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. 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. 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. 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. 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. 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. The second manner in which FDA addressed concerns was by approving  the four TMJ implants with certain conditions. 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. 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. 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. 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. 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. 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. 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. 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. 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.
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.