A meeting of the Circulatory System Devices Panel was held on October 11, 2007. The Panel discussed and made recommendations regarding clinical trial designs for carotid artery stenting (CAS) in patients not at high risk for adverse events from surgical revascularization. The meeting was closed to the public from 8:00 AM until 10:00 AM to permit discussion and review of trade secret and/or confidential material.
The percutaneous delivery of a vascular stent to treat carotid artery stenosis and reduce the risk of stroke and death represents a minimally invasive treatment option for carotid revascularization. Since 2004, FDA has approved five carotid stent systems for the treatment of symptomatic and asymptomatic high-grade carotid artery stenosis in patients considered to be at high risk for adverse events from surgical revascularization via carotid endarterectomy (CEA). Patients with carotid artery stenosis who are not at high risk for adverse events from CEA represent a much larger potential patient population for CAS. However, while several randomized, controlled trials (RCTs) comparing CAS to CEA in the non-high-risk population have been initiated, none have yet been completed. In addition, it is not clear whether data from other controlled study designs could also be used to develop a reasonable assurance of safety and effectiveness for CAS in the lower risk population and thereby support a Premarket Approval (PMA) application.
The purpose of this meeting was to determine which study designs are suitable for evaluating CAS in the non-high-risk patient population. FDA also requested that the panel identify study design modifications that might improve current subject enrollment and data collection.
Call to Order
Dr. Yancy called the meeting to order at 10:00 AM. James Swink, Executive Secretary for the Circulatory System Devices Advisory Panel, read the conflict of interest statement into the record. All members and consultants were in compliance. Based on the agenda and all financial interests reported by the Panel members and consultants, a conflict of interest waiver was issued in accordance with 18 U.S.C. Section 208 (b)(3) to Dr. Clyde Yancy and Dr. C. Edwin Gravereaux. The waivers allowed all to participate in the deliberations. Copies of these waivers may be obtained by visiting the Agency’s website at http://www.fda.gov/ohrms/dockets/ac/cdrh07.htm#circulatory or by submitting a written request to the Agency’s Freedom of Information Office, Room 6-30 of the Parklawn Building.
Overview of Carotid Artery Stenting
FDA presented an overview of the clinical and regulatory landscape for CAS. This presentation included a review of the clinical significance of stroke, carotid artery stenosis, and currently available treatment options, a discussion of currently available clinical data and the statistical considerations associated with randomized and non-randomized studies, and a summary of current medical society recommendations on carotid revascularization. The presentation also included current FDA recommendations for conducting a clinical trial in the non-high-risk population.
In the afternoon, the panel was given the opportunity to address FDA’s questions. The panel was in general agreement that RCTs would provide the best evidence to support both the proof of concept of CAS in the non-high-risk population and the safety and effectiveness of individual carotid stenting systems. The panel also made the following comments regarding clinical studies in this population:
- Sufficient clinical equipoise exists regarding CEA and CAS in the non-high-risk population, such that RCTs comparing CAS and CEA are appropriate. Barriers to enrollment in and completion of RCTs include economic factors and pre-existing physician and subject treatment preferences.
- While RCTs are expected to provide highest-level evidence that CAS is an appropriate treatment option in the non-high-risk population, non-randomized studies evaluating CAS may be appropriate after this evidence is available. While methods exist to mitigate bias and confounding in these non-randomized studies, some residual concerns are expected to remain.
- Provided CAS has been shown to be safe and effective in the non-high-risk population, a non-inferiority RCT comparing two carotid stent systems may be an appropriate study design for evaluating new CAS systems. Key considerations with this study design are the differential adverse event rates for symptomatic and asymptomatic subjects and the absolute adverse event rates.
- Important considerations when designing a CAS trial include long-term follow-up, a narrow non-inferiority margin, a standardized medical regimen for all subjects, and incorporation of the newest CAS technology.
- The use of clinical trial networks, presentation of aggregate results, participation of multiple sponsors and manufacturers, and collection of additional data from subjects outside the United States may facilitate timely trial completion. Each of these approaches may present its own challenges.
Contact: James Swink, Executive Secretary,
(240) 276-4179 James.Swink@fda.hhs.gov
Transcripts may be purchased from: (written requests only)
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Food and Drug Administration
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