Investigational Device Exemptions
When should investigators use this route to study a new device?
The views and opinions in this article are those of the author and do not necessarily reflect those of the US FDA, the US Department of Health and Human Services, or the Public Health Service.
Clinical studies of significant risk devices in the US require prior FDA and institutional review board (IRB) approval. Significant risk devices are those that present the potential for serious risk to the health, safety, or welfare of a subject. A significant risk device may be an implant; a life-supporting or life-sustaining device; or a device of substantial importance in diagnosing curing, mitigating, or treating disease, or in otherwise preventing impairment of human health. Interested parties can obtain FDA approval to study such devices through the submission of an Investigational Device Exemptions (IDE) application.
THE IDE APPLICATION PROCESS
In order to encourage development of useful devices and at the same time protect public health and safety, the FDA has established an IDE regulation that lists the information to be included in an IDE application. Prospective investigators must provide adequate information to justify the proposed study based on reports of prior investigations of the device and an explanation as to how risks to the subjects will be minimized. The clinical protocol must be designed to collect valid scientific evidence. Additional requirements ensure that the investigators will generate appropriate records and reports, distribution of the investigational device will be controlled, the study will be adequately monitored, and informed consent will be obtained.
The FDA has 30 days after the receipt of an IDE application to approve the investigation as proposed, approve it with modifications or conditions, or disapprove it. The reasons the FDA may disapprove the application are summarized in the regulation and include: 1) there has been a failure to comply with any requirements of the laws and regulations; 2) the application contains false information or omits material information required by the regulation; 3) there is reason to believe that the risks to the subjects may outweigh the potential benefits to the subjects and the importance of the knowledge to be gained; 4) the informed consent is inadequate, the investigation is scientifically unsound, or there is reason to believe that the device is ineffective; or 5) it is otherwise unreasonable to begin the investigation owing to the way in which the device is to be used or the inadequacy of the report of prior investigations.
An IDE may be submitted by the manufacturer of a device or by a responsible investigator who wishes to conduct a clinical investigation; in either case, the same regulations apply. The development of endovascular grafts has made sponsor-investigator (SI) IDEs popular, as they allow clinicians to conduct studies using devices made by combining off-the-shelf devices. SI IDEs also permit investigators to study subsets of patients that were not included in the manufacturer-sponsored studies. The FDA again received a large number of SI IDEs when carotid stenting became popular. These applications differed from those submitted for endovascular grafts in that they usually were not for unique devices or patient populations. Rather, the carotid-related SI IDEs were more or less extensions of the manufacturer-sponsored IDEs.
IDEs FOR ENDOVASCULAR GRAFTS AND CAROTID STENTS
There are currently about 24 manufacturer-sponsored and 37 SI active IDEs for endovascular grafts. Roughly seven manufacturer-sponsored and 50 SI active IDEs exist for carotid stents. The number of new IDEs each year—and hence the number of patients exposed to these investigational devices—has increased significantly over the past 5 years.
Table 1 presents the numbers of new IDEs that have been approved each fiscal year (October 1 through September 30) for endovascular grafts, carotid stents, and other devices reviewed by the Peripheral Vascular Devices Branch (PVDB) of the Division of Cardiovascular Devices. More than 180 active IDEs are managed by the PVDB. This number reflects the inclusion of IDEs submitted before the 1998 fiscal year that are still active, as well as the subtraction of IDEs that are no longer active, regardless of when they were submitted. None of these numbers reflect the applications that have been reviewed and disapproved.
LIMITING CAROTID STENT SI IDEs
The FDA recently became concerned that an excessive number of patients were being exposed to carotid stenting, which is an unapproved and unproven technology from a regulatory perspective. In addition, it seemed unlikely that the information collected in SI studies would be accessible or of much scientific value when evaluating applications for marketing approval. A decision was made, therefore, not to approve any additional SI studies for carotid stenting or to approve any expansions for existing studies (exceptions may be made if an IDE proposes to test a unique hypothesis). The policy decision was made this fall, and since then, the FDA has issued at least 12 disapproval letters. The response to the submission of a SI IDE for carotid stenting would likely include the following language in a disapproval letter:
??Since the device for this indication for use is investigational, its risk profile has not yet been fully characterized, nor has its effectiveness been determined in the subject patient population. ?[the] FDA believes that it is not appropriate to subject additional patients to the risk of this investigational device.?
Many seasoned investigators worry that this type of policy is not in patients’ best interest. They have commented that even if new potential investigators are kept from initiating studies, it is not appropriate to extend this rule globally. However, the regulations do not provide the FDA with a mechanism to distinguish between specific investigators—or specific manufacturers, for that matter. The only criteria under consideration are quite straightforward: The study in question either will provide useful scientific knowledge, or it won’t. The evidence either supports the exposure of additional patients to the device, or it doesn’t.
DATA COLLECTION IS PARAMOUNT
To avoid the need for the FDA to impose restrictions on additional types of SI studies, investigators and manufacturers need to work together to self-regulate the use of investigational devices. Emphasis should be placed on the need to collect useful, unique information. Manufacturers, and not the FDA, have the responsibility to screen the numerous requests they get regarding access to investigational devices, just as it is their responsibility to select investigators for their own studies. Investigators must acknowledge that the purpose of IDE studies is to collect data, not simply to allow treatment of patients with novel devices.
Manufacturers may request an expansion of their study to allow for continued access to their device by their investigators while the FDA premarket review is underway. They may also submit a “treatment use” IDE, which allows for the enrollment of a large number of additional investigational sites in situations where there is no alternate device available. In other words, the tools are available within the regulations to allow a researcher to continue to study an investigational device without the need for a sponsor-investigator IDE. The sponsor-investigator IDE should be reserved for use when the alternative options are not possible or appropriate.
Dorothy B. Abel is a Regulatory Review Scientist with the US FDA Center for Devices and Radiological Health in Rockville, Maryland; she is also a regular columnist for Endovascular Today. Ms. Abel may be reached at (301) 443-8262, ext. 165; firstname.lastname@example.org.