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. 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. 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. 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. 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. 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 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. 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. 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 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. 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. 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.

Summary:
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. 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.