General and Plastic Surgery Devices; Effective Date of Requirement for Premarket Approval of the Silicone Inflatable Breast Prosthesis

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 878

[Docket No. 91N-0281]

RIN 0910-AZ17

General and Plastic Surgery Devices; Effective Date of

Requirement for Premarket Approval of the Silicone Inflatable Breast

Prosthesis

AGENCY: Food and Drug Administration, HHS.

[[Page 45156]]

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is issuing a final rule

to require the filing of a premarket approval application (PMA) or a

notice of completion of a product development protocol (PDP) for the

silicone inflatable breast prosthesis, a generic type of medical device

intended to augment or reconstruct the female breast. This device is

made of a silicone shell that is inflated with sterile isotonic saline.

Commercial distribution of this device must cease unless a manufacturer

or importer has filed with FDA a PMA or PDP for its version of the

silicone inflatable breast prosthesis within 90 days of the effective

date of this regulation. This regulation reflects FDA's exercise of its

discretion to require PMA's or PDP's for preamendments devices and is

consistent with FDA's stated priorities and Congress' requirement that

class III devices are to be regulated by FDA's premarket review. This

action is being taken under the Federal Food, Drug, and Cosmetic Act

(the act), as amended by the Medical Device Amendments of 1976 (the

amendments), the Safe Medical Devices Act of 1990, and the Food and

Drug Administration Modernization Act of 1997.

EFFECTIVE DATE: August 18, 1999.

FOR FURTHER INFORMATION CONTACT: Stephen P. Rhodes, Center for Devices

and Radiological Health (HFZ-410), Food and Drug Administration, 9200

Corporate Blvd., Rockville, MD 20850, 301-594-3090.

SUPPLEMENTARY INFORMATION:

I. Introduction

In the Federal Register of June 24, 1988 (53 FR 23856), FDA

published a final rule classifying into class III (premarket approval)

the silicone inflatable breast prosthesis, a medical device. Section

878.3530 (21 CFR 878.3530) of FDA's regulations setting forth the

classification of the silicone inflatable breast prosthesis applies to:

(1) Any silicone inflatable breast prosthesis that was in commercial

distribution before May 28, 1976, and (2) any device that FDA has found

to be substantially equivalent to a silicone inflatable breast

prosthesis in commercial distribution before May 28, 1976.

In an advanced notice of proposed rulemaking published in the

Federal Register of January 6, 1989 (54 FR 550), the agency identified

the silicone inflatable breast prosthesis as one of the high-priority

devices that would be subject to PMA or PDP requirements. FDA issued a

notice in the Federal Register of September 26, 1991 (56 FR 49098),

requiring manufacturers to disseminate information on risks associated

with the silicone gel-filled breast prosthesis and the silicone

inflatable breast prosthesis. FDA stated that either type of breast

prosthesis would be misbranded under the act if its labeling did not

provide adequate information for patients.

In the Federal Register of January 8, 1993 (58 FR 3436), FDA

published a proposed rule, under section 515(b) of the act (21 U.S.C.

360e(b)), to require the filing of PMA's or PDP's for the classified

silicone inflatable breast prosthesis and all substantially equivalent

devices. In accordance with section 515(b)(2)(A) of the act, FDA

included in the preamble, the agency's proposed findings regarding: (1)

The degree of risk of illness or injury designed to be eliminated or

reduced by requiring the device to meet the premarket approval

requirements of the act, and (2) the benefits to the public from use of

the device.

The preamble also provided an opportunity for interested persons to

submit comments on the proposed rule and the agency's proposed

findings. Under section 515(b)(2)(B) of the act, it also provided an

opportunity for interested persons to request a change in the

classification of the device based on new information relevant to its

classification. Any petition requesting a change in the classification

of the silicone inflatable breast prosthesis was required to be

submitted by January 25, 1993. The comment period initially closed on

March 6, 1993. In the Federal Register of March 10, 1993 (58 FR 13230),

FDA extended the comment period for 30 days to April 8, 1993, to ensure

that there was adequate time for preparation and submission of comments

on the proposed rule.

The agency received 134 comments in response to the January 8,

1993, proposed rule. These comments were from individuals,

manufacturers, professional societies, and consumer and health groups.

Most of the comments supported the proposed rule.

In the Federal Register of June 28, 1995 (60 FR 33608), FDA issued

a notice announcing the availability of an updated patient risk

information booklet, entitled ``Information for Women Considering

Saline-filled Breast Implants.'' The information booklet provided

prospective patients with information about possible risks involved

with silicone inflatable breast prostheses. FDA gave the updated

information booklet to the manufacturers of saline-filled breast

implants (silicone inflatable breast prostheses) to include with their

labeling. FDA intended that physicians who perform breast implant

surgery give this information to their patients as they considered

implantation of a silicone inflatable breast prosthesis.

FDA is aware that new information on the device has become

available since the proposed rule was published in January 1993. On

June 2, 1999, the Institute of Medicine (IOM) released a comprehensive

review of the published literature and ongoing studies on both saline-

filled and silicone gel-filled breast implants entitled ``Safety of

Silicone Breast Implants.'' Both of these types of implants have a

silicone elastomer shell. The IOM made a clear distinction between

local complications and systemic health concerns. The IOM determined

that there was insufficient evidence to establish that breast implants

cause systemic health effects such as autoimmune disease. The IOM

concluded that there is ``no definitive evidence linking breast

implants to cancer, immunological diseases, neurological problems, or

other systemic diseases. On the basis of our committee's review of the

data, we concluded that women with breast implants are no more likely

than other women to develop these systemic illnesses.'' However, the

IOM also concluded that local complications are ``the primary safety

issue with silicone breast implants.'' These local complications

include rupture, pain, capsular contracture, disfigurement, and serious

infection, which may lead to medical interventions and repeat

surgeries. The agency believes that local complications should be

addressed in a PMA or PDP submission. Therefore, while it is possible

that the level of risk presented by the device may differ somewhat from

that described in the proposal, FDA nevertheless believes that the

risks to health identified in the proposed rule still exist for the

device and consequently, should be addressed in PMA's or PDP's for the

device.

This regulation is final upon publication and requires PMA's or

notices of completion of a PDP for all silicone inflatable breast

prostheses classified under Sec. 878.3530 and all devices that are

substantially equivalent to them. PMA's or notices of completion of a

PDP for these devices must be filed with FDA within 90 days of the

effective date of this regulation. (See section 501(f)(1)(A) of the act

(21 U.S.C. 351(f)(1)(A)).) This regulation does not include the

silicone gel-filled breast prosthesis (21 CFR 878.3540).

[[Page 45157]]

II. Summary and Analysis of Comments and FDA's Response

A. General Comments

1. FDA received comments from 116 women consumers and six health

professionals supporting the proposed call for PMA's or PDP's. Sixty-

four of the women consumers were reconstruction or augmentation

patients who were dissatisfied with their implants. These women

believed that their breast implants have caused them adverse health

effects. Fourteen of these breast implant recipients provided medical

histories and patient records to support their belief that their

illnesses are associated with their breast implants. Seven other

comments also expressed the belief that breast prostheses cause adverse

health effects. The other 43 women did not indicate whether or not they

had been implanted with breast implants. Nineteen of these 43 comments

recommended that silicone inflatable breast prostheses be recalled and

banned until long-term safety and effectiveness studies are completed.

Some comments recommended that silicone gel-filled breast prostheses be

recalled and banned. Thirty-one women expressed strong opinions that

the risks associated with all breast implants are unacceptable.

FDA does not believe that the available evidence supports a

conclusion that either banning or recalling the device would be

appropriate. Rather, FDA believes that requiring the submission of

PMA's or PDP's for the silicone inflatable breast prosthesis will

provide FDA an opportunity to assess more fully the risks and benefits

of these devices in order to determine whether there is reasonable

assurance of their safety and effectiveness, or absent such an

assurance what regulatory course should be taken.

The comments addressing the silicone gel-filled breast implant are

not within the scope of this rule. In the Federal Register of April 10,

1991 (56 FR 14620), FDA issued a final rule requiring the submission of

PMA's or PDP's for the silicone gel-filled breast prosthesis.

2. One comment stated that PMA's or PDP's are not necessary for

this device because adequate studies on silicone toxicity already exist

establishing the safety and effectiveness of the silicone inflatable

breast prosthesis. This comment stated that the extensive published

research has not found any causal relationship between silicone-

containing breast prostheses and the adverse events observed in some

women with these devices. Other comments stated that existing

information on the silicone gel-filled breast prosthesis and on other

types of silicone-containing prostheses in use (the chin prosthesis (21

CFR 878.3550); the ear prosthesis (21 CFR 878.3590), and the finger

joint prosthesis (21 CFR 888.3230)) provide adequate information to

support the safety and effectiveness of the silicone inflatable breast

prosthesis.

FDA is aware of the existence of information on silicone and

silicone-containing prostheses and expects that applicants may include

such information in their submissions to establish the safety and

effectiveness of the silicone inflatable breast prosthesis. FDA will

consider all information contained in PMA's or PDP's in determining

whether there is reasonable assurance of the safety and effectiveness

of these devices.

3. Four comments suggested that additional guidance on the data

requirements for PMA's be made available before publishing the final

rule. One of these comments also requested an open dialogue between

FDA, the industry, and the scientific and medical communities to

develop a consensus on the preclinical and clinical data necessary to

establish the safety and effectiveness of the device, and reissuance of

the proposed rule with a longer timeframe.

The 1993 proposed rule provided guidance on the appropriate data to

be included in the PMA for the silicone inflatable breast prosthesis.

Although section 515(b) of the act does not require the agency to

provide specific guidance on the contents of specific PMA's, FDA has

issued a ``Draft Guidance for the Preparation of PMA Application for

Silicone Inflatable (Saline) Breast Prostheses'' in November 1994 and a

revised draft guidance in January 1995 (the 1995 guidance document).

The 1995 guidance document is available from the internet at

``www.fda.gov/cdrh/ode/odegr532.html''. In order to receive the ``Draft

Guidance for Silicone Inflatable (Saline) Breast Prostheses'' via your

fax machine, call CDRH Facts-On-Demand (FOD) system at 800-899-0381 or

301-827-0111 from a touch-tone telephone. At the first voice prompt

press 1 to access DSMA Facts, at the second voice prompt press 2, and

then enter the document number (223) followed by the pound sign (#).

Follow the remaining voice prompts to complete you request.

In June 1996, FDA sent known manufacturers of the silicone

inflatable breast prosthesis a letter describing the recommended data

for a PMA. The period of time between the classification of the device

in 1988 and the date by which PMA's must be filed is more than 10

years. Thus, FDA believes that sufficient time and guidance has been

provided to allow sponsors to develop the data for a PMA submission.

FDA agrees that dialogue with industry and with the scientific and

medical community is important; FDA staff have been and continue to be

accessible to discuss PMA and PDP content information with industry and

the scientific and medical community.

4. Two comments suggested that postapproval studies could be used

to support approval of the silicone inflatable breast prosthesis, and

another comment suggested the use of FDA's postmarket surveillance

authority.

FDA notes that, by definition, postapproval studies are studies

performed after the approval of a PMA and that postmarket surveillance

studies are studies used to acquire additional performance information

about a device already determined to be reasonably safe and effective.

In the 1993 proposed rule, FDA stated that postapproval studies would

be required to fully assess the potential carcinogenicity and

teratogenicity of any approved silicone inflatable breast prostheses.

In the 1995 guidance document, FDA restated this need for postapproval

studies and added that postapproval studies would also be needed to

assess the potential for causing adverse immunological effects and/or

connective tissue disorders.

5. One comment objected that Congress never intended ``old''

preamendments medical devices to undergo the same scrutiny as ``new''

postamendments medical devices.

FDA does not believe that Congress intended to differentiate

between ``old'' preamendments devices and ``new'' postamendments

devices with respect to the requirement that valid scientific evidence

is needed to support PMA approval. Neither section 513(a)(3) (21 U.S.C.

360c(a)(3)) nor section 515(d) of the act makes any distinction between

``old'' and ``new'' devices with regard to any aspect of the

requirement for PMA approval. Evidence that constitutes valid

scientific evidence within the meaning of Sec. 860.7(c)(2) (21 CFR

860.7(c)(2)) may be submitted in support of a PMA or PDP, but it will

remain the agency's judgment whether the submitted evidence provides

reasonable assurance of safety and effectiveness.

6. Six comments stated that tissue expanders should be not be

included in the call for PMA's or PDP's. Five comments said that tissue

expanders intended for short-term use are unclassified devices. One

comment

[[Page 45158]]

suggested that the tissue expander intended for short-term use should

be classified into class II and that the tissue expander intended for

long-term use should be classified into class III.

Saline-filled silicone tissue expanders are used for general

surgical procedures, as well as for breast implantation surgery. FDA

agrees that tissue expanders intended for short-term use or for general

surgical purposes are unclassified devices and are not covered in this

final rule. FDA plans to initiate classification procedures for that

device at a future date. However, saline inflatable tissue expanders

that meet the definition of a silicone inflatable breast prosthesis are

included in this final rule.

7. One comment said the risk section should be rewritten because it

reflects an agency bias against the silicone inflatable breast

prosthesis, in that it equates the risks associated with the silicone

inflatable breast prosthesis with those of the silicone gel-filled

breast prosthesis.

FDA disagrees. The preamble to the proposed rule clearly states

that much of the literature cited in the risk section of the proposed

rule referred specifically to the silicone inflatable breast

prosthesis. The agency cited information about other silicone devices

only where there was no documentation specific to the silicone

inflatable breast prosthesis. Comparison of risk information between

devices should not be confused with an equation of risk.

B. Fibrous Capsular Contraction

8. There were six comments on the risk of fibrous capsular

contracture. These comments indicated that fibrous capsule formation

occurs around any implanted device and that this is part of the healing

process. They stated that, although this risk to health is a frequent

outcome, it is not life-threatening, and should be considered a

relatively minor risk to health.

FDA agrees that fibrous capsular contracture is usually not life-

threatening and that normal fibrous capsule formation is part of the

wound healing process after the implantation of any prosthesis. Fibrous

capsular contracture, however, is associated with clinical changes

ranging from a nearly imperceptible deformation of the implant to

marked distortion and firmness, often accompanied by tenderness, pain,

and discomfort. Significant fibrous capsular contracture, Baker grades

3 and 4, may require surgical removal of the device, making contracture

a serious risk to health. As stated in the 1995 guidance document, FDA

is requesting time-course data on the rate and frequency of fibrous

capsular contracture.

C. Deflation

9. There were seven comments on the risk of deflation. Two comments

said that deflation is not life-threatening, two characterized

deflation as being of low or no risk, and three said it is infrequent.

FDA agrees that this risk to health is not life-threatening.

However, deflation of the silicone inflatable breast prosthesis

eliminates the benefit of the device. In addition, the recipient may

then elect to have her implant surgically explanted and have a second

breast prosthesis implanted. This additional surgery makes deflation a

potentially serious adverse event. As noted in the 1995 guidance

document, FDA requested information to address the incidence of

deflation and rupture for this device.

D. Infection

10. Four comments stated that the incidence of infection associated

with the implantation of silicone inflatable breast prostheses is not

any higher than it is for other implantation surgeries. One comment

said that FDA needs an accurate determination of the incidence of

infection in women implanted with silicone inflatable breast

prostheses.

FDA believes that it is important for studies submitted in a PMA or

PDP to provide accurate information on the incidence of infection

associated with the implantation of the silicone inflatable breast

prosthesis.

E. Interference With Early Tumor Detection

11. Several comments stated that mammography may be more difficult

to perform and that it may be less effective for the early detection of

tumors in women with breast implants. Two other comments disagreed,

stating that there are no data showing that the presence of breast

implants has hindered or delayed the detection of breast tumors. The

same comments stated that implantation of the device under the

pectoralis muscles may reduce the interference with mammography, that

interference can be overcome with special detection procedures, and

that cancer detection does not rely solely on mammography.

FDA agrees that the presence of a silicone inflatable breast

prosthesis may interfere with the standard mammography procedures used

to screen patients for breast cancer. The device may produce a shadow

on the radiograph that obscures visualization of a significant portion

of the breast. In addition, the prosthesis compresses overlying breast

tissue, reducing contrast and making mammographic assessment more

difficult. Mammography of the augmented or reconstructed breast

requires special techniques, which may result in increased exposure to

radiation. Even under the best of circumstances, silicone inflatable

breast prostheses are likely to limit the effectiveness of this

examination for breast cancer detection. As stated in the 1995 guidance

document, FDA is requesting information on the potential interference

of the silicone inflatable breast prosthesis on the ability of

mammography to detect tumors in breast tissue.

F. Human Carcinogenicity

12. Nine comments said that there is no established correlation

between cancer and women with a silicone inflatable breast prosthesis.

They stated that silicone causes solid state tumors in rodents, a

phenomenon thought to be restricted to rodents and not applicable to

humans. They also stated that epidemiological studies have not found

that women with breast implants are at an increased risk for cancer.

FDA believes that the potential carcinogenicity for this device

remains unknown. The agency continues to believe that carcinogenicity

is a potential risk that must be assessed in a PMA or PDP.

G. Human Teratogenicity

13. There were five comments related to human teratogenicity. Three

comments stated that there is no evidence that the silicone inflatable

breast prosthesis is teratogenic. Two comments stated that

teratogenicity is a remote risk, which could be addressed in

postapproval studies. One comment stated that seven studies published

between 1975 and 1993 (including the literature FDA cited in the

proposed rule), in conjunction with the absence of reports of defects

among children born to women who have undergone mammary augmentation/

reconstruction with silicone implants, indicates that teratogenicity is

not an identified or a potential risk to health.

FDA agrees that there are no published studies showing that

silicone inflatable prostheses are associated with toxic reproductive

effects or teratogenic effects. However, FDA believes that

teratogenicity and/or reproductive effects of silicone elastomers

remain potential risks that should be assessed in a PMA or PDP. This

information was requested in the proposed rule and in the 1995 guidance

document.

[[Page 45159]]

H. Adverse Immunological Effects and/or Connective Tissue Disorders

14. Five comments stated that no definitive link between silicone

and autoimmune diseases has been established. These comments stated

that the incidence of these diseases in women with breast implants is

no higher than it is in women without breast implants. Two of these

comments suggested that some women may be more genetically susceptible

to the immunological effects than others. As stated previously, 71

consumer comments expressed the belief that breast implants cause

unacceptable adverse health effects. One physician reported that his

patients with breast prostheses had a higher than expected prevalence

of positive antinuclear antibody (ANA) test results. Because there was

no difference in the ANA test results between patients with gel-filled

and saline-filled breast prostheses, this comment attributed the

positive ANA results for both patient populations to the silicone shell

of the prostheses.

FDA agrees that no definitive causal relationship has been

established between immunological effects and/or connective tissue

disorders and the silicone inflatable breast prosthesis. FDA is aware

of the concerns expressed in the consumer comments. FDA also recognizes

that a positive ANA test without clinical symptoms is a nonspecific

finding. In the 1995 guidance document, FDA recommended that recipients

of silicone inflatable breast prostheses be regularly monitored for the

occurrence of such adverse events for a minimum of 10 years

postimplantation. FDA continues to believe that adverse immunological

effects and/or connective tissue disorders remain potential risks that

must be assessed in a PMA or PDP, but FDA does not believe that 10

years of prospective data collection on a specific product will be

necessary to do so.

I. Calcification

15. Several comments stated that calcification is not life-

threatening and is of unknown clinical significance. Other comments

suggest that calcification: (1) May occur in as many as 25 percent of

breast implant patients; (2) is rare; (3) is closely associated with

capsular contracture; (4) may complicate the interpretation of

mammograms; and (5) may cause abrasions of the silicone shell of the

device if the calcium salt crystals have sharp edges, making the

implant more susceptible to rupture.

FDA believes that there is not much information on the incidence

and effects of calcification in women implanted with silicone

inflatable breast prostheses. FDA believes that calcification remains

an uncharacterized potential risk to health. Consequently, as stated in

the proposed rule, FDA believes that PMA's or PDP's for this device

should include time-course information on the incidence of

calcification.

J. Biological Effects of Silica

16. Several comments stated that fumed amorphous silica is so

tightly bound in the silicone elastomer shell of the silicone

inflatable breast prosthesis that the fumed amorphous silica is

biologically inactive. For that reason, these comments believed that

the presence of fumed amorphous silica is not a risk to health of the

silicone inflatable breast prosthesis.

FDA does not believe there is sufficient information to eliminate

fumed amorphous silica as a potential risk to health associated with

the silicone inflatable breast prosthesis, particularly since the

amount of fumed amorphous silica is varied in order to achieve the

desired physical characteristics of the shell. Consequently, the agency

believes that this potential risk to health should be addressed in a

PMA or PDP.

K. Interference With Breast Feeding

17. Several comments stated that the presence of the silicone

inflatable breast prosthesis could potentially interfere with the

breast feeding of infants. The comments objected that claims that

breast implants have no effect on the nursing of infants are

unsubstantiated.

FDA agrees that interference with breast feeding of infants is a

potential risk to health presented by this device because the implants

may reduce the ability of breast feeding women to deliver an adequate

quantity of milk. Although most augmentation patients are of

childbearing age, there are no data on this potential risk. FDA

believes that PMA's or PDP's for the silicone inflatable breast

prosthesis should contain information on the effect of the device on

the breast feeding of infants.

L. Benefits of the Device

18. One comment stated that a positive psychological benefit for

the silicone inflatable breast prosthesis should be assumed. Other

comments maintained that the published studies have already established

that breast prostheses provide a positive psychological benefit.

The agency believes that the potential psychological benefits

offered by the device are an important part of the device's efficacy.

Consequently, FDA believes the psychological benefit of the silicone

inflatable breast prosthesis should be demonstrated in clinical trials

and reported in a PMA or PDP application.

19. Seven comments stated that the determination of psychological

benefit is problematic for several reasons: (1) There are no validated

standardized psychological tests for measuring psychological benefit;

(2) existing tests for psychological well-being and self-esteem are

confounded by multiple life variables, including the patient's general

health, sexual functioning, and understanding of the potential

complications when making the decision to have a silicone inflatable

breast prosthesis implanted; and (3) there is a lack of suitable

controls for both reconstruction and augmentation patients. One comment

suggested that benefit be assessed with ``quality of life''

questionnaires, using patients as their own controls and assessing a

wide range of variables. Another comment stated that it would be

``unduly burdensome and needlessly distressful'' to subject women

requesting breast implants to psychological assessment testing.

Among the seven comments there was general agreement that patients

should be followed for a long period of time after the surgery, perhaps

even 10 to 15 years. This is complicated because, during this period,

other issues related to self-esteem and a feeling of well-being may

confound the determination of psychological benefit. Some comments

stated that the assessment of psychological benefit should be different

for reconstruction and augmentation patients.

FDA agrees that designing studies to assess the psychological

benefit of implantation with a silicone inflatable breast prosthesis

may be difficult. In the 1995 guidance document, FDA suggested that the

effectiveness of the device can be measured by assessing: (1) The

degree of maintenance (if applicable) or of enhancement of a woman's

psychological well-being postimplantation, and (2) the anatomical

effect provided by the device. FDA added that both assessments should

be balanced against any illness or injury associated with the use of

the device. FDA further stated that the level of benefit derived from

the device may depend on whether the device is used for augmentation

mammoplasty, correction of congenital or traumatic breast anomalies, or

reconstruction mammoplasty after tumor removal, and recommended that

benefit data be stratified by these categories of use. The agency will

accept

[[Page 45160]]

a variety of types of scientific evidence in support of a PMA or PDP,

as long as the data constitute valid scientific evidence within the

meaning of Sec. 860.7(c)(2).

M. Need for Risk Benefit Information

20. Three comments agreed that risk/benefit data should be

collected, but questioned the need to include such data in a PMA.

FDA believes that it is appropriate for PMA's or PDP's to contain

risk/benefit data to enable the agency to determine whether there is

reasonable assurance of the safety and effectiveness of the silicone

inflatable breast prosthesis.

N. PMA Contents

21. FDA received two extensive comments on the types of

manufacturing information, preclinical testing, and clinical data that

should be required in a PMA for a silicone inflatable breast

prosthesis, as well as several general comments on the appropriate

contents of a PMA.

FDA believes that the points raised in these comments are addressed

in great detail in the 1995 draft guidance. The guidance addresses all

types of data, including manufacturing, preclinical, and clinical,

expected to be submitted. Additionally, manufacturers already have

begun submitting manufacturing and preclinical data to the agency in

preparation for the call for PMA's or PDP's.

III. Findings With Respect to Risks and Benefits

A. Degree of Risk

1. Fibrous Capsular Contracture

Contracture, the formation of a constricting fibrous layer around

the silicone inflatable breast prosthesis, is a risk associated with

both augmentation and reconstruction mammoplasty. Contracture may

result in excessive breast firmness, discomfort, pain, disfigurement,

displacement of the implant, and psychological trauma. Procedures,

including corrective surgery or surgical removal of the device and

adjacent tissue, may be required to relieve the symptoms associated

with contracture. The effects of contracture can vary from a reduced

satisfaction with the device to causing a woman to seek explantation of

the device. Although severe cases are rare, less severe contracture is

the most common adverse event associated with the silicone inflatable

breast prosthesis.

2. Deflation

The deflation of a silicone inflatable breast prosthesis is the

loss of saline volume from the device as a result of rupture, valve

failure, or a defect in the device. Deflation is not life-threatening,

but the loss of saline destroys the shape of the implant, and surgery

may be required to remove and replace it. Because of the need for an

additional surgery, deflation is a serious adverse event. Deflation

incidence data, as a function of time after implantation, are not

currently available.

3. Infection

Infection is a risk associated with any surgical implant procedure,

including implantation of the silicone inflatable breast prosthesis.

Compromised device sterility and surgical techniques may be major

contributing factors to this risk. Skin and bacteremic flora may also

have a role in infection in the periprosthetic area. Infection may

increase fibrous capsular contracture and result in a need for removal

of the device.

4. Interference With Early Tumor Detection

The presence of a silicone inflatable breast prosthesis may

interfere with standard mammography procedures by producing a shadow

that obscures visualization, or by reducing contrast by compressing

overlying breast tissue. Mammography of the augmented breast requires

special techniques and skills and may result in increased exposure to

radiation.

5. Human Carcinogenicity

The potential for developing cancer as a result of the long-term

implantation of silicone inflatable breast prostheses cannot be

eliminated as a potential risk associated with the silicone inflatable

breast prosthesis.

6. Human Teratogenicity

Although FDA is not aware of data indicating that the silicone

inflatable breast prosthesis is associated with teratogenic and

reproductive effects, the potential for teratogenicity and other

reproductive adverse effects as a result of long-term implantation of

the device cannot be eliminated as a possible risk to health.

Reproductive effects are particularly important because many

augmentation patients are of childbearing age.

7. Adverse Immunological Effects and/or Connective Tissue Disorders

The potential for developing immunological effects and/or

connective tissue disorders as a result of long-term exposure to the

silicone inflatable breast prosthesis remains uncertain. Since the

publication of the proposed rule 5 years ago, new epidemiological data

(Refs. 1 and 2) addressing the relationship between the device and

autoimmune diseases or connective tissue diseases indicate that

silicone breast prostheses have not caused a large increase in the

incidence of connective tissue disease in women with breast implants.

However, the possibility of a smaller increased risk of immunological

effects, or of an atypical, as yet undefined, syndrome or disease,

cannot be eliminated based on these data.

8. Calcification

Calcification of the fibrous capsule surrounding the silicone

inflatable breast prosthesis involves the deposition of mineral salts

in the capsule. Neither the incidence nor the risk to health of

calcification are established.

9. Biological Effects of Silica

Amorphous fumed silica is bound to the silicone in the elastomeric

shell of the silicone inflatable breast prosthesis. Silica presents a

potential risk which should be addressed in a PMA or PDP.

B. Benefits of the Device

The silicone inflatable breast prosthesis is intended to

reconstruct or augment the female breast. Reconstruction or

augmentation surgery is elective in nature, although implantation of a

silicone inflatable breast prosthesis is often an integral part of the

reconstructive patient's total treatment.

Although a definitive psychological study to assess the benefits of

the silicone inflatable breast prosthesis may be difficult to conduct,

FDA believes data are needed to document whether the device is

effective for its intended use.

IV. Final Rule

Under section 515(b)(3) of the act, FDA is adopting the findings as

published in the preamble to the proposed rule and is issuing this

final rule to require premarket approval of the generic type of device,

the silicone inflatable breast prosthesis, by revising

Sec. 878.3530(c).

Under the final rule, a PMA or a notice of completion of a PDP is

required to be filed on or before November 17, 1999, for any silicone

inflatable breast prosthesis that was in commercial distribution before

May 28, 1976, or that has been found by FDA to be substantially

equivalent to such a device on or before November 17, 1999. An approved

PMA or a declared completed PDP is required to be in effect for any

such device on or before 180 days after FDA files the application.

[[Page 45161]]

Any other silicone inflatable breast prosthesis that was not in

commercial distribution before May 28, 1976, or that has not been found

by FDA to be substantially equivalent to such a device on or before

November 17, 1999, is required to have an approved PMA or a declared

completed PDP in effect before it may be marketed.

If a PMA or a notice of completion of a PDP for a silicone

inflatable breast prosthesis is not filed on or before the 90th day

past the effective date of this regulation, that device will be deemed

adulterated under section 501(f)(1)(A) of the act , and commercial

distribution of the device will be required to cease immediately. The

device may, however, be distributed for investigational use, if the

requirements of the investigational device exemption (IDE) regulations

(part 812) (21 CFR part 812) are met.

Under Sec. 812.2(d) of the IDE regulations, FDA hereby stipulates

that, on the effective date of this rule, the exemptions from the IDE

requirements in Sec. 812.2(c)(1) and (c)(2) will no longer apply to

clinical investigations of the silicone inflatable breast prosthesis.

Further, FDA concludes that investigational silicone inflatable breast

prostheses are significant risk devices as defined in Sec. 812.3(m) and

advises that, as of the effective date of this rule, the requirements

of the IDE regulations regarding significant risk devices will apply to

any clinical investigation of a silicone inflatable breast prosthesis.

For any silicone inflatable breast prosthesis that is not the subject

of a timely filed PMA or PDP, an IDE must be in effect under

Sec. 812.20 on or before 90 days after the effective date of this

regulation or distribution of the device must cease. FDA advises all

persons presently sponsoring a clinical investigation involving the

silicone inflatable breast prosthesis to submit an IDE application to

FDA no later than 60 days after the effective date of this final rule

to avoid the interruption of ongoing investigations.

V. Environmental Impact

The agency has determined under 21 CFR 25.30(h) that this action is

of a type that does not individually or cumulatively have a significant

effect on the human environment. Therefore, neither an environmental

assessment nor an environmental impact statement is required.

VI. Analysis of Impacts

FDA has examined the impacts of the final rule under Executive

Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612), as

amended by subtitle D of the Small Business Regulatory Enforcement

Fairness Act of 1996 (Public Law 104-121), and the Unfunded Mandates

Reform Act of 1995 (Public Law 104-4). Executive Order 12866 directs

agencies to assess all costs and benefits of available regulatory

alternatives and, when regulation is necessary, to select regulatory

approaches that maximize net benefits (including potential economic,

environmental, public health and safety, and other advantages;

distributive impacts; and equity). The agency believes that this final

rule is consistent with the regulatory philosophy and principles

identified in the Executive Order. The Office of Management and Budget

(OMB) has determined that this final rule is a significant regulatory

action subject to review under the Executive Order.

If a rule has a significant economic impact on a substantial number

of small entities, the Regulatory Flexibility Act requires agencies to

analyze regulatory options that would minimize any significant impact

of a rule on small entities. FDA expects that up to seven manufacturers

will submit a PMA or PDP for the silicone inflatable breast prosthesis.

FDA estimates that it costs up to $1 million to submit a PMA or PDP. As

noted previously, the silicone inflatable breast prosthesis was

classified into class III on June 24, 1988, and FDA published a

proposed rule to require a PMA or PDP for this device on January 8,

1993. Thus, manufacturers have long been aware of the need to develop

information in support of a PMA or a PDP. Moreover, since the

publication of the proposed rule, FDA has been working closely with

manufacturers to assist them in preparing for the submission of a PMA

or a PDP. FDA, therefore, believes that this final rule will not be an

undue burden on these manufacturers. The agency therefore certifies

that the final rule will not have a significant economic impact on a

substantial number of small entities. Therefore, under the Regulatory

Flexibility Act, no further analysis is required.

VII. Paperwork Reduction Act of 1995

This proposed rule contains information collection provisions that

are subject to review by OMB under the Paperwork Reduction Act of 1995

(44 U.S.C. 3501-3530). The burden hours required for Sec. 878.3530(c)

are reported and approved under OMB Control No. 0910-0231.

VIII. References

The following references have been placed on display in the Dockets

Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers

Lane, rm. 1061, Rockville, MD 20852. These references may be seen in

the office above between 9 a.m. and 4 p.m., Monday through Friday.

1. Hennekens, C. H., I. Lee, N. Cook, P. R. Hebert, E. W.

Karlson, F. LaMotte, J. E. Manson, and J. E. Buring, ``Self-reported

Breast Implants and Connective-Tissue Diseases in Female Health

Professionals,'' Journal of the American Medical Association,

275:616-621, 1996.

2. Silverman, B. G., S. L. Brown, R. A. Bright, R. G. Kaczmarek,

J. B. Arrowsmith-Lowe, and D. A. Kessler, ``Reported Complications

of Silicone Gel Breast Implants: An Epidemiologic Review,'' Annals

of Internal Medicine, 124:744-756, 1996.

3. Institute of Medicine, ``Safety of Silicone Breast

Implants,'' National Academy Press, Washington, DC, 1999.

List of Subjects in 21 CFR Part 878

Medical devices.

Therefore, under the Federal Food, Drug, and Cosmetic Act and under

authority delegated to the Commissioner of Food and Drugs, 21 CFR part

878 is amended as follows:

PART 878--GENERAL AND PLASTIC SURGERY DEVICES

1. The authority citation for 21 CFR part 878 continues to read as

follows:

Authority: 21 U.S.C. 351, 360, 360c, 360e, 360j, 360l, 371.

2. Section 878.3530 is amended by revising paragraph (c) to read as

follows:

Sec. 878.3530 Silicone inflatable breast prosthesis.

* * * * *

(c) Date PMA or notice of completion of a PDP is required. A PMA or

a notice of completion of a PDP is required to be filed with the Food

and Drug Administration on or before November 17, 1999, for any

silicone inflatable breast prosthesis that was in commercial

distribution before May 28, 1976, or that has, on or before November

17, 1999, been found to be substantially equivalent to a silicone

inflatable breast prosthesis that was in commercial distribution before

May 28, 1976. Any other silicone inflatable breast prosthesis shall

have an approved PMA or a declared completed PDP in effect before being

placed in commercial distribution.

Dated: March 29, 1999.

William K. Hubbard,

Senior Associate Commissioner for Policy, Planning and Legislation.

[FR Doc. 99-21508 Filed 8-18-99; 8:45 am]

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