Evaluating Thoracic Endovascular Grafts
There has been recent progress in the evaluation of thoracic endovascular grafts—and not just for the treatment of aneurysms.
The views and opinions in this article are those of the author and do not necessarily reflect those of the US Food and Drug Administration (FDA), the US Department of Health and Human Services, or the Public Health Service.
THORACIC REGULATORY EXPERIENCE
The FDA has approved three endovascular grafts for the treatment of descending thoracic aortic aneurysms (TAAs) in contrast to six for the treatment of abdominal aortic aneurysms (AAAs). All of the approved thoracic endovascular grafts have similar indications, that is, for the treatment of aneurysms of the descending thoracic aorta in patients with suitable anatomy for endovascular repair. The more recently approved devices are also indicated for the treatment of saccular aneurysms and/or penetrating ulcers, because these indications were included in the clinical studies of these devices. Table 1 provides a list of the currently approved endovascular grafts with their respective general indications. Different levels of detail for the definition of suitable anatomy are included in the indications for use statements for these devices. These details are not included in the table because they are not significant for the purposes of this article.
In short, there has been less experience in regulating thoracic endovascular grafts as compared to AAA devices, and there have not been any devices approved for treatment of transections or dissections.
REPORTED PROBLEMS WITH THORACIC ENDOVASCULAR GRAFTS
Understandably, some of the types and incidence of problems reported for thoracic endovascular grafts in the literature and at conferences have been different from those reported for AAA devices. Some of the more common problems reported for thoracic devices have included the following:
- Poor apposition to the vessel wall
- Maldeployment (eg, stent flip)
- Aortic perforation
- Retrograde dissection
- Type III endoleak
Many of these events tend to be associated with treatment of transections or dissections or implantation of the device in the aortic arch—all situations that would be considered off-label use in the United States.
Information regarding off-label use was provided in previous issues of this publication.1,2 Subsequently, an article coauthored by a group from the Center for Devices and Radiological Health at the FDA was published in the Journal of Vascular and Interventional Radiology.3 This article defines off-label use as follows:
A device's labeling (including the indications for use) is approved by the FDA on the basis of data submitted by the manufacturer. The use of a device for an indication other than that in the cleared or approved labeling is referred to as "off-label use."
We consider the labeling important to communicate information relevant to the specified indications for use. If a device is used off-label, the information in the label may or may not be relevant to the clinician in using the device to treat the patient. As such, it would be preferable to have sponsors conduct studies that could be used to support labeling their devices for the indications for which their devices are being used. For example, as the marketed thoracic endovascular grafts are indicated for treatment of aneurysms, but are being used to treat dissections, manufacturers should consider conducting appropriate clinical studies to support changes in the labeling to include treatment of dissections.
In October 2008, the FDA provided the venue for a meeting hosted by the Society for Vascular Surgery and attended by manufacturers, clinicians, and FDA staff to discuss the challenges in evaluating nonaneurysmal indications. During this meeting, the participants discussed the possibility of using a performance goal, based on 30-day mortality, to serve as the primary endpoint for a study of endovascular grafts intended to treat acute complicated type B aortic dissections. Since this meeting, several societies (the Society for Vascular Surgery, the Society for Interventional Radiology, the Society for Thoracic Surgery, and the American Association for Thoracic Surgery) have been working together to capture previously collected investigational device exemption data for patients treated with endovascular grafts for an acute complicated type B aortic dissection. This registry may help the sponsor of a clinical study in establishing a reasonable performance goal for safety for this indication; however, the performance goal could also be supported by literature for medical and open surgical management. The goal would be established and justified by the clinical study sponsor by determining the reported rate(s) and setting a goal considering an acceptable difference from the reported rate(s) due to variability or anticipated differences in patient populations. This comparison to the 30-day mortality-based performance goal could be enhanced by monitoring the safety and effectiveness of the device over time in the clinical studies. Additional comparison information for these other outcomes of interest may also be captured in the registry.
A similar concept for capturing information for use in the design of clinical studies of the use of endovascular grafts for the treatment of traumatic transections has also been discussed. The registry may be expanded to include patients treated for traumatic transections, and this information may be helpful for comparison in clinical studies for this indication. The use of descriptive statistics if the device already has an aneurysm indication may be possible because the effectiveness of the device for treatment of a transection would likely be no worse than that for an aneurysm, provided no device-related issues were identified.
This registry will not be expanded to capture information regarding patients treated for aneurysms as there are more data available in the literature for this indication as compared to the others.
Regarding the long list of other potential lesion types that could be treated using endovascular grafts, the participants at the October meeting indicated that each lesion type could not be evaluated in separate studies, but it may be beneficial for a sponsor to capture the treatment of other lesions in a separate study arm.
POSTAPPROVAL STUDIES AND POSTMARKET SURVEILLANCE
As a reminder, postapproval studies are an important mechanism for the continued evaluation of endovascular grafts after premarket approval. There have been postapproval study requirements for all of the devices listed in Table 1, including the need to collect and report 5-year clinical study data. In addition to planning to demonstrate the safety and effectiveness of an endovascular graft for the treatment of various thoracic lesions, a manufacturer should be prepared to work with the Epidemiology Branch in the Office of Surveillance and Biometrics at FDA to design an appropriate postapproval study.
Additionally, after a device is approved for any indication, a manufacturer is required per the conditions of approval for the device to:
…, report to the FDA whenever they receive or otherwise become aware of information, from any source, that reasonably suggests that a device marketed by the manufacturer or importer:
- May have caused or contributed to a death or serious injury; or
- Has malfunctioned and such device or similar device marketed by the manufacturer or importer would be likely to cause or contribute to a death or serious injury if the malfunction were to recur.
This Medical Device Reporting (MDR) applies to use of the device both on- and off-label. As such, the system may be helpful in capturing information on problems associated with the real-world use of thoracic endovascular grafts. Physicians should help with this effort by providing event reports to manufacturers and FDA, when appropriate.
Additional information on MDR is available at: www.fda.gov/cdrh/devadvice/351.html.
AN ADDITIONAL ENDOVASCULAR GRAFT CHALLENGE
Regardless of the indication statement for an endovascular graft, there is a continuing problem with obtaining what has been considered adequate imaging over time to monitor these devices. In addition, this imaging is associated with radiation exposure. Although there have been several publications suggesting the use of alternative forms of imaging for follow-up, few prospectively designed analyses have been done to validate the alternative imaging protocols. Perhaps in future clinical studies of endovascular grafts, it would be helpful to incorporate concurrent evaluations of follow-up strategies. For example, it may be of benefit to attempt to prospectively identify patients for whom early or later follow-up computed tomography scans could be waived based on prior demonstrations of effective exclusion of the lesion and other favorable conditions, such as reasonably long and straight landing zone coverage by the endovascular graft. Although such analyses may not be necessary to demonstrate the safety and effectiveness of the device to support a marketing approval, this information may be of use to the medical community in identifying appropriate follow-up plans.
At FDA, our goal is to have properly labeled devices available to clinicians to provide reasonable treatment options for patients. At this time, there are no endovascular grafts with broad indications for the treatment of thoracic lesions in the United States. Since it may not be possible to conduct statistically based studies for each individual indication, it is unclear whether a broad indication may be supported for these devices, possibly using data available for the treatment of aneurysms, transection, and dissection. We are continuing to work with the medical community to identify appropriate strategies to evaluate thoracic endovascular grafts, which should lead to improved labeling for these devices.
Dorothy B. Abel is a Regulatory Review Scientist with the US FDA Center for Devices and Radiological Health in Rockville, Maryland and a regular columnist for Endovascular Today. She may be reached at (301) 796-6366; email@example.com.
Commentary: Alternative Approval Mechanisms
by Rodney White, MD
Thoracic aortic endografts have been shown in preliminaryinvestigations to treat indications beyond thoracic aorticaneurysms and have demonstrated a significant reduction inprocedural morbidity and mortality, including paraplegia. Ofparticular interest is the role of these devices in redefining thetreatment of aortic dissections and traumatic transections.Because of the apparent benefit in these critical indications, theFood and Drug Administration (FDA) has wisely agreed to thedevelopment of alternative study designs, avoiding the needfor the collection of concurrent control data, to expeditebroader-labeled indications for appropriately designed devices.
In response to the suggestion that the FDA would consideralternative approval mechanisms, the Society for VascularSurgery (SVS) Outcomes Committee in collaboration with theSociety for Vascular and Interventional Radiology (SIR), theSociety for Thoracic Surgery (STS), and the AmericanAssociation for Thoracic Society (AATS) have established adatabase that collects data using standardized definitionsfrom studies that were performed using FDA-approvedInvestigational Device Exemption (IDE) protocols utilizing thoracicendografts to treat aortic dissections and traumatic transections.The data collection was funded solely by the academicsocieties. Extensive analysis of data from 5 institutions(Arizona Heart Institute, Cleveland Clinic Foundation, Harbor-UCLA Medical Center, Stanford University, and UnionMemorial Hospital) that have FDA-approved single-center IDEprotocols to evaluate the utility of thoracic endografts forthese indications has been completed. The data collectionand analysis was performed by the SVS administration andthe New England Research Institutes, Inc. to create MasterAccess Files available through the SVS that has been submittedto the FDA and can be used to define a performance goalby manufacturers performing studies that broaden the indicationsfor thoracic endografts.
The first Master Access File has been completed andincludes approximately 100 patients who had acute thoracicaortic dissection with malperfusion syndromes, and a secondfile of approximately 60 patients with acute aortic transectionsis anticipated to be completed by the end of August.
Using this mechanism, the results of contemporary datausing thoracic endografts for acute aortic dissections and traumatictransections from an IDE-level dataset can be complimentedby other sources of available data regarding this therapyand potentially provide comparative information that canbe used to expedite studies and provide approval for devices ina cost-effective and responsible manner in the current “offlabel”environment.
For information regarding the Master Access Files, contact SarahMurphy, Assistant Director, Socioeconomics and Professional Affairs,Society for Vascular Surgery, 633 North Saint Clair Street, 24th Floor,Chicago, Illinois 60611. Ms. Murphy may be reached at (312) 334-2305; firstname.lastname@example.org.
Rodney White, MD, is Vascular Surgery Division Chief,Vascular Surgery Fellowship Program Director and ViceChairman of Research, Harbor-UCLA Medical Center, andProfessor of Surgery, David Geffen School of Medicine at UCLAin Torrance, California. Dr. White may be reached email@example.com