Medical Devices: FDA's Approval of Four Temporomandibular Joint Implants
Published: 2007-09-17T00:00:00

Fast Facts:

Highlights:
section_title: Why GAO Did This Study
paragraphs: 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.
section_title: What GAO Found
paragraphs: 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.

section_title: Letter
paragraphs: 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. 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. 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. 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 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.
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.
subsections: section_title: Background
paragraphs: 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.
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.
Prior to the marketing of most Class III devices, FDA must approve a PMA  application. 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 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.” 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. 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. 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.
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. Others are  time-limited, such as continuing a clinical study for a specified number of  years after the approval of a device.
section_title: FDA Raised Concerns on All Implants and Addressed Many by Obtaining Additional Information and Establishing Conditions of Approval
paragraphs: 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.
subsections: section_title: FDA Raised Concerns That Generally Applied to All Four TMJ Implants
paragraphs: 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.
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.
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.
section_title: FDA Obtained Additional Information from Sponsors and Required Conditions of Approval to Address Most, but Not All, Concerns
paragraphs: 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.
section_title: Concerns Raised about Two Implants Resulted in Differing Opinions among FDA Officials Regarding Approval
paragraphs: 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.
section_title: FDA Monitored Compliance through Review of the Sponsors’ Annual Reports It Received and Required Some Sponsors to Take Additional Action
paragraphs: 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.
subsections: section_title: FDA Reviewed the Annual Reports It Received, but Some Were Missing
paragraphs: 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.
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.
section_title: FDA Required Some Sponsors to Take Additional Actions to Comply with Their Conditions of Approval
paragraphs: 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. 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. 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). 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 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. 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.
section_title: Agency Comments
paragraphs: 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.
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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.
section_title: Appendix I: Concerns Left Unaddressed upon FDA Approval of TMJ Implants
paragraphs: 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.
section_title: Appendix II: Comments from the Department of Health and Human Services
section_title: Appendix III: GAO Contact and Staff Acknowledgments
subsections: section_title: Acknowledgments
paragraphs: 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.