Medical Devices: FDA Ordered Postmarket Studies to Better Understand Safety Issues, and Many Studies Are Ongoing
Released: 2015-10-29T00:00:00

Letter

Background

FDA may order a postapproval study for a device at the time FDA approves that device for marketing through its premarket approval (PMA) process or its humanitarian device exemption (HDE) process (for devices that treat rare diseases or conditions).the length of a postapproval study, but according to FDA guidance, the There are no statutory limits on device manufacturer and FDA agree on the study plan, which includes a study design (e.g., randomized clinical trial or other study design), the study’s data source, and time frame for when the manufacturer will complete required reports.

In contrast, FDA may order a postmarket surveillance study at the time of approval or clearance for certain devices or any time thereafter as long as certain criteria are met. (See table 1.) FDA may order a postmarket surveillance study not only for PMA and HDE devices, but also for devices that are cleared through the less stringent 510(k) premarket notification process—also known as the 510(k) process. FDA may order postmarket surveillance studies if failure of the device would be reasonably likely to have serious adverse health consequences, and such studies may be ordered when FDA officials identify an issue with a device FDA is through adverse advent reports or reviews of scientific literature.authorized to order postmarket surveillance studies for a duration of up to 36 months, but the time frame may be extended if the manufacturer and FDA are in agreement. Additionally, FDA may order a study with a longer duration if the device is expected to have significant use in pediatric populations and an extended period is necessary to assess issues like the impact of the device on children’s growth or development.

Manufacturers must periodically report to FDA information on these postmarket studies such as the progress of the study. Table 2 describes the various status categories that apply to postmarket studies.

FDA Ordered Most Postapproval Studies for Cardiovascular Devices and Most Were Making Adequate Progress

FDA Ordered Most Postapproval Studies for Cardiovascular Devices and Most Were Designed as Prospective Cohort Studies

Cardiovascular devices, such as stents and heart valves, accounted for 56 percent of the 313 postapproval studies ordered from January 1, 2007, through February 23, 2015. Orthopedic and general and plastic surgery devices were the second and third most common subjects of postapproval studies, respectively. FDA also ordered postapproval studies for another 11 medical specialties, which are included in the other category. (See table 3.)

The number of postapproval studies for cardiovascular devices varied from year to year, with the most cardiovascular device studies ordered in 2008 and 2012. (See fig. 1.) In general, FDA orders a postapproval study to obtain specific information on the postmarket performance of or experience with an approved device. For example, the increase in the number of postapproval studies ordered for cardiovascular devices in 2008 reflects that FDA has required that each new implantable cardioverter defibrillator lead undergo a postapproval study.

Other includes devices for ophthalmic (e.g., intraocular lens); obstetrics and gynecology (e.g., permanent birth control system); gastroenterology-urology (e.g., gastric banding system); anesthesiology (e.g., computer assisted personalized sedation system); clinical chemistry (e.g., artificial pancreas device system); dental (e.g., bone grafting material); ear, nose, and throat (e.g., implantable hearing system); general hospital (e.g., infusion pump); microbiology (e.g., human papillomavirus test); neurology (e.g., intracranial aneurysm flow diverter); and pathology (e.g., breast cancer detection test).

The PMA process is the more stringent of FDA’s premarket review processes and requires the manufacturer to supply evidence providing reasonable assurance that the device is safe and effective before the device is legally available on the U.S. market.

February 23, 2015, were for devices approved through the PMA process.

In terms of study design, more than two-thirds (69 percent) of the 313 postapproval studies ordered during the timeframe we examined were prospective cohort studies—that is, studies in which a group using a particular device was compared to a second group not using that device, over a long period of time. (See fig. 2.) For example, one postapproval prospective cohort study was designed to follow patients who received a certain type of breast implant over a 10-year period and to collect information on complications as they occur.

Additionally, postapproval studies were conducted using a variety of data sources, including newly collected data and medical device registries. Nearly two-thirds (196 studies) of the postapproval studies we examined relied upon new data collected by the manufacturer; and about one-third (98 studies) used data collected from registries—that is, a data system to collect and maintain structured records on devices for a specified time frame and population.maintained by the manufacturer or another organization, such as a (See table 4.) Registries may be created and medical specialty’s professional association. For example, FDA has established a National Medical Device Registry Task Force to further examine the implementation of registries in postmarket surveillance. According to FDA, registries play a unique role in the postmarket surveillance of medical devices because they can provide additional detailed information about patients, procedures, and devices. For example, registries can help assess device performance by collecting information on patients with similar medical conditions.

Most of the Postapproval Studies FDA Ordered Were Ongoing and Making Adequate Progress, According to FDA

About 72 percent of the postapproval studies we examined (or 225 of the 313 studies ordered) were categorized as ongoing as of February 2015. An additional 20 percent were completed and the remaining 8 percent were inactive. (See fig. 3.)

Further analysis of FDA data on the 225 ongoing postapproval studies showed 81 percent (or 182 studies) to be progressing adequately, while the remaining 19 percent (43 studies) were delayed as of February 2015. The 182 ongoing postapproval studies considered to be progressing adequately—that is, the study was pending, the protocol or plan was pending, or progress was adequate—had been ongoing for an average of 37 months, or a little over 3 years.

Similarly, the 43 ongoing postapproval studies considered to be delayed—that is protocol/plan overdue, or progress inadequate—had been ongoing for an average of 39 months or a little over 3 years. Delayed studies include studies for which FDA had not approved a study plan within 6 months of the PMA approval date (3 studies) or studies which had begun, but had not progressed as intended (40 studies).

According to FDA officials, a key reason for a study’s delay may be limited patient enrollment into the postapproval study. FDA officials said they work with manufacturers to address manufacturers’ inability to enroll patients, in part, by suggesting different strategies to improve enrollment, such as hiring a dedicated person for recruitment or reducing the cost of the study device to make it competitive with conventional treatments.

Twenty percent (or 62 studies) of the 313 postapproval studies were categorized as completed as of February 23, 2015—that is, FDA determined that the manufacturer had fulfilled the study order and had closed the study. As table 5 shows, on average, these completed postapproval studies took about 36 months, or 3 years, with the longest study taking almost 7 years. The remaining 8 percent (or 26 studies) were categorized as inactive. Postapproval studies that are considered inactive include studies that, for example, involve a device that is no longer being marketed or the study’s research questions are no longer relevant.

FDA Ordered Most Postmarket Surveillance Studies for Orthopedic, General/Plastic Surgery, and Obstetrics/ Gynecology Devices and Many Were Consolidated into Ongoing Studies

FDA Ordered Most Postmarket Surveillance Studies for Orthopedic, General/Plastic Surgery, and Obstetrics/Gynecology Devices Resulting from Concerns about Metal-on- Metal Implants and Certain Kinds of Implantable Surgical Mesh

FDA ordered 392 postmarket surveillance studies, half of which (196 studies) were for orthopedic medical devices, from May 1, 2008, through February 24, 2015. In 2011 alone, FDA ordered 176 studies for orthopedic devices following safety concerns about metal-on-metal hip implants, including potential bone or tissue damage from metal particles. (See fig. 4.) An additional 40 percent (or 158 studies) of the postmarket surveillance studies FDA ordered were for devices used in general and plastic surgery and obstetrics and gynecology procedures. FDA ordered 121 postmarket surveillance studies for devices in these medical specialties in 2012, following safety concerns about the use of implanted surgical mesh used for urogynecologic procedures, such as severe pain. About 10 percent of the postmarket surveillance studies were for devices in other medical specialties.

Other includes general hospital (e.g., intravascular administration set), cardiovascular (e.g., vena cava filter), dental (e.g., temporomandibular joint implant), immunology, neurology, ophthalmic, and physical medicine devices.

Between May 1, 2008, and February 24, 2015, about 94 percent of the postmarket surveillance studies ordered were for devices cleared through the 510(k) premarket notification process.regarding metal-on-metal implants and implantable surgical mesh used for urogynecologic procedures that arose after the devices were cleared through the 510(k) process, according to FDA officials.

Most of the Postmarket Surveillance Studies FDA Ordered Were Inactive, and Many of Those Had Been Consolidated into Ongoing Studies

About 88 percent of the postmarket surveillance studies we examined (or 344 out of 392 studies) were categorized as inactive. (See fig. 5.) A study might be categorized as inactive, for example, because it had been consolidated, meaning that a manufacturer was able to combine an order for a postmarket surveillance study with other related study orders into a single study. For example, if FDA issued 22 orders for postmarket surveillance studies for different models of metal-on-metal implants from a single manufacturer, the manufacturer could combine all of the orders into a single study covering all of the devices, and the other 21 orders for postmarket surveillance studies would be categorized as consolidated and considered inactive. About 31 percent (or 108 studies) were inactive because they had been consolidated into another study.

Another 31 percent of the inactive studies (or 107 studies) were categorized by FDA as either terminated, meaning the study was no longer relevant because, for example, the manufacturer changed the indication for use that was the subject of the postmarket surveillance study, or withdrawn by FDA because the manufacturer demonstrated the objective of the study using publicly available data and FDA agreed with the results. The remaining 38 percent (or 129 studies) were categorized as other—that is, the status does not fit in another category because, for example the device is no longer being marketed. However, according to FDA officials, if the manufacturer does begin marketing the device again, then it will have to conduct the study.

The inactive category for postmarket surveillance studies includes studies with one of four FDA study statuses: (1) other—that is, the study status does not fit another category, because, for example, the device is no longer being marketed or is being redesigned; (2) consolidated—that is, the study was one of many postmarket surveillance studies ordered and the manufacturer, with the approval of FDA, consolidated these multiple studies into a single study; (3) terminated—that is, studies that were terminated by FDA because they were no longer relevant (e.g., the manufacturer changed the indication for use that was the subject of the postmarket surveillance study); or (4) withdrawn—that is, studies that were withdrawn because the manufacturer demonstrated the objective of the study using publicly available data and FDA agreed with the results.

While 88 percent of the postmarket surveillance studies in our analysis were inactive, the remaining 12 percent (or 48 studies) were either still ongoing or completed as of February 24, 2015. Specifically, 10 percent (or 40 studies) were categorized as ongoing, while 2 percent (or 8 studies) were completed. Of the 40 ongoing postmarket surveillance studies, more than half were progressing adequately, while the rest were delayed. Further analysis showed the following:

The 21 ongoing postmarket surveillance studies that FDA considered to be progressing adequately had been ongoing for an average of 33 months, or about 2.7 years. (See table 6.)

The 19 ongoing postmarket surveillance studies that FDA considered to be delayed had been ongoing for an average of 49 months or about 4 years. Delayed studies included studies for which FDA had not approved a study plan within 6 months of ordering the study or studies that had begun but were not progressing as intended. According to FDA, postmarket surveillance studies may be delayed for reasons similar to postapproval studies, such as difficulty enrolling patients into the study.

Regarding the eight completed postmarket surveillance studies, the average length of time to complete the study—that is, the time from the study order to the date FDA determined that the manufacturer had fulfilled the study order and had closed the study—was about 29 months or 2.4 years. FDA generally may order a manufacturer to conduct a postmarket surveillance study for up to 36 months unless the manufacturer and FDA agree to an extended time frame.

Agency Comments

We provided a draft of this report to the Secretary of Health and Human Services. HHS provided technical comments that were incorporated, as appropriate.

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If you or your staff have any questions about this report, please contact me at (202) 512-7114 or crossem@gao.gov. Contact points for our Offices of Congressional Relations and Public Affairs are on the last page of this report. GAO staff who made major contributions to this report are listed in appendix I.

Appendix I: GAO Contact and Staff Acknowledgments

GAO Contact

Staff Acknowledgments

In addition to the contact named above, Kim Yamane, Assistant Director; Britt Carlson; Carolyn Fitzgerald; Sandra George; Cathleen Hamann; and Gay Hee Lee were major contributors to this report.