[Federal Register: August 19, 1999 (Volume 64, Number 160)]
[Rules and Regulations]
[Page 45155-45161]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr19au99-3]
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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