Medical Devices
FDA's Approval of Four Temporomandibular Joint Implants Gao ID: GAO-07-996 September 17, 2007It is estimated that over 10 million people in the United States suffer from jaw joint and muscle disorders. Artificial temporomandibular joint (TMJ) implants have been used to replace the jaw joint in some patients in an effort to decrease pain and increase jaw function. The safety and effectiveness of these implants, like other medical devices, is overseen by the Food and Drug Administration (FDA), an agency within the Department of Health and Human Services (HHS). Two implants used in the 1970s and 1980s that were later removed from the market caused severe side effects for some patients. In 1998, FDA began to require certain TMJ implant manufacturers sponsoring these devices to demonstrate the implants' safety and effectiveness before receiving approval. Since 1998, four TMJ implants from three sponsors were approved. In response to your request, GAO described (1) the types of concerns raised by FDA and how it addressed these concerns for the implants approved since 1998 and (2) how FDA has monitored sponsors' compliance with conditions of approval. GAO examined documentation related to the four TMJ implants approved by FDA since 1998 and sponsors' annual reports, which FDA uses to monitor compliance with conditions of approval. GAO also interviewed FDA officials, TMJ implant sponsors, and patient advocacy groups.
FDA officials raised concerns during the approval process that were similar for all four TMJ implants. These concerns generally involved the adequacy of the sponsors' clinical study protocols, patient follow-up, engineering testing, and other matters, such as device labeling. FDA addressed many, but not all, concerns upon approval. Some concerns were addressed by obtaining additional information from sponsors to clarify and supplement data contained in their device applications before approval. Other concerns were addressed when FDA approved the implants but required sponsors to comply with certain conditions of approval, such as continuing clinical studies postmarket and collecting patient data. Because FDA staff, who review the device applications, and FDA management, who approve the devices for marketing, held differing views as to whether the implants' health benefits outweighed its risks, they did not agree on the approval decisions of two of the four TMJ implants. FDA management acknowledged that the concerns raised about the implants were legitimate. However, they ultimately concluded that the benefits provided by these two devices outweighed the concerns and approved both devices to help patients obtain relief from chronic pain. FDA monitored sponsors' compliance with conditions of approval by evaluating information contained in their annual reports. FDA often required additional actions by the sponsors to resolve questions that were raised through its review of these reports. However, GAO found that not all annual reports were received by FDA. At the time GAO conducted its work, FDA had only received 13 of 18 required reports. One implant sponsor did not submit 5 of 7 required annual reports. FDA has requested these reports and has issued draft guidance on annual report submissions to all medical device sponsors. In addition, when reviewing the available annual reports to determine if sponsors were complying with conditions of approval, many of the submitted reports did not provide FDA with sufficient information to assess compliance. FDA required these TMJ implant sponsors to provide additional information to address this lack of sufficient information. In most instances, once FDA received additional information from the sponsors, the annual reports were considered adequate. However, one sponsor submitted several annual reports for both of its devices that FDA said lacked sufficient information regarding patient follow-up and also underreported problems experienced by patients associated with the devices. FDA notified the sponsor that it must address these concerns, but the sponsor repeatedly provided inadequate responses. This situation ultimately led FDA to inspect the sponsor's records and file an administrative complaint for civil monetary penalties against the sponsor for failure to file certain reports with FDA. On July 6, 2007, an administrative law judge ruled in favor of FDA. In commenting on a draft of this report, HHS provided clarification on postmarket requirements for approved devices and updated information on the administrative complaint for civil monetary penalties.
GAO-07-996, Medical Devices: FDA's Approval of Four Temporomandibular Joint Implants
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Report to Congressional Requesters:
United States Government Accountability Office:
GAO:
September 2007:
Medical Devices:
FDA's Approval of Four Temporomandibular Joint Implants:
FDA's Approval of TMJ Implants:
GAO-07-996:
GAO Highlights:
Highlights of GAO-07-996, a report to congressional requesters.
Why GAO Did This Study:
It is estimated that over 10 million people in the United States suffer
from jaw joint and muscle disorders. Artificial temporomandibular joint
(TMJ) implants have been used to replace the jaw joint in some patients
in an effort to decrease pain and increase jaw function. The safety and
effectiveness of these implants, like other medical devices, is
overseen by the Food and Drug Administration (FDA), an agency within
the Department of Health and Human Services (HHS). Two implants used in
the 1970s and 1980s that were later removed from the market caused
severe side effects for some patients. In 1998, FDA began to require
certain TMJ implant manufacturers sponsoring these devices to
demonstrate the implants‘ safety and effectiveness before receiving
approval. Since 1998, four TMJ implants from three sponsors were
approved.
In response to your request, GAO described (1) the types of concerns
raised by FDA and how it addressed these concerns for the implants
approved since 1998 and (2) how FDA has monitored sponsors‘ compliance
with conditions of approval. GAO examined documentation related to the
four TMJ implants approved by FDA since 1998 and sponsors‘ annual
reports, which FDA uses to monitor compliance with conditions of
approval. GAO also interviewed FDA officials, TMJ implant sponsors, and
patient advocacy groups.
What GAO Found:
FDA officials raised concerns during the approval process that were
similar for all four TMJ implants. These concerns generally involved
the adequacy of the sponsors‘ clinical study protocols, patient follow-
up, engineering testing, and other matters, such as device labeling.
FDA addressed many, but not all, concerns upon approval. Some concerns
were addressed by obtaining additional information from sponsors to
clarify and supplement data contained in their device applications
before approval. Other concerns were addressed when FDA approved the
implants but required sponsors to comply with certain conditions of
approval, such as continuing clinical studies postmarket and collecting
patient data. Because FDA staff, who review the device applications,
and FDA management, who approve the devices for marketing, held
differing views as to whether the implants‘ health benefits outweighed
its risks, they did not agree on the approval decisions of two of the
four TMJ implants. FDA management acknowledged that the concerns raised
about the implants were legitimate. However, they ultimately concluded
that the benefits provided by these two devices outweighed the concerns
and approved both devices to help patients obtain relief from chronic
pain.
FDA monitored sponsors‘ compliance with conditions of approval by
evaluating information contained in their annual reports. FDA often
required additional actions by the sponsors to resolve questions that
were raised through its review of these reports. However, GAO found
that not all annual reports were received by FDA. At the time GAO
conducted its work, FDA had only received 13 of 18 required reports.
One implant sponsor did not submit 5 of 7 required annual reports. FDA
has requested these reports and has issued draft guidance on annual
report submissions to all medical device sponsors. In addition, when
reviewing the available annual reports to determine if sponsors were
complying with conditions of approval, many of the submitted reports
did not provide FDA with sufficient information to assess compliance.
FDA required these TMJ implant sponsors to provide additional
information to address this lack of sufficient information. In most
instances, once FDA received additional information from the sponsors,
the annual reports were considered adequate. However, one sponsor
submitted several annual reports for both of its devices that FDA said
lacked sufficient information regarding patient follow-up and also
underreported problems experienced by patients associated with the
devices. FDA notified the sponsor that it must address these concerns,
but the sponsor repeatedly provided inadequate responses. This
situation ultimately led FDA to inspect the sponsor‘s records and file
an administrative complaint for civil monetary penalties against the
sponsor for failure to file certain reports with FDA. On July 6, 2007,
an administrative law judge ruled in favor of FDA.
In commenting on a draft of this report, HHS provided clarification on
postmarket requirements for approved devices and updated information on
the administrative complaint for civil monetary penalties.
[hyperlink, http://www.gao.gov/cgi-bin/getrpt?GAO-07-996].
To view the full product, including the scope and methodology, click on
the link above. For more information, contact Marcia Crosse at (202)
512-7114 or crossem@gao.gov
[End of section]
Contents:
Letter:
Results in Brief:
Background:
FDA Raised Concerns on All Implants and Addressed Many by Obtaining
Additional Information and Establishing Conditions of Approval:
FDA Monitored Compliance through Review of the Sponsors' Annual Reports
It Received and Required Some Sponsors to Take Additional Action:
Agency Comments:
Appendix I: Concerns Left Unaddressed upon FDA Approval of TMJ
Implants:
Appendix II: Comments from the Department of Health and Human Services:
Appendix III: GAO Contact and Staff Acknowledgments:
Tables:
Table 1: GAO Categorization of Concerns Raised by FDA during the PMA
Process for TMJ Implants:
Table 2: GAO Categorization of Concerns Left Unaddressed by FDA during
the Premarket Approval Process for TMJ Implants:
Figure:
Figure 1: Illustration of Temporomandibular Joint:
Abbreviations:
FDA: Food and Drug Administration:
HHS: Department of Health and Human Services:
MAUDE: Manufacturer and User Facility Device Experience Database:
PMA: premarket approval TMJ temporomandibular joint:
United States Government Accountability Office:
Washington, DC 20548:
September 17, 2007:
The Honorable Edward M. Kennedy:
Chairman:
Committee on Health, Education, Labor, and Pensions:
United States Senate:
The Honorable Tom Harkin:
United States Senate:
The Honorable Herb Kohl:
United States Senate:
The National Institutes of Health report that over 10 million people in
the United States suffer from temporomandibular joint (i.e., jaw joint)
and muscle disorders. Although most people have relatively mild forms
of these disorders, others experience long-term persistent and
debilitating pain. Artificial temporomandibular joint (TMJ) implants
have been used to replace the jaw joint in an effort to decrease pain
and increase jaw function for this latter group.
The Food and Drug Administration (FDA), an agency within the Department
of Health and Human Services (HHS), is responsible for overseeing the
safety and effectiveness of medical devices, including TMJ implants.
Beginning in 1976, medical devices, including TMJ implants, were
allowed to enter the market without the submission of safety and
effectiveness information to FDA if the devices were determined to be
"substantially equivalent" to previously marketed devices.[Footnote 1]
Many patients who received certain TMJ implants--one that was on the
market prior to 1976 and one that entered the market in 1983 and was
deemed substantially equivalent to a pre-1976 device--faced severe
consequences associated with the materials contained in the implants.
These included chronic pain, bone degeneration, and implant
fragmentation or displacement. In 1991, one device was recalled by FDA,
and in 1993, the other was voluntarily discontinued by the
manufacturer--who is also known as the sponsor--of the implant.
On December 30, 1998, FDA issued regulations requiring certain TMJ
implant sponsors to submit a premarket approval (PMA) application.
Applications were required for TMJ implants marketed prior to May 28,
1976, and for such implants deemed substantially equivalent to a device
marketed prior to May 28, 1976. The PMA process requires sponsors to
demonstrate the safety and effectiveness of their devices before
receiving approval. To demonstrate safety and effectiveness of these
devices, sponsors conduct clinical studies and perform engineering
tests on the implant, such as testing the implant's strength, and
include the results in the PMA application submitted for FDA's review.
As part of the PMA process, FDA staff evaluate these studies through a
review of the implant applications, and FDA management makes decisions
regarding approval for marketing the implants. Since the implementation
of these requirements, four TMJ implant applications from three
sponsors have been submitted for approval. FDA conditionally approved
all four devices--meaning the sponsors had to comply with specific
conditions established by FDA, following approval. For example, these
sponsors were required to conduct postmarket studies, among other
conditions. Given your concerns for patients with temporomandibular
joint and muscle disorders, you expressed interest in FDA's safety
requirements for, and oversight of, TMJ implants.
This report examines (1) the types of concerns raised by FDA and how it
addressed concerns raised during the TMJ implant approval process since
December 30, 1998, when it began requiring data on implant safety and
effectiveness and (2) how FDA has monitored TMJ sponsors' compliance
with conditions of approval.
To determine how FDA addressed the concerns raised during the PMA
process, we reviewed documentation provided by FDA for each of the four
TMJ implants approved since December 30, 1998: (1) TMJ Concepts
implant, (2) TMJ Implants, Inc., total joint implant, (3) TMJ Implants,
Inc., partial joint implant, and (4) Walter Lorenz implant.[Footnote 2]
We identified FDA's concerns related to safety and effectiveness and
the methods used to address these concerns through a review of internal
documents, such as the approval review package. Among other documents,
this package includes results of FDA's reviews of the PMA application,
a recommendation regarding approval, and final decisions for each
implant. Throughout our review we considered concerns addressed by FDA
as those in which the agency identified an issue concerning safety and
effectiveness of an implant and dealt with the issue by contacting the
sponsor. We also reviewed FDA's correspondence with the TMJ implant
sponsors. In addition, to further understand FDA's concerns, we
examined summaries of meetings held by FDA's dental products panel--an
advisory body of external experts convened to provide advice to the
agency--on each of the four PMA applications. An FDA official indicated
that although the agency may not have documentation of all concerns
raised during the PMA process, the documents we reviewed contained the
most complete information possible to address our objectives.
Therefore, it is possible that other relevant documents existed that we
were unable to review. We grouped concerns raised during the PMA
process into broad categories, such as study protocol, patient follow-
up, and engineering testing.[Footnote 3] In addition, we further sorted
these categories to provide additional explanations on the types of
concerns we identified. We also identified actions taken by FDA such as
whether FDA approved the device with conditions to address certain
concerns. We discussed our determinations of whether and how concerns
were addressed with FDA officials to gain their confirmation. However,
we did not evaluate the appropriateness of FDA's approval decisions for
each of the implants or its assessment of the medical, scientific, or
engineering data provided by the sponsors. To better inform our
discussion of concerns raised during the PMA process for TMJ implants,
we contacted the three TMJ implant sponsors[Footnote 4] and several
groups representing patients with temporomandibular joint and muscle
disorders, including the TMJ Association, the TMJ and Orofacial Pain
Society of America, and the Jaw Joints & Allied Musculo-Skeletal
Disorders Foundation, Inc.
To determine how FDA has monitored TMJ implant sponsors' compliance
with the conditions of approval, we reviewed annual reports, which FDA
required from the three TMJ implant sponsors as a condition of
approval. Among other things, these annual reports provide the sponsors
an opportunity to update FDA on the status of their required conditions
of approval. We discussed the status of conditions of approval with FDA
officials to obtain their views on sponsors' compliance with these
conditions and collected related documentation. In addition, we
gathered information related to FDA's overall efforts to collect and
review annual reports. With the exception of FDA's review of annual
reports, this report focuses on how FDA addressed concerns raised
during the PMA process and excludes FDA's postmarket oversight
activities.[Footnote 5]
Through our interviews with FDA officials and our examination of
documents provided, we determined that the data we used were
sufficiently reliable for purposes of this report. We conducted our
review from October 2006 through August 2007 in accordance with
generally accepted government auditing standards.
Results in Brief:
FDA officials raised similar concerns for all four TMJ implants' PMA
applications. We grouped these concerns into four main categories:
study protocol, patient follow-up, engineering testing, and other
concerns, such as device labeling. For example, FDA found that all the
studies supporting the four PMA applications had deficient patient
follow-up, which made it difficult to determine outcomes over time,
such as improvement in patient symptoms. FDA used two methods to
address many, but not all, concerns upon approval. FDA addressed some
concerns raised in the approval process by obtaining additional
information from sponsors to clarify and supplement data contained in
their PMA applications before approval. FDA addressed other concerns by
approving the TMJ implants but requiring sponsors to comply with
certain conditions of approval. As a condition of approval, FDA
required the sponsors to continue their clinical studies postmarket and
to collect data on patients for all four implants for at least 3 years.
Because FDA staff, who review the device applications, and FDA
management, who approve the devices for marketing, held differing views
as to whether an implant's health benefits outweighed its risks, they
did not agree on the approval decisions of two of the four TMJ
implants, both sponsored by TMJ Implants, Inc. Ultimately, both devices
were approved. FDA management acknowledged that the concerns raised
about these implants were legitimate; however, they concluded that the
need for the devices outweighed these concerns. According to FDA
management, they approved the devices primarily because they play an
important role in helping patients obtain relief from chronic pain and
there did not appear to be a prohibitory risk associated with the
devices.
FDA monitored sponsors' compliance with conditions of approval by
evaluating information contained in their annual reports and often
required additional actions by the sponsors to resolve questions raised
through its review of the reports. Although a total of 18 annual
reports should have been submitted to FDA at the time we conducted our
work, only 13 had been received by the agency. One implant sponsor--TMJ
Concepts--did not submit 5 of 7 required annual reports. FDA has since
requested these reports and has issued draft guidance to all medical
device sponsors, which outlines best practices for submitting annual
reports. When reviewing the annual reports from all of the sponsors to
determine if conditions of approval were met, we found that 7 of the 13
submitted reports did not provide FDA with sufficient information to
assess compliance. To address the lack of sufficient data provided in
these 7 annual reports, specifically with regard to patient history and
patient follow-up, FDA contacted the sponsors and required them to
provide additional information. TMJ Implants, Inc., submitted several
annual reports for both of its devices that lacked sufficient
information regarding patient follow-up. In addition, FDA said the
sponsor also underreported problems experienced by patients--known as
adverse events--associated with the devices. FDA issued letters to the
sponsor asking it to resolve these concerns, yet the sponsor repeatedly
provided inadequate responses. This situation ultimately led FDA to
file an administrative complaint for civil monetary penalties against
the sponsor, which resulted in a decision from an administrative law
judge in favor of FDA on July 6, 2007. A separate decision is expected
on the amount of the penalties to be assessed, after which either side
may appeal.
In commenting on a draft of this report, HHS provided clarification on
the postmarket requirements that apply to approved devices. In
addition, it updated information concerning the administrative
complaint for civil monetary penalties.
Background:
Symptoms of temporomandibular joint and muscle disorders vary but
typically include pain of the jaw joint and surrounding muscles. Other
symptoms include limited or no movement of the jaw joint, clicking or
grating in the jaw joint when opening or closing the mouth, headaches,
and shoulder or back pain. According to the National Institutes of
Health, most patients' symptoms improve significantly or disappear
within weeks or months, while a smaller number of patients have
significant long-term symptoms. Trauma to the jaw or jaw joint can
contribute to temporomandibular joint and muscle disorders in some
instances; however, the causes of most cases of temporomandibular joint
and muscle disorders are unknown.
There are a range of treatments available for temporomandibular joint
and muscle disorders; some are conservative and temporary while others
are irreversible. Experts recommend that the most conservative
treatment be used to relieve symptoms before irreversible treatments
are used. Conservative treatments can include taking pain medications,
using a splint or bite guard, applying ice packs, or eating soft food.
Irreversible treatments include grinding down the teeth to change a
person's bite or surgical procedures such as replacing all or a portion
of the jaw joint with TMJ implants. Total TMJ implants replace both the
upper (articular fossa) and lower (condyle) portions of the jaw joint,
whereas partial TMJ implants replace only the upper portion. (See fig.
1.) TMJ implants may improve the function of the jaw joint, however,
pain, which is a chief complaint of many who suffer from
temporomandibular joint and muscle disorders, is not always relieved.
Figure 1: Illustration of Temporomandibular Joint:
[See PDF for image]
Source: Reprinted with permission from the American Association of Oral
and Maxillofacial Surgeons.
[End of figure]
Medical devices, including TMJ implants, are regulated by FDA, through
its Center for Devices and Radiological Health. TMJ implants are
classified as Class III devices. Class III devices include those that
present a significant risk of illness or injury to the
patient.[Footnote 6]
Prior to the marketing of most Class III devices, FDA must approve a
PMA application.[Footnote 7] The PMA review requires sufficient and
valid scientific evidence to assure that a medical device is safe and
effective for its intended use. In making this determination, FDA
officials--including FDA staff known as the review team[Footnote 8] and
two levels of FDA management--must consider if there is reasonable
assurance that the probable benefits to health of the device outweigh
any probable risks. They must also consider whether the device is
effective by evaluating data provided by the sponsor for "clinically
significant results."[Footnote 9] The review team examines clinical
studies of the device involving human subjects, engineering testing
performed on the device, and other aspects of the PMA application such
as device labeling. It may also obtain input from one of its external
advisory boards--in the case of TMJ implants, its dental products
panel--for its evaluation and recommendation regarding approval. If the
review team has concerns about the PMA application it contacts the
sponsor for more information.[Footnote 10] In some cases the review
team may determine that it needs significant additional information to
complete the scientific review, in which case it issues a deficiency
letter to the device sponsor indicating the information that is needed.
The sponsor can respond by submitting an amendment to the original
application. The review team can continue to issue deficiency letters
and receive amendments from sponsors until it determines that it has
the information needed to make a recommendation regarding approval.
Once the PMA review is complete, the review team makes a recommendation
regarding approval. This recommendation is subject to review by the two
levels of FDA management. Along with the recommendation, information
provided by the sponsor and the review team's assessment of the PMA
application, including the individual reviews, such as engineering,
clinical, and statistical reviews, and a team leader summary, are
forwarded. The review team sends this package to the first level of
management. If this level of management agrees with the review team's
recommendation, the review package is sent to the second level for
final review.[Footnote 11] The second level of management may concur or
override the decision made at the previous management level. Management
can make a recommendation regarding approval even if some concerns
regarding the PMA remain unaddressed; however, a device can only be
approved for marketing if FDA concludes that its benefits outweigh its
risks. If a member of the review team or the first level of FDA
management disagrees with the final decision, an internal "respectful
disagreement memo" can be written indicating the reason for the
disagreement.[Footnote 12]
FDA decisions regarding approval of devices can take four forms: (1)
issuing an order approving the application, which allows the sponsor to
begin marketing the device; (2) sending the sponsor an "approvable"
letter indicating that the sponsor needs to provide more information;
(3) issuing a "not approvable" letter informing the sponsor of the
application's weaknesses; or (4) issuing an order denying approval of
the application.
Once a device has been approved, the sponsor must comply with
postmarket regulations and restrictions that apply to the device. FDA
may also impose postmarket approval or condition of approval
requirements that apply specifically to the device that is the subject
of the PMA. Conditions of approval can include requirements such as the
continuation of a clinical study to collect additional data. Some
conditions of approval do not expire, such as reporting adverse events
and submitting annual reports, including a summary of all changes to
the device.[Footnote 13] Others are time-limited, such as continuing a
clinical study for a specified number of years after the approval of a
device.
FDA Raised Concerns on All Implants and Addressed Many by Obtaining
Additional Information and Establishing Conditions of Approval:
In their review of the four PMA applications, FDA officials raised
concerns that were similar for all four devices. FDA addressed many
concerns raised in the approval process by obtaining additional
information from sponsors to clarify and supplement data contained in
their PMA applications. It also approved all four devices but required
sponsors to comply with conditions of approval. However, some concerns
were left unaddressed upon approval. In addition, the FDA review team
and two levels of FDA management did not agree on the assessment of the
safety and effectiveness of the two TMJ Implants, Inc., devices.
Ultimately, according to FDA management, the primary justification for
approving these devices was that the potential benefit to the patients
outweighed the concerns raised and there did not appear to be a
prohibitory risk associated with the devices.
FDA Raised Concerns That Generally Applied to All Four TMJ Implants:
We grouped the concerns FDA raised during the PMA process into four
main categories: study protocol, patient follow-up, engineering
testing, and other concerns. These categories and types of concerns are
shown in table 1.
Table 1: GAO Categorization of Concerns Raised by FDA during the PMA
Process for TMJ Implants:
Categories of concerns: Study protocol;
Types of concerns included in categories:
* Inadequate or inaccurate clinical study results, including:
- Inaccurate measurement of data (e.g., problems with procedures used
to measure pain over time)[A];
- Data not separated appropriately (e.g., results from different
implants analyzed together)[A];
- Questionable conduct by sponsor (e.g., underreporting of adverse
events)[A];
- Incomplete or insufficient data to draw conclusions[A];
- Lack of long-term data collection[A];
- Unsupported or poorly defined indications for use[A];
* Lack of patient history data, including:
- Patients' clinical diagnosis unknown (e.g., rheumatoid arthritis,
cancer)[A];
- Patients' treatment history unknown (e.g., first implant, multiple
implants);
- Original sample size of study too small.
Categories of concerns: Patient follow-up[B];
Types of concerns included in categories:
* Lack of patient follow-up, including:
- Long-term data lacking due to poor follow-up[A];
- Number of patients in study too small due to poor follow-up[A].
Categories of concerns: Engineering testing;
Types of concerns included in categories:
* Inadequate wear testing, including:
- Analysis of wear debris from implant lacking[A];
- No examination for wear of implants removed from patients[A];
- No analysis of wear on natural condyle[A,C];
* Inadequate fatigue testing[A,D];
* Other engineering testing inadequate[A].
Categories of concerns: Other;
Types of concerns included in categories:
* Inadequate device labeling[A];
* Unaddressed microbiology,[E] packaging, and shelf-life issues;
* Incomplete sponsor manufacturing inspections.
Source: GAO analysis of FDA documents.
Notes: This table applies to the four TMJ implants approved since
December 30, 1998.
[A] These concerns were also raised by the dental products panel in its
review of the PMA applications for the four implants.
[B] Patient follow-up refers to the number of patients who remain in a
study over time.
[C] The TMJ Concepts, TMJ Implants, Inc., total implant, and Walter
Lorenz implants replace both the articular fossa (the upper portion of
the temporomandibular joint) and the condyle (the lower portion). The
TMJ Implants, Inc., partial implant only replaces the articular fossa,
therefore there were concerns related to its effects on a patient's
natural condyle.
[D] Fatigue testing refers to the amount of weight an implant can bear
without breaking. Tests are conducted to ensure that the implant can
withstand the weight that a functioning jaw joint would encounter
during activities such as talking and chewing.
[E] Microbiology issues relate to the sponsors' processes to ensure the
devices are sterile when shipped to the device user.
[End of table]
From FDA's review of the PMA applications, we observed similar concerns
across most PMA applications. For example:
* All four PMA applications had incomplete or insufficient data to draw
conclusions from the clinical studies. For example, FDA officials were
concerned that because the Walter Lorenz clinical study was primarily
conducted at one site, the physician at this site might have more
expertise in implanting the device than a typical physician,
potentially biasing the results. Officials were uncertain if equally
favorable results would be obtained at other sites when the implant
procedure was performed by less-experienced physicians.
* All four PMA applications had deficient patient follow-up
information, which prevented a satisfactory evaluation of the study
results, such as improvement in patient symptoms and survivability of
the implant.[Footnote 14]
* In three of the four PMA applications, concerns were raised about the
lack of information specifying the clinical diagnosis of the patients
included in their clinical studies. This made it difficult for the
review team to interpret the types of clinical conditions for which the
devices are appropriate.
* In three of the four PMA applications, concerns existed regarding
inaccurate measurement of data. For example, neither TMJ Concepts's nor
TMJ Implants, Inc.'s, total implant clinical data followed the same
cohort of patients over time. This made it difficult for the review
team to determine whether the device produced improvements in patients.
The clinical data for TMJ Implants, Inc.'s, partial implant were
compromised because medications used by patients were not documented in
the study. Any use of medications could have affected patient outcomes.
* In three of the four PMA applications, the review team indicated that
additional implant wear and fatigue testing needed to be conducted. For
example, the team wanted TMJ Implants, Inc., (total implant) to conduct
wear debris analysis. This analysis could help determine if material
wears off the implant over time, which could be absorbed into the
patient's body.
FDA Obtained Additional Information from Sponsors and Required
Conditions of Approval to Address Most, but Not All, Concerns:
FDA addressed the concerns it raised in its review of the PMA
applications in two ways: (1) by communicating with sponsors and
collecting additional information from them and (2) by approving the
devices with conditions. FDA addressed many of its concerns by
clarifying and collecting information for sponsors' PMA applications,
before approving the devices. For example, FDA officials met with
representatives of TMJ Concepts and TMJ Implants, Inc., (partial
implant) to discuss concerns, such as unsupported indications for use
of the device and inconsistent patient follow-up in the clinical
studies. In addition, in many instances throughout the review process,
FDA officials wrote the sponsors--highlighting problems with the
applications--and reviewed their written responses. For example, FDA
sent e-mails to Walter Lorenz regarding concerns related to the
microbiology, packaging, and shelf life of its device. Walter Lorenz
replied to FDA's questions and requests for information and these
concerns were addressed. Correspondence between FDA officials and
sponsors often continued for at least 3 months and in most cases longer
until concerns were addressed.
The second manner in which FDA addressed concerns was by approving the
four TMJ implants with certain conditions. A condition of approval
common to all four TMJ implants included the requirement that a
postmarket study be conducted, which would collect patient data for at
least 3 years. This condition of approval addressed FDA's concerns
regarding study protocol and patient follow-up. Other conditions of
approval addressed concerns related to a lack of patient history data
and inadequate wear testing, among others. TMJ Concepts and TMJ
Implants, Inc., (total implant) were required to include patient
history data in their postmarket studies. Further, TMJ Concepts and TMJ
Implants, Inc., (partial implant) were required to conduct wear
analysis in order to address concerns related to inadequate wear
testing.
While FDA addressed the majority of concerns for each implant, we
identified some concerns that remained unaddressed--concerns that were
not offset or countered by a condition of approval or by FDA
correspondence with the sponsor--upon approval. FDA officials examined
these unaddressed concerns during the PMA process. However, they
determined that the probable benefits of the devices outweighed the
probable risks and therefore approved them. The unaddressed concerns
for the devices were as follows and are expanded upon in appendix I:
* TMJ Concepts: The unaddressed concerns related to inadequate and
inaccurate study results. For example, FDA officials indicated that
data for implants on the right and left sides of the jaw should have
been analyzed separately, but the data collected did not allow for this
type of analysis.
* TMJ Implants, Inc. (total implant): The unaddressed concerns related
to the category of other concerns--unaddressed microbiology, packaging,
and shelf-life issues. For example, there was a concern regarding the
procedures used for implants that will be shipped multiple times, which
could occur if a physician shipped an unused implant back to the
sponsor.
* TMJ Implants, Inc. (partial implant): The majority of the unaddressed
concerns related to inadequate and inaccurate study results and lack of
patient history data. For example, there were concerns that the
indications for use the sponsor cited in the device labeling were not
supported by the clinical study. In addition, information about
patients' treatment history was not included in the study, so it was
unknown whether patients tried more conservative treatments before
receiving the device. The remaining unaddressed concerns related to
other topics--unaddressed microbiology, packaging, and shelf-life
issues and outstanding manufacturing inspection matters.
* Walter Lorenz: The unaddressed concern related to lack of patient
history data, specifically that the sponsor generalized the clinical
study results to all patients, even though patients in the study had
varying clinical histories.
Concerns Raised about Two Implants Resulted in Differing Opinions among
FDA Officials Regarding Approval:
Although FDA's review team and FDA management agreed that the TMJ
Concepts and Walter Lorenz implants should be approved with conditions,
there was disagreement among the review team and the two levels of
management related to the approval of both TMJ Implants, Inc., devices.
The review team recommended that the TMJ Implants, Inc., (total
implant) application be considered not approvable. The team had
concerns because it felt that the enrollment in the sponsor's clinical
study was too small to draw significant conclusions related to the
safety and effectiveness of the device. In addition, the review team
believed the indications for use of the device were unsupported.
However, the first level of FDA management recommended that the device
be approved because it has a role in the treatment of TMJ and muscle
disorders. The second level of management agreed with this
recommendation. In its approval decision, FDA management acknowledged
that there were concerns about the quality and quantity of clinical
data provided by the sponsor. However, it stated that either good
engineering data or good clinical data was acceptable to approve a
device--not necessarily both--and that it deemed the engineering data
for the TMJ Implants, Inc., total implant to be satisfactory. Further,
FDA management indicated that the clinical data were not expected to be
of high quality because the sponsor was a small manufacturer, the data
available at the time of approval did not indicate an extraordinary
problem with the implanted devices, and the data provided appeared
consistent and favorable. The total implant was approved with
conditions to address the FDA review team's concerns mentioned above.
There was also conflict regarding the decision to approve the TMJ
Implants, Inc., (partial implant) application. Although the second
level of management ultimately approved the device for marketing with
conditions, both the FDA review team and first level of management
found that there was insufficient data to assure that the device was
safe and effective. The review team recommended that the device be
considered not approvable. The first level of management agreed with
this recommendation for the following reasons:
* The data were limited due to lack of patient follow-up. For example,
the group of patients with 2-year and 3-year follow-up data in the
sponsor's clinical study was too small to draw significant conclusions
about the device. Of approximately 100 patients with implants, only 29
completed the 24-month follow-up. Only 11 patients completed the
intended 36-month follow-up.
* Outstanding concerns existed related to (1) questionable conduct by
the sponsor in classifying and reporting adverse events, (2) lack of
engineering testing to determine the long-term effect of the partial
TMJ implant on the natural condyle, (3) unsupported indications for use
of the device, and (4) lack of data on patients' clinical and treatment
history.
While the second level of management recognized and agreed with the
scientific concerns that had been raised, the sponsor was sent an
approvable letter requiring minor application changes, such as revised
device labeling, and the device was eventually approved. An internal
memo outlining the second level of management's approval decision
stated that there was a compelling argument in favor of approving the
device. It argued that there appeared to be a small group of patients,
although poorly defined, for whom the device seemed to provide an
option for relief of chronic pain. In addition, it noted that there did
not appear to be a prohibitory risk associated with the device in
patients who are appropriately educated about all treatment
alternatives, their disorder, and the device, and this information is
provided in the implant's labeling. However, the approval memo also
stated that the decision to approve the partial implant did not imply
that the previous concerns raised by the review team and first level of
management related to the inadequacy of the data were reversed. Of
these concerns raised, those related to engineering testing on the
device's effect on the natural condyle were addressed through
conditions of approval; the others remained unaddressed.
Upon the approval of the partial implant, two individuals--a member of
the review team and an official from the first level of FDA management-
-wrote "respectful disagreement memos." Their memos indicated that they
did not agree with the second level of management's decision to approve
the TMJ implants, Inc., (partial implant) application for marketing.
These memos outlined concerns raised during the PMA process related to
the safety and effectiveness of the device. The concerns highlighted in
these memos were that (1) lack of patient follow-up in the clinical
study potentially biased the results, and consequently, the sponsor's
claim that the implant resulted in decreased patient pain was
unsupported, (2) the clinical study protocol lacked scientific rigor,
and (3) outstanding questions remained related to the indications for
using the device. In addition, a member of the review team told us that
the conditions of approval did not mitigate the concerns she
highlighted in her respectful disagreement memo.
FDA Monitored Compliance through Review of the Sponsors' Annual Reports
It Received and Required Some Sponsors to Take Additional Action:
In order to evaluate how the sponsors complied with the conditions of
approval, FDA received and reviewed the majority of the required annual
reports from TMJ implant sponsors. However, the review team had not
received most of the required annual reports from one sponsor. Of the
annual reports the review team evaluated, some of them were incomplete
and FDA required sponsors to take additional actions to ensure
compliance with conditions of approval. In addition, the FDA review
team had concerns about one sponsor's--TMJ Implants, Inc.--annual
reports. FDA found that these reports lacked sufficient information
that prevented them from monitoring safety and effectiveness. This
eventually led FDA to investigate the sponsor, resulting in the
subsequent filing of an administrative complaint for civil monetary
penalties for the company's failure to file certain adverse event
reports with FDA.
FDA Reviewed the Annual Reports It Received, but Some Were Missing:
FDA received and reviewed all required annual reports for TMJ Implants,
Inc., total and partial implants between 2002 and 2006 and the Walter
Lorenz implant in 2006. However, the review team was missing five of
seven required annual reports between 2000 and 2006 from TMJ Concepts.
It was not until we requested to review these reports that FDA
contacted the sponsor to obtain the missing information. In addition,
FDA officials told us that they are developing an improved postmarket
surveillance effort to assist sponsors with annual report submission.
As part of this effort, FDA recently issued draft guidance on October
26, 2006, which outlines FDA's recommendations for submitting annual
reports.[Footnote 15]
Though many annual reports were missing from TMJ Concepts, FDA was able
to review the two annual reports submitted by the sponsor in 2000 and
2004. For both reports, TMJ Concepts included information related to a
number of conditions of approval, such as providing data on its
postmarket study and including a patient quality of life question in
that study. In 2000, the sponsor did not comply with the condition of
approval to separate data by patients' clinical histories, but did
complete this in its 2004 annual report. Therefore, in 2004, TMJ
Concepts addressed all conditions of approval except one--submitting
annual reports each year. Although all conditions of approval were not
met and FDA was not able to review 5 years of annual reports, FDA found
that the 2000 and 2004 annual reports provided adequate data and no
additional information was required of the sponsor for those two
reports.
FDA Required Some Sponsors to Take Additional Actions to Comply with
Their Conditions of Approval:
FDA evaluated information contained in the 13 annual reports it
received and found that 7 reports--6 from TMJ Implants, Inc., (3 for
the total joint implant and 3 for the partial joint implant) and 1 from
Walter Lorenz--did not provide sufficient information to assess their
compliance with conditions of approval.[Footnote 16] For 1 of the 7
annual reports, FDA directed TMJ Implants, Inc., to submit new
information about changes to the approved labeling and to the
manufacturing processes for its total implant. FDA sent deficiency
letters to the sponsors regarding the other 6 annual reports. These
deficiency letters required the sponsors to address questions regarding
the lack of certain data that relate to the safety and effectiveness of
the devices, including patient history, patient follow-up, and adverse
events. For example, in its 2006 annual report, Walter Lorenz was
required to submit data on its postmarket clinical study. During the
review of these data, the FDA review team identified concerns about
data that were included in the report and sent a deficiency letter to
the sponsor to resolve this issue. FDA officials discussed the
deficiency letter with the sponsor and are waiting for a response.
FDA took further steps to obtain compliance from TMJ Implants, Inc.,
which had not responded adequately to FDA's 2002 deficiency letter
requesting additional information, following receipt of the sponsor's
annual reports for its total and partial TMJ implants.[Footnote 17]
Specifically, in 2002 FDA indicated that TMJ Implants, Inc. had not
followed up with the required number of patients during its postmarket
study. Also, the sponsor was not submitting adverse events, which it
described in its annual reports, to FDA's Manufacturer and User
Facility Device Experience Database (MAUDE).[Footnote 18] The sponsor
reported that the reason for the implant removals was not specifically
due to the failure of the implant and therefore concluded that they did
not need to be reported as adverse events. However, after reviewing the
2003 annual reports where there was still a lack of adverse event
reporting, FDA issued a deficiency letter. This letter informed the
sponsor that all removed implants should be reported to the MAUDE
system. In addition, supplemental data were required to be submitted
for the conditions of approval related to patient follow-up and adverse
event reporting. After FDA's review of the sponsor's 2004 annual
reports, the outstanding concerns from the 2002 and 2003 reports
remained. For example, issues regarding lack of patient follow-up were
unresolved. At the time of the 2004 annual reports, the sponsor
submitted data for 75 out of a total of 183 patients for whom data
should have been provided. The sponsor maintained that the events
related to the removed devices were not caused by device failure or
function and concluded that they did not require reporting to FDA.
Subsequently, FDA took action on the 2004 annual reports by sending
another deficiency letter to the sponsor. In addition, FDA required
that the sponsor submit a complete account of all patients to clarify
its analysis of patients who were lost to follow-up.
According to FDA officials, the sponsor's response to these deficiency
letters did not resolve the outstanding concerns. As a result, the
review team raised the concerns with FDA's Office of Compliance and the
sponsor was inspected from July 29 through August 11, 2003. During its
inspection, FDA found that the sponsor's devices may have malfunctioned
or caused or contributed to serious injuries. The inspection results
also showed these adverse events had not been reported by the sponsor
as required. In response to these findings, FDA issued a warning
letter[Footnote 19] on February 24, 2004, requiring the sponsor to
submit written medical device reports for specific adverse events
detailed in the letter within 15 working days of receipt.[Footnote 20]
When the sponsor did not adequately respond to the warning letter, FDA
filed an administrative complaint on July 14, 2005, for civil monetary
penalties, which resulted in a decision from an administrative law
judge in favor of FDA on July 6, 2007. A separate decision is expected
on the amount of the penalties to be assessed, after which either side
may appeal. The FDA's Office of Regulatory Affairs instructed the
review team not to pursue any deficiencies found in the sponsor's
annual reports until the matter is resolved. Therefore, the review team
has reviewed TMJ Implants, Inc.'s, 2005 and 2006 annual reports, but
decisions on the sponsor's compliance with the conditions of approval
are pending.
Agency Comments:
In commenting on a draft of this report, HHS provided clarification on
the postmarket requirements that apply to approved devices and updated
information concerning the administrative complaint for civil monetary
penalties. We revised our report to reflect these comments. It also
provided technical comments, which we incorporated, as appropriate.
HHS's comments appear in appendix II.
As arranged with your offices, unless you publicly announce the
contents of this report earlier, we plan no further distribution of it
until 30 days after its issue date. At that time we will send copies of
this report to the Secretary of HHS, the Commissioner of the FDA,
relevant congressional committees, and other interested parties. We
will also make copies available to others upon request. In addition,
this report will be available at no charge on GAO's Web site at
[hyperlink, http://www.gao.gov].
If you or your staffs have any questions concerning this report, please
contact me at (202) 512-7114 or crossem@gao.gov. Contact points for our
Offices of Congressional Relations and Public Affairs may be found on
the last page of this report. GAO staff who made major contributions to
this report are listed in appendix III.
Signed by:
Marcia Crosse:
Director, Health Care:
[End of section]
Appendix I: Concerns Left Unaddressed upon FDA Approval of TMJ
Implants:
While the Food and Drug Administration (FDA) addressed most concerns
for each of the four temporomandibular joint (TMJ) implants we
reviewed, we identified a number of concerns that were left
unaddressed--concerns that were not offset or countered by a condition
of approval or by FDA correspondence with the sponsor--upon approval.
These unaddressed concerns fell into two of the four categories of
concerns we identified previously: study protocol and other concerns.
Table 2 lists the unaddressed concerns using the categories we
established in table 1.
Table 2: GAO Categorization of Concerns Left Unaddressed by FDA during
the Premarket Approval Process for TMJ Implants:
Concerns left unaddressed by FDA, sorted by sponsor: TMJ Concepts: Data
on the effectiveness and survivability of the implant over time are not
reliable because of flawed analyses;
Categories of concerns[A]: Study protocol;
Types of concerns included in categories[B]: Inadequate or inaccurate
clinical study results.
Concerns left unaddressed by FDA, sorted by sponsor: TMJ Concepts: Data
on right and left side of the prostheses need to be analyzed
separately; however, the sponsor did not provide data to allow for this
analysis;
Categories of concerns[A]: Study protocol;
Types of concerns included in categories[B]: Inadequate or inaccurate
clinical study results.
Concerns left unaddressed by FDA, sorted by sponsor: TMJ Implants, Inc.
(total implant): The data that demonstrate the performance of the
implant will not diminish as a result of shipping and distribution are
limited and questionable. In addition, there are specific concerns
regarding the procedures that will be used for implants that will be
shipped multiple times;
Categories of concerns[A]: Other concerns;
Types of concerns included in categories[B]: Unaddressed microbiology,
packaging, and shelf-life issues.
Concerns left unaddressed by FDA, sorted by sponsor: TMJ Implants, Inc.
(total implant): More information is needed related to shelf life and
packaging of the implant;
Categories of concerns[A]: Other concerns; Types of concerns included
in categories[B]: Unaddressed microbiology, packaging, and shelf-life
issues.
Concerns left unaddressed by FDA, sorted by sponsor: TMJ Implants, Inc.
(partial implant: Data that indicate the performance of the implant
will not diminish as a result of manufacturing processes must be
submitted;
Categories of concerns[A]: Other concerns;
Types of concerns included in categories[B]: Incomplete sponsor
manufacturing inspections.
Concerns left unaddressed by FDA, sorted by sponsor: TMJ Implants, Inc.
(partial implant: The sponsor has not yet submitted data related to
outstanding microbiology, packaging, and shelf-life issues for its
total implant, which it must do before approval of the partial implant;
Categories of concerns[A]: Other concerns;
Types of concerns included in categories[B]: Unaddressed microbiology,
packaging, and shelf-life issues.
Concerns left unaddressed by FDA, sorted by sponsor: TMJ Implants, Inc.
(partial implant: Clarification and definition of patient inclusion
criteria for the clinical study is needed to understand the clinical
conditions of patients who received the implant;
Categories of concerns[A]: Study protocol;
Types of concerns included in categories[B]: Lack of patient history
data.
Concerns left unaddressed by FDA, sorted by sponsor: TMJ Implants, Inc.
(partial implant: The sponsor has not provided a summary of
preoperative conditions of patients enrolled in the study;
Categories of concerns[A]: Study protocol;
Types of concerns included in categories[B]: Lack of patient history
data.
Concerns left unaddressed by FDA, sorted by sponsor: Concerns left
unaddressed by FDA, sorted by sponsor: The data do not indicate if
patients enrolled in the clinical study have confounding conditions,
which could affect results;
Categories of concerns[A]: Study protocol;
Types of concerns included in categories[B]: Lack of patient history
data.
Concerns left unaddressed by FDA, sorted by sponsor: Concerns left
unaddressed by FDA, sorted by sponsor: The sponsor did not provide
information on patients' past history, such as treatment history, to
substantiate the use of an implant;
Categories of concerns[A]: Study protocol;
Types of concerns included in categories[B]: Lack of patient history
data.
Concerns left unaddressed by FDA, sorted by sponsor: Concerns left
unaddressed by FDA, sorted by sponsor: The sponsor did not provide
specific information about the nature of other treatments used with
patients in the study;
Categories of concerns[A]: Study protocol;
Types of concerns included in categories[B]: Lack of patient history
data.
Concerns left unaddressed by FDA, sorted by sponsor: Concerns left
unaddressed by FDA, sorted by sponsor: The use of broad diagnostic
terms, such as internal derangement--displacement of the jaw joint--
makes it impossible to adequately identify patients who are candidates
for this surgical treatment;
Categories of concerns[A]: Study protocol;
Types of concerns included in categories[B]: Inadequate or inaccurate
clinical study results.
Concerns left unaddressed by FDA, sorted by sponsor: Concerns left
unaddressed by FDA, sorted by sponsor: The sponsor needs to provide
more clearly defined indications and support for these indications;
Categories of concerns[A]: Study protocol;
Types of concerns included in categories[B]: Inadequate or inaccurate
clinical study results.
Concerns left unaddressed by FDA, sorted by sponsor: Concerns left
unaddressed by FDA, sorted by sponsor: The sponsor has not provided
data on the adverse events associated with the device; Categories of
concerns[A]: Study protocol;
Types of concerns included in categories[B]: Inadequate or inaccurate
clinical study results.
Concerns left unaddressed by FDA, sorted by sponsor: Walter Lorenz;
Categories of concerns[A]: [Empty]; Types of concerns included in
categories[B]: [Empty].
Concerns left unaddressed by FDA, sorted by sponsor: Walter Lorenz: The
sponsor generalizes data for all study subjects when they have
different clinical history indicators;
Categories of concerns[A]: Study protocol;
Types of concerns included in categories[B]: Lack of patient history
data.
Source: GAO analysis of FDA documents.
Notes: This table applies to the four TMJ implants approved since
December 30, 1998.
[A] We categorized concerns raised during the PMA approval process into
four categories: study protocol, patient follow-up, engineering
testing, and other concerns.
[B] This column provides detail on the type of concern within the
category to which the unaddressed concern relates. See table 1 for the
four categories and the types of concerns we placed within these
categories.
[End of table]
[End of section]
Appendix II: Comments from the Department of Health and Human Services:
Department of Health and Human Services:
Office of the Assistant Secretary of Legislation:
Washington, D.C. 20201:
July 27, 2007:
Marcia Crosse:
Director, Health Care:
U.S. Government Accountability Office:
Washington, DC 20548:
Dear Ms. Crosse:
Enclosed are the Department's comments on the U.S. Government Office
Accountability Office's (GAO) draft report entitled: Medical Devices:
FDA's Approval of Four Temporomandibular Joint Implants (GAO 07-996).
The Department appreciates the opportunity to review and comment on
this report before its publication.
Sincerely,
Signed by:
Vincent J. Ventimiglia:
Assistant Secretary for Legislation:
General Comments Of The Department Of Health And Human Services (HHS)
On The U.S. Government Office Accountability Office's (GAO) DRAFT
Report Entitled: Medical Devices: FDA'S Approval Of Four
Temporomandibular Joint Implants (GAO 07-996):
1. Replace the last two sentences of the summary cover page with the
following:
This situation ultimately led FDA to inspect the sponsor's records and
file an administrative complaint for civil monetary penalties against
the sponsor for failure to file certain reports with FDA. On July 6,
2007, the Administrative Law Judge ruled in favor of FDA.
2. Replace the last paragraph on page 9 with the following:
Once a device has been approved, the sponsor must comply with
postmarket regulations and restrictions that apply to the device.
Postmarket regulatory requirements that apply to devices include
adverse event reporting and compliance with current Good Manufacturing
Practices. Devices subject to premarket approval must also comply with
annual report requirements, which include the requirement to report a
summary of all changes to the device. FDA may also impose requirements
in the Premarket Approval order; such requirements, known as postmarket
approval or condition of approval requirements, apply specifically to
the device that is the subject of the PMA. Conditions of approval can
include requirements such as the continuation of a clinical study to
collect additional data. Some conditions of approval do not expire,
such as the conditions of reporting adverse events and submitting
annual reports, while others are time limited, such as continuing a
clinical study for a specified number of years after the approval of a
device.
3. On page 20, 6 lines from the bottom, replace "This matter has not
yet... issued shortly" with the following:
which resulted in a decision from the Administrative Law Judge in favor
of FDA on July 6, 2007. TMJ Implants has thirty days in which the
company may appeal this ruling.
[End of section]
Appendix III: GAO Contact and Staff Acknowledgments:
GAO Contact:
Marcia Crosse, (202) 512-7114 or crossem@gao.gov:
Acknowledgments:
In addition to the contact named above, Geraldine Redican-Bigott,
Assistant Director; Deirdre Brown; Cathy Hamann; Julian Klazkin;
Michaela M. Monaghan; and Sari B. Shuman made key contributions to this
report.
[End of section]
Footnotes:
[1] Medical devices may be deemed substantially equivalent to devices
marketed prior to 1976 through the premarket notification process,
referred to as the 510(k) process, which does not require the
submission of additional information on the safety and effectiveness of
the device. Substantial equivalence means, for example, that a device
has the same intended use and same technological characteristics as a
marketed device.
[2] The TMJ Concepts implant PMA application was approved in July 1999,
the TMJ Implants, Inc., total joint implant PMA application was
approved in January 2001, the TMJ Implants, Inc., partial joint implant
PMA application was approved in February 2001, and the Walter Lorenz
implant PMA application was approved in September 2005.
[3] Study protocol and patient follow-up concerns relate to the
clinical studies sponsors must conduct to prove that their devices are
safe and effective. Engineering testing refers to testing that is
conducted on the TMJ implant to ensure it can withstand daily jaw
activity.
[4] One of the three sponsors, TMJ Implants, Inc., declined to speak
with us.
[5] We included FDA's monitoring of the conditions of approval, through
the use of annual reports, in the scope of our work because these
conditions relate to concerns raised in the PMA process. We excluded
other FDA postapproval issues unrelated to concerns raised by FDA
during the approval process. Many of FDA's postapproval activities for
medical devices were reviewed recently in an Institute of Medicine
report: Marilyn J. Field and Hugh Tilson, Safe Medical Devices for
Children (Washington, D.C.: The National Academies Press, 2006),
[hyperlink, http://www.nap.edu/catalog/11313.html] (downloaded Oct. 16,
2006). In addition, FDA announced plans to improve postmarket programs
for medical devices in November 2006.
[6] While TMJ implants designed to treat temporomandibular joint and
muscle disorders are classified as Class III devices, those that are
used for a temporary period, such as to treat cancer patients with bone
plate restructuring, are classified as Class II devices. Such devices
present less risk than Class III devices. Class II TMJ implants have an
intended use of 1 year or less. This review only includes the four
Class III TMJ implants approved since December 30, 1998.
[7] Submission of a PMA application is required for Class III devices
unless the device was on the market prior to the enactment of the
Medical Device Amendments of 1976 (Pub. L. No. 94-295) and FDA has not
published a regulation requiring PMA submissions for the device. FDA
issued regulations on December 30, 1998, requiring sponsors of all
Class III TMJ implants to submit a PMA application for approval.
[8] Each review team includes an engineer, statistician, and clinician
who assess the PMA application.
[9] DA regulations do not define "clinically significant results." See
21 C.F.R. § 860.7(e)(1). However, an FDA official stated such results
indicate that use of the device would have a positive effect on the
disease being treated according to the standards of care for the
related field.
[10] For example, the review team may resolve application issues
through meetings, phone calls, letters, or e-mails with the sponsor.
[11] If the first level of management disagrees with the review team's
recommendation regarding approval, the manager prepares a different
recommendation and includes it in the review package that is forwarded
to the second level of management, which makes the final decision
regarding approval.
[12] An FDA official told us that it is not uncommon for officials to
write respectful disagreement memos when they feel strongly about their
divergent views. He explained that this type of disagreement is an
indicator of a healthy review process, in which officials are
encouraged to think independently and thoroughly examine all aspects of
a new device to help ensure its safety and effectiveness.
[13] The regulations require these reports to be filed at intervals
specified by FDA, and FDA has required reports annually. See 21 C.F.R.
§ 814.82 (a)(7) (2006).
[14] Survivability of the implant refers to the implant's ability to
function in the jaw as originally intended over time.
[15] The draft guidance, which was available for public comment for 90
days after issuance, advises sponsors on how to best organize data and
present the required information and what to expect from FDA in
response to its annual report submission. This includes a new response
format to standardize the review process and indicates that annual
reports be reviewed by FDA within 90 days of receipt.
[16] FDA received a total of 13 annual reports from the four TMJ
implant sponsors: 2 annual reports from TMJ Concepts, 5 annual reports
from TMJ Implants, Inc., for the total implant, 5 annual reports from
TMJ Implants, Inc., for the partial implant, and 1 from Walter Lorenz.
[17] TMJ Implants, Inc., submitted two annual reports each year after
approval; one for the total implant and one for the partial implant.
[18] Manufacturers are required to submit reports to FDA, which are
included in its MAUDE database, whenever they receive information that
reasonably suggests that one of their marketed devices (1) may have
caused or contributed to a death or serious injury, or (2) has
malfunctioned and that a recurrence would be likely to cause or
contribute to a death or serious injury. Medical device user facilities
and distributors also have responsibilities to report certain adverse
events associated with medical devices or to maintain records of such
events. In addition to these reports, FDA's MAUDE system includes
reports that are voluntarily submitted by manufacturers, clinicians,
and patients.
[19] FDA may issue a warning letter to a sponsor if it believes that
one or more of its products or practices violates the Federal Food,
Drug, and Cosmetic Act, its implementing regulations, or other federal
statutes. It is one of the principal methods used by FDA to achieve
voluntary compliance with the applicable laws and regulations.
[20] TMJ Implants, Inc., did not submit adverse event reports to the
MAUDE database within 15 days of receiving the warning letter from FDA.
However, from June 24, 2004, through March 27, 2007, 52 adverse events
related to TMJ Implants, Inc., devices have been reported into the
MAUDE database. Of those, 17 were reported by TMJ Implants, Inc., and
all were determined by the sponsor not to be related to the device
itself but to surgical complications, the surgeon, or other factors
beyond the sponsor's control.
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