[Federal Register Volume 81, Number 32 (Thursday, February 18, 2016)]
[Rules and Regulations]
[Pages 8146-8149]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2016-03331]


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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 Total 
Metal-on-Metal Semi-Constrained Hip Joint Systems

AGENCY: Food and Drug Administration, HHS.

ACTION: Final order.

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SUMMARY: The Food and Drug Administration (FDA) is issuing a final 
order to require the filing of a premarket approval application (PMA) 
or a notice of completion of a product development protocol (PDP) for 
the 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.

DATES: This order is effective on February 18, 2016.

FOR FURTHER INFORMATION CONTACT: Sergio M. de del Castillo, Center for 
Devices and Radiological Health, 10903 New Hampshire Ave., Bldg. 66, 
Rm. 1538, Silver Spring, MD 20993, 301-796-6419.

SUPPLEMENTARY INFORMATION: 

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 (Pub. L. 101-629), the 
Food and Drug Administration Modernization Act of 1997 (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, established 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(d) 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.
    Although, under the FD&C Act, the manufacturer of a preamendments 
class III device may respond to the call for PMAs by filing a PMA or a 
notice of completion of a PDP. In practice, the option of filing a 
notice of completion of a PDP has rarely been used. For simplicity, 
although the PDP option remains available to manufacturers in response 
to a final order under section 515(b) of the FD&C Act, this document 
will refer only to the requirement for the filing of, and obtaining 
approval of, a PMA.
    On July 9, 2012, FDASIA was enacted. Section 608(a) of FDASIA 
amended section 513(e) of the FD&C Act, changing the process for 
reclassifying a device from rulemaking to an administrative order. 
Section 608(b) of FDASIA 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.
    FDA is requiring PMAs for total metal-on-metal (MoM) semi-
constrained hip joint systems (heretofore referenced as ``MoM hips''), 
which include the following two specific 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.
    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: (1) Publication of a proposed order 
in the Federal Register; (2) a meeting of a device classification panel 
described in section 513(b) of the FD&C Act; and (3) consideration of 
comments from all affected stakeholders, including patients, payors, 
and providers. FDA published a proposed order to require PMAs for MoM 
hips in the Federal Register of January 18, 2013 (78 FR 4094), and 
convened a meeting of a device classification panel for MoM hips as 
discussed in the proposed order and in this document.
    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.
    A preamendments class III device may be commercially distributed 
without a PMA until 90 days after FDA issues a final order (a final 
rule issued

[[Page 8147]]

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 MoM hips, the 
later of these two time periods is the 90-day period. Therefore, 
section 501(f)(2)(B) of the FD&C Act requires that a PMA for such 
devices be filed within 90 days of the date of issuance of this final 
order. If a PMA is not filed for such devices within 90 days after the 
issuance of this final order, the devices will 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 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 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 may be subject to injunction under section 302 of the FD&C Act 
(21 U.S.C. 332), and the individuals responsible for such shipment may 
be subject to prosecution under section 303 of the FD&C Act (21 U.S.C. 
333).
    FDA held a meeting of a device classification panel described in 
section 513(b) of the FD&C Act with respect to MoM hips on August 8, 
2001, and therefore, has met this requirement under section 515(b)(1) 
of the FD&C Act. The panel recommended that the devices remain in class 
III because there was insufficient information to establish special 
controls; the panel also agreed unanimously that MoM hips are for a use 
which is of substantial importance in preventing impairment of human 
health (Ref. 1). FDA is not aware of new information that would provide 
a basis for a different recommendation or findings, and the recent 
reports and evaluations discussed in the proposed order further support 
that reclassification of MoM hips is not appropriate. Furthermore, the 
problems identified in the medical device reporting systems and recalls 
for MoM hips further indicate the need to review these devices under a 
PMA to provide reasonable assurance of their safety and effectiveness.
    FDA received and has considered several sets of comments from nine 
commenters on the proposed order, as discussed in section II.

II. Public Comments in Response to the Proposed Order

    In response to the January 18, 2013 (78 FR 4094), proposed order to 
require premarket approval for MoM hips, FDA received several sets of 
comments from nine commenters. These comments, as well as the Agency's 
consideration of them, are summarized further in this section.
    Six commenters generally agreed with FDA's proposal to require PMAs 
for MoM hips. One commenter (the American Academy of Orthopaedic 
Surgeons, also referred to as AAOS) stated that the existing data is 
not adequate to support reclassification of MoM hips because special 
controls could not be established to provide a reasonable assurance of 
device safety and effectiveness. This comment echoes the findings and 
recommendations of the August 8, 2001, panel.
    Another commenter stated that MoM hip resurfacing devices should be 
classified as Class III; however, MoM hip resurfacing devices are not 
regulated under 21 CFR 888.3320 or 21 CFR 888.3330 and are not the 
subject of this order.
    Several commenters requested that all currently marketed MoM hips 
be removed from the market, either through a FDA-initiated recall or 
voluntary action by the device manufacturer.
    As explained in more detail in section III of this order, if a PMA 
for a currently marketed MoM hip is not filed on or before the 90th day 
past the effective date of this order, that device will be deemed 
adulterated under section 501(f)(1)(A) of the FD&C Act, and commercial 
distribution of the device must cease immediately. FDA intends to take 
appropriate action to ensure compliance with the 90-day deadline for 
the submission of PMAs. The Agency believes this information adequately 
addresses the commenters' concern.
    One commenter recommended standardizing the modularity and other 
design features of MoM hips to mitigate adverse events attributed to 
the manufacturing process for these devices. The Agency does not 
believe sufficient information exists to establish any manufacturing 
standards or specific technical specifications for MoM hips that could 
potentially be generalized for this technology to mitigate adverse 
events.
    One commenter requested that the Agency set revision surgery 
standards. Revision surgery involves a complex clinical decision that 
falls within the practice of medicine, which FDA generally does not 
regulate. In addition, insufficient information exists to establish any 
standards for revision surgery. FDA notes, however, that the American 
Association of Hip and Knee Surgeons, the American Academy of 
Orthopaedic Surgeons, and the Hip Society issued a consensus statement 
regarding assessment of risks in patients implanted with MoM hips, 
including factors to consider for revision surgery, based on currently 
available information (Ref. 2). FDA's Web site for MoM hips also 
provides some general considerations regarding revision surgery (Ref. 
3).
    One commenter requested that MoM hips not be used in women, 
including those of child-bearing age, and children who are still 
growing (i.e., skeletally immature). As noted in the proposed order and 
as presented during the June 27-28, 2012, panel meeting, labeling for 
MoM hips includes warnings or contraindications for skeletally immature 
patients and patients who are pregnant or who may become pregnant (Ref. 
4). In addition, the Agency will review all data included in the 
required PMA for a MoM hip to determine what information needs to be 
included in the device labeling to assure its safe and effective use, 
including any warnings and contraindications. The removal of any 
current contraindications for these patient populations would need to 
be supported by valid scientific evidence, in accordance with 21 CFR 
860.7.
    One commenter requested the adoption of standards for metal ion 
levels in the serum of patients implanted with a MoM hip. As discussed 
in detail during the June 28, 2012, panel meeting, there are challenges 
to implementing metal ion testing into clinical evaluations of patients 
treated with MoM hips, as well as challenges in the interpretation of 
metal ion testing results (Ref. 5). For example, the equipment and 
expertise required to conduct such testing are currently not widely 
available in health care facilities. In addition, there can be 
significant variability in test results, based on a number of factors, 
including

[[Page 8148]]

the laboratory conducting the testing (inter-laboratory variability) 
and the specific MoM hip implanted in the patient. Further, 
insufficient information exists to establish a definitive correlation 
between metal ion levels and clinical outcomes. Therefore, the Agency 
does not believe such standards can be adequately developed at this 
time. Nonetheless, the Agency acknowledges the importance of using 
metal ion levels within the overall clinical assessment of patients 
implanted with MoM hips. On May 6, 2011, under section 522 of the FD&C 
Act (21 U.S.C. 360l), FDA ordered manufacturers of MoM hips to conduct 
postmarket surveillance studies of these devices. As part of these 
studies, manufacturers are required to study the effects of metal ion 
concentrations in the bloodstream. The Agency will use the data from 
these studies to determine if any additional recommendations can be 
developed with respect to metal ion levels.
    One commenter stated that FDA should affirmatively assert that 
common law liability claims relating to MoM hips that are included 
under this final order, which were cleared through the 510(k) process 
before the effective date of this final order, should not be preempted 
under section 521 of the FD&C Act (21 U.S.C. 360k). Section 521 of the 
FD&C Act includes an express preemption provision that preempts certain 
state requirements that are ``different from, or in addition to'' 
certain Federal requirements applicable to devices. Two Supreme Court 
cases: Medtronic, Inc. v. Lohr, 518 U.S. 470 (1996) and Riegel v. 
Medtronic, Inc., 552 U.S. 312 (2008), address the scope of this 
provision. In Lohr, the Court held that design defect, manufacturing, 
and failure to warn claims relating to a 510(k)-cleared device were not 
preempted because there were no Federal ``requirements'' imposed by the 
510(k) review where (1) the device could ``take any particular form for 
any particular reason,'' and (2) the general Federal manufacturing and 
labeling requirements were not specific to the device in question. Id. 
at 493, 497-502. In contrast, the Court determined in Riegel that the 
PMA review imposed Federal ``requirements'' under section 521 of the 
FD&C Act because FDA required that the PMA-approved device be made with 
almost no deviations from the specifications in the approved PMA. 552 
U.S. at 323. The Riegel Court went on to hold that the Riegels' common 
law claims were preempted where New York law imposed requirements on 
the PMA-approved device that were ``different from, or in addition to'' 
the Federal requirements. Id. at 327-330. As seen in these cases, the 
preemption analysis under section 521 of the FD&C Act depends on 
whether ``requirements'' imposed by State law are different from or in 
addition to ``requirements'' imposed by Federal law. This determination 
involves resolution of a number of critical factual issues, including 
identifying the applicable State and Federal (if any) requirements that 
relate to the claims asserted, defining the scope of those 
requirements, and evaluating their relationship to one another. 
Although Lohr may be relevant to the situation described in the 
comment, FDA notes that the inquiry into preemption needs to consider 
the context and all relevant facts. The situation described in the 
comment is fairly generalized, and as such, FDA believes it would not 
be helpful to opine on this issue at this point in time.
    Finally, several comments recommended actions that address broader 
issues or programmatic areas, such as changes to the postmarket 
surveillance process for all class III medical devices, recommendations 
for research studies, and the establishment of a ``trust fund'' for 
healthcare reimbursement of failed MoM hips. These requests are outside 
the scope of the regulatory actions described in this order.

III. The Final Order

    Under section 515(b)(3) of the FD&C Act, FDA is adopting its 
findings as published in the proposed order (78 FR 4094), and is 
issuing this final order to require the filing of a PMA for MoM hips, 
which specifically includes the following two device types: 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. This final order will 
revise 21 CFR part 888.
    Under the final order, a PMA is required to be filed on or before 
May 18, 2016, for any of these preamendments class III devices that 
were 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 May 18, 2016. An applicant of a device subject to this order 
that was legally in commercial distribution before May 28, 1976, or 
that has been found to be substantially equivalent to a device that was 
legally in commercial distribution before May 28, 1976, may continue 
marketing such class III device during FDA's review of the PMA provided 
that the PMA is filed on or before May 18, 2016. However, if FDA denies 
approval of the PMA, then the device will be deemed adulterated under 
section 501(f)(1)(A) of the FD&C Act, and commercial distribution of 
the device must cease immediately. Any other device subject to this 
order is required to have an approved PMA in effect before it may be 
marketed. 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.''
    If a PMA for any of the preamendments class III devices subject to 
this order is not filed on or before May 18, 2016, that device will be 
deemed adulterated under section 501(f)(1)(A) of the FD&C Act, and 
commercial distribution of the device must cease immediately. FDA 
requests that manufacturers take action to prevent the further use of 
MoM hips for which no PMA has been filed.
    The device may, however, be distributed for investigational use, if 
the applicable requirements of the IDE regulations (part 812), 
including obtaining IDE approval, are met on or before 90 days after 
the effective date of this order. There will be no extended period for 
filing an IDE or exemption from the IDE requirements (see Sec.  
812.2(d)), and clinical studies may not be initiated without 
appropriate IDE approvals, as required.

IV. Analysis of 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.

V. Paperwork Reduction Act of 1995

    This final order refers to previously approved collections of 
information found in FDA regulations. These collections of information 
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 812 have been approved under 
OMB control number 0910-0078; the collections of information in 21 CFR 
part 807, subpart E, have been approved under OMB control number 0910-
0120;

[[Page 8149]]

the collections of information in 21 CFR part 814, subpart B, have been 
approved under OMB control number 0910-0231; and the collections of 
information under 21 CFR part 801 have been approved under OMB control 
number 0910-0485.

VI. Codification of Orders

    Prior to the amendments by FDASIA, section 515(b) of the FD&C Act 
provided for FDA to issue regulations to require approval of an 
application for premarket approval for preamendments devices or devices 
found substantially equivalent to preamendments devices. Section 515(b) 
of the FD&C Act, as amended by FDASIA, provides for FDA to require 
approval of an application for premarket approval for such devices by 
issuing a final order following the issuance of a proposed order in the 
Federal Register. FDA will continue to codify the requirement for an 
application for premarket approval in the Code of Federal Regulations 
(CFR). Therefore, under section 515(b)(1) of the FD&C Act, as amended 
by FDASIA, in this final order, FDA is requiring approval of an 
application for premarket approval for total MoM semi-constrained hip 
joint systems, which include the following two specific 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; 
and the Agency is making the language in 21 CFR 888.3320 and 888.3330 
consistent with this final order.

VII. References

    The following references are on display in the Division of Dockets 
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852, and are available for viewing by 
interested persons between 9 a.m. and 4 p.m., Monday through Friday; 
they are also available electronically at http://www.regulations.gov. 
FDA has verified the Web site addresses, as of the date this document 
publishes in the Federal Register, but Web sites are subject to change 
over time.

1. FDA, Orthopaedic and Rehabilitation Devices Panel transcript, 
August 8, 2001. Available at http://www.fda.gov/ohrms/dockets/ac/01/transcripts/3780t1.rtf.
2. Kwon et al. ``Risk Stratification Algorithm for Management of 
Patients with Metal-on-Metal Hip Arthroplasty.'' Journal of Bone and 
Joint Surgery, American Volume, 96:e4, 2014.
3. FDA, Metal-on-Metal Hip Implants Web site, Information for 
Orthopaedic Surgeons. Available at http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/ImplantsandProsthetics/MetalonMetalHipImplants/ucm241667.htm.
4. FDA, Orthopaedic and Rehabilitation Devices Panel, FDA Executive 
Summary, June 27-28, 2012. Available at http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/MedicalDevices/MedicalDevicesAdvisoryCommittee/OrthopaedicandRehabilitationDevicesPanel/UCM309302.pdf.
5. FDA, Orthopaedic and Rehabilitation Devices Panel transcript, 
June 28, 2012. Available at http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/MedicalDevices/MedicalDevicesAdvisoryCommittee/OrthopaedicandRehabilitationDevicesPanel/UCM313605.pdf.

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, 21 CFR part 
888 is 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 a 
notice of completion of a PDP is required to be filed with the Food and 
Drug Administration on or before May 18, 2016, 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 May 18, 2016, been found to be substantially equivalent to 
a 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 a 
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 a 
notice of completion of a PDP is required to be filed with the Food and 
Drug Administration on or before May 18, 2016, 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 May 18, 2016, been found to be substantially 
equivalent to a 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 a declared completed PDP in effect before being placed 
in commercial distribution.

    Dated: February 11, 2016.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2016-03331 Filed 2-17-16; 8:45 am]
 BILLING CODE 4164-01-P