[Federal Register Volume 60, Number 65 (Wednesday, April 5, 1995)]
[Rules and Regulations]
[Pages 17208-17216]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-8383]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
21 CFR Part 876
[Docket No. 92N-0382]
Gastroenterology-Urology Devices; Effective Date of Requirement
for Premarket Approval of Testicular Prosthesis
AGENCY: Food and Drug Administration, HHS.
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
testicular prosthesis, a generic type of a surgically implanted medical
device intended to simulate the presence of a testicle within the male
scrotum. Commercial distribution of this device must cease, unless a
manufacturer or importer has filed with FDA a PMA or a notice of
completion of a PDP for its version of the testicular prosthesis within
90 days of the effective date of this regulation. This regulation
reflects FDA's exercise of its discretion to require a PMA or notice of
completion of a PDP for preamendments devices.
EFFECTIVE DATE: April 5, 1995.
FOR FURTHER INFORMATION CONTACT: Mark D. Kramer, Center for Devices and
Radiological Health (HFZ-470), Food and Drug Administration, 9200
Corporate Blvd., Rockville, MD 20850, 301-594-2194.
SUPPLEMENTARY INFORMATION:
I. Introduction
In the Federal Register of January 6, 1989 (54 FR 550), the agency
identified the testicular prosthesis as one of the high-priority
devices that would be subject to PMA or PDP requirements. This
rulemaking is consistent with FDA's stated priorities and Congress'
requirement that class III devices are to be regulated by FDA's
premarket approval review. This action is being taken under the Medical
Device Amendments of 1976 (Pub. L. 94-295). The preamble to this rule
responds to comments received on the proposal to require the filing of
a PMA or a notice of completion of a PDP.
This regulation is final upon publication and requires a PMA or a
notice of completion of a PDP for all testicular prostheses classified
under Sec. 876.3750 (21 CFR 876.3750) and all devices that are
substantially equivalent to them. A PMA or a notice 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
Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C.
351(f)(1)(A)).)
In the Federal Register of November 23, 1983 (48 FR 53012 at
53024), FDA issued a final rule classifying the testicular prosthesis
into class III (premarket approval). Section 876.3750 of FDA's
regulations setting forth the classification of the testicular
prosthesis intended for medical use applies to: (1) Any testicular
prosthesis that was in commercial distribution before May 28, 1976, and
(2) any device that FDA has found to be substantially equivalent to a
testicular prosthesis in commercial distribution before May 28, 1976.
In the Federal Register of January 13, 1993 (58 FR 4116), FDA
published a proposed rule to require the filing, under section 515(b)
of the act (21 U.S.C. 360e(b)), of a PMA or notice of completion of a
PDP for the classified testicular prosthesis and all substantially
equivalent devices (hereinafter referred to as the January 1993
proposed rule). In accordance with section 515(b)(2)(A) of the act, FDA
included in the preamble to the proposal 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 (58 FR 4116 at 4118).
The preamble to the January 1993 proposed rule also provided an
opportunity for interested persons to submit comments on the proposed
rule and the agency's proposed findings and, under section 515(b)(2)(B)
of the act (21 U.S.C. 360e(b)(2)(B)), provided the 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 testicular
prosthesis was required to be submitted by January 28, 1993. The
comment period initially closed on March 15, 1993. Because of one
request, FDA extended the comment period for 60 days to May 14, 1993,
to ensure adequate time for preparation and submission of comments (58
FR 15119, March 19, 1993).
FDA did not receive any petitions requesting a change in the
classification of the testicular prosthesis. The agency did receive a
total of five comments in response to the January 1993 proposed rule.
These represent comments from individuals, manufacturers, and
professional societies. The comments primarily addressed issues
relating to the significant risks associated with the use of testicular
prostheses, and the preclinical and clinical data needed to support a
future PMA application.
II. Summary and Analysis of Comments and FDA's Response
A. General Comments
1. One comment stated that it appears that FDA has chosen solid
silicone elastomer testicular implants for disparate treatment from
other silicone implants, even though the basic chemistry, ingredients,
and many manufacturing steps are very similar to other class II
implantable silicone products. The comment requested that FDA describe
the differences between silicone gel-filled and solid silicone
elastomer testicular implants, and between silicone gel-filled mammary
prostheses and solid silicone elastomer testicular prostheses.
FDA disagrees with this comment. The testicular prosthesis was
classified into class III in 1983 because insufficient information
existed to determine that general controls would provide reasonable
assurance of the safety and effectiveness of the device or to establish
a performance standard to provide this assurance. The possible risks
identified at the time of classification included: (1) The possible
migration of silicone gel from the interior of the prosthesis to
adjacent tissue (with or without rupture of the silicone elastomer
shell), and (2) possible long-term toxic effects of the silicone
polymers from which the prosthesis is fabricated. Therefore, requiring
premarket approval for the testicular prosthesis is consistent with the
intent to regulate this device as a class III device even in 1983. FDA
notes that no requests for a change in [[Page 17209]] classification
based on new information relevant to the classification of the device
were submitted in response to the January 1993 proposed rule.
While FDA recognizes that some of the risks of silicone gel
testicular prostheses may not necessarily apply to the solid silicone
elastomer testicular prosthesis, the requirement that PMA's be
submitted applies to the generic class of device comprised of all
testicular prostheses. In addition, while FDA recognizes that some of
the risks of silicone gel mammary prostheses may not necessarily apply
to solid or silicone gel-filled testicular prostheses, the testicular
prosthesis is similar in materials and construction to the silicone
gel-filled breast prosthesis and, therefore, many of the risks
associated with the use of the silicone gel-filled breast prosthesis
may also be associated with the solid silicone and silicone gel-filled
testicular prosthesis.
2. One comment stated that FDA's inclusion of prospective clinical
data requirements in the proposed rule has resulted in a timetable for
ultimate PMA submission that appears unreasonable and creates an undue
burden on manufacturers. The comment stated that, had firms initiated
PMA studies prior to the publication of the proposed rule, they could
not have anticipated the new requirements.
FDA disagrees with this comment. More than 10 years have passed
since these devices were classified into class III by final regulation.
Furthermore, the risks to health detailed in the proposed rule remain
consistent with those identified at the time of classification. FDA
believes that, consistent with congressional intent, manufacturers have
had notice and ample opportunity to gather the information necessary to
provide reasonable assurance of the safety and effectiveness of these
devices. It is not responsible to suggest that Congress intended
manufacturers to remain passive and not develop PMA's until a
regulation became final. Indeed, the act specifically requires
submissions 30 months after the final classification of a preamendments
device or within 90 days of a final regulation, whichever is later.
(See section 501(f)(2)(B) of the act). Thus, it is clear that Congress
intended that manufacturers anticipate a final regulation and be
prepared to submit appropriate applications or discontinue distribution
of their devices.
3. One comment stated that FDA's treatment of ear and testicular
prostheses (both cosmetic implants) is disparate, because no
psychological data was required for ear prostheses, and suggested that
the proposed requirement for psychological data is unprecedented in the
regulation process.
FDA disagrees with this comment. Ear and testicular prostheses are
different devices, and have been classified by different panels. Ear
prostheses, which are class II devices, were classified by the General
and Plastic Surgery Panel. The review of such plastic surgery
prostheses, such as chin prostheses, takes into consideration the
quality of life of the patient. FDA notes that psychological data is
only part of the effectiveness evaluation outlined in the proposed
rule. Moreover, the request for such data is not unprecedented. Such
data also were required in PMA's for silicone gel breast implants.
4. One comment stated that FDA should recognize that the solid
silicone elastomer testicular prostheses available today are much
improved in quality and are implanted using refined surgical techniques
that minimize many risks implicated with their early use.
FDA acknowledges that the design of certain testicular prostheses
and surgical techniques have evolved over time. FDA believes that
neither the literature nor other data currently available to FDA
definitively describe differences in the incidence of problems
attributable to device design and/or variations in surgical procedures.
Sufficient information exists identifying the risks detailed in the
proposed rule as risks to health associated with the testicular
prosthesis. FDA is requiring the submission of PMA's for this device in
order to determine whether these risks can be controlled to provide
reasonable assurance of the safety and effectiveness of these devices
for their intended use. Even a decline in the incidence of these risks
would not be a sufficient reason to abandon the regulation to require
PMA's for testicular prostheses, absent a clear delineation and
understanding of those risks.
5. One comment stated that Congress never intended ``old''
(preamendments) devices to be subjected to the same scrutiny as ``new''
devices under the premarket approval requirements.
FDA disagrees with this comment. FDA does not believe that Congress
intended to differentiate between ``old'' and ``new'' devices with
respect to the requirement that valid scientific evidence support a PMA
approval. Neither sections 513(a)(3) nor 515(d) of the act (21 U.S.C.
360c(a)(3)) makes any distinction between ``old'' and ``new'' devices
with regard to the requirements for approval. However, FDA does expect
that more retrospective data, which, by its historical character, is
generally less detailed and rigorous than prospectively gathered data,
would be available for use in supporting the approval of ``old'' as
opposed to ``new'' devices. Scientific evidence, including
retrospectively gathered data, is acceptable to support a PMA approval,
as long as the data constitute valid scientific evidence within the
meaning of Sec. 860.7(c)(2) (21 CFR 860.7(c)(2)).
6. One comment stated that the proposed rule did not address how
amendments to PMA's submitted prior to panel review will be handled,
and requested that the agency clarify the administrative procedures
applicable to such PMA amendments.
PMA amendments submitted prior to advisory panel review will be
evaluated to determine whether the information is sufficiently
substantive to be considered a ``major'' amendment. A major amendment
may extend the review period for up to 180 days as outlined in 21 CFR
814.37(c)(1).
7. One comment stated that FDA should refrain from promulgating the
final rule without the specific guidance documents defining certain
preclinical and clinical testing requirements.
FDA disagrees with this comment. Section 515(b) of the act does not
require FDA to provide guidance for tests for PMA's prior to issuing a
call for PMA's. While FDA outlined numerous manufacturing, preclinical,
and clinical studies that suggest the content of a PMA for a testicular
prosthesis, and issued a detailed guidance document for such PMA's in
March 1993, that was discussed at a public meeting of the
Gastroenterology and Urology Devices Advisory Panel in April 1993,
these tests were suggestive and not intended to bind a PMA applicant to
any specific study or set of studies. FDA's ``Draft Guidance for the
Content of PMA Applications for Testicular Prostheses'' is available
upon request from the Division of Small Manufacturers Assistance (HFZ-
220), Center for Devices and Radiological Health, 1350 Piccard Dr.,
Rockville, MD 20850.
8. One comment suggested that FDA should reopen the dialogue with
industry, scientific, and medical communities in order to develop a
consensus on the exact scope and nature of some of the preclinical,
material, and clinical data requirements.
FDA agrees that the dialogue with industry and the scientific and
medical communities should remain open regarding the information needed
to support a PMA. FDA staff have been and continue to be accessible to
discuss these requirements as requested. [[Page 17210]]
B. Risks
9. Two comments suggested that the list of risks do not represent
``significant risks'' of testicular prosthesis implantation. The
contention was that FDA has not clearly differentiated between
significant risks, potential risks, and potential adverse effects, and
that FDA should limit identification of risks to those which have been
reasonably shown to be significant risks. The comment noted that the
potential effects may be divided into short-term effects and long-term
effects.
FDA disagrees with this comment. The proposed rule clearly
differentiated risks that have been observed with testicular prostheses
from those that are potential risks. Erosion, extrusion, displacement,
fibrous capsular contracture, infection, and silicone gel leakage are
risks that have been reported specifically for the testicular
prosthesis. Carcinogenicity, human reproductive and teratogenic
effects, immune related connective tissue disorders (immunological
sensitization), biological effects of silica, and degradation of
polyurethane foam covering some implants were identified as potential
risks that, based on review of all available information, FDA believes
are relevant to the testicular prosthesis. While FDA agrees that the
risks of any implant fall into the broad categories of short-term and
long-term risks, FDA believes that many of the risks identified are
both short and long-term in nature, rather than exclusively short or
long-term.
10. One comment suggested that since erosion, extrusion, and/or
displacement are readily correctable by medical intervention, and since
revision surgery is possible if explant is necessary, they should not
be considered significant risks. Furthermore, the comment suggested
that displacement is not a commonly reported adverse event, nor can the
prosthesis migrate to a variety of locations within the body.
FDA disagrees with this comment. Insufficient information is
available to determine the frequency of these events or their effects.
Furthermore, because these risks can necessitate revision surgery or
explant, FDA believes they are appropriately identified as significant
risks. However, FDA agrees that it was not accurate to state that the
prosthesis can ``migrate to a variety of locations within the body,''
but notes that the prosthesis can migrate to, in front of, or behind
the contralateral testis or above the scrotum. The discussion of this
risk has been modified accordingly.
11. Several comments stated that certain references cited in the
proposed rule failed to demonstrate a causal relationship or a strong
association between the implantation of a testicular prosthesis and the
onset of risks, such as carcinogenicity, teratogenicity, and autoimmune
diseases or connective tissue disorders.
FDA agrees that the references cited do not establish or refute the
existence of a causal relationship between testicular prostheses and
these risks. However, the literature cited by FDA provides evidence
that these potential risks are associated with the device and are not
trivial. Consequently, investigation of these risks in support of a PMA
is necessary.
12. Two comments regarding the potential carcinogenicity of
silicone were received. The comments make the contention that the
animal studies reported are irrelevant because the observed sarcomas
were solely due to physical (solid state) carcinogenesis and such risks
are not applicable to humans.
FDA disagrees with these comments. Carcinogenicity is a putative
risk secondary to implantation of any material. After review of all
available information, the agency continues to believe that
carcinogenicity is a potential risk that must be assessed in a PMA.
13. Three comments were on the subject of reproductive and
teratogenic effects of the testicular prosthesis. These comments stated
that, because the majority of prostheses are placed in middle-aged to
elderly men who have had testicular removal as treatment for prostatic
cancer, the human reproductive concern is irrelevant. These comments
also stated that: (1) There are no reports of adverse effects of
testicular prostheses on reproduction, or teratogenic effects on
offspring of patients with such prostheses; (2) FDA misinterpreted the
results of the literature cited; and (3) only silicone rubber or
silicone gel products which contain or are synthesized from
phenylmethyl silicones have potential effects on the male reproductive
system.
FDA agrees with the comments that, to date, there are no published
studies showing reproductive toxic effects or teratogenic effects
associated with implantation of silicone materials. While some authors
may have concluded that silicone is not a teratogen, FDA believes that
there have been no well-designed studies using silicone testicular
implants to determine potential human reproductive and teratogenic
risks. FDA believes that information in the form of well-designed,
single generation animal studies would be appropriate. Additionally, a
PMA applicant may choose to submit appropriate human studies, or
properly gathered and analyzed historical data, to establish the
teratogenic potential of a silicone testicular prosthesis.
FDA agrees that the requirement for reproductive toxicity and
teratogenicity information for PMA's should apply for those silicone
rubber or silicone gel testicular prostheses which contain or are
synthesized from phenylmethyl silicones, but the agency notes that this
testing should also be conducted for other silicones until the
reproductive and teratogenic profiles of these materials are
established.
Finally, FDA agrees that the human reproductive concern may not
apply to some testicular implant recipients. However, because a sizable
portion of the implant population consists of young males, the concern
is relevant. After reviewing all available data, FDA believes that the
prolonged contact young males would have with the device presents a
potential risk of reproductive effects and teratogenicity in humans.
14. Two comments stated that fibrous capsule formation is a normal
wound healing process and, in the case of a testicular prosthesis, aids
in keeping the implant in place and preventing migration to other parts
of the body. The comments stated that this response occurs following
implantation of almost any material and should not be considered a
complication or adverse event associated with implantation of
testicular prostheses. One comment stated that the incidence rate of
fibrous capsular contracture is low, while the second stated that it
has never been reported; both argued that it should not be listed as a
significant risk.
FDA agrees that fibrous capsule formation is a normal wound healing
process that can occur following implantation of almost any material.
The agency disagrees, however, that fibrous capsular contracture is not
a significant risk of the testicular prosthesis. Fibrous capsular
contracture may result in excessive scrotal firmness, discomfort, pain,
disfigurement, and displacement of the implant. Moreover, sufficient
information exists to identify capsular contracture as a risk to health
associated with the testicular implant. FDA believes that literature
case reports and product complaints to the manufacturer do not
necessarily capture all problems with medical devices.
15. Two comments suggested that the incidence of infection occurs
at a rate consistent with other prosthetic implant surgeries and is
seldom serious and, [[Page 17211]] therefore, that infection should not
be considered a significant risk.
FDA disagrees with this comment. While the incidence of infection
may be similar to other prosthetic devices, data are needed to
specifically quantify its incidence and effect. Infection often leads
to surgical removal of the implant and, therefore, is a potentially
serious adverse event. After review of all available information, FDA
continues to believe that infection is a significant risk associated
with the testicular prosthesis.
16. Several comments were received on the subject of immune related
connective tissue disorders or immunological sensitization. The
comments make the following contentions: (1) Silicone stimulates a
cell-mediated response only when administered under extraordinary
conditions with an adjuvant; (2) there is no evidence to date that hard
silicone elastomer has immune system adjuvant properties; (3) recent
surveys of populations of women with connective tissue disorders have
demonstrated no increase in disease prevalence in women with silicone
breast implants; and (4) since scientific studies of women with
silicone mammary prostheses have not shown a risk for development of
connective tissue disorders, implantees with silicone testicular
implants, which have less than one thirtieth the volume of a breast
implant, should also not be at risk of connective tissue disorders.
FDA disagrees with these comments. The adjuvant effect of silicone
gel is established in animal studies (Ref. 1). A recent study (Ref. 2)
suggests that some women with silicone gel-filled breast prostheses may
develop atypical immunologic reactions. Therefore, the agency continues
to believe that the potential risk of immune related connective tissue
disorders or immunological sensitization to implanted silicone
testicular prostheses must be assessed in a PMA.
17. One comment stated that, while the scientific evidence to date
does not demonstrate any cause and effect relationship between the
testicular silicone implant and the subsequent development of
autoimmune diseases, additional research needs to be completed.
FDA agrees with this comment.
18. Two comments stated that fumed, amorphous silica is tightly
incorporated into the silicone elastomer shell of the testicular
prostheses and, as a result, has very different (and reduced)
biological activity.
FDA does not believe that there is sufficient information available
to conclude that amorphous (fumed) silica does not produce the same
kind of biological effects as crystalline silica. Furthermore, while
the silica reinforcer material may not be extractable, it can be
potentially exposed or shed in the form of particles from the elastomer
by the process of abrasive wear. Therefore, FDA believes it is
necessary that data demonstrating the safety of amorphous silica should
be submitted in PMA's.
C. Benefits
19. One comment stated that it is important to recognize the value
of a psychological benefit to patients using these devices, and that
although it is more difficult to document and quantify a psychological
benefit than a physical benefit, the preponderance of evidence showing
a psychological benefit should not be underestimated nor undervalued.
FDA agrees with this comment, and has outlined the data needed to
demonstrate the psychological benefit of the testicular prosthesis.
D. Manufacturing
20. One comment stated that cooperation between manufacturers and
raw materials suppliers is necessary in order to obtain the
manufacturing data required in a PMA.
FDA agrees that a cooperative relationship between manufacturers
and raw materials suppliers will make the manufacturing data
requirements easier to complete, but the agency notes that much of the
materials information needed is on the finished, sterilized device.
21. One comment suggested that the manufacturing information
section should be revised to allow the referencing of master file
submissions, with more limited chemical characterization (e.g., Fourier
Transform Infrared Spectroscopy (FTIR)) to confirm chemical
composition, and mechanical testing to establish criteria for lot to
lot variability in the cured product.
FDA disagrees with this comment. While proprietary manufacturing
information and, perhaps, testing results may be part of a master file,
additional information beyond formulation data is needed to document
the safety of the materials used to construct the device. The
additional information must consist of testing that is more sensitive
to process variation than routine FTIR and mechanical tests on the
cured product. The chemical, physical, and mechanical properties of the
final device are affected not only by the starting raw materials, but
by the chemical reaction, processing, and subsequent sterilization of
these raw materials to make the final device. Only the device
manufacturer, not the raw material supplier, has control over these
processes. Consequently, referral to a device master file is not, in
itself, adequate to assess the safety of the final sterilized device.
22. One comment noted that the supply of silicone raw materials is
in jeopardy due to market withdrawal by several manufacturers. This
comment suggested that a guidance document is needed to determine
acceptable equivalency and data requirements.
FDA agrees that market withdrawal of silicone raw materials by
several manufacturers may limit their availability. In the Federal
Register of July 6, 1993 (58 FR 36207), FDA published a notice of
availability of a guidance entitled ``Guidance for Manufacturers of
Silicone Devices Affected by Withdrawal of Dow Corning Silastic
Materials.'' The guidance describes the testing procedures to be
followed by manufacturers in determining the equivalency of the
materials.
E. Extraction Testing
23. One comment stated that the concept of exhaustive extraction
and identification and quantification of all chemicals is relatively
recent and thus requires method development and validation tantamount
to the creation of a new science.
FDA disagrees with this comment. Numerous literature references
describe extraction, identification, and quantification of individual
silicone components from a variety of matrices using a variety of
extraction solvents. While more limited, references exist for
supercritical fluid extraction of the low molecular weight components
from silicone elastomers. This is not a new science. FDA recognizes the
difficulty in quantifying the amount of more than 35 separate
components possible given the materials of interest, however present
state-of-the-art allows this to be done.
24. One comment stated that FDA's request for molecular
characterization of elastomer intermediates, outer shell, patch, and
other component parts is not possible since, with the exception of the
internal gel component, the parts are composed of solid cured
elastomeric material. Furthermore, the comment stated that FDA's
request for determination of residual volatile and nonvolatile cyclic
compounds is a duplication of the requirement for analysis of
extractables set forth in the preclinical data section of the proposed
rule.
FDA agrees that this section was unclear. Because only a limited
amount of chemical characterization can be [[Page 17212]] done on
highly crosslinked polymers, it is important to characterize the
immediate precursors to assure the quality of the base polymers and
crosslinking agents. Regarding the determination of residual volatile
and nonvolatile cyclic compounds, FDA agrees that this requirement
should apply only to the individual structural components (outer shell,
patch, internal gel, suture tab, polyurethane foam covering, and any
other materials) as they are found in the final sterilized device as
described in the preclinical data section, and should not apply to
material intermediates and precursors.
25. One comment stated that the requirement of ``complete
identification and quantification of all chemicals'' is untenable and
unattainable, and should be modified to allow manufacturers to focus on
identification and quantification of those substances whose presence in
the finished device is known or reasonably anticipated based on
composition of starting materials, known additives, reaction
byproducts, and potential residues or contaminants from reagents used
in processing.
FDA disagrees with this comment. Identification and quantification
of the majority of chemicals below a molecular weight of 1,500 for
silicones, as specified in the guidance, is possible. For other
polymeric materials, different criteria may be acceptable and should be
discussed with FDA on a case-by-case basis. While FDA agrees that
knowledge of the formulation will assist in predicting what might be
found in the final product, it will not delineate what or how much is
actually in the final product nor assess how the manufacturing process
will affect the final product. Knowledge of the formulation will also
help in selecting the appropriate analytical methodology to be used for
the analysis.
26. One comment stated that analysis of extractables and subsequent
toxicity testing should be performed entirely on the final product,
rather than separate structural components, and that FDA should
establish threshold limits for extractives based on molecular
characteristics.
FDA agrees with the first part of this comment, but notes that the
analyst should be aware of the drawback to testing the final product in
toto. For example, wide variation in the size of the structural
components and their proximity to each other in the final device may
result in erroneous conclusions being made regarding the chemical
identity and source of extract components. Furthermore, the outside
shell of an intact device may preclude exhaustive extraction of the
interior gel within a reasonable period of time. Nor does testing of an
intact device simulate a prosthesis that has ruptured in vivo. Separate
testing of the individual components (materials/adhesives) of the final
device is acceptable provided that the formulation of the test
specimens is identical to the formulation of the materials used in the
actual device and has been subjected to the same curing, post-curing,
processing, and sterilization modes as the final whole device. Such
testing would also allow an increase in specimen size to accommodate
the collection of sufficient extract to perform any analytical and
biocompatibility testing. Adjustment of the analytical results on a
weight basis can then be calculated for the intact device. Regarding
the establishment of threshold limits, FDA agrees in theory, but notes
that present limited knowledge of toxicity based on molecular
characteristics, especially with respect to siloxanes, makes the
establishment of threshold limits impossible.
27. One comment stated that FDA should define what is meant by
``exhaustive extraction''.
FDA's ``Draft Guidance for the Content of PMA Applications for
Testicular Prostheses'' provides detailed guidance on extraction for
silicone implants. This guidance is available upon request from the
Division of Small Manufacturers Assistance (HFZ-220) (see address above
in section II A of this document).
F. Physical Testing
28. One comment stated that it seems unnecessary for FDA to require
characterization of a physical or chemical property unless it is
relevant to the intended use of the device.
FDA notes that no specific physical property tests were cited in
the comment. FDA believes that all of the physical property tests
identified in the proposed rule are relevant to the intended use of the
device.
29. Two comments stated that the testicular prosthesis is too small
to use the American Society for Testing and Materials (ASTM) test
methods D412 and D624 as stated in the proposed rule, which specify
specimen size and test methodology, based on a relationship between a
ratio of thickness to area for a known coupon size and configuration.
The comment suggested that the ASTM test methods can be used if slabs
representing the device formulation are prepared for testing, according
to both ASTM D412 and D624.
FDA agrees with this comment. The use of downsized dies for testing
smaller samples obtained from finished sterilized devices may be
employed. Test slabs mimicking the formulation of the materials used in
the actual device and subjected to the same processing and
sterilization modes could also be used. This would also apply to the
samples used for testing of the integrity of adhered or fused joints.
Evaluation of biodegradation effects on physical properties of
elastomeric components could be accomplished by physical testing of
test slabs explanted from animals.
30. One manufacturer noted that, in its experience, there has never
been a case of a testicular implant failure from shell abrasion, and
questioned the need for abrasion testing. The comment noted that only
two explants had been received in the manufacturer's 9-year history
with the device.
FDA disagrees with this comment. The fact that the manufacturer has
received only two explanted devices in its 9-year history with the
device is not a sufficient reason for dismissing abrasion as a
potential failure mode for the device. In addition, other potential
adverse effects are associated with abrasion, such as release of
silica, inflammation, and granuloma formation.
G. Biocompatibility Testing
31. Two comments stated that mutagenicity and other toxicity
testing be required to use mixtures of total extractables rather than
individual components.
FDA agrees with this comment.
32. One comment noted that biodegradation testing may require
miniature implants in animals, and suggested that the biodegradation
studies should consist of microscopy studies, as well as chemical
characterization which would be indicative of any degradation process.
FDA agrees with this comment.
33. One comment stated that histopathology should not be required
for acute toxicity studies because the duration of the study is
insufficient for developing tissue responses.
FDA agrees with this comment.
34. One comment stated that the preclinical requirements exceed the
Tripartite Biocompatibility Guidance for Medical Devices (Ref. 3) and
even the science of biocompatibility testing.
FDA disagrees with this comment. The agency notes that the
biocompatibility requirements were based on the Tripartite
Biocompatibility Guidance for Medical Devices.
35. One comment suggested that testing of nonpolar solvent extracts
for a variety of biocompatibility tests is not [[Page 17213]] relevant
to the devices currently on the market.
FDA disagrees with this comment. The proposed rule suggests that,
at a minimum, ethanol, ethanol/saline (1:9), and dichloromethane should
be used. Solvents should be chosen that are expected to solubilize the
low molecular weight migrants in a reasonable period of time, thus
facilitating exhaustive extraction--not to mimic in vivo conditions.
Inasmuch as the chemical nature of all the migrants is not known, it is
advisable to use solvents with varying chemical characteristics.
36. One comment suggested that for extracts composed of substances
possessing innocuous structures and having low potential exposures,
either no testing or only minimal testing should be required.
FDA disagrees with this comment. There is currently limited
knowledge of what is and what is not ``innocuous'' based solely on
chemical structure. The potential exposure can only be based on the
maximum amount found in the final product by analytical tests. However,
since polysiloxanes contain many, perhaps more than 35, chemical
components as a byproduct of the synthesis, FDA agrees that it is
difficult to individually test all components found in the extract.
Therefore, FDA will accept testing of the mixtures of total
extractables rather than of individual components.
37. One comment stated that the pharmacokinetics testing outlined
requires methodology that does not currently exist for solid
elastomeric silicone.
FDA agrees in general with the comment regarding solid elastomeric
silicone products. However, if the solid elastomers contain leachable
components, FDA believes they should be subjected to pharmacokinetics
testing.
H. Clinical Investigations
38. Several comments suggested that many of the safety and
effectiveness questions raised in the proposed rule can be addressed by
evaluation of the available published clinical data, collection and
analysis of retrospective epidemiological data and, if necessary,
initiation of postmarketing followup studies.
FDA agrees that long-term retrospective epidemiological data, if
collected properly, can be very useful in identifying long-term issues
pertaining to safety and effectiveness. However, FDA believes it is
necessary to require randomized (if at all possible), prospective
studies to establish the short-term (in this case, up to 5 years or
until physical maturity of the subject) safety and effectiveness data
of the testicular implant. Only prospective data collected under a
well-designed protocol can adequately address issues of safety and
effectiveness relevant to the current population of implant users.
39. One comment stated that FDA focused almost exclusively on
``well-controlled studies'' while ignoring other valid scientific
evidence as defined in Sec. 860.7(c)(2).
FDA disagrees with this comment. Although Sec. 860.7(f) does allow
valid scientific evidence other than well-controlled investigations,
Sec. 860.7(e)(2) notes that ``The valid scientific evidence used to
determine the effectiveness of a device shall consist principally
[emphasis added] of well-controlled investigations.'' Therefore, well-
controlled investigations are not only appropriate, but required, with
other ``valid scientific evidence'' to be considered in a supporting
role. In fact, FDA encourages the submission of all well-documented,
valid retrospective data, which are presented in an organized manner.
40. One comment stated that FDA did not identify the duration of
the clinical trial needed to establish safety and effectiveness, and
suggested that while life-long data are ideally needed, some reduced
amount of data should be identified to allow continued distribution of
the testicular prosthesis.
FDA notes that the proposed rule suggested that 5-year clinical
data, or data collected until the physical maturity of the subject
(whichever occurs later) is needed, and that post-approval studies will
be needed to address the various long-term issues identified.
41. Two comments requested clarification of what would constitute
an adequate control, suggesting that the controls need to be tailored
to the specific questions being asked, and that multiple control groups
may therefore be necessary. One comment stated that meaningful control
data may be either unimportant or impossible to obtain. One comment
suggested that the patient should be his own control due to the
difficulty in identifying and recruiting an appropriate control group
for a male without one or both testicles.
FDA agrees that controls need to be tailored to the specific
questions under investigation, and that multiple control groups may
therefore be necessary. FDA strongly disagrees that ``meaningful
control data may be unimportant.'' However, if ``meaningful control
data may be * * * impossible to obtain'', the sponsor must rigorously
demonstrate this for the relevant hypothesis. FDA agrees that it may be
very difficult or impractical to recruit an appropriate control group.
If the sponsor can satisfactorily demonstrate this to be the case, the
subject may serve as his own control.
42. One comment noted that epidemiological clinical testing would
require many years of patient enrollment to address only hypothetical
concerns.
FDA agrees in part with this comment. FDA's ``Guidance to
Manufacturers on the Development of Required Post-approval
Epidemiologic Study Protocols for Testicular Implants'' permits
manufacturers to document whether conditions are too rare to detect in
a reasonable study. It also emphasizes that valid case-control studies
and retrospective cohort studies are welcome. The guidance is available
upon request from the Division of Small Manufacturers Assistance (HFZ-
220) (see address above in section II A of this document).
43. One comment suggested that two generation human testing would
be needed for teratology testing.
FDA believes that single generation animal studies, properly
gathered and analyzed historical clinical data, or other valid
scientific evidence would also be appropriate in determining the
teratogenic potential of the testicular prosthesis.
I. Need for Psychological Data
44. One comment stated that the psychological benefits of the
testicular prosthesis do not need to be evaluated using standardized
testing and quantification of benefits because: (1) Studies are
available in which patient satisfaction with testicular prostheses has
been assessed; (2) the notion that the absence of one or both testicles
produces adverse psychological effects on boys and adult males appears
to be universally accepted; (3) several anecdotal reports strongly
support the use of testicular prostheses for patients with congenital
or other absence of testes; and (4) manufacturers make no claims
regarding the psychological benefit of the device.
FDA disagrees with these comments. The studies cited were either so
small as to be considered anecdotal, did not describe the assessment
tools used, used no systematic assessment of the psychological impact
of the prostheses, or consisted of particular subpopulations whose
applicability to the general population would be questionable. These
shortcomings underscore the need for FDA's request for a systematic
assessment using reliable and valid measures of the
[[Page 17214]] psychosocial consequences of testicular implants.
Regardless of the actual claims made, it is clear that the testicular
prosthesis is implanted for its psychosocial benefit to the implant
recipient.
45. One comment stated that the intended use of the testicular
prosthesis is to construct or reconstruct the size and contour of the
male testicle, and that before and after size measurements would be
sufficient to demonstrate effectiveness beyond any reasonable doubt.
Furthermore, to expect manufacturers to conduct psychological testing
in the absence of an FDA-recognized validated test instrument is not
appropriate.
FDA disagrees with this comment. While before and after size
measurements would be sufficient to show the anatomical effect of the
implant, FDA believes that testicular prostheses are primarily used for
the psychological benefit. FDA agrees with an earlier comment which
stated that the psychological benefit should neither be underestimated
nor undervalued. Finally, FDA notes that section 515(b) of the act does
not require FDA to provide guidance for tests for PMA's prior to
issuing a call for PMA's. While FDA outlined the principles of the
psychological/psychosocial data needed in the proposed rule, in the
``Draft Guidance for Preparation of PMA Applications for Testicular
Prostheses,'' and at a public meeting of the Gastroenterology and
Urology Devices Advisory Panel in April 1993, these tests were
suggestive and not intended to bind a PMA applicant to any specific
study or set of studies.
46. One comment stated that requiring documentation of
psychological benefits through further well-controlled presurgical,
immediate postsurgical, and long-term psychological studies using
standardized, validated test instruments is inappropriate and would
appear to fall outside the intent of the act. Congress intended that
medical devices perform as intended, not that they necessarily produce
therapeutic effects.
FDA disagrees with this comment. Section 860.7(e)(1) states that
there is ``reasonable assurance that a device is effective when it can
be determined, based upon valid scientific evidence, that in a
significant portion of the target population, the use of the device * *
* will provide clinically significant results.'' FDA believes that it
is necessary that a PMA demonstrate that the device has a beneficial
therapeutic effect, rather than merely demonstrating that a device
functions in accordance with its design.
47. One comment stated that psychological testing of the juvenile
segment of the potential patient population is impractical and
inappropriate, and that FDA should provide specific guidelines on any
required psychological testing.
FDA agrees that it may not be feasible to effectively assess the
psychosocial impact of testicular prosthesis implantation on children
12 years of age and younger. However, FDA believes that children over
12 years of age should be tested, since sexuality and the physical
manifestations of sexuality are psychologically very important to
pubescent and adolescent children. Manufacturers are encouraged to
contact FDA regarding specific guidelines on this testing.
III. Findings With Respect to Risks and Benefits
A. Degree of Risk
1. Extrusion/erosion of the testicular prosthesis. Extrusion and
erosion of the testicular implant through the scrotal wall are among
the most common complications associated with the use of these devices.
Prosthesis extrusion is usually associated with concurrent wound
dehiscence in instances where the device was inserted through a scrotal
incision. Skin erosion has been reported following implantation of the
testicular prosthesis due to the presence of a Dacron suture tab,
insertion of an oversized device, or aggressive dissection of the
subdartos pocket, and could result in subsequent infection or device
extrusion. It has been suggested that the rate of extrusion due to
wound dehiscence is between 3 and 8 percent.
2. Displacement of the testicular prosthesis. Displacement, or
migration, is another commonly reported adverse event. The prosthesis
can migrate in front of or behind the contralateral testis or above the
scrotum. Displacement can be caused by either inadequate scrotal
distension prior to insertion or improper surgical placement/fixation.
3. Fibrous capsular contracture. Fibrous capsular contracture, the
formation of a constricting fibrous layer around the prosthesis, has
been associated with the presence of testicular implants. Capsular
contracture may result in excessive scrotal firmness, discomfort, pain,
disfigurement, and displacement of the implant.
Although the etiological factors of capsular contracture have not
been reported with testicular implants, several factors have been
suggested with the breast implant, including hematoma, infection, and
foreign body reaction. Despite these reports, no single factor has been
demonstrated to be the sole cause of contracture. The etiology of
contracture is not understood.
4. Infection. Infection, a risk of any surgical implant procedure,
is associated with the use of testicular implants. As in any
implantation procedure, compromised device sterility and surgical
techniques may be major contributing factors to this risk. Usually, the
occurrence of infection necessitates the removal of the prosthesis. It
has been suggested with the silicone gel-filled breast prosthesis that
infection may also contribute to the early development of capsular
contracture.
5. Human carcinogenicity. Carcinogenesis has been widely discussed
as a reputed risk secondary to implantation of any material. Evidence
from the literature indicates that, in animal studies, different forms
of silicone have been associated with various types of cancer. Cases of
several types of cancer in humans have been reported in association
with various forms of implanted silicone.
6. Human reproductive and teratogenic effects. The effect of
certain silicone compounds on the reproductive potential of the male is
largely unknown. It has been reported that at least one form of
organosiloxane, which is known to be present in some silicone gels,
mimics estrogens in the male rat leading to rapid testicular atrophy.
Teratogenesis includes the origin or mode of production of a
malformed fetus and the disturbed growth processes involved in the
production of a malformed fetus. Studies using silicone fluid in
animals have been minimal, and yield contradictory and inconclusive
results. Prolonged contact with either the solid silicone device, or
the silicone gel-filled membrane and its components, presents a
potential risk of teratogenicity in humans. Additionally, the
theoretical risk of abnormalities appearing later in life in normally
appearing offspring also warrants investigation.
The risk of adverse reproductive and teratogenic effects from
testicular implants exists only in the subset of patients who have a
single prosthesis with a unilateral, functional testicle.
7. Immune related connective tissue disorders--immunological
sensitization. Immunological sensitization may be a serious risk
associated with the implantation of a testicular prosthesis. Immune
related connective tissue disorders have been reported in women who
have silicone gel-filled prostheses or who have had silicone injections
in augmentation mammoplasty. There are clinical reports of several
patients who [[Page 17215]] have undergone augmentation mammoplasty
with silicone gel-filled breast prostheses and later presented with
connective tissue disease-like syndromes. Because testicular prostheses
consist of similar silicone elastomers and gels, further study of the
potential risk of immune related connective tissue disorders in humans
with these implants is warranted.
8. Biological effects of silica. Amorphous (fumed) silica is bound
to the silicone in the elastomer of the testicular prosthesis, and may
be fibrogenic and immunogenic. Fumed silica and the silicone shell each
elicit cellular responses in rats. The biological effects of silica,
particularly the immunologic component of these reactions, present a
potential risk and need to be examined.
The following potential risk pertains only to the gel-filled
silicone rubber testicular prosthesis:
9. Silicone gel leakage and migration. Silicone gel leakage and
migration from the silicone elastomer envelope, either from rupture of
the envelope or by leaking of the gel through the envelope (gel
``bleed''), are also significant risks of silicone gel-filled
testicular prostheses. Rupture of the envelope with gel leakage and
subsequent migration may be secondary to surgical technique or
mechanical stresses such as routine manual massage, trauma, and wear on
the envelope, and necessitates removal of the prosthesis. In addition
to the above, silicone gel-filled breast implants, which are similar to
testicular implants in materials and construction, are reported to
``bleed'' micro amounts of silicone through the intact silicone
elastomer shell into the surrounding tissues. Although diffusion of
silicone gel through the elastomer shell has not specifically been
measured in the testicular prosthesis, gel bleed continues to be a
theoretical risk with this device and needs to be evaluated. Migration
of the gel into the human body presents the potential for development
of adverse effects such as granulomas or lymphadenopathy. The ultimate
fate of migrating silicone gel within the body is currently not well
understood.
The following potential risk is associated only with those
testicular prostheses that are polyurethane foam covered:
10. Degradation of polyurethane foam. The polyurethane foam
material that has been used to cover some testicular prostheses is
known to degrade over time with a potential breakdown product of 2,4
diaminotoluene (TDA), a known carcinogen in animals. The fate of the
degraded product in vivo is unknown to date, and the use of this
material in testicular implants may have been discontinued. Case
reports of the polyurethane foam covered silicone gel-filled breast
implant indicate that there is greater difficulty with the removal of
this type of prosthesis due to a fragmented polyurethane shell and/or
capsular tissue ingrowth. Foreign body responses have been reported
concurrent with the use of the polyurethane foam covered testicular
prosthesis in humans.
B. Benefits of the Device
The testicular prosthesis is intended to simulate the presence of a
testicle within the male scrotum, and is indicated in subjects who are
missing one or both testes due to either congenital or acquired
reasons. Testicular prosthesis implantation is a discretionary surgical
procedure performed for psychological, rather than for other medical
reasons.
Testicular prostheses are commonly used to correct congenital
anomalies in young males who are born without one or both testicles
(i.e., testicular agenesis or atrophy). Additionally, such devices are
often implanted subsequent to removal of one or both testes for one of
several reasons: Malignant cancer of the prostate, testicular cancer,
testicular torsion, cryptorchidism, failed orchiopexy, epididymitis/
orchitis, or testicular trauma.
Men facing orchiectomy (removal of the testicles) may experience
depression that accompanies this degenerative change in body image.
Such feelings of depression have been equated to the experiences of
women who have undergone mastectomy or hysterectomy. Shame and feelings
of inferiority are common, and can lead to anxiety, personality
changes, changes in one's customary lifestyle, fear of sexual
rejection, and psychogenic impotence. It has also been reported that a
visible defect in a child's genital region may result in feelings of
inferiority, leading to social isolation. Such occurrences may produce
psychologic problems, and have an affect upon the child's emotional
development and sexual identity. Implantation of a testicular
prosthesis may help to alleviate such feelings in males of all ages,
thereby improving quality of life. The studies which have been
published indicate that recipients of testicular prostheses exhibit a
high degree of satisfaction with their surgery.
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 testicular prosthesis, by revising Sec. 876.3750(c).
Under the final rule, a PMA or a notice of completion of a PDP is
required to be filed with FDA within 90 days of the effective date of
this regulation for any testicular 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 the 90th day
past the effective date of this regulation. An approved PMA or declared
completed PDP is required to be in effect for any such device on or
before 180 days after FDA files the application. Any other testicular
prosthesis that was not in commercial distribution before May 28, 1976,
or that has not, on or before 90 days after the effective date of this
regulation, been found by FDA to be substantially equivalent to a
testicular prosthesis that was in commercial distribution before May
28, 1976, is required to have an approved PMA or declared completed PDP
in effect before it may be marketed.
If a PMA or notice of completion of a PDP for a testicular
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 (21 CFR part 812)
are met.
Under Sec. 812.2(d) (21 CFR 812.2(d)) of the IDE regulations, FDA
hereby stipulates that the exemptions from the IDE requirements in
Sec. 812.2(c)(1) and (c)(2) will no longer apply to clinical
investigations of the testicular prosthesis. Further, FDA concludes
that investigational testicular prostheses are significant risk devices
as defined in Sec. 812.3(m) and advises that, as of the effective date
of Sec. 876.3750(c), the requirements of the IDE regulations regarding
significant risk devices will apply to any clinical investigation of a
testicular prosthesis. For any testicular prosthesis that is not
subject to a timely filed PMA or notice of completion of a 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 for
investigational purposes must cease. FDA advises all persons presently
sponsoring a clinical investigation involving the testicular prosthesis
to submit an IDE application to FDA no later than 60 days after the
effective date [[Page 17216]] of this final rule to avoid the
interruption of ongoing investigations.
V. Environmental Impact
The agency has determined under 21 CFR 25.24(a)(8) and (e)(4) 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 (Pub. L. 96-354).
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. In addition, the final
rule is not a significant regulatory action as defined by the Executive
Order and so is not subject to review under the Executive Order.
The Regulatory Flexibility Act requires agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. Because the manufacturers of these devices have been
aware for a long time, more than 10 years, of the need to prepare PMA's
for these devices, the agency 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. References
The following references have been placed on display in the Dockets
Management Branch (HFA-305), Food and Drug Administration, rm. 1-23,
12420 Parklawn Dr., Rockville, MD 20857 and may be seen by interested
persons between 9 a.m and 4 p.m. Monday through Friday.
1. Naim, J., and R.J. Lanzafame, ``The Adjuvant Effect of
Silicone Gel on Antibody Formation in Rats,'' Immunological
Investigations, 22(2):151-161, 1993.
2. Bridges, A. J., C. Conley, G. Wang, D. E. Burns, and F. B.
Vasey, ``A Clinical and Immunologic Evaluation of Women With
Silicone Breast Implants and Symptoms of Rheumatic Disease,'' Annals
of Internal Medicine, 118(12):929-936, 1993.
3. Tripartite Biocompatibility Guidance for Medical Devices,
Office of Device Evaluation General Program Memorandum #87-1, April
24, 1987.
List of Subjects in 21 CFR Part 876
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
876 is amended as follows:
PART 876--GASTROENTEROLOGY-UROLOGY DEVICES
1. The authority citation for 21 CFR part 876 is revised to read as
follows:
Authority: Secs. 501, 510, 513, 515, 520, 522, 701 of the
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 351, 360, 360c,
360e, 360j, 3601, 371).
2. Section 876.3750 is amended by revising paragraph (c) to read as
follows:
Sec. 876.3750 Testicular prosthesis.
* * * * *
(c) Date premarket approval application (PMA) or notice of product
development protocol (PDP) is required. A PMA or notice of completion
of a PDP is required to be filed with the Food and Drug Administration
on or before July 5, 1995, for any testicular prosthesis that was in
commercial distribution before May 28, 1976, or that has on or before
July 5, 1995, been found to be substantially equivalent to a testicular
prosthesis that was in commercial distribution before May 28, 1976. Any
other testicular prosthesis shall have an approved PMA or a declared
completed PDP in effect before being placed in commercial distribution.
Dated: March 13, 1995.
D. B. Burlington,
Director, Center for Devices and Radiological Health.
[FR Doc. 95-8383 Filed 4-4-95; 8:45 am]
BILLING CODE 4160-01-F
