[Federal Register Volume 64, Number 160 (Thursday, August 19, 1999)]
[Rules and Regulations]
[Pages 45155-45161]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-21508]


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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]
BILLING CODE 4160-01-F