Document ID: FDA-2011-N-0661-0001
Agency: fda
Document Type: Proposed Rule
Title: Effective Date of Requirement for Premarket Approval for Two Class III Preamendments Devices
Posted Date: 2013-01-18T05:00Z

[Federal Register Volume 78, Number 13 (Friday, January 18, 2013)]
[Proposed Rules]
[Pages 4094-4100]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2013-01006]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 888

[Docket No. FDA-2011-N-0661]

Effective Date of Requirement for Premarket Approval for Two 
Class III Preamendments Devices

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed order.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to require 
the filing of a premarket approval application (PMA) or a notice of 
completion of a product development protocol (PDP) for the following 
two class III preamendments devices: Hip joint metal/metal semi-
constrained, with a cemented acetabular component, prosthesis; and hip 
joint metal/metal semi-constrained, with an uncemented acetabular 
component, prosthesis. The Agency is also summarizing its proposed 
findings regarding the degree of risk of illness or injury designed to 
be eliminated or reduced by requiring the devices to meet the statute's 
approval requirements and the benefits to the public from the use of 
the devices. In addition, FDA is announcing the opportunity for 
interested persons to request that the Agency change the classification 
of any of the aforementioned devices based on new information. This 
action implements certain statutory requirements.

DATES: Submit either electronic or written comments on the proposed 
order by April 18, 2013. FDA intends that, if a final order based on 
this proposed order is issued, anyone who wishes to continue to market 
the device will need to file a PMA or a notice of completion of a PDP 
within 90 days of the publication of the final order. See section X of 
this document for the proposed effective date of a final order based on 
this proposed order.

ADDRESSES: You may submit comments, identified by Docket No. FDA-2011-
N-0661, by any of the following methods:

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the instructions for submitting comments.

Written Submissions

    Submit written submissions in the following ways:
     FAX: 301-827-6870.
     Mail/Hand delivery/Courier (for paper or CD-ROM 
submissions): Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
    Instructions: All submissions received must include the Agency name 
and Docket No. FDA-2011-N-0661 for this rulemaking. All comments 
received may be posted without change to http://www.regulations.gov, 
including any personal information provided. For additional information 
on submitting comments, see the ``Comments'' heading of the 
SUPPLEMENTARY INFORMATION section of this document.
    Docket: For access to the docket to read background documents or 
comments received, go to http://

[[Page 4095]]

www.regulations.gov and insert the docket number, found in brackets in 
the heading of this document, into the ``Search'' box and follow the 
prompts and/or go to the Division of Dockets Management, 5630 Fishers 
Lane, Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Michael Ryan, Food and Drug 
Administration, Center for Devices and Radiological Health, 10903 New 
Hampshire Ave., Bldg. 66, Rm. 1615, Silver Spring, MD 20993-0002, 301-
796-6283.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Background--Regulatory Authorities
II. Dates New Requirements Apply
III. Proposed Findings With Respect to Risks and Benefits
IV. Devices Subject to This Proposal
    A. Hip Joint Metal/Metal Semi-Constrained, With a Cemented 
Acetabular Component, Prosthesis (21 CFR 888.3320)
    1. Identification
    2. Summary of Data
    3. Risks to Health
    4. Benefits of the Device
    B. Hip Joint Metal/Metal Semi-Constrained, With an Uncemented 
Acetabular Component, Prosthesis (21 CFR 888.3330)
    1. Identification
    2. Summary of Data
    3. Risks to Health
    4. Benefits of the Device
V. PMA Requirements
VI. PDP Requirements
VII. Opportunity To Request a Change in Classification
VIII. Environmental Impact
IX. Paperwork Reduction Act of 1995
X. Proposed Effective Date
XI. Comments
XII. References

I. Background--Regulatory Authorities

    The Federal Food, Drug, and Cosmetic Act (the FD&C Act), as amended 
by the Medical Device Amendments of 1976 (the 1976 amendments) (Pub. L. 
94-295), the Safe Medical Devices Act of 1990 (the SMDA) (Pub. L. 101-
629), the Food and Drug Administration Modernization Act of 1997 
(FDAMA) (Pub. L. 105-115), the Medical Device User Fee and 
Modernization Act of 2002 (Pub. L. 107-250), the Medical Devices 
Technical Corrections Act (Pub. L. 108-214), the Food and Drug 
Administration Amendments Act of 2007 (Pub. L. 110-85), and the Food 
and Drug Administration Safety and Innovation Act (FDASIA) (Pub. L. 
112-144), among other amendments, establish a comprehensive system for 
the regulation of medical devices intended for human use. Section 513 
of the FD&C Act (21 U.S.C. 360c) established three categories (classes) 
of devices, reflecting the regulatory controls needed to provide 
reasonable assurance of their safety and effectiveness. The three 
categories of devices are class I (general controls), class II (special 
controls), and class III (premarket approval).
    Under section 513 of the FD&C Act, devices that were in commercial 
distribution before the enactment of the 1976 amendments, May 28, 1976 
(generally referred to as preamendments devices), are classified after 
FDA has: (1) Received a recommendation from a device classification 
panel (an FDA advisory committee); (2) published the panel's 
recommendation for comment, along with a proposed regulation 
classifying the device; and (3) published a final regulation 
classifying the device. FDA has classified most preamendments devices 
under these procedures.
    Devices that were not in commercial distribution prior to May 28, 
1976 (generally referred to as postamendments devices), are 
automatically classified by section 513(f) of the FD&C Act into class 
III without any FDA rulemaking process. Those devices remain in class 
III and require premarket approval unless, and until, the device is 
reclassified into class I or II or FDA issues an order finding the 
device to be substantially equivalent, in accordance with section 
513(i) of the FD&C Act, to a predicate device that does not require 
premarket approval. The Agency determines whether new devices are 
substantially equivalent to predicate devices by means of premarket 
notification procedures in section 510(k) of the FD&C Act (21 U.S.C. 
360(k)) and 21 CFR part 807.
    A preamendments device that has been classified into class III and 
devices found substantially equivalent by means of premarket 
notification (510(k)) procedures to such a preamendments device or to a 
device within that type (both the preamendments and substantially 
equivalent devices are referred to as preamendments class III devices) 
may be marketed without submission of a PMA until FDA issues a final 
order under section 515(b) of the FD&C Act (21 U.S.C. 360e(b)) 
requiring premarket approval. Section 515(b)(1) of the FD&C Act directs 
FDA to issue an order requiring premarket approval for a preamendments 
class III device.
    On July 9, 2012, FDASIA was enacted. Section 608(b) of FDASIA (126 
Stat. 1056) amended section 515(b) of the FD&C Act changing the process 
for requiring premarket approval for a preamendments class III device 
from rulemaking to an administrative order.
    Section 515(b)(1) of the FD&C Act sets forth the process for 
issuing a final order. Specifically, prior to the issuance of a final 
order requiring premarket approval for a preamendments class III 
device, the following must occur: Publication of a proposed order in 
the Federal Register; a meeting of a device classification panel 
described in section 513(b) of the FD&C Act; and consideration of 
comments from all affected stakeholders, including patients, payors, 
and providers. FDA has held a meeting of a device classification panel 
described in section 513(b) of the FD&C Act with respect to metal/metal 
hip systems, and therefore, has met this requirement under section 
515(b)(1) of the FD&C Act. As explained further in section IV of this 
document, a meeting of a device classification panel described in 
section 513(b) of the FD&C Act took place in 2001 to discuss whether 
metal/metal hip systems should be reclassified or remain in class III 
and the panel recommended that the devices remain in class III because 
there was insufficient information to establish special controls. FDA 
is not aware of new information that would provide a basis for a 
different recommendation or findings. Indeed, the additional 
information received since the 2001 panel meeting and discussed further 
in section IV of this document highlights the need to review these 
devices under a PMA and reinforces the recommendation and findings of 
the panel.
    Section 515(b)(2) of the FD&C Act provides that a proposed order to 
require premarket approval shall contain: (1) The proposed order, (2) 
proposed findings with respect to the degree of risk of illness or 
injury designed to be eliminated or reduced by requiring the device to 
have an approved PMA or a declared completed PDP and the benefit to the 
public from the use of the device, (3) an opportunity for the 
submission of comments on the proposed order and the proposed findings, 
and (4) an opportunity to request a change in the classification of the 
device based on new information relevant to the classification of the 
device.
    Section 515(b)(3) of the FD&C Act provides that FDA shall, after 
the close of the comment period on the proposed order, consideration of 
any comments received, and a meeting of a device classification panel 
described in section 513(b) of the FD&C Act, issue a final order to 
require premarket approval or publish a document terminating the 
proceeding together with the reasons for such termination. If FDA 
terminates the proceeding, FDA is required to initiate

[[Page 4096]]

reclassification of the device under section 513(e) of the FD&C Act, 
unless the reason for termination is that the device is a banned device 
under section 516 of the FD&C Act (21 U.S.C. 360f).
    A preamendments class III device may be commercially distributed 
without a PMA or a notice of completion of a PDP until 90 days after 
FDA issues a final order (a final rule issued under section 515(b) of 
the FD&C Act prior to the enactment of FDASIA is considered to be a 
final order for purposes of section 501(f) of the FD&C Act (21 U.S.C. 
351(f))) requiring premarket approval for the device, or 30 months 
after final classification of the device under section 513 of the FD&C 
Act, whichever is later. For metal/metal hip systems, the preamendments 
class III devices that are the subject of this proposal, the later of 
these two time periods is the 90-day period. Since these devices were 
classified in 1987, the 30-month period has expired (52 FR 33686 at 
33706, September 4, 1987). Therefore, if the proposal to require 
premarket approval for metal/metal hip systems is finalized, section 
501(f)(2)(B) of the FD&C Act requires that a PMA or a notice of 
completion of a PDP for such device be filed within 90 days of the date 
of issuance of the final order. If a PMA or notice of completion of a 
PDP is not filed for such device within 90 days after the issuance of a 
final order, the device would be deemed adulterated under section 
501(f) of the FD&C Act.
    Also, a preamendments device subject to the order process under 
section 515(b) of the FD&C Act is not required to have an approved 
investigational device exemption (IDE) (see part 812 (21 CFR part 812)) 
contemporaneous with its interstate distribution until the date 
identified by FDA in the final order requiring the filing of a PMA for 
the device. At that time, an IDE is required only if a PMA or notice of 
completion of a PDP has not been filed. If the manufacturer, importer, 
or other sponsor of the device submits an IDE application and FDA 
approves it, the device may be distributed for investigational use. If 
a PMA or notice of completion of a PDP is not filed by the later of the 
two dates, and the device is not distributed for investigational use 
under an IDE, the device is deemed to be adulterated within the meaning 
of section 501(f)(1)(A) of the FD&C Act, and subject to seizure and 
condemnation under section 304 of the FD&C Act (21 U.S.C. 334) if its 
distribution continues. Other enforcement actions include, but are not 
limited to, the following: Shipment of devices in interstate commerce 
will be subject to injunction under section 302 of the FD&C Act (21 
U.S.C. 332), and the individuals responsible for such shipment will be 
subject to prosecution under section 303 of the FD&C Act (21 U.S.C. 
333). In the past, FDA has requested that manufacturers take action to 
prevent the further use of devices for which no PMA or notice of 
completion of a PDP has been filed and may determine that such a 
request is appropriate for the class III devices that are the subject 
of this proposed order, if finalized.
    In accordance with section 515(b) of the FD&C Act, interested 
persons are being offered the opportunity to request reclassification 
of two types of metal/metal hip systems, the preamendments class III 
devices that are the subject of this proposal.

II. Dates New Requirements Apply

    In accordance with section 515(b) of the FD&C Act, FDA is proposing 
to require that a PMA or a notice of completion of a PDP be filed with 
the Agency for two preamendments class III devices, hip joint metal/
metal semi-constrained, with a cemented acetabular component, 
prosthesis, and hip joint metal/metal semi-constrained, with an 
uncemented acetabular component, prosthesis, within 90 days after 
issuance of any final order based on this proposal. An applicant whose 
device was legally in commercial distribution before May 28, 1976, or 
whose device has been found to be substantially equivalent to such a 
device, will be permitted to continue marketing such class III device 
during FDA's review of the PMA or notice of completion of the PDP 
provided that the PMA or notice of completion of the PDP is timely 
filed. FDA intends to review any PMA for the device within 180 days, 
and any notice of completion of a PDP for the device within 90 days of 
the date of filing. FDA cautions that under section 515(d)(1)(B)(i) of 
the FD&C Act, the Agency may not enter into an agreement to extend the 
review period for a PMA beyond 180 days unless the Agency finds that 
``the continued availability of the device is necessary for the public 
health.''
    FDA intends that under Sec.  812.2(d), the publication in the 
Federal Register of any final order based on this proposal will include 
a statement that, as of the date on which a PMA or a notice of 
completion of a PDP is required to be filed, the exemptions from the 
requirements of the IDE regulations for preamendments class III devices 
in Sec.  812.2(c)(1) and (c)(2) will cease to apply to any device that 
is: (1) Not legally on the market on or before that date, or (2) 
legally on the market on or before that date but for which a PMA or 
notice of completion of a PDP is not filed by that date, or for which 
PMA approval has been denied or withdrawn.
    If a PMA or notice of completion of a PDP for a class III device is 
not filed with FDA within 90 days after the date of issuance of any 
final order requiring premarket approval for the device, the device 
would be deemed adulterated under section 501(f) of the FD&C Act. The 
device may be distributed for investigational use only if the 
requirements of the IDE regulations are met. The requirements for 
significant risk devices include submitting an IDE application to FDA 
for review and approval. An approved IDE is required to be in effect 
before an investigation of the device may be initiated or continued 
under Sec.  812.30. FDA, therefore, recommends that IDE applications be 
submitted to FDA at least 30 days before the end of the 90-day period 
after the issuance of the final order to avoid interrupting any ongoing 
investigations.

III. Proposed Findings With Respect to Risks and Benefits

    As required by section 515(b) of the FD&C Act, FDA is publishing 
its proposed findings regarding: (1) The degree of risk of illness or 
injury designed to be eliminated or reduced by requiring that these 
devices have an approved PMA or a declared completed PDP, and (2) the 
benefits to the public from the use of the devices.
    These findings are based on the reports and recommendations of the 
advisory committee (panel) for the classification of these devices 
along with information submitted in response to the 515(i) Order (74 FR 
16214, April 9, 2009), and any additional information that FDA has 
obtained. Additional information regarding the risks as well as 
classification associated with these device types can be found in the 
following proposed and final rules and notices published in the Federal 
Register: 47 FR 29052 (July 2, 1982), 52 FR 33686 (September 4, 1987), 
54 FR 550 (January 6, 1989), 59 FR 23731 (May 6, 1994), and 67 FR 57024 
(September 6, 2002).

IV. Devices Subject to This Proposal

A. Hip Joint Metal/Metal Semi-Constrained, With a Cemented Acetabular 
Component, Prosthesis (21 CFR 888.3320)

1. Identification
    A hip joint metal/metal semi-constrained, with a cemented 
acetabular component, prosthesis is a two-part device intended to be 
implanted to replace a hip joint. The device limits

[[Page 4097]]

translation and rotation in one or more planes via the geometry of its 
articulating surfaces. It has no linkage across-the-joint. This generic 
type of device includes prostheses that consist of a femoral and an 
acetabular component, both made of alloys, such as cobalt-chromium-
molybdenum. This generic type of device is limited to those prostheses 
intended for use with bone cement (21 CFR 888.3027).
2. Summary of Data
    The 1982 Orthopedic Device Classification Panel (the 1982 Panel) 
recommended that while general controls alone were not sufficient, 
sufficient information existed to establish a performance standard to 
provide a reasonable assurance of safety and effectiveness for metal/
metal hip systems. FDA disagreed with the 1982 Panel's recommendation 
and classified the devices as class III stating insufficient 
information existed to support the conclusion that performance 
standards or general controls will provide reasonable assurance of the 
safety and effectiveness of these devices.
    On August 8, 2001, the Orthopaedic and Rehabilitation Devices Panel 
(the Panel) recommended five to two that the hip joint metal/metal 
semi-constrained prostheses (cemented and uncemented) not be 
reclassified from class III to class II. The Panel concluded the 
following:
     There was insufficient clinical and preclinical testing 
information to establish special controls.
     The length and rate of long-term patient followup data 
were inadequate to demonstrate that special controls would provide 
reasonable assurance of the safety and effectiveness of these devices.
     In terms of preclinical testing, the Panel also concluded 
that validation of wear simulation, non-ideal preclinical wear testing, 
and biological evaluation of metallic wear debris generated by the 
device were not established. The particle size of the metallic wear 
debris generated by these devices is substantially smaller than the 
particle size of the metallic wear debris generated by other hip joint 
prostheses and the short-and long-term biological effects from human 
retrievals or preclinical evaluation of these smaller size metallic 
wear particles are unknown.
    FDA agreed with the Panel and believes the Panel's concerns are 
still relevant today. Current wear testing methods for metal/metal 
bearings are limited, and importantly can underestimate bearing wear by 
an order of magnitude compared to clinical outcomes. There are also no 
standardized wear methods or consensus among researchers for 
investigating joint micro-separation, dislocation, cup deformation, 
demanding gait activities and third-body abrasion. In addition, there 
is a lack of wear measurements from retrieved metal/metal bearings, so 
it is a challenge to correlate wear rates from modern devices to 
adverse events demonstrated clinically like pseudotumors. To complicate 
matters further, metal/metal bearings have shown unpredictable wear 
trends in simulator testing, which have not been explained. Therefore, 
it is a challenge to introduce sufficient special controls to mitigate 
the risks of modern metal/metal hip devices. The summary of information 
provided in response to FDA's order issued under sections 515(i) and 
519 of the FD&C Act (21 U.S.C. 360e(i) and 360i) (refer to docket FDA-
2009-M-0101) is not adequate to identify special controls sufficient to 
ensure safety and effectiveness and therefore not adequate to support 
reclassification of metal/metal hip systems.
    Recent reports and evaluations further support that 
reclassification of metal/metal hip systems is not appropriate. The 
United Kingdom's (UK) Medicines and Healthcare Products Regulatory 
Agency (MHRA) published several alerts in 2010 outlining concerns 
associated with metal/metal hip systems, including soft tissue 
reactions (Ref. 1). The final report, published in October 2010, 
outlines that acetabular cup angle, femoral head size, and metal ion 
levels are all risk factors that will affect the outcome of metal/metal 
hip systems. Moreover, a recent publication in the Journal of Bone and 
Joint Surgery outlines case reports of arthroprosthetic cobaltism in 
metal/metal hip patients (Ref. 2).
    The Australian Orthopaedic Association National Joint Replacement 
Registry's Hip and Knee Arthroplasty Annual Report of 2010 states that 
the ``metal/metal bearing surface has the highest risk of revision 
compared to all other bearing surfaces.'' The report found the 
cumulative percent revision rate at 7 years is 6.3 percent for metal/
metal, compared to 4.0 percent for ceramic/ceramic, 3.7 percent for 
ceramic/polyethylene and 4.2 percent for metal/polyethylene (Ref. 3).
    In December 2011, the American Academy of Orthopedic Surgeons 
(AAOS) published ``Modern Metal-on-Metal Hip Implants: A Technology 
Overview'' (Ref. 4). The AAOS overview provides a summary of clinical 
outcomes in patients with metal/metal hip systems in comparison to 
other bearing surface combinations, addresses patient, implant, and 
surgical factors that may predict successful and unsuccessful outcomes 
of metal/metal hip systems and discusses the prevalence of adverse 
clinical problems from metal/metal hip systems in comparison to other 
bearing surface combinations. The report concludes that ``analyses 
conducted on objective patient-oriented outcomes by two joint 
registries indicate that, overall, patients who receive metal-on-metal 
total hip arthroplasty and hip resurfacing are at greater risk for 
revision than patients who receive total hip arthroplasty using a 
different bearing surface combination.'' The report references the 
aforementioned Australian registry.
    A recent article published in a scientific journal raised serious 
concerns about the failure rates of metal/metal hip systems for the UK 
population (Ref. 5). This peer-reviewed journal article presented the 
following findings regarding primary metal/metal total hip 
replacements: (1) Increased failure rate at 5 years for metal/metal 
total hip replacements related to larger head sizes; (2) significantly 
higher risk for revision in female patients (Note: In the United 
States, labeling includes warnings to discourage the use of metal/metal 
total hip replacements in females of child bearing age); and (3) 
revisions for dislocation in men with metal/metal hip replacements were 
slightly lower, showing some benefit to larger head sizes.
    These reports, as well as recent recalls of devices from the U.S. 
market, have indicated that preclinical testing currently used to 
support marketing clearance of these devices has not been sufficient to 
mitigate the risks associated with these devices and identify potential 
clinically-relevant failure modes. These reports suggest that 
additional study is necessary before special controls can be identified 
and these devices can be reclassified.
3. Risks to Health
    a. Loss or reduction of joint function. Improper design or 
inadequate mechanical properties of the device, such as its lack of 
strength and resistance to wear, may result in the loss or reduction of 
joint function due to excessive wear, fracture, deformation of the 
device components, or loosening of the device in the surgical cavity.
    b. Adverse tissue reaction. Inadequate biological or mechanical 
properties of the device or its breakdown products, such as its lack of 
biocompatibility, may result in an adverse tissue reaction due to 
dissolution or wearing away of the

[[Page 4098]]

articulating surfaces of the device and the release of materials from 
the device to the surrounding tissues and the systemic circulation.
    c. Increased risk of premature device failure. Elevated adverse 
event rates for these devices may lead to an increased risk of 
premature revision.
    d. Infection. The presence of the prosthesis within the body may 
lead to an increased risk of infection.
    The distinctive risks associated with metal/metal total hip 
replacements in comparison to other types of bearing surfaces are the 
wear particles generated and release of metal ions. These wear 
particles and metal ions may cause adverse tissue reactions in addition 
to the standard osteolysis seen with different bearings for total hip 
replacements and may lead to an increased risk of premature device 
revision. These adverse tissue reactions include metallosis, 
hypersensitivity/allergy, tumor (pseudo) or aseptic lymphocyte 
dominated vasculitis associated lesion (ALVAL).
4. Benefits of the Device
    The hip joint metal/metal semi-constrained, with a cemented 
acetabular component, prosthesis is intended to be implanted to replace 
a hip joint. Like other artificial hip devices on the market, the 
potential benefits intended from implantation of the device are relief 
of disabling pain and restoration of joint function, which may result 
in a return to daily activities and an improved quality of life. Metal/
metal hip prostheses offer the potential to be especially beneficial in 
young, active patients.

B. Hip Joint Metal/Metal Semi-Constrained, With an Uncemented 
Acetabular Component, Prosthesis (21 CFR 888.3330)

1. Identification
    A hip joint metal/metal semi-constrained, with an uncemented 
acetabular component, prosthesis is a two-part device intended to be 
implanted to replace a hip joint. The device limits translation and 
rotation in one or more planes via the geometry of its articulating 
surfaces. It has no linkage across-the-joint. This generic type of 
device includes prostheses that consist of a femoral and an acetabular 
component, both made of alloys, such as cobalt-chromium-molybdenum. The 
femoral component is intended to be fixed with bone cement. The 
acetabular component is intended for use without bone cement (21 CFR 
888.3027).
2. Summary of Data
    The 1982 Panel recommended that while general controls alone were 
not sufficient, sufficient information existed to establish a 
performance standard to provide a reasonable assurance of safety and 
effectiveness for metal/metal hip systems. FDA disagreed with the 1982 
Panel's recommendation and classified the devices as class III stating 
that insufficient information existed to support the conclusion that 
performance standards or general controls will provide reasonable 
assurance of the safety and effectiveness of these devices.
    On August 8, 2001, the Panel recommended five to two that the hip 
joint metal/metal semi-constrained prostheses (cemented and uncemented) 
not be reclassified from class III to class II. The Panel concluded the 
following:
     There was insufficient clinical and preclinical testing 
information to establish special controls.
     The length and rate of long-term patient followup data 
were inadequate to demonstrate that special controls would provide 
reasonable assurance of the safety and effectiveness of these devices.
     In terms of preclinical testing, the Panel also concluded 
that validation of wear simulation, non-ideal preclinical wear testing, 
and biological evaluation of metallic wear debris generated by the 
device were not established. The particle size of the metallic wear 
debris generated by these devices is substantially smaller than the 
particle size of the metallic wear debris generated by other hip joint 
prostheses and the short-and long-term biological effects from human 
retrievals or preclinical evaluation of these smaller size metallic 
wear particles are unknown.
    FDA agreed with the Panel and believes the Panel's concerns are 
still relevant today. Current wear testing methods for metal/metal 
bearings are limited, and importantly can underestimate bearing wear by 
an order of magnitude compared to clinical outcomes. There are also no 
standardized wear methods or consensus among researchers for 
investigating joint micro-separation, dislocation, cup deformation, 
demanding gait activities, and third-body abrasion. In addition, there 
is a lack of wear measurements from retrieved metal/metal bearings, so 
it is a challenge to correlate wear rates from modern devices to 
adverse events demonstrated clinically like pseudotumors. To complicate 
matters further, metal/metal bearings have shown unpredictable wear 
trends in simulator testing, which have not been explained. Therefore, 
it is a challenge to introduce sufficient special controls to mitigate 
the risks of modern metal/metal hip devices. The summary of information 
provided in response to FDA's order issued under sections 515(i) and 
519 of the FD&C Act (refer to docket FDA-2009-M-0101) is not adequate 
to identify special controls sufficient to ensure safety and 
effectiveness and therefore not adequate to support reclassification of 
metal/metal hip systems.
    Recent reports and evaluations further support that 
reclassification of metal/metal hip systems is not appropriate. The 
MHRA published several alerts in 2010 outlining concerns associated 
with metal/metal hip systems, including soft tissue reactions. The 
final report, published in October 2010, outlines that acetabular cup 
angle, femoral head size, and metal ion levels are all risk factors 
that will affect the outcome of metal/metal hip systems (Ref. 1). 
Moreover, a recent publication in the Journal of Bone and Joint Surgery 
outlines case reports of arthroprosthetic cobaltism in metal/metal hip 
patients (Ref. 2).
    The Australian Orthopaedic Association National Joint Replacement 
Registry's Hip and Knee Arthroplasty Annual Report of 2010 states that 
the ``metal/metal bearing surface has the highest risk of revision 
compared to all other bearing surfaces.'' The report found the 
cumulative percent revision rate at 7 years is 6.3 percent for metal/
metal, compared to 4.0 percent for ceramic/ceramic, 3.7 percent for 
ceramic/polyethylene and 4.2 percent for metal/polyethylene (Ref. 3).
    In December 2011, AAOS published ``Modern Metal-on-Metal Hip 
Implants: A Technology Overview'' (Ref. 4). The AAOS overview provides 
a summary of clinical outcomes in patients with metal/metal hip systems 
in comparison to other bearing surface combinations, addresses patient, 
implant and surgical factors that may predict successful and 
unsuccessful outcomes of metal/metal hip systems and discusses the 
prevalence of adverse clinical problems from metal/metal hip systems in 
comparison to other bearing surface combinations. The report concludes 
that ``analyses conducted on objective patient-oriented outcomes by two 
joint registries indicate that, overall, patients who receive metal-on-
metal total hip arthroplasty and hip resurfacing are at greater risk 
for revision than patients who receive total hip arthroplasty using a 
different bearing surface combination.'' The report references the 
aforementioned Australian registry.

[[Page 4099]]

    A recent article published in a scientific journal raised serious 
concerns about the failure rates of metal/metal hip systems for the UK 
population (Ref. 5). This peer-reviewed journal article presented the 
following findings regarding primary metal/metal total hip 
replacements: (1) Increased failure rate at 5 years for metal/metal 
total hip replacements related to larger head sizes; (2) significantly 
higher risk for revision in female patients (Note: In the United 
States, labeling includes warnings to discourage the use of metal/metal 
total hip replacements in females of child bearing age); and (3) 
revisions for dislocation in men with metal/metal hip replacements were 
slightly lower, showing some benefit to larger head sizes.
    These reports, as well as recent recalls of devices from the U.S. 
market, have indicated that preclinical testing currently used to 
support marketing clearance of these devices has not been sufficient to 
mitigate the risks associated with these devices and identify potential 
clinically-relevant failure modes. These reports suggest that 
additional study is necessary before special controls can be identified 
and these devices can be reclassified.
3. Risks to Health
    a. Loss or reduction of joint function. Improper design or 
inadequate mechanical properties of the device, such as its lack of 
strength and resistance to wear, may result in the loss or reduction of 
joint function due to excessive wear, fracture, deformation of the 
device components, or loosening of the device in the surgical cavity.
    b. Adverse tissue reaction. Inadequate biological or mechanical 
properties of the device or its breakdown products, such as its lack of 
biocompatibility or resistance to wear, may result in an adverse tissue 
reaction due to dissolution or wearing away of the articulating 
surfaces of the device and the release of materials from the device to 
the surrounding tissues and the systemic circulation.
    c. Increased risk of premature device failure. Elevated adverse 
event rates for these devices may lead to an increased risk of 
premature revision.
    d. Infection. The presence of the prosthesis within the body may 
lead to an increased risk of infection.
    The distinctive risks associated with metal/metal total hip 
replacements in comparison to other types of bearing surfaces are the 
wear particles generated and release of metal ions. These wear 
particles and metal ions may cause adverse tissue reactions in addition 
to the standard osteolysis seen with different bearings for total hip 
replacements and may lead to an increased risk of premature device 
revision. These adverse tissue reactions include metallosis, 
hypersensitivity/allergy, tumor (pseudo) or ALVAL.
4. Benefits of the Device
    The hip joint metal/metal semi-constrained, with an uncemented 
acetabular component, prosthesis is intended to be implanted to replace 
a hip joint. Like other artificial hip devices on the market, the 
potential benefits intended from implantation of the device are relief 
of disabling pain and restoration of joint function, which may result 
in a return to daily activities and an improved quality of life. Metal/
metal hip prostheses offer the potential to be especially beneficial in 
young, active patients.

V. PMA Requirements

    A PMA for these devices must include the information required by 
section 515(c)(1) of the FD&C Act. Such a PMA should also include a 
detailed discussion of the risks identified previously, as well as a 
discussion of the effectiveness of the device for which premarket 
approval is sought. In addition, a PMA must include all data and 
information on: (1) Any risks known, or that should be reasonably 
known, to the applicant that have not been identified in this document; 
(2) the effectiveness of the device that is the subject of the 
application; and (3) full reports of all preclinical and clinical 
information from investigations on the safety and effectiveness of the 
device for which premarket approval is sought.
    A PMA must include valid scientific evidence to demonstrate 
reasonable assurance of the safety and effectiveness of the device for 
its intended use (see Sec.  860.7(c)(1) (21 CFR 860.7(c)(1))). Valid 
scientific evidence is ``evidence from well-controlled investigations, 
partially controlled studies, studies and objective trials without 
matched controls, well-documented case histories conducted by qualified 
experts, and reports of significant human experience with a marketed 
device, from which it can fairly and responsibly be concluded by 
qualified experts that there is reasonable assurance of the safety and 
effectiveness of a device under its conditions of use * * *. Isolated 
case reports, random experience, reports lacking sufficient details to 
permit scientific evaluation, and unsubstantiated opinions are not 
regarded as valid scientific evidence to show safety or 
effectiveness.'' (see Sec.  860.7(c)(2)).

VI. PDP Requirements

    A PDP for any of these devices may be submitted in lieu of a PMA, 
and must follow the procedures outlined in section 515(f) of the FD&C 
Act. A PDP must provide, among other things: (1) A description of the 
device, (2) preclinical trial information (if any), (3) clinical trial 
information (if any), (4) a description of the manufacturing and 
processing of the device, (5) the labeling of the device, and (6) all 
other relevant information about the device. In addition, the PDP must 
include progress reports and records of the trials conducted under the 
protocol on the safety and effectiveness of the device for which the 
completed PDP is sought.

VII. Opportunity To Request a Change in Classification

    Before requiring the filing of a PMA or notice of completion of a 
PDP for a device, FDA is required by section 515(b)(2)(D) of the FD&C 
Act to provide an opportunity for interested persons to request a 
change in the classification of the device based on new information 
relevant to the classification. Any proceeding to reclassify the device 
will be under the authority of section 513(e) of the FD&C Act.
    A request for a change in the classification of these devices is to 
be in the form of a reclassification petition containing the 
information required by 21 CFR 860.123, including new information 
relevant to the classification of the device.

VIII. Environmental Impact

    The Agency has determined under 21 CFR 25.34(b) 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.

IX. Paperwork Reduction Act of 1995

    This proposed order refers to collections of information that are 
subject to review by the Office of Management and Budget (OMB) under 
the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520).
    The collections of information in 21 CFR part 814 have been 
approved under OMB control number 0910-0231. The collections of 
information in 21 CFR part 807, subpart E, have been approved under OMB 
control number 0910-0120. The effect of this order, if finalized, is to 
shift certain devices from the 510(k) premarket notification process to 
the PMA process. To account for this change, FDA intends to transfer 
some of the burden from OMB control number

[[Page 4100]]

0910-0120, which is the control number for the 510(k) premarket 
notification process, to OMB control number 0910-0231, which is the 
control number for the PMA process. FDA estimates that it will receive 
seven new PMAs as a result of this order, if finalized. Based on FDA's 
most recent estimates, this will result in a 2,421 hour burden 
increase. FDA also estimates that there will be seven fewer 510(k) 
submissions as a result of this order, if finalized. Based on FDA's 
most recent estimates, this will result in a 318 hour burden decrease. 
Therefore, on net, FDA expects a burden hour increase of 2,103 due to 
this proposed regulatory change.
    The collections of information in 21 CFR part 812 have been 
approved under OMB control number 0910-0078.

X. Proposed Effective Date

    FDA is proposing that any final order based on this proposed order 
become effective 90 days after date of publication of the final order 
in the Federal Register.

XI. Comments

    Interested persons may submit either written comments regarding 
this document to the Division of Dockets Management (see ADDRESSES) or 
electronic comments to http://www.regulations.gov. It is only necessary 
to send one set of comments. Identify comments with the docket number 
found in brackets in the heading of this document. Received comments 
may be seen in the Division of Dockets Management between 9 a.m. and 4 
p.m., Monday through Friday, and will be posted to the docket at http://www.regulations.gov.

XII. References

    The following references have been placed on display in the 
Division of Dockets Management (see ADDRESSES), and may be seen by 
interested persons between 9 a.m. and 4 p.m., Monday through Friday.

1. Medicines and Healthcare Products Regulatory Agency (MHRA), 
``Report of the Expert Advisory Group Looking at Soft Tissue 
Reactions Associated With Metal-on-Metal Hip Replacements,'' 
October, 2010.
2. Tower, S. S., ``Arthroprosthetic Cobaltism: Neurological and 
Cardiac Manifestations in Two Patients with Metal-on-Metal 
Arthroplasty: A Case Report,'' Journal of Bone and Joint Surgery, 
92, 2847-2851, 2010.
3. Australian Orthopaedic Association National Joint Replacement 
Registry, Hip and Knee Arthroplasty Annual Report 2010. Adelaide: 
Australian Orthopaedic Association, 2010.
4. American Academy of Orthopedic Surgeons (AAOS), ``Modern Metal-
on-Metal Hip Implants: A Technology Overview,'' December 2011.
5. A.J. Smith, et al., ``Failure Rates of Stemmed Metal-on-Metal Hip 
Replacements: Analysis of Data From the National Joint Registry of 
England and Wales,'' Lancet, 2012:S0140-6736(12)60353-5, March 13, 
2012.

List of Subjects in 21 CFR Part 888

    Medical devices.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, it is 
proposed that 21 CFR part 888 be amended as follows:

PART 888--ORTHOPEDIC DEVICES

0
1. The authority citation for 21 CFR part 888 continues to read as 
follows:

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

0
2. Section 888.3320 is amended by revising paragraph (c) to read as 
follows:

Sec.  888.3320  Hip joint metal/metal semi-constrained, with a cemented 
acetabular component, prosthesis.

* * * * *
    (c) Date PMA or notice of completion of 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 [A DATE WILL BE ADDED 90 DAYS AFTER 
DATE OF PUBLICATION OF A FUTURE FINAL ORDER IN THE Federal Register], 
for any hip joint metal/metal semi-constrained prosthesis with a 
cemented acetabular component that was in commercial distribution 
before May 28, 1976, or that has, on or before [A DATE WILL BE ADDED 90 
DAYS AFTER DATE OF PUBLICATION OF A FUTURE FINAL ORDER IN THE Federal 
Register], been found to be substantially equivalent to any hip joint 
metal/metal semi-constrained prosthesis with a cemented acetabular 
component that was in commercial distribution before May 28, 1976. Any 
other hip joint metal/metal semi-constrained prosthesis with a cemented 
acetabular component shall have an approved PMA or declared completed 
PDP in effect before being placed in commercial distribution.
0
3. Section 888.3330 is amended by revising paragraph (c) to read as 
follows:

Sec.  888.3330  Hip joint metal/metal semi-constrained, with an 
uncemented acetabular component, prosthesis.

* * * * *
    (c) Date PMA or notice of completion of 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 [A DATE WILL BE ADDED 90 DAYS AFTER 
DATE OF PUBLICATION OF A FUTURE FINAL ORDER IN THE Federal Register], 
for any hip joint metal/metal semi-constrained prosthesis with an 
uncemented acetabular component that was in commercial distribution 
before May 28, 1976, or that has, on or before [A DATE WILL BE ADDED 90 
DAYS AFTER DATE OF PUBLICATION OF A FUTURE FINAL ORDER IN THE Federal 
Register], been found to be substantially equivalent to any hip joint 
metal/metal semi-constrained prosthesis with an uncemented acetabular 
component that was in commercial distribution before May 28, 1976. Any 
other hip joint metal/metal semi-constrained prosthesis with an 
uncemented acetabular component shall have an approved PMA or declared 
completed PDP in effect before being placed in commercial distribution.

    Dated: January 14, 2013.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2013-01006 Filed 1-17-13; 8:45 am]
BILLING CODE 4160-01-P