, aromatic amines, if polyurethanes are used, and heavy metals and residues of catalysts. Residues of ethylene oxide and ethylene chlorohydrin should be reported if ethylene oxide is used for sterilization, as well as additives and adjuvants used in the manufacture of the device, such as plasticizers, antioxidants, etc. All experimental methodology (e.g., GPC, GLC/MS, GLC/AED, and FTIR) and raw data (including instrument reports) should be provided along with all chromatograms, spectrograms, etc. The practical quantitative limit (PQL) (see "Compilation of EPA's Sampling and Analysis Methods," Lewis publishers, 1992) should be provided when the analyte of interest is not detected.